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Dr. Anton Bilchik, MD
Surgical Specialist, Oncology Specialist (cancer)
27 years of experience
Accepting new patients

Credentials

Education ?

Medical School
University Of The Witwatersrand (1985)
Foreign school

Awards & Distinctions ?

Awards  
One of America's Leading Experts on:
Carcinoid Tumor
Colectomy
Colon Cancer (Colonic Neoplasm)
Colorectal Cancer (Colorectal Neoplasm)
Cryosurgery
Hepatectomy
Laparoscopy
Liver Cancer (Liver Neoplasm)
Lymph Node Excision
Castle Connolly America's Top Doctors® (2002 - 2008, 2010 - 2015)
Castle Connolly America's Top Doctors® for Cancer (2005 - 2007, 2009 - 2012, 2014 - 2015)
Patients' Choice Award (2012)
Compassionate Doctor Recognition (2012)
Associations
American Board of Surgery
Carcinoid Cancer Foundation
American Hepato-pancreato-biliary Association
American Society of Clinical Oncology

Affiliations ?

Dr. Bilchik is affiliated with 2 hospitals.

Hospital Affiliations

Score

Rankings

  • Cedars-Sinai Medical Center *
    8700 Beverly Blvd, West Hollywood, CA 90048
    •  
    Top 25%
  • Saint John`s Health Center
  • * This information was reported to Vitals by the doctor or doctor's office.

    Publications & Research

    Dr. Bilchik has contributed to 117 publications.
    Title Predictors of Occult Nodal Metastasis in Colon Cancer: Results from a Prospective Multicenter Trial.
    Date March 2010
    Journal Surgery
    Excerpt

    The relationship between primary colon cancer and occult nodal metastases (OMs) detected by cytokeratin immunohistochemistry (CK-IHC) is unknown. We sought to investigate the correlation of clinicopathologic features of colon cancer with OMs and to identify predictors of OM.

    Title Targeted Lymph Node Evaluation in Colorectal Cancer: a Decade of Progress!
    Date March 2009
    Journal Journal of Surgical Oncology
    Title Current and Emerging Trends in the Treatment of Early-stage Colorectal Cancer: Importance of a Multidisciplinary Approach.
    Date March 2009
    Journal Hematology/oncology Clinics of North America
    Title Prognostic Relevance of Occult Nodal Micrometastases and Circulating Tumor Cells in Colorectal Cancer in a Prospective Multicenter Trial.
    Date January 2009
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: Nodal micrometastasis and circulating tumor cells detected by multimarker quantitative real-time reverse transcription-PCR (qRT-PCR) may have prognostic importance in patients with colorectal cancer. EXPERIMENTAL DESIGN: Paraffin-embedded sentinel lymph nodes from 67 patients and blood from 34 of these patients were evaluated in a prospective multicenter trial of sentinel lymph node mapping in colorectal cancer. Sentinel lymph nodes were examined by H&E staining and cytokeratin immunohistochemistry. Sentinel lymph nodes and blood were examined by a four-marker qRT-PCR assay (c-MET, melanoma antigen gene-A3 family, beta1-->4-N-acetylgalactosaminyltransferase, and cytokeratin-20); qRT-PCR results were correlated with disease stage and outcome. RESULTS: In H&E-negative sentinel lymph node patients that recurred, cytokeratin immunohistochemistry and qRT-PCR detected metastasis in 30% and 60% of patients, respectively. Disease-free survival differed significantly by multimarker qRT-PCR upstaged sentinel lymph node (P = 0.014). qRT-PCR analysis of blood for circulating tumor cells correlated with overall survival (P = 0.040). CONCLUSION: Molecular assessment for micrometastasis in sentinel lymph node and blood specimens may help identify patients at high risk for recurrent colorectal cancer, who could benefit from adjuvant therapy.

    Title Prognostic Variables for Resection of Colorectal Cancer Hepatic Metastases: an Evolving Paradigm.
    Date December 2008
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Title Hepatic Cytoreductive Surgery for Neuroendocrine Cancer.
    Date July 2008
    Journal Surgical Oncology Clinics of North America
    Excerpt

    Patients with gut-based metastatic neuroendocrine tumors (NET) often present late in the course of their slowly progressive disease, when cancer has extended beyond the point of reasonable expectation for surgical cure. At this stage of disease, the tumor's overwhelming hormonal production often significantly impairs the patient's quality of life. Unlike patients with other malignancies that might involve a heavy burden of hepatic metastatic disease, many patients with metastatic NET continue to live for a long time despite escalating hormone-related symptoms. This establishes the justification and rationale for cytoreduction, a noncurative surgical intervention that reduces tumor burden and hormonal burden and thereby can significantly increase symptom-free survival in the setting of an often slow but inevitable disease progression.

    Title Significance of the Lymph Node Ratio in Stage Iii Colon Cancer.
    Date June 2008
    Journal Annals of Surgical Oncology
    Title Perioperative Risks of Bevacizumab and Other Biologic Agents for Hepatectomy: Theoretical or Evidence Based?
    Date May 2008
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Title Preoperative Serum Ta90-ic As an Adjunct to Serum Ca 19-9 in the Diagnosis of Pancreatic Malignancy: a Pilot Study.
    Date April 2008
    Journal Current Surgery
    Excerpt

    PURPOSE: Because TA90, a 90-kDa immunogenic tumor-associated antigen, is expressed by pancreatic cancer cells, we hypothesized that the serum level of its immune complex with IgG (TA90-IC) might be a useful marker for diagnosis of pancreatic malignancy. We also wanted to compare TA90-IC with CA 19-9 in the diagnosis of pancreatic cancer. METHODS: We undertook a retrospective study of prospectively collected sera from patients with histopathologically proven pancreatic malignancies. Patient sera were analyzed for TA90-IC and CA 19-9. Sera of sex-matched and age-matched healthy volunteers (controls) were analyzed for TA90-IC. The study was conducted at a tertiary medical center. Twenty-one patients with pancreatic malignancies and 29 controls, from whom sera had been obtained and cryopreserved, were included. A positive TA90-IC level was defined as an optical density >/= 0.410 at 405 nm following an enzyme-linked immunosorbent assay based on a murine monoclonal antibody. CA 19-9 levels were determined by immunoradiometric assay performed at outside laboratories (normal range, 0 to 37 U/mL). RESULTS: Of the 21 patients, 14 had positive TA90-IC levels and 18 had increased CA 19-9 levels (67% vs 86%; p = 0.157). The TA90-IC levels were significantly higher in the cancer group than in the control group (p = 0.0003). Of the 3 patients with normal CA 19-9 levels, 2 had positive TA90-IC levels. The combination of both markers identified 95% of patients with pancreatic malignancy, a significantly higher diagnostic rate than that of either marker alone (p = 0.014). TA90-IC sensitivity was higher for stage II and III disease than for stage IV disease (82% vs 50%). CONCLUSIONS: TA90-IC assay may improve the prediction of pancreatic malignancy when used in combination with CA 19-9 levels. Because TA90-IC appears to have improved diagnostic accuracy with smaller tumor burden, the role of TA90-IC as an adjunct to CA 19-9 in screening and monitoring progression of early disease warrants further investigation.

    Title Thermal Ablation of Hepatic Malignancy: Useful but Still Not Optimal.
    Date March 2008
    Journal European Journal of Surgical Oncology : the Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology
    Excerpt

    The mortality associated with primary and metastatic hepatic malignancies remains high because few patients are candidates for hepatic resection or transplantation. Resection is the most effective treatment for liver tumors but may be contraindicated by factors such as the tumor's location; hepatic transplantation can cure primary hepatocellular carcinoma and underlying cirrhosis, but a donor may not be immediately available. When resection or transplantation is not possible, thermal ablation is a reasonable therapeutic option. Effective destruction of tumors can be achieved with low recurrence rates and minimal complications or risk of death. In patients with primary hepatic malignancy, ablation treatment does not preclude subsequent transplantation. Although radiofrequency ablation is currently the most widely used thermal ablative technique for hepatic malignancy, microwave ablation is gaining popularity and eventually may prove to be more effective.

    Title Is Routine Use of Sentinel Node Biopsy Justified in Colon Cancer?
    Date February 2008
    Journal Annals of Surgical Oncology
    Title New Approaches to Assessing and Treating Early-stage Colon and Rectal Cancer: Summary Statement from 2007 Santa Monica Conference.
    Date January 2008
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    The 2007 Santa Monica Conference on Assessing and Treating Early-Stage Colon and Rectal Cancer, a multidisciplinary meeting of leaders in surgery, medical and radiation oncology, and pathology, was convened on January 12 to 13, 2007. The purpose of the meeting was to assess current data and issues in the field and to develop recommendations for advancing patient care and clinical research. Topics included pathologic assessment and staging, transanal versus laparoscopic versus open resection, adjuvant therapy, genetic testing and counseling, cooperative group strategies, and the use of biological therapies and novel agents. A review of the key issues discussed, as well as conclusions and recommendations considered significant to the field, is summarized below and presented at greater length in the individual manuscripts and accompanying discussion that comprise the full conference proceedings. Although the management of early-stage colon and rectal cancers remains a challenge for all of us, the development and use of new technologies and methods of assessment and treatment over the past several decades is yielding encouraging results. A variety of opportunities to further improve outcomes were addressed in this forum, including recommendations that specific protocols be adopted regarding surgical and pathologic dissection and reporting, particularly for stage II disease; the corollary need to increase active multidisciplinary collaboration; and the development of comprehensive consensus guidelines and recommendations to standardize care in early-stage colorectal cancer.

    Title Management of T2 Gallbladder Cancer: Are Practice Patterns Consistent with National Recommendations?
    Date December 2007
    Journal American Journal of Surgery
    Excerpt

    BACKGROUND: The national recommendation for the management of localized T2 gallbladder cancer (GBCA) is radical cholecystectomy. Although reported survival for localized T2 disease has been poor, groups have documented improvement with radical resection. We hypothesized that a discrepancy exists between national recommendations and current practice patterns. METHODS: Patients diagnosed with localized T2 GBCA between 1988 and 2002 were identified from the Surveillance, Epidemiology, and End Results registry. Age, sex, race, ethnicity, extent of surgery, and overall survival were assessed. Surgical procedure was categorized as cholecystectomy alone (CS), cholecystectomy plus lymph node dissection (CS+LN), radical cholecystectomy (RCS), or other. Survival calculations were made using the Kaplan-Meier method and compared with the log-rank test. RESULTS: Of 382 patients with pathologically confirmed T2 GBCA, 280 were women. The median patient age was 75 years. A total of 238 patients underwent CS, 76 underwent CS+LN, and 14 underwent RCS. The remaining 54 patients underwent a lesser or no procedure and were excluded from comparative analysis. The median survival was 14 months for all patients and 14, 14, and 8 months for subgroups treated with CS, CS+LN, and RCS, respectively. Rates of 5-year survival were 23%, 24%, and 36% for CS, CS+LN, and RCS subgroups, respectively. There was no significant difference in survival rates between RCS and CS+LN, or between RCS and CS. CONCLUSIONS: The majority of patients with T2 GBCA in the United States are not managed according to current national recommendations.

    Title Epigenetic Silencing of Cyclooxygenase-2 Affects Clinical Outcome in Gastric Cancer.
    Date November 2007
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: Overexpression of cyclooxygenase-2 (COX-2) in gastric cancer has been shown to enhance tumor progression. We investigated whether silencing by promoter region hypermethylation of the COX-2 gene contributes to disease outcome in gastric cancer. MATERIALS AND METHODS: COX-2 methylation status was initially assessed by capillary array electrophoresis methylation-specific polymerase chain reaction (CAE-MSP) and COX-2 protein expression by immunohistochemistry (IHC) in 40 primary gastric cancer tissues in a pilot study. Prognostic end points of correlative studies of COX-2 methylation status were time to recurrence, overall survival, and standard clinicopathologic features. CAE-MSP analysis was then validated in a second independent gastric cancer population (n = 137). RESULTS: COX-2 methylation was detected in 23% and 28% of the pilot and validation patient groups, respectively. COX-2 expression (IHC) in gastric tumors inversely correlated with COX-2 gene methylation status in the pilot study (P = .02). COX-2 methylation in tumors was significantly associated with lower T, N, and TNM stage in the validation patient group (P = .02, P = .006, and P = .008, respectively). Patients with COX-2 methylated tumors had significantly longer time to recurrence and improved overall survival in a multivariate analysis in the validation patient group (hazard ratio[HR], 0.49; 95% CI, 0.24% to 0.99%; HR, 0.62; 95% CI, 0.38% to 0.99%, respectively). CONCLUSION: Hypermethylation of COX-2 gene promoter was identified as an independent prognostic factor in gastric cancer patients. The results suggest promoter hypermethylation to be an important regulatory mechanism of COX-2 expression in gastric cancer and an important prognostic biomarker.

    Title Resecting Lymph Nodes in Colon Cancer: More Than a Staging Operation?
    Date November 2007
    Journal Annals of Surgical Oncology
    Title Prognostic Impact of Micrometastases in Colon Cancer: Interim Results of a Prospective Multicenter Trial.
    Date November 2007
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE: The 25% rate of recurrence after complete resection of stage II colon cancer (CC) suggests the presence of occult nodal metastases not identified by hematoxylin and eosin staining (H&E). Interim data from our ongoing prospective multicenter trial of sentinel node (SN) biopsy indicate a 29.6% rate of micrometastases (MM) identified by immunohistochemical staining (IHC) of H&E-negative SNs in CC. We hypothesized that these MM have prognostic importance. METHODS: Between March 2001 and August 2006, 152 patients with resectable colorectal cancer were enrolled in the trial. IHC and quantitative RT-PCR (qRT) assay were performed on H&E-negative SNs. Results were correlated with disease-free survival. RESULTS: The sensitivity of lymphatic mapping was significantly better in CC (75%) than rectal cancer (36%), P<0.05. Of 92 node-negative CC patients 7 (8%) were upstaged to N1 and 18 (22%) had IHC MM. Four patients negative by H&E and IHC were positive by qRT. At a mean follow-up of 25 months, 15 patients had died from noncancer-related causes, 12 had developed recurrence, 5 had died of CC (2 with macrometastases, 3 with MM), and 7 were alive with disease. The 12 recurrences included 4 patients with SN macrometastases and 6 with SN MM (2 by IHC, 4 by qRT). One of the 2 SN-negative recurrences had other positive lymph nodes by H&E. All patients with CC recurrences had a positive SN by either H&E/IHC or qRT. No CC patient with a negative SN by H&E and qRT has recurred (P=0.002). CONCLUSION: This is the first prospective evaluation of the prognostic impact of MM in colorectal cancer. These results indicate that the detection of MM may be clinically relevant in CC and may improve the selection of patients for adjuvant systemic chemotherapy. Patients with CC who are node negative by cumulative detection methods (H&E/IHC and qRT) are likely to be cured by surgery alone.

    Title Image of the Month. Serrated Adenomatous Polyposis.
    Date October 2007
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Title Role of Repeated Hepatectomy in the Multimodal Treatment of Hepatic Colorectal Metastases.
    Date July 2007
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    HYPOTHESIS: Multimodal treatment consisting of repeated hepatectomy and adjuvant systemic chemotherapy for liver-confined recurrence of colorectal cancer can yield long-term survival comparable with that associated with primary hepatectomy. DESIGN: Retrospective analysis. SETTING: A prospective database at a tertiary referral cancer center. PATIENTS: Review of 274 consecutive liver resections identified 64 patients who underwent resection of hepatic colorectal metastases without ablation followed by adjuvant irinotecan hydrochloride- or oxaliplatin-based systemic chemotherapy. MAIN OUTCOME MEASURES: Median and 5-year overall and disease-free survival after primary and repeated hepatectomy. RESULTS: At median follow-up of 40 months, median and 5-year overall survival after hepatectomy were 60 months and 53%, respectively; median and 5-year disease-free survival were 33 months and 25%, respectively. Multivariate analysis showed that less than 1 year between colectomy and liver resection (P = .001), more than 3 metastases (P = .001), no repeated hepatectomy (P = .01), and lymph node-positive primary colon cancer (P = .02) were independently predictive of worse survival. Of 28 patients (44%) with liver-confined recurrence, 19 (30%) underwent repeated hepatectomy; at median follow-up of 38 months, median and 5-year overall survival after repeated hepatectomy were 48 months and 44%, respectively. No risk factors were identified in multivariate analysis. In patients with recurrence, median and 5-year overall survival measured from primary hepatectomy were 70 months and 73%, respectively, with repeated hepatectomy vs 43 months and 43%, respectively, without repeated hepatectomy (P = .03). CONCLUSION: Multimodal treatment of recurrent colorectal cancer confined to the liver should begin with consideration of repeated hepatectomy.

    Title Close Collaboration Between Surgeon and Pathologist is Essential for Accurate Staging of Early Colon Cancer.
    Date July 2007
    Journal Annals of Surgery
    Title Improving Resectability of Hepatic Colorectal Metastases: Expert Consensus Statement.
    Date December 2006
    Journal Annals of Surgical Oncology
    Title Unfavourable Prognosis Associated with K-ras Gene Mutation in Pancreatic Cancer Surgical Margins.
    Date November 2006
    Journal Gut
    Excerpt

    BACKGROUND: Despite intent to cure surgery with negative resection margins, locoregional recurrence is common in pancreatic cancer. AIMS: To determine whether detection of K-ras gene mutation in the histologically negative surgical margins of pancreatic cancer reflects unrecognised disease. PATIENTS: Seventy patients who underwent curative resection for pancreatic ductal adenocarcinoma were evaluated. METHODS: All patients had surgical resection margins (pancreatic transection and retroperitoneal) that were histologically free of invasive cancer. DNA was extracted from these paraffin embedded surgical margins and assessed by quantitative real time polymerase chain reaction to detect the K-ras gene mutation at codon 12. Detection of K-ras mutation was correlated with standard clinicopathological factors. RESULTS: K-ras mutation was detected in histologically negative surgical margins of 37 of 70 (53%) patients. A significant difference in overall survival was demonstrated between patients with margins that were K-ras mutation positive compared with negative (median 15 v 55 months, respectively; p = 0.0008). By univariate and multivariate analyses, detection of K-ras mutation in the margins was a significant prognostic factor for poor survival (hazard ratio (HR) 2.8 (95% confidence interval (CI) 1.5-5.3), p = 0.0009; and HR 2.8 (95% CI 1.4-5.5), p = 0.004, respectively). CONCLUSIONS: Detection of cells harbouring K-ras mutation in histologically negative surgical margins of pancreatic cancer may represent unrecognised disease and correlates with poor disease outcome. The study demonstrates that molecular-genetic evaluation of surgical resection margins can improve pathological staging and prognostic evaluation of patients with pancreatic ductal adenocarcinoma.

    Title More Extensive Nodal Dissection Improves Survival for Stages I to Iii of Colon Cancer: a Population-based Study.
    Date November 2006
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE: To determine whether analyzing more lymph nodes in colon cancer specimens improves survival. SUMMARY BACKGROUND DATA: Increasing the number of lymph nodes analyzed has been reported to correlate with improved survival in patients with node-negative colon cancer. METHODS: The Surveillance, Epidemiology, and End Results database was queried for all patients undergoing resection for histologically confirmed colon cancer between the years 1988 and 2000. Patients were excluded for distant metastases or if an unknown number of nodes was sampled. The number of nodes sampled was categorized into 0, 1 to 7, 8 to 14, and > or =15 nodes. Survival curves constructed using the Kaplan-Meier method were compared using log rank testing. A Cox proportional hazard model was created to adjust for year of diagnosis, age, race, gender, tumor grade, tumor size, TNM stage, and percent of nodes positive for tumor. RESULTS: The median number of lymph nodes sampled for all 82,896 patients was 9. For all stages examined, increasing nodal sampling was associated with improved survival. Multivariate regression demonstrated that patients who had at least 15 nodes sampled as compared with 1 to 7 nodes experienced a 20.6% reduction in mortality independent of other patient and tumor characteristics. CONCLUSIONS: Adequate lymphadenectomy, as measured by analysis of at least 15 lymph nodes, correlates with improved survival, independent of stage, patient demographics, and tumor characteristics. Currently, most procedures do not meet this guideline. Future trials of adjuvant therapy should include extent of lymphadenectomy as a stratification factor.

    Title Lymphatic Mapping and Sentinel Node Analysis: Current Concepts and Applications.
    Date November 2006
    Journal Ca: a Cancer Journal for Clinicians
    Excerpt

    Since the introduction of sentinel node biopsy in 1990 as a minimally invasive surgical technique for the diagnosis of melanoma lymphatic metastases, the number of applications has expanded. We review applications and the current status of sentinel node biopsy in melanoma, breast, colon, gastric, esophageal, head and neck, thyroid, and lung cancer. Variations on techniques specific to each organ are explained, and the current role of sentinel node biopsy in diagnosis and treatment is discussed.

    Title Radiofrequency Ablation of Hepatic Metastases from Colorectal Cancer: Are Newer Generation Probes Better?
    Date November 2006
    Journal The American Surgeon
    Excerpt

    Second-generation radiofrequency ablation (RFA) probes and their successors have more power, shorter ablation times, and an increased area of ablation compared with the first-generation probes used before 2000. We examined whether the use of the newer probes has improved the clinical outcome of RFA for hepatic metastases of colorectal cancer at our tertiary cancer center. Of 160 patients who underwent RFA between 1997 and 2003, 52 had metastases confined to the liver: 21 patients underwent 46 ablations with the first-generation probes and 31 patients underwent 58 ablations with the newer probes. The two groups had similar demographic characteristics. At a median follow-up of 26.2 months, patients treated with the newer probes had a longer median disease-free survival (16 months vs 8 months, P < 0.01) and a lower rate of margin recurrence (5.2% vs 17.4%); eight patients had no evidence of disease and one patient was alive with disease. By contrast, of the 46 patients treated with the first-generation probes, 2 patients had no evidence of disease and 1 patient was alive with disease. Newer-generation probes are associated with lower rates of margin recurrence and higher rates of disease-free survival after RFA of hepatic metastases from colorectal cancer.

    Title Treatment Disparities in Hispanic Rectal Cancer Patients: a Seer Database Study.
    Date November 2006
    Journal The American Surgeon
    Excerpt

    Although Hispanics demonstrate a low overall incidence of rectal cancer, mortality rates have not decreased relative to non-Hispanic whites. To determine if this was in part due to racial disparities in care, we compared rates of neoadjuvant therapy and sphincter-preserving surgery between Hispanics and non-Hispanic whites diagnosed with rectal cancer using the Surveillance, Epidemiology, and End Results (SEER) database. The study population was comprised of 2,573 Hispanics (55.4% male) and 28,395 non-Hispanic whites (56.6% male). Rates of neoadjuvant radiation were 13.5 per cent for Hispanics compared with 10.4 per cent for non-Hispanic whites (P < 0.001). In a Cox proportional hazards model adjusting for nodal status, tumor size, and T stage, non-Hispanic whites were significantly less likely to have received neoadjuvant therapy (hazard ratio, 0.72; P < 0.001; 95% confidence interval 0.63-0.83). Rates of sphincter preservation were 67 per cent for Hispanics and 70 per cent for non-Hispanic whites (P = 0.003). Non-Hispanic whites were significantly more likely to have received a sphincter-preserving operation than Hispanics (hazard ratio, 1.076; P = 0.019; 95% confidence interval 1.02-1.27). We conclude that Hispanics are significantly more likely to receive neoadjuvant therapy but are less likely to receive sphincter-sparing operations for rectal cancer compared with non-Hispanic whites. Further studies are required to assess the impact of these treatment disparities on patient outcome.

    Title Colorectal Cancer Screening and Surveillance: Current Standards and Future Trends.
    Date October 2006
    Journal Annals of Surgical Oncology
    Excerpt

    Its prevalence, long premalignant course, and favorable response to early intervention make colorectal cancer an ideal target for screening regimens. The success of these regimens depends on accurate assessment of risk factors, patient compliance with scheduled visits and tests, and physician knowledge of screening strategies. We review the current recommendations for colorectal cancer screening in general and at-risk populations, comment on surveillance methods in high-risk patients, and examine current trends that will likely influence screening regimens in the future.

    Title Sentinel Lymph Node Mapping with Gi Cancer.
    Date August 2006
    Journal Cancer Metastasis Reviews
    Excerpt

    Precise evaluation of lymph node status is one of the most important factors in determining clinical outcome in treating gastro-intestinal (GI) cancer. Sentinel lymph node (SLN) mapping clearly has become highly feasible and accurate in staging GI cancer. The lunchtime symposium focused on the present status of SLN mapping for GI cancer. Dr. Kitigawa proposed a new strategy using sentinel node biopsy for esophageal cancer patients with clinically early stage disease. Dr. Uenosono reported on whether the SLN concept is applicable for gastric cancer through his analysis of more than 180 patients with cT1-2, N0 tumors. The detection rate was 95%, the false negative rate of lymph node metastasis including micro-metastasis was 4%, and accuracy was 99% in gastric cancer patients with cT1N0. Dr. Bilchik recommended the best technique for identifying SLNs in colorectal cancer: a combination of radiotracer and blue dye method, emphasizing that this technique will become increasingly popular because of the SLN concept, with improvement in staging accuracy. He stressed that this novel procedure offers the potential for significant upstaging of GI cancer. Dr. Saha emphasized that SLN mapping for colorectal cancer is highly successful and accurate in predicting the presence or absence of nodal disease with a relatively low incidence of skip metastases. It provided the "right nodes" to the pathologists for detailed analysis for appropriate staging and treatment with adjuvant chemotherapy. Although more evidence from large-scale multicenter clinical trials is required, SLN mapping may be very useful for individualizing multi-modal treatment for esophageal cancer and might be widely acceptable even for GI cancer.

    Title Chemokine Receptor Cxcr4 Expression in Patients with Melanoma and Colorectal Cancer Liver Metastases and the Association with Disease Outcome.
    Date August 2006
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE: To determine the role of chemokine receptor (CR) expression in patients with melanoma and colorectal cancer (CRC) liver metastases. SUMMARY BACKGROUND DATA: Murine and in vitro models have identified CR as potential factors in organ-specific metastasis of multiple cancers. Chemokines via their respective receptors have been shown to promote cell migration to distant organs. METHODS: Patients who underwent hepatic surgery for melanoma or CRC liver metastases were assessed. Screening cDNA microarrays of melanoma/CRC cell lines and tumor specimens were analyzed to identify CR. Microarray data were validated by quantitative real-time RT-PCR (qRT) in paraffin-embedded liver metastases. Migration assays and immunohistochemistry were performed to verify CR function and confirm CR expression, respectively. RESULTS: Microarray analysis identified CXCR4 as the most common CR expressed by both cancers. qRT demonstrated CXCR4 expression in 24 of 27 (89%) melanoma and 28 of 29 (97%) CRC liver metastases. In vitro treatment of melanoma or CRC cells with CXCL12, the ligand for CXCR4, significantly increased cell migration (P < 0.001). Low versus high CXCR4 expression in CRC liver metastases correlated with a significant difference in overall survival (median 27 months vs. 10 months, respectively; P = 0.036). In melanoma, low versus high CXCR4 expression in liver metastases demonstrated no difference in overall survival (median 11 months vs. 8 months, respectively; P = not significant). CONCLUSIONS: CXCR4 is expressed and functional on melanoma and CRC cells. The ligand for CXCR4 is highly expressed in liver and may specifically attract melanoma and CRC CXCR4 (+) cells. Quantitative analysis of CXCR4 gene expression in patients with liver metastases has prognostic significance for disease outcome.

    Title Prospective Multicenter Trial of Staging Adequacy in Colon Cancer: Preliminary Results.
    Date July 2006
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    HYPOTHESIS: Lymph node evaluation is an important prognostic factor in colorectal cancer (CRC). A 25% recurrence rate in patients with node-negative CRC suggests that current staging practices are inadequate. Focused analysis of the sentinel node (SN) by multiple sectioning and immunohistochemistry improves staging accuracy. DESIGN: Prospective phase 2 multicenter trial. SETTING: Tertiary referral cancer centers. PATIENTS: Between March 2001 and June 2005, 132 patients were enrolled with clinical stage I and II CRC in a prospective multicenter trial (R01-CA90484). INTERVENTION: During a standard oncologic resection, lymphatic mapping was performed and the SN identified either by the surgeon or the pathologist. Hematoxylin-eosin staining was performed on all lymph nodes and immunohistochemistry, on lymph nodes negative by hematoxylin-eosin staining. MAIN OUTCOME MEASURES: Micrometastases greater than 0.2 mm but less than 2 mm and isolated tumor cells less than 0.2 mm were defined according to the sixth edition of the American Joint Committee on Cancer Cancer Staging Manual. RESULTS: The 63 men and 69 women had a median age of 74 years. Sixty-eight patients (52%) underwent a right hemicolectomy; 3 (2.3%), a transverse colectomy; 9 (7%), a left colectomy; 15 (11%), a sigmoid colectomy; 34 (26%), a low anterior resection; 1 (1%), an abdominal perineal resection; and 2 (2%), a total colectomy. Of the 111 evaluable primary tumors, 19 (17%) were T1 lesions; 17 (15%), T2; 72 (65%), T3; and 3 (2.7%), T4 tumors. Thirty-three patients (30%) were classified as stage I; 46 (41%), stage II, and 32 (29%), stage III. The SN was identified by the surgeon in 127 patients (96%) and by the pathologist in 5 patients (4%). The median number of SNs and total lymph nodes examined were 3 and 14.5, respectively. The sensitivity of lymphatic mapping and SN analysis was 88.2% and the false-negative rate, 7.4% (6/81). Of the 6 false-negative results, 4 were attributed to lymphatic channels obliterated by tumor. Upstaging occurred in 28 patients (23.6%). CONCLUSIONS: In a multicenter trial, ultrastaging of colon cancer is feasible and accurate. In stage II CRC, 24% of patients had nodal carcinoma cells not detected by conventional staging methods. Surgical technique (adequate lymph node retrieval) and focused pathological analysis may improve staging accuracy and the selection of patients for chemotherapy. The unnecessary toxicity and expense of chemotherapy may be avoided in those patients who are truly node negative.

    Title Long-term Survival After Radiofrequency Ablation of Complex Unresectable Liver Tumors.
    Date July 2006
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    HYPOTHESIS: Radiofrequency ablation (RFA) may improve survival of high-risk patients with unresectable and refractory tumors. DESIGN: Retrospective analysis of a prospective database. SETTING: A tertiary referral cancer center. PATIENTS AND METHODS: Between November 1, 1997, and January 31, 2005, we performed 219 RFA procedures to ablate 521 hepatic tumors in 181 patients. RESULTS: Of the 181 patients, 52% were male and 48% were female, and the mean age was 61.3 years (age range, 27-91 years). Radiofrequency ablation was performed via celiotomy (n = 135), via laparoscopy (n = 48), or percutaneously (n = 36). In 106 patients (79%), RFA was used in combination with surgical resection. The most common tumors included colorectal cancer (40.9%), hepatocellular carcinoma (14.9%), carcinoid tumor (13.8%), melanoma (9.4%), and breast cancer (5.0%). The average number of tumors per patient was 3.3 tumors. The average number of RFA-treated lesions per procedure was 2.38 lesions; the mean lesion size was 3.56 cm (lesion size range, 0.8-9.0 cm). At a mean follow-up of 33.2 months (follow-up range, 12-91 months), overall survival was 48.3 months for carcinoid tumors, 25.2 months for hepatocellular carcinoma, 18.5 months for melanoma, 29.7 months for colorectal cancer, and 30.1 months for breast cancer. Seventy-eight patients (43%) developed recurrences. Of 521 tumors that were treated, 125 (24%) recurred; the incidence of local recurrence was 28% for tumors larger than 3 cm vs 18% for tumors 3 cm or smaller (P = .04). Twenty-nine patients underwent serial ablations. Seventy-one patients (39%) were disease free at last follow-up. CONCLUSION: A significant number of patients whose hepatic malignancies are unresectable or refractory to chemotherapy may be considered for RFA as part of a multimodality therapeutic regimen. In these patients, RFA is safe and may prolong survival.

    Title Increased Integrity of Free Circulating Dna in Sera of Patients with Colorectal or Periampullary Cancer: Direct Quantitative Pcr for Alu Repeats.
    Date June 2006
    Journal Clinical Chemistry
    Excerpt

    BACKGROUND: Cell-free DNA circulating in blood is a candidate biomarker for malignant tumors. Unlike uniformly truncated DNA released from apoptotic nondiseased cells, DNA released from dead cancer cells varies in size. We developed a novel method to measure the ratio of longer to shorter DNA fragments (DNA integrity) in serum as a potential biomarker for patients with colorectal cancer (CRC) or periampullary cancers (PACs). METHODS: Sera from 32 patients with CRC (3 stage I, 14 stage II, 6 stage III, and 9 stage IV patients), 19 patients with PACs (2 stage I, 9 stage II, 1 stage III, and 7 stage IV patients), and 51 healthy volunteers were assessed by quantitative real-time PCR of ALU repeats (ALU-qPCR) with 2 sets of primers (115 and 247 bp) amplifying different lengths of DNA. We used serum directly as a template for ALU-qPCR without DNA purification. DNA integrity was determined as ratio of qPCR results of 247-bp ALU over 115-bp ALU. RESULTS: ALU-qPCR had a detection limit of 0.01 pg of DNA. Eliminating DNA purification reduced technical artifacts and reagent/labor costs. Serum DNA integrity was significantly increased for stage I/II and III/IV CRC and stage I/II and III/IV PACs (P = 0.002, P = 0.006, P = 0.022, and P <0.0001, respectively). ROC curves for detecting CRC and PACs had areas under the curves of 0.78 and 0.80, respectively. CONCLUSIONS: Direct ALU-qPCR is a robust, highly sensitive, and high-throughput method to measure serum DNA integrity. DNA integrity is a potential serum biomarker for detection and evaluation of CRC and PACs.

    Title The Clinical Significance of Magea3 Expression in Pancreatic Cancer.
    Date April 2006
    Journal International Journal of Cancer. Journal International Du Cancer
    Excerpt

    The MAGEA gene family that encodes cancer testis antigens is differentially expressed in many cancers. Though MAGEA3 expression has been detected in gastrointestinal malignancies, its role in pancreatic ductal adenocarcinoma (PDAC) has not been well established. We assessed 57 patients who underwent intent-to-cure surgery for PDAC. Total RNA from paraffin-embedded pancreatic tumors was extracted and assessed for MAGEA3 gene expression by an optimized probe-based quantitative real-time RT-PCR (qRT) assay. MAGEA3 gene expression was detected by qRT in 25 (44%) patients. For the entire cohort, detection of MAGEA3 expression was associated with significantly decreased overall survival (median, 16 vs 33 months; log-rank, p = 0.032). When clinicopathologic factors, including age, gender, stage, tumor extent, lymph node metastasis, tumor grade, perineural invasion and lymphovascular invasion were assessed by univariate analysis, MAGEA3 gene expression and tumor grade were significant prognostic factors for poor survival (HR 2.1, 95% CI: 1.0-4.4, p = 0.041; and HR 3.7, 95% CI: 1.8-7.6, p = 0.0004, respectively). Immunohistochemistry (IHC) was performed and confirmed MAGEA3 protein in PDAC specimens. In conclusion, MAGEA3 is differentially expressed in patients with PDAC; its expression correlates with significantly worse survival. Molecular assessment for MAGEA3 should be considered to improve prognostic evaluation and to identify eligible patients for potential immune-based therapy.

    Title The Utility of Estrogen Receptor, Progesterone Receptor, and Her-2/neu Status to Predict Survival in Patients Undergoing Hepatic Resection for Breast Cancer Metastases.
    Date March 2006
    Journal American Journal of Surgery
    Excerpt

    BACKGROUND: Hepatic metastases from breast cancer signal a dismal prognosis, with a median survival of 9.5 months. METHODS: Twenty breast cancer patients with liver metastases underwent hepatic resection, biopsy, or ablation between 1995 and 2004. Hormone receptor status and Her-2/neu expression of primary and metastatic tumors were correlated with overall survival. RESULTS: At a mean follow-up of 39 months after hepatic resection, median survival was 32 months. Patients undergoing anatomic resection with or without ablation lived significantly longer than those undergoing more limited resections (46 vs. 25 months, P = .016). Survival was significantly greater in patients with estrogen receptor (ER)-positive primary (P = .02) and metastatic (P < .004) tumors, Her-2/neu-positive metastases (P = .02), </=2 hepatic metastases (P < .002), and age >50 years at metastasectomy (P = .02). CONCLUSIONS: The ER status of the primary tumor and ER and Her-2/neu status of hepatic metastases, in addition to other clinical factors, may help select patients who would benefit from hepatic metastasectomy.

    Title Neoadjuvant Chemotherapy for Metastatic Colon Cancer: a Cautionary Note.
    Date February 2006
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Title Quality Control Issues in the Management of Colon Cancer Patients.
    Date August 2005
    Journal European Journal of Surgical Oncology : the Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology
    Excerpt

    Quality assurance in colon cancer demands a multidisciplinary effort involving general practitioners, surgeons, radiologists, gastroenterologists, medical oncologists, and pathologists, among others. Maximal improvements in survival will result when colon cancer screening, diagnosis, staging, treatment and surveillance are optimized. We seek to identify those issues most relevant to the quality of care we provide our colon cancer patients.

    Title Lymphatic Mapping and Sentinel Node Analysis in Colon Cancer.
    Date May 2005
    Journal Clinical Colorectal Cancer
    Excerpt

    Accurate staging of colon cancer is prognostically and therapeutically important. By identifying those patients who would most benefit from adjuvant chemotherapy, accurate staging should decrease recurrence rates and improve overall survival. Lymphatic mapping and sentinel node analysis allow for a focused review of the lymph nodes, which are most likely to harbor a metastasis and may make ultrastaging techniques, such as immunohistochemistry and reverse-transcriptase polymerase chain reaction, more practical. The prognostic significance of micrometastatic disease detected via ultrastaging techniques remains controversial.

    Title Chemokine Receptor Cxcr4 Expression in Colorectal Cancer Patients Increases the Risk for Recurrence and for Poor Survival.
    Date May 2005
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: Liver metastasis is the predominant cause of colorectal cancer (CRC) related mortality. Chemokines, soluble factors that orchestrate hematopoetic cell movement, have been implicated in directing cancer metastasis, although their clinical relevance in CRC has not been defined. Our hypothesis was that the chemokine receptor CXCR4 expressed by CRC is a prognostic factor for poor disease outcome. METHODS: CRC cell lines (n = 6) and tumor specimens (n = 139) from patients with different American Joint Committee on Cancer (AJCC) stages of CRC were assessed. Microarray screening of select specimens and cell lines identified CXCR4 as a prominent chemokine receptor. CXCR4 expression in tumor and benign specimens was assessed by quantitative real-time reverse transcription polymerase chain reaction and correlated with disease recurrence and overall survival. RESULTS: High CXCR4 expression in tumor specimens (n = 57) from AJCC stage I/II patients was associated with increased risk for local recurrence and/or distant metastasis (risk ratio, 1.35; 95% CI, 1.09 to 1.68; P = .0065). High CXCR4 expression in primary tumor specimens (n = 35) from AJCC stage IV patients correlated with worse overall median survival (9 months v 23 months; RR, 2.53; 95% CI, 1.19 to 5.40; P = .016). CXCR4 expression was significantly higher in liver metastases (n = 39) compared with primary CRC tumors (n = 100; P < .0001). CONCLUSION: CXCR4, a well-characterized chemokine receptor for T-cells, is differentially expressed in CRC. CXCR4 gene expression in primary CRC demonstrated significant associations with recurrence, survival, and liver metastasis. The CXCR4-CXCL12 signaling mechanism may be clinically relevant for patients with CRC and represents a potential novel target for disease-directed therapy.

    Title Epigenetic Inactivation of Id4 in Colorectal Carcinomas Correlates with Poor Differentiation and Unfavorable Prognosis.
    Date May 2005
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    PURPOSE: ID4 gene is a member of the inhibitor of DNA binding (ID) family proteins that inhibit DNA binding of basic helix-loop-helix transcription factors. The epigenetic inactivation of ID4 gene on colorectal cancer (CRC) development and its clinical significance was assessed. EXPERIMENTAL DESIGN: In CRC cell lines, ID4 methylation status of the promoter region was assessed by methylation-specific PCR and bisulfite sequencing. The mRNA expression level was assessed by quantitative real-time reverse transcription-PCR. The methylation status of 9 normal epithelia, 13 adenomas, 92 primary CRCs, and 26 liver metastases was assessed by methylation-specific PCR. ID4 protein expression was assessed by immunohistochemistry analysis of tissue specimen. RESULTS: CRC cell lines were shown to be hypermethylated, and mRNA expression was suppressed and could be restored by 5-aza-cytidine treatment. In clinical specimens from normal epithelia, adenomas, primary CRCs, and liver metastases, the frequency of ID4 hypermethylation was 0 of 9 (0%), 0 of 13 (0%), 49 of 92 (53%), and 19 of 26 (73%), respectively, with a significant elevation according to CRC pathological progression. Methylation status of primary CRCs significantly correlated with histopathological tumor grade (P = 0.028). Immunohistochemistry analysis showed ID4 expression of normal colon epithelia, adenomas, and unmethylated primary CRCs but not hypermethylated CRC specimens. Among 76 American Joint Committee on Cancer stage I to IV patients who had undergone curative surgical resection, overall survival was significantly poorer in patients with hypermethylated ID4 bearing tumors (P = 0.0066). CONCLUSIONS: ID4 gene is a potential tumor suppressor gene for which methylation status may play an important role in the CRC progression.

    Title Allelic Imbalance of Apaf-1 Locus at 12q23 is Related to Progression of Colorectal Carcinoma.
    Date December 2004
    Journal Oncogene
    Excerpt

    APAF-1 gene, located at chromosome locus 12q23, is a key factor in the mitochondrial apoptotic pathway downstream of p53, and is a potential tumor suppressor gene. We hypothesized that APAF-1 gene dysfunction due to allelic imbalance (AI) contributes to the development and progression of colorectal carcinoma (CRC). AI at APAF-1 locus and microsatellite instability (MIN) in CRCs and adenomas were assessed by multiple microsatellite markers. The frequency of AI significantly increased with tumor progression; 0 of 33 (0%) adenomas, 14 of 49 (29%) primary CRCs, and 18 of 34 (53%) liver metastases had AI. A total of 12 metastases were matched with corresponding primary CRCs; in 11 of 12 (92%) pairs, the metastasis had same AI status as the corresponding primary tumor. APAF-1 mRNA transcription level was significantly decreased with AI in liver metastases (P=0.009). Promoter hypermethylation was found in three of 35 (9%) primary CRCs and one of 15 (7%) liver metastases by methylation-specific PCR but was not correlated with AI. MIN was observed in 11 of 49 (23%) primary CRCs and was a favorable prognostic factor. Our results suggest that APAF-1 gene haploinsufficiency caused by AI increases with tumor progression, and relates to hepatic metastasis.

    Title Peptide Nucleic Acid Clamp Pcr: a Novel K-ras Mutation Detection Assay for Colorectal Cancer Micrometastases in Lymph Nodes.
    Date August 2004
    Journal International Journal of Cancer. Journal International Du Cancer
    Excerpt

    Inaccurate staging of colorectal cancer (CRC) has been attributed to the failure to detect lymph node metastases by conventional pathology. We have previously reported the use of lymphatic mapping to accurately identify those lymph nodes most likely to harbor micrometastatic disease and permit focused pathologic examination. Mutation of K-ras allele at codons 12 or 13 occurs frequently in early stages of CRC development. The purpose of our study was to assess sentinel lymph nodes (SLN) for occult CRC micrometastases using a unique peptide nucleic acid (PNA) clamp PCR assay specific for K-ras mutations. Seventy-two paraffin-embedded primary CRC and paired SLN were evaluated by PNA clamp PCR for K-ras mutations. Thirty primary tumors (42%) were positive for K-ras mutations, and in 5 of these cases the SLN were positive for metastases by Hematoxylin and Eosin staining. PNA clamp PCR identified occult metastases in an additional 6 patients, upstaging 24% of K-ras positive primary CRCs (p = 0.014). No K-ras mutations were detected among the 20 noncancer lymph nodes assessed. This study demonstrates the utility, specificity and sensitivity of PNA clamp PCR assay in identifying occult micrometastases in the SLN of CRC patients by single-base mutation analysis.

    Title Novel Effective Drugs and Evolving Ablation Technology: a More Comprehensive Approach to Hepatic Malignancies.
    Date August 2004
    Journal Annals of Surgical Oncology
    Title Historical Review of Lymphatic Mapping in Gastrointestinal Malignancies.
    Date June 2004
    Journal Annals of Surgical Oncology
    Excerpt

    The advent of sentinel lymph node mapping (SLNM) has had a profound impact on the surgical management of breast cancer and melanoma over the past decade. However, SLNM in gastrointestinal malignancies is still in its infancy. The role of SLNM in gastrointestinal malignancies is to increase staging accuracy and to reduce the understaging associated with standard surgical and pathological techniques. Numerous authors have described the successful use of SLNM in colon, rectal, gastric, esophageal, and anal canal malignancies, with a high degree of accuracy and upstaging by detailed pathological analysis of the sentinel nodes. Over the past 2 years, research and publications related to gastrointestinal lymphatic mapping have dramatically increased worldwide.

    Title Radiofrequency Ablation of Hepatic Malignancies: Inexpensive and Minimally Invasive but Should It Replace Resection?
    Date February 2004
    Journal Annals of Surgical Oncology
    Title Differential Expression of Thymidylate Synthase in Colorectal Tumors and Matched Lymph Nodes: Impact on Adjuvant Treatment.
    Date November 2003
    Journal The American Surgeon
    Excerpt

    Although the expression of thymidylate synthase (TS) in metastatic colorectal cancer (CRC) may be a better predictor of response to 5-fluorouracil chemotherapy than TS expression in primary CRC, this enzyme has not been well studied in tumor-draining regional lymph nodes. We retrospectively examined TS expression in 12 primary CRC lesions (pT3) and matched sentinel lymph nodes. Of the 8 primary tumors that were TS-positive, 50 per cent (4/8) had tumor-positive lymph nodes and 50 per cent (4/8) had tumor-negative nodes. Of the 4 primary tumors that were TS-negative, 75 per cent (3/4) had tumor-positive nodes and 25 per cent (1/4) had tumor-negative nodes [kappa = -0.1386, 95 per cent confidence interval: (-0.4820, 0.2048), P = 0.4284]. Of the 8 TS-positive primaries, 25 per cent (2/8) had TS-positive nodes and 75 per cent (6/8) had TS-negative nodes. Of the 4 TS-negative primaries, 50 per cent (2/4) had TS-positive nodes and 50 per cent (2/4) had TS-negative nodes [kappa = -0.0131, 95 per cent confidence interval: (-0.2958, 0.2696), P = 0.9274]. Two of the three TS-negative primaries that had metastasized to regional lymph nodes were associated with TS-positive lymph nodes. Our findings indicate that expression of TS by a primary CRC does not correlate with nodal metastases or nodal TS expression. Nodal expression of TS may be important in predicting response to 5-fluorouracil when a primary CRC is TS-negative.

    Title Lymphatic Mapping and Sentinel Lymphadenectomy for Early-stage Melanoma: Therapeutic Utility and Implications of Nodal Microanatomy and Molecular Staging for Improving the Accuracy of Detection of Nodal Micrometastases.
    Date November 2003
    Journal Annals of Surgery
    Excerpt

    OBJECTIVE: Lymphatic mapping and sentinel lymphadenectomy (LM/SL) have been applied to virtually all solid neoplasms since our original description of LM/SL for melanoma. Our objectives were to determine the diagnostic and therapeutic utility of LM/SL, investigate carbon dye for mapping the microanatomy of lymphatic flow within the sentinel node (SN), and determine the prognostic accuracy of molecular assessment of the SN. METHODS: Since 1985, 1599 patients with AJCC Stage I/II melanoma have been treated by LM/SL at our institution and 4590 have been treated by wide excision (WE) without nodal staging. We examined the incidence of clinical nodal recurrence after WE alone, the incidence of subclinical nodal metastases found by LM/SL, and the incidence of nodal recurrence in basins with histopathology-negative SNs. RESULTS: In 1514 LM/SL patients with a primary of known Breslow thickness, the incidence of metastasis in nodes claimed to be sentinel was 7.3%, 19.7%, 33.2%, and 39.7% for primary lesions </=1.0, 1.01-2.0, 2.01-4.0, and >4.0 mm, respectively. In 3652 WE-only patients, the corresponding rates of nodal recurrence were 12.0%, 32.0%, 34.4%, and 30.1%. Thus, LM/SL detected only 60% of expected nodal metastases from primary melanomas <2.01 mm. Forty of 1599 (3.1%) patients developed recurrence in basins with immunohistochemistry (IH)-negative SNs. To determine whether nonrandom intranodal distribution of tumor cells could explain missed SN metastases, we coinjected carbon particles and blue dye during LM/SL in 166 patients: 25 (16%) patients had nodal metastases, all of which were found only in nodal subsectors containing carbon particles. When paraffin-embedded SNs from a subset of 162 IH-negative patients were re-examined by quantitative multimarker reverse-transcriptase polymerase chain reaction (qRT) assay, 49 (30%) gave positive signals. These patients had a significantly higher risk of disease recurrence and death than did patients whose IH and qRT results were negative (p < 0.0001). Comparison of 287 prognostically matched pairs of patients who underwent immediate (after LM/SL) versus delayed (after observation) dissection of nodal metastases revealed 5-, 10-, and 15-year survival rates of 73%, 69%, and 69% versus 51%, 37%, and 32%, respectively (P < or = 0.001). CONCLUSIONS: SN assessment based on intranodal compartmentalization of lymphatic flow (carbon dye mapping) should increase the accuracy of IH and, in combination with multimarker qRT assessment, will allow confident identification of most patients for whom surgery alone is curative. Our data suggest a significant therapeutic benefit for immediate dissection based on identification of a tumor-involved SN.

    Title Lymphatic Mapping and Sentinel Node Analysis to Optimize Laparoscopic Resection and Staging of Colorectal Cancer: an Update.
    Date September 2003
    Journal Cancer Control : Journal of the Moffitt Cancer Center
    Excerpt

    BACKGROUND: Laparoscopic colectomy for colorectal cancer (CRC) has been criticized because of the potential for inadequate nodal dissection and incomplete staging. Lymphatic mapping (LM) and sentinel lymph node (SLN) analysis can improve the accuracy of staging in open colectomy, but its utility during laparoscopic colectomy is unknown. METHODS: Between 1996 and 2002, 30 patients with clinically localized colorectal neoplasms or premalignant polyps underwent subserosal or submucosal injection of isosulfan blue dye via a colonoscope, via a percutaneously inserted spinal needle, or through a hand port. Blue-stained lymphatics were visualized through the laparoscope and followed to the SLN, which was tagged. The colectomy was completed in standard fashion. All lymph nodes were stained by hematoxylin and eosin, and multiple sections of each SLN were examined by immunohistochemical (IHC) staining using cytokeratin antibody. RESULTS: An SLN was identified laparoscopically in all patients. The SLN accurately predicted the tumor status of the nodal basin in 93% of cases. In 8 cases (29%), an unexpected lymphatic drainage pattern altered the extent of mesenteric resection, and in 4 cases (14%), tumor deposits were identified only by IHC and limited to the SLN. CONCLUSIONS: This study, which updates a preliminary report (Am Surg. 2002;68:561-565) confirms that SLN mapping during laparoscopic colon resection can alter the margins of resection and may improve staging by allowing a focused pathologic examination of the SLN, although direct comparison with the "gold standard" of open CRC with adequate lymphadenectomy will be required. Better ultrastaging of CRC lymph nodes may more accurately assign patients to prospective protocols to assess the significance of nodal micrometastases or isolated tumor cells.

    Title Combination Probe and Dye-directed Lymphatic Mapping Detects Micrometastases in Early Colorectal Cancer.
    Date July 2003
    Journal Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract
    Excerpt

    Nodal metastasis is the single most important prognostic factor in early colorectal cancer (CRC). Lymphatic mapping can identify sentinel nodes for focused histopathologic examination and thereby improve the nodal staging of CRC; however, the optimal technique for identifying sentinel nodes in CRC is unclear. We hypothesized that a combination of radiotracer and blue dye would more accurately identify tumor-positive sentinel nodes than blue dye alone. Lymphatic mapping was performed in 48 consecutive patients undergoing resection for CRC and in two original patients who underwent sentinel node mapping in 1996. Prior to resection, 1% vital blue dye and radiotracer were injected around the tumor in the subserosal layer. Nodes were designated as sentinel by blue coloration and/or radioactivity. Lymphatic mapping identified at least one sentinel node in 49 patients. Focused examination of multiple sentinel node sections by means of hematoxylin and eosin and immunohistochemical analysis showed that sentinel nodes accurately predicted the status of the nodal basin in 93.8% (46 of 49) of patients. Of the 19 patients with nodal metastases, 11 had macrometastases (>.2 mm), three had micrometastases (between 2 mm and 0.2 mm), and five had isolated tumor cells or clusters (<.2 mm) identified by immunohistochemical analysis only. Patients had significantly fewer blue/radioactive ("hot") nodes than blue-only nodes (1.38 vs. 2.48 per patient; P = 0.0001). It is important to note that nodal metastases were more common in blue/hot nodes than in blue-only nodes (27.3% [19 of 68] vs. 8.8% [11 of 124]; P = 0.005). Dual-agent lymphatic mapping more accurately identifies sentinel node metastases than blue dye alone. In addition, this technique allows a more focused histopathologic examination of these nodes, in conjunction with the revised American Joint Committee on Cancer guidelines, and thereby offers the potential for significant upstaging of CRC.

    Title Cryosurgical Ablation of Liver Tumors in Colon Cancer Patients Increases the Serum Total Ganglioside Level and then Selectively Augments Antiganglioside Igm.
    Date July 2003
    Journal Cryobiology
    Excerpt

    Cryosurgical ablation (CSA) of tumors induces disruptive necrosis. Necrosis may release tumor gangliosides into circulation and they may augment serum antiganglioside antibodies depending on the nature of gangliosides released. The hypothesis is tested by determining the level of serum total gangliosides (STG) and their antibody titers in the sera of colon cancer patients with cryoablated liver tumors. As controls, we examined the sera of patients who underwent radiofrequency ablation (RFA) and regular surgery (RS), none of which cause disruptive necrosis. The STG level (expressed as lipid-bound sialic acids, LBSA) is higher (p(2)<0.001) in 35 patients (stage IV) than in 38 healthy case-controls (median 23.48 mg/dL, Q-range 7.1 vs 16.04 mg/dL, Q-range 4.5). The mean STG level increased significantly to 31.2+/-6.0mg/dL (p(2)<0.03) after CSA. Concomitantly, the IgM titer against colon cancer-associated gangliosides (GM(2), GD(1a), GT(1b)), increased significantly, but no increase was observed against normal tissue gangliosides (GM(3) or GM(1)). Also after RFA and RS, no such increase was observed either in the level of STG or in IgM titer against tumor gangliosides. The results suggest that CSA-induced necrosis might have acted as an adjuvant, because purified gangliosides without exogenous adjuvants even after repeated immunization failed to elicit antibody response. The post-CSA decline in the STG level correlated with the increase in the antibodies, suggesting a homeostatic role of the antibodies.

    Title Arterial Chemotherapy As Adjuvant and Palliative Treatment of Hepatic Colorectal Metastases: an Update.
    Date June 2003
    Journal Surgical Oncology Clinics of North America
    Excerpt

    Regional hepatic chemotherapy with FUDR significantly improves local recurrence rates and may impact overall survival in patients with hepatic colorectal metastases. The results of prospective randomized trials confirm that careful patient selection, a thorough knowledge of intricate hepatic arterial anatomy, and an understanding of the pharmacokinetics and delivery of FUDR optimize treatment efficacy. A multimodality approach that includes adjuvant therapy in addition to cytoreductive surgery offers promise for the treatment of unresectable hepatic metastases. Because many tumors recur in extrahepatic sites, the addition of novel systemic agents such as CPT-11 may further reduce recurrences. Molecular analysis of the tumor may ultimately help select patients who are good candidates for regional chemotherapy.

    Title Colorectal Carcinoma Nodal Staging. Frequency and Nature of Cytokeratin-positive Cells in Sentinel and Nonsentinel Lymph Nodes.
    Date June 2003
    Journal Archives of Pathology & Laboratory Medicine
    Excerpt

    CONTEXT: Nodal staging accuracy is important for prognosis and selection of patients for chemotherapy. Sentinel lymph node (SLN) mapping improves staging accuracy in breast cancer and melanoma and is being investigated for colorectal carcinoma. OBJECTIVE: To assess pathologic aspects of SLN staging for colon cancer. DESIGN: Sentinel lymph nodes were identified with a dual surgeon-pathologist technique in 51 colorectal carcinomas and 12 adenomas. The frequency of cytokeratin (CK)-positive cells in mesenteric lymph nodes, both SLN and non-SLN, was determined along with their immunohistochemical characteristics. RESULTS: The median number of SLNs was 3; the median number of total nodes was 14. The CK-positive cell clusters were detected in the SLNs of 10 (29%) of 34 SLN-negative patients. Adjusted per patient, SLNs were significantly more likely to contain CK-positive cells than non-SLNs (P <.001). Cell clusters, cytologic atypia, and/or coexpression of tumor and epithelial markers p53 and E-cadherin were supportive of carcinoma cells. Single CK-positive cells only, however, could not be definitively characterized as isolated tumor cells; these cells generally lacked malignant cytologic features and coexpression of tumor and epithelial markers and in 2 cases represented mesothelial cells with calretinin immunoreactivity. Colorectal adenomas were associated with a rare SLN CK-positive cell in 1 (8%) of 12 cases. CONCLUSIONS: Sentinel lymph node staging with CK-immunohistochemical analysis for colorectal carcinomas is highly sensitive for detection of nodal tumor cells. Cohesive cell clusters can be reliably reported as isolated tumor cells. Single CK-positive cells should be interpreted with caution, because they may occasionally represent benign epithelial or mesothelial cells.

    Title Modulators of Ceramide Metabolism Sensitize Colorectal Cancer Cells to Chemotherapy: a Novel Treatment Strategy.
    Date April 2003
    Journal Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract
    Excerpt

    Irinotecan is a first-line chemotherapeutic agent for patients with metastatic colorectal cancer (CRC). Response rates of less than 40% underscore the problem of treating CRC with irinotecan. Our studies have shown that chemosensitization correlates with high levels of ceramide, whereas resistance correlates with high levels of glucosylceramide (GlcCer). The purpose of this study was to characterize the role of ceramide in irinotecan-mediated CRC cell death. We used four human CRC cell lines to assess ceramide metabolism, cell viability, and apoptosis after treatment with irinotecan. Fumonisin B(1) (FB(1)) and 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) were used to inhibit de novo ceramide synthesis and GlcCer production, respectively. L-threo-dihydrosphingosine (safingol) was used to inhibit secondary proliferative pathways mediated by an atypical protein kinase C that is activated by ceramide. Irinotecan elicited dose- and time-dependent increases in ceramide, which preceded apoptosis. When FB(1) was added to irinotecan, CRC cell death was significantly decreased. A significant increase in intracellular levels of GlcCer also was noted after treatment with irinotecan. When GlcCer production was blocked by treating cells with PPMP in addition to irinotecan, ceramide levels increased to 228% of control values and cell death increased by 88%, compared to irinotecan alone. When irinotecan was combined with both PPMP and safingol, cell death was increased by 225% to 325%, compared to irinotecan lone. CRC cell death due to irinotecan is mediated, at least in part, by the de novo synthesis of ceramide. Blocking further metabolism of ceramide can enhance this cytotoxicity. Targeting ceramide pathways is a novel strategy for the treatment of patients with CRC.

    Title Radiofrequency Ablation in 447 Complex Unresectable Liver Tumors: Lessons Learned.
    Date April 2003
    Journal Annals of Surgical Oncology
    Excerpt

    BACKGROUND: Radiofrequency ablation (RFA) is a promising technique for unresectable hepatic malignancies. We reviewed our RFA experience to identify variables affecting local recurrence. METHODS: Patients undergoing RFA between 1997 and 2001 were reviewed for demographics, tumor size, pathology, diagnosis, recurrence, procedures, survival, and complications. RESULTS: The 447 unresectable liver tumors were ablated in 198 procedures. The 153 patients averaged 61.9 years of age and 1.25 RFA procedures per patient. Follow-up averaged 11 months. Serial ablations were performed in 28 patients, 8 of whom are without evidence of disease. Tumors were most commonly carcinomas of colorectal, hepatocellular, breast, and melanoma histologies. Colorectal carcinomas and hepatomas individually recurred more frequently than all other tumor types combined in univariate analyses (P =.009 and P =.008, respectively). Patients with multiple tumors ablated recurred significantly more frequently (P =.001). Size was also significant in univariate and multivariate analyses (P =.0032 and <.0001, respectively). Eighteen patients experienced 36 complications. CONCLUSIONS: Size has the highest correlation with local recurrence, but multiple tumors and pathology may also predict local recurrence risk. Large, complex lesions can be safely serially ablated, but because of morbidity and recurrence, RFA should not replace resection as the primary treatment of resectable liver tumors.

    Title Effect of Lymphatic Mapping on the New Tumor-node-metastasis Classification for Colorectal Cancer.
    Date March 2003
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: Sensitive detection methods and accurate reporting are necessary to determine the prognostic significance of micrometastases (MM) and isolated tumor cells (ITCs) in lymph nodes that drain colorectal cancers (CRCs). This study examined the role of lymphatic mapping (LM) in the application of the new tumor-node-metastasis (TNM) classification for MM and ITC. PATIENTS AND METHODS: All patients at the John Wayne Cancer Institute underwent LM immediately before standard resection of primary CRC between 1996 and 2001. Sentinel nodes (SNs) were identified using blue dye and/or radiotracer and were examined by hematoxylin-eosin (H&E) staining, cytokeratin immunohistochemistry, and multilevel sectioning. The comparison group comprised 370 patients whose primary CRCs were resected without LM during the same period at the same institution. RESULTS: LM was successfully performed in 115 of 120 (96%) patients and correctly predicted the tumor status of the nodal basin in 110 of 115 (96%) patients. Thirty-seven patients (32%) were lymph node-positive by H&E, ITC and MM were found in 23 patients (29.4%) whose lymph nodes were negative by H&E. Tumor deposits were found in the SN only in 29 patients (50%). Nodal involvement was identified for 14.3%, 30%, 74.6%, and 83.3% of T1, T2, T3, and T4 tumors, respectively, in the study group, and for 6.8%, 8.5%, 49.3%, and 41.8% of T1, T2, T3, and T4 tumors, respectively, in the comparison group. The study group had a higher percentage of nodal metastases (53% v 36%; P <.01) and a higher incidence of MM and ITC (29.4% v 1.9%; P <.0001). The mean number of lymph nodes found in the study group (14) was also significantly more than the number found in the comparison group (10; P <.00001). CONCLUSION: Conventional examination of lymph nodes for CRC is inadequate for the detection of MM and ITC as described in the new TNM classification. Thus, LM and focused SN analysis should be considered to fully stage CRC.

    Title The Use of Molecular Profiling of Early Colorectal Cancer to Predict Micrometastases.
    Date January 2003
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    BACKGROUND: Approximately one third of node-negative colorectal cancers (CRCs) recur, suggesting the failure to detect occult disease. Lymphatic mapping followed by focused analysis of the sentinel node is highly accurate in identifying micrometastases. HYPOTHESIS: Because aberrant genetic changes occur early in tumor progression and are associated with lymphatic metastases, we hypothesized that the molecular profiling of specific tumor markers in the primary tumor might predict that tumor's metastatic potential. DESIGN: A prospective patient series. PATIENTS AND INTERVENTIONS: Forty consecutive patients with early CRC underwent lymphatic mapping after subserosal injection of 1 mL of isosulfan blue dye. All lymph nodes were examined by hematoxylin-eosin (HE) staining, and multiple sections of each sentinel node were examined by HE and cytokeratin immunohistochemistry (CK-IHC) staining. Primary tumors were analyzed for p53 expression using IHC staining and for beta-human chorionic gonadotropin (beta-hCG), hepatocyte growth factor receptor (c-Met), and universal melanoma antigen (uMAGE) messenger RNA expression using reverse-transcriptase polymerase chain reaction and electrochemiluminescence. RESULTS: Nine patients (23%) had positive nodes by routine HE staining. Of the remaining 31 patients with negative nodes on HE staining, 8 tumors (26%) were upstaged by CK-IHC identification of occult micrometastases. There was a direct correlation between the number of markers and the T stage (P =.001). The expression of p53, beta-hCG, c-Met, and uMAGE in primary tumors was significantly higher in the presence of nodal micrometastases vs no metastases (P =.03). CONCLUSIONS: Sentinel lymphatic mapping is an accurate method of detecting micrometastases in CRC. Molecular profiling of primary CRC tumors, similar to that used for breast cancer, may be important in predicting metastatic potential and determining which patients may benefit from adjuvant therapy.

    Title Systemic Irinotecan or Regional Floxuridine Chemotherapy Prolongs Survival After Hepatic Cryosurgery in Patients with Metastatic Colon Cancer Refractory to 5-fluorouracil.
    Date December 2002
    Journal Clinical Colorectal Cancer
    Excerpt

    Most colorectal cancers metastatic to the liver are resistant to chemotherapy and are not amenable to surgical resection. This study evaluated our 6-year experience (July 1992-July 1998) in treating patients with unresectable hepatic colorectal metastases refractory to systemic 5-fluorouracil (5-FU). One hundred fifty-three patients underwent cryosurgical ablation (CSA) of 5-FU-resistant hepatic metastases. The patients then received either hepatic arterial floxuridine (FUDR), systemic CPT-11, or no postoperative adjuvant chemotherapy. Number, size, and location of hepatic metastases, carcinoembryonic antigen (CEA) levels, and type of postoperative treatment were analyzed. One to 15 lesions were frozen (median number, 3; median size, 6 cm), for a total of 73 synchronous and 80 metachronous lesions. Overall median survival was 28.4 months from the date of diagnosis of liver metastases and 16.1 months from the time of CSA. After cryosurgery alone, median survival was 13 months, which was significantly shorter than the post-CSA survival of 23.6 months with adjuvant CPT-11 and 21.2 months with hepatic FUDR (P = 0.007). Predictors of survival included preoperative CEA, postoperative reduction in CEA, and adjuvant chemotherapy (P < 0.05). Neither size, number of lesions, nor tumor location impacted survival. At a median follow-up of 13 months, 67% of patients have recurred (35% hepatic, 16% extrahepatic, and 49% both). Twenty percent of the recurrences were in the lobe of the CSA site. The 25 patients who underwent a second CSA had a median survival of 28.4 months from CSA and 40 months from the date of diagnosis of liver metastases. These data indicate that CSA offers an effective alternative for unresectable patients resistant to 5-FU. Systemic CPT-11 or regional FUDR may further prolong survival after CSA.

    Title Serum Total Gangliosides and Ta90-ic Levels: Novel Immunologic Markers in Colorectal Cancer.
    Date October 2002
    Journal Cancer Journal (sudbury, Mass.)
    Excerpt

    BACKGROUND: Because of the challenge in defining prognostic markers predictive of recurrence or progression, carcinoembryonic antigen (CEA) remains the most frequently used marker in colorectal cancer, despite its low sensitivity. We hypothesized that TA90-IC status and serum ganglioside levels might be useful markers and might be of prognostic significance in colorectal cancer. METHODS: Serum samples from 68 patients undergoing surgical treatment for histologically proven colorectal cancer were analyzed for the presence of CEA, serum gangliosides, and TA90-IC. Forty-one patients had node-negative disease, whereas 27 patients had limited metastatic disease. The intent was curative resection, even for patients with metastatic disease. Cryopreserved serum specimens were analyzed in a blinded fashion for total serum ganglioside levels (by an assay that detects lipid-associated sialic acids), for CEA, and for TA90-IC (by a murine monoclonal antibody-based enzyme-linked immunosorbent assay). A positive value for TA90-IC levels was defined as an optical density (OD) of more than 0.410 at 405 nm. RESULTS: Serum ganglioside levels were elevated more frequently than CEA concentrations (84% vs 44%). The combination of serum ganglioside and CEA values was more sensitive (88%) than CEA value alone (44%) in identifying patients with early-stage colorectal cancer. TA90-IC levels were elevated more frequently than CEA concentrations (56% vs 32%). The combination of TA90-IC and CEA values was more sensitive (72%) than CEA value alone (32%) in identifying patients with advanced-stage colorectal cancer. At an enzyme-linked immunosorbent assay cutoff level of 0.410, 15 (56%) patients had positive TA90-IC values. Fourteen patients alive with residual disease had a median OD TA90-IC level of 0.879, and only three patients had levels below the OD cutoff value of 0.410. Thirteen patients with no evidence of disease had a median level of 0.277, and only four patients had OD levels > or = 0.410. TA90-IC was significantly higher in the alive with residual disease patients than those rendered no evidence of disease (P = 0.02). CONCLUSIONS: We speculate that a multiple-marker analysis that combines CEA values with serum ganglioside and TA90-IC values may be more sensitive than CEA value alone for detecting colorectal cancer. The potential prognostic significance of TA90-IC status in advanced disease warrants further investigation.

    Title Lymphatic Mapping of Nodal Micrometastasis in Colon Cancer: Putting the Cart Before the Horse?
    Date September 2002
    Journal Annals of Surgical Oncology
    Title One Hundred Consecutive Cases of Sentinel Lymph Node Mapping in Early Colorectal Carcinoma: Detection of Missed Micrometastases.
    Date August 2002
    Journal Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract
    Excerpt

    Almost one third of patients with "node-negative" colorectal carcinoma (CRC) develop systemic disease. This implies that these patients have occult disease that is inadequately treated by surgery alone. We have coupled sentinel lymph node mapping and a focused pathologic examination to detect occult nodal micrometastases in CRC. Since 1996, sentinel lymph node mapping has been performed in 100 consecutive patients undergoing colectomy for CRC. Peritumoral injection of 0.5 to 1.0 ml of isosulfan blue dye was performed to demonstrate the sentinel node(s). All lymph nodes in the resection specimen were examined by routine hematoxylin and eosin staining. In addition, a focused examination of multiple sections of the sentinel nodes was performed using both hematoxylin and eosin and cytokeratin immunohistochemical analysis (CK-IHC). Overall, lymphatic mapping successfully demonstrated one to four sentinel lymph nodes in 97 (97%) of 100 patients. These sentinel nodes accurately reflected the status of the nodal basin in 92 (95%) of 97 patients. All five of the false negative cases occurred in T3/T4 tumors, and three of the five occurred during the first 30 cases in the experience. Unexpected lymphatic drainage was encountered in eight patients (8%) and altered the operative approach. Twenty-six patients were node positive by routine hematoxylin and eosin staining. Of the remaining 74 patients with hematoxylin and eosin-negative nodes, an additional 18 patients (24%) were upstaged by identification of occult nodal micrometastases that were missed on routine hematoxylin and eosin staining but detected on multiple sections (n = 5) or by CK-IHC (n = 13). The sentinel lymph nodes were the only positive nodes in 19 cases. Sentinel lymph node mapping may be performed in CRC with a high degree of success and accuracy. A focused pathologic examination of the sentinel node detects micrometastatic disease that is missed by conventional techniques in a significant proportion of patients with early CRC. Further studies are necessary to elucidate the clinical relevance of these micrometastases.

    Title A Novel Lymphatic Mapping Technique to Improve Localization and Staging of Early Colon Cancer During Laparoscopic Colectomy.
    Date July 2002
    Journal The American Surgeon
    Excerpt

    Encouraging results from our previous studies of sentinel lymph node (SLN) mapping in colorectal cancer (CRC) prompted investigation of its feasibility and accuracy during laparoscopic colectomy for early CRC. Between 1996 and 2000, 14 patients with clinically localized colorectal neoplasms underwent colonoscopic tattooing of the primary site and SLN mapping. In each case 0.5 to 1 cm3 of isosulfan blue dye was injected submucosally via the colonoscope. The blue-stained lymphatics were visualized through the laparoscope and followed to the SLN, which was marked with a clip, and laparoscopic colectomy was completed in the routine fashion. All lymph nodes were examined by hematoxylin and eosin (H&E) staining; in addition each SLN was subjected to focused examination by multisectioning and immunohistochemical staining using cytokeratin antibody. In all 14 patients the primary neoplasm and an SLN were identified laparoscopically. An average of 13.5 total lymph nodes and 1.7 SLNs per patient were identified. The SLN correctly reflected the tumor status of the nodal basin in 93 per cent of the cases. In four cases with unexpected lymphatic drainage, the extent of mesenteric resection was altered. In two cases (14%), nodal involvement was micrometastatic, confined to an SLN, and identified only by immunohistochemical staining. Lymphatic mapping caused no complications and added only 10 to 15 minutes to the overall operative time. Comparison of results in this group with results for a matched group of 14 patients undergoing SLN mapping during open colon resection showed that the laparoscopic technique had similar rates of accuracy and success. These preliminary findings indicate that colonoscopic/laparoscopic SLN mapping during laparoscopic colon resection is a feasible and technically simple means of identifying the primary colorectal neoplasm and its SLN. Focused pathologic examination of this node can upstage CRC and thereby may improve selection of patients for adjuvant chemotherapy.

    Title Ultrastaging of Early Colon Cancer Using Lymphatic Mapping and Molecular Analysis.
    Date July 2002
    Journal European Journal of Cancer (oxford, England : 1990)
    Excerpt

    Approximately one-third of node-negative colon cancers will recur, possibly due to understaging and inadequate pathological examination of lymph nodes (LNs). We evaluated the sensitivity, accuracy and feasibility of staging based on lymphatic mapping, focused examination, and molecular analysis of the sentinel node (SN) in patients with primary colorectal carcinoma. Between 1996 and 2000, 100 patients with colon carcinoma (CRC) underwent lymphatic mapping immediately after peritumoral injection of 1.0 cc of isosulphan blue dye. All LNs in the CRC specimen were examined by routine haematoxylin and eosin (H&E) staining. Sentinel nodes were examined by step serial sectioning, cytokeratin immunohistochemistry (CK-IHC) and/or reverse transcriptase-polymerase chain reaction (RT-PCR) analysis in an attempt to identify occult micrometastatic disease. Lymphatic mapping was successful in 97% of the cases. There were 5 false-negative cases, predominately associated with T3/T4 tumours. Aberrant lymphatic drainage was identified in 8 patients (8%) altering the operative approach. 26 patients had H&E-positive LNs. In 74 patients who were node-negative by routine H&E, 18 (24%) had occult nodal micrometastases missed on routine H&E examination, but detected by focused analysis of the SN. RT-PCR analysis of the SN was performed in 40 patients, 26 of which were negative by H&E and CK-IHC. In 12/26 (46%) of these patients, there was additional evidence of micrometastatic disease. In this study, focused examination of the SN in conjunction with RT-PCR analysis identified micrometastatic disease in a significant number of node-negative patients. This may have important implications when selecting patients for adjuvant treatment protocols.

    Title Systemic Irinotecan and Regional Floxuridine After Hepatic Cytoreduction in 185 Patients with Unresectable Colorectal Cancer Metastases.
    Date April 2002
    Journal Annals of Surgical Oncology
    Excerpt

    BACKGROUND: This study evaluated our 7-year experience treating unresectable colorectal cancer (CRC) hepatic metastases refractory to systemic 5-fluorouracil. METHODS: A total of 185 patients with unresectable 5-fluorouracil-resistant CRC hepatic metastases underwent surgical cytoreduction. Postoperatively patients received either hepatic arterial floxuridine (FUDR) and systemic irinotecan as part of a phase II trial or no further treatment. RESULTS: Of the 185 patients undergoing surgical cytoreduction, 71 patients received adjuvant irinotecan/FUDR. There were no appreciable differences in synchronous or metachronous lesions or the median number or size of lesions between treatment groups. At a median follow-up of 20 months, there were fewer recurrences in patients treated with postoperative irinotecan/FUDR compared with untreated patients for both hepatic and extrahepatic recurrences. Progression-free and overall survival were longer for patients who received irinotecan/FUDR compared with patients who did not receive adjuvant therapy. The 2-year survival rate was significantly better for patients receiving adjuvant therapy compared with patients receiving no additional treatment. Predictors of improved survival included a preoperative carcinoembryonic antigen level <100 ng/dl, >30% postoperative reduction in carcinoembryonic antigen level, and adjuvant therapy. CONCLUSIONS: Combined therapy with irinotecan/FUDR may improve the results of surgical cytoreduction for unresectable CRC hepatic metastases.

    Title Laparoscopic Radiofrequency Ablation of Unresectable Hepatic Malignancies. A Phase 2 Trial.
    Date February 2002
    Journal Surgical Endoscopy
    Excerpt

    BACKGROUND: Radiofrequency ablation (RFA) of hepatic malignancies has been performed successfully via a percutaneous route or at laparotomy. We analyzed the efficacy and utility of laparoscopic intraoperative ultrasound and RFA in patients with unresectable hepatic malignancies. METHODS: Between November 1997 and November 1999, 27 patients with unresectable hepatic malignancies and no evidence of extrahepatic disease were entered in a phase 2 trial of laparoscopic intraoperative ultrasound and RFA. Real-time ultrasonography was used to guide RFA, and lesions were ablated at a temperature of 100 degrees C for 10 min. Overlapping ablations were performed for larger lesions. RESULTS: Additional tumors were identified in 10 (37%) of the 27 study patients by laparoscopy and laparoscopic intraoperative ultrasound despite extensive preoperative imaging. Radiofrequency ablation of 85 hepatic tumors yielded no mortality and only one case of postoperative bleeding. During a mean follow-up period of 14 months, four tumors (4.7%) locally recurred. Of the 27 patients, 11 (41%) remain free of disease at this writing; (22%) are alive with disease; and 10 (37%) have died with disease. CONCLUSION: Laparoscopic RFA and intraoperative ultrasound constitute a safe and accurate method for ablation of unresectable hepatic tumors.

    Title Lymphatic Mapping Improves Staging During Laparoscopic Colectomy for Cancer.
    Date February 2002
    Journal Surgical Endoscopy
    Excerpt

    BACKGROUND: Recently, lymphatic mapping (LM) of the sentinel lymph node (SN) has been coupled with ultrastaging methods to diagnose nodal micrometastases from colorectal cancer (CRC). We have developed a technique for LM at the time of laparoscopic colon resection (LCR). METHODS: Between August 1996 and February 2000, 11 patients with small early-stage CRC underwent laparoscopic LM and LCR. The primary tumor/polyp site was visualized through a colonoscope and either tattooed preoperatively with a carbon dye (India ink), or stained intraoperatively by peritumoral injection of isosulfan blue dye. Immediately after intraoperative injection of blue dye, efferent lymphatic channels were visualized through the laparoscope and followed to the SN. Each blue-stained SN was marked with a suture or clip. RESULTS: In all 11 cases, laparoscopic LM identified between one and three SN draining the primary tumor. LM added ~15-20 min to the operating time. The SN correctly reflected the nodal status of the entire specimen in all cases. In the one node-positive case, micrometastases were found only in an SN and only after cytokeratin immunohistochemistry (CK-IHC). In four cases, LM demonstrated unexpected primary lymphatic drainage that prompted an increase in the margins of resection. CONCLUSIONS: LM during laparoscopic colectomy for CRC may be useful to mark the primary tumor site and to demonstrate lymphatic drainage that can alter the margins of resection. Focused examination of SN identifies occult micrometastases that up-stage CRC.

    Title Aberrant Drainage and Missed Micrometastases: the Value of Lymphatic Mapping and Focused Analysis of Sentinel Lymph Nodes in Gastrointestinal Neoplasms.
    Date January 2002
    Journal Annals of Surgical Oncology
    Excerpt

    Lymph node analysis is essential for staging gastrointestinal (GI) neoplasms. Our group has conducted several studies of intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) for the staging of GI neoplasms. LM is performed following injection of 0.5-1 ml of isosulfan blue dye, and blue-stained sentinel lymph nodes (SLNs) are analyzed by hematoxylin and eosin (H&E) staining, multiple sectioning, and cytokeratin immunohistochemistry. In feasibility trials, LM identified at least one SLN in 121 of 126 patients. Of the 58 cases with nodal metastasis, 50 (89%) had at least one positive SLN and 24 (42%) had nodal metastasis only in the SLN. In 25 cases, tumor deposits were identified by multiple sectioning (n = 8) or immunohistochemistry (n = 17) only. In 10 cases (8%), LM identified aberrant lymphatic drainage that altered the extent of the lymphadenectomy. Our cumulative experience indicates that focused analysis of the SLNs draining GI neoplasms can increase the detection of micrometastases and may improve selection of patients for adjuvant treatment.

    Title Hepatic Cytoreduction Followed by a Novel Long-acting Somatostatin Analog: a Paradigm for Intractable Neuroendocrine Tumors Metastatic to the Liver.
    Date January 2002
    Journal Surgery
    Excerpt

    BACKGROUND: Optimal management of symptomatic neuroendocrine tumors that metastasize to the liver is controversial. We investigated aggressive hepatic cytoreduction and postoperative administration of octreotide long-acting release (LAR), a long-acting somatostatin analog. METHODS: Between December 1992 and August 2000, 31 patients underwent hepatic surgical cytoreduction (20 carcinoid, 10 islet cell, and 1 medullary). All patients had progressive symptoms refractory to conventional therapy. RESULTS: Hepatic cytoreduction (resection, cryosurgery, and/or radiofrequency ablation) eliminated symptoms in 27 patients (87%) and decreased secretion of hormones by an overall mean of 59%. When minor symptoms returned and/or hormonal levels increased during follow-up, adjuvant therapy was started. Ten patients received adjuvant octreotide LAR once a month, and 21 received other adjuvants. At a median postoperative follow-up of 26 months, 16 patients had progressive/recurrent disease, 13 had died of their disease, and 2 remained free of disease. Median symptom-free interval was 60 months (95% confidence interval, 48-72) with octreotide LAR and 16 months (95% confidence interval, 10-29) with other adjuvants (P = .0007). Two-year symptom-free survival rate was 100% with octreotide LAR and 33% with other adjuvants. CONCLUSIONS: Hepatic surgical cytoreduction can palliate progressive symptoms associated with liver metastases from intractable neuroendocrine tumors. Postoperative adjuvant therapy with octreotide LAR can prolong symptom-free survival.

    Title Solid and Papillary Epithelial Neoplasms of the Pancreas: Aggressive Resection for Cure.
    Date January 2002
    Journal The American Surgeon
    Excerpt

    Solid and papillary epithelial neoplasms of the pancreas (SPENP) are extremely rare and usually affect young women. We retrospectively reviewed our experience with pancreatic neoplasms from 1986 to the present and identified nine patients with SPENP. All nine patients were female with a mean age of 32 years (range 16-66). All patients presented with gastrointestinal complaints including pain, mass, dyspepsia, or bloating and were subsequently diagnosed with a tumor of the pancreas by CT scan. All patients underwent surgical resection. Two patients had tumors located in the head of the pancreas and underwent a pancreaticoduodenectomy. The remainder had tumors located in the tail of the pancreas and underwent distal pancreatectomy. Pathology demonstrated solid and papillary or solid and cystic pseudopapillary neoplasm of the pancreas. Three tumors were positive for both vimentin and alpha-1 antitrypsin on immunohistochemical studies, and three were positive for neuron-specific enolase. All nine patients underwent curative resection and are alive without any evidence of recurrence with a mean follow-up of 5.4 years. SPENP is considered to be a low-grade malignancy with an excellent prognosis. Prompt diagnosis and surgical resection can result in cure.

    Title Cancervax, an Allogeneic Tumor Cell Vaccine, Induces Specific Humoral and Cellular Immune Responses in Advanced Colon Cancer.
    Date October 2001
    Journal Annals of Surgical Oncology
    Excerpt

    BACKGROUND: The immunogenicity of the polyvalent tumor cell vaccine CancerVax has been correlated with the survival of patients receiving active immunotherapy for melanoma. Because the various antigens expressed on the vaccine are common to colon adenocarcinoma cells, we examined the survival impact of immune responses elicited by CancerVax in patients with advanced colon cancer refractory to standard therapy. METHODS: Twenty-seven patients with American Joint Committee on Cancer (AJCC) stage IV colorectal adenocarcinoma were entered prospectively into the study. CancerVax was coadministered with bacille Calmette-Guerin (BCG) for the first 2 weeks of vaccine treatment. Blood was drawn at the start of therapy and every 2 weeks thereafter to measure serum titers of immunoglobulin (Ig)G and IgM against TA90 (a 90-kD immunogen common to colon cancer and CancerVax cells) and against purified protein derivative (PPD), a nontumor control antigen. Cellular immune responses were evaluated by delayed-type hypersensitivity (DTH) reaction to vaccine cells and to PPD. Mean follow-up time was 17.5 months. RESULTS: There was a significant (P = .0001) increase in anti-TA90 IgG and IgM titers and in DTH response to vaccine cells. Humoral and skin responses to TA90 did not correlate with responses to PPD (P = .199 for IgM, P = .958 for IgG, and P = .149 for DTH). This suggests that these responses are not a manifestation of general immune competence. The median overall survival (OS) was 21.9 months for the entire group. Overall survival was higher among patients whose IgMTA90 titer was >800 (P = .003) or whose disease-free interval exceeded 12 months (P = .031). Multivariate Cox regression analysis-using age, sex, disease-free interval, disease status, extent of metastasis, humoral responses, and DTH responses-found only peak IgMTA90 titer to be a significant predictor of overall survival (P = .0365). CONCLUSIONS: CancerVax can induce measurable humoral and cellular immune responses to tumor-associated antigens in patients with advanced-stage colon cancer. These responses correlate with overall survival. This novel therapeutic regimen for patients with advanced colon cancer merits further investigation.

    Title Repeat Hepatic Cryotherapy for Metastatic Colorectal Cancer.
    Date August 2001
    Journal Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract
    Excerpt

    This study evaluated the risks and benefits of repeat hepatic cryotherapy for recurrent, unresectable hepatic metastases from colorectal carcinoma. Review of a prospective database identified 195 patients who underwent hepatic cryotherapy for metastatic colorectal carcinoma during a 7-year period. Of the 14 patients who underwent successful repeat cryotherapy for recurrences confined to the liver, 86% had Duke's stage D colorectal carcinoma at initial diagnosis. The median age of the 14 patients was 58 years (range 41 to 77 years). The median number of hepatic metastases was three at the first cryotherapy and two at the second cryotherapy. At a median follow-up of 71 months, the mean survival times from original diagnosis, first cryotherapy, and second cryotherapy were 53, 42, and 19 months, respectively. At the most recent follow-up, eight patients (57%) have died of their disease, four (29%) are alive with disease, and two (14%) have no evidence of disease. The mean interval between the first and second cryotherapies was 23 months. The complication rates after the first and second cryotherapies were 7% and 14%, respectively. One patient developed a wound dehiscence after the first cryotherapy. Following the second cryotherapy, one patient had a small bowel obstruction and another had a pleural effusion. There was no perioperative mortality. Repeat cryotherapy for recurrent, unresectable hepatic metastases from colorectal cancer is safe and improves survival. However, a prospective trial is needed to validate the efficacy of systemic therapy and to better define the indications for repeat hepatic cryotherapy.

    Title Validation of Lymphatic Mapping in Colorectal Cancer: in Vivo, Ex Vivo, and Laparoscopic Techniques.
    Date May 2001
    Journal Annals of Surgical Oncology
    Excerpt

    BACKGROUND: The use of lymphatic mapping (LM) is being investigated to improve the staging of colorectal cancer (CRC) and thereby identify patients who might benefit from adjuvant chemotherapy. This study evaluated in vivo, laparoscopic, and ex vivo approaches for the ultrastaging of CRC. METHODS: Seventy-five CRC patients were enrolled in a study of LM with peritumoral injection of isosulfan blue dye. LM was undertaken during open colon resection (OCR) in 64 patients, during laparoscopic colon resection (LCR) in 9 patients, and after specimen removal (ex vivo) in 2 patients. Ex vivo LM was also undertaken in 6 patients after unsuccessful in vivo LM. All nodes were examined by hematoxylin and eosin (H&E) staining; in addition, sentinel lymph nodes (SNs) were multisectioned and examined by immunohistochemical staining with cytokeratin (CK-IHC). RESULTS: At least one SN was identified in 72 patients (96%). In vivo LM identified SNs in 56 of 64 (88%) patients undergoing OCR and in 9 of 9 (100%) patients undergoing LCR. Ex vivo LM was undertaken as the initial mapping procedure in 2 cases of intraperitoneal colon cancer and after in vivo LM had failed in 6 cases of extraperitoneal rectal carcinoma; an SN was identified in 7 of the 8 cases. Focused examination of the SN correctly predicted nodal status in 53 of 56 OCR cases, 9 of 9 LCR cases, and 6 of 7 ex vivo cases. Multiple sections and CK-IHC identified occult micrometastases in 13 patients (17%), representing 10 OCR, 1 LCR, and 2 ex vivo cases. CONCLUSIONS: LM of drainage from a primary CRC can be accurately performed in vivo during OCR or LCR. Ex vivo LM can be applied when in vivo techniques are unsuccessful and may be useful for rectal tumors. During LCR, colonoscopic injection can be used to mark the primary tumor and define the lymphatic drainage so that adequate resection margins are obtained. These LM techniques improve staging accuracy in CRC.

    Title Molecular Staging of Early Colon Cancer on the Basis of Sentinel Node Analysis: a Multicenter Phase Ii Trial.
    Date April 2001
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE: Approximately 30% of patients with American Joint Committee on Cancer stage I or II colorectal cancer (CRC) develop systemic disease. We hypothesized that multimarker reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of sentinel lymph nodes (SNs) draining a primary CRC could detect micrometastases not detected by conventional histopathologic analysis. PATIENTS AND METHODS: In a multi-institutional study, 40 patients with primary CRC underwent dye-directed lymphatic mapping at the time of colon resection. Each dye-stained SN was tagged, and the tumor and regional nodes were resected en bloc. All lymph nodes were examined by conventional hematoxylin and eosin (HE) staining. In addition, each SN was cut into multiple sections for cytokeratin immunohistochemical (CK-IHC) staining and for RT-PCR and electrochemiluminescent detection of three markers: beta-chain human chorionic gonadotropin, hepatocyte growth factor receptor, and universal melanoma-associated antigen. Whenever possible, RT-PCR assay was also performed on primary tumor tissue. The detection sensitivity of individual markers was 10(-3) to 10(-4) microg of RNA and one to five tumor cells in 10(7) lymphocytes of healthy donors. RESULTS: One to three SNs were identified in each patient. An average of 15 nodes were removed from each CRC specimen. No nonsentinel (untagged) node contained evidence of tumor if all tagged (sentinel) nodes in the same specimen were histopathology tumor-negative. HE staining of SNs identified tumor in 10 patients (25%), and CK-IHC of SNs identified occult micrometastases in four patients (10%) whose SNs were negative by HE. Of the remaining 26 patients with no evidence of SN involvement by HE or CK-IHC, 12 (46%) had positive RT-PCR results. The number of markers expressed in each SN correlated (P <.04) with the T stage of the primary tumor. There was 79% concordance in marker expression for the respective pairs (n = 38) of primary tumor and histopathologically positive SNs, and 86% (12 of 14) concordance between RT-PCR positive and histopathologically positive SNs. CONCLUSION: Identification and focused examination of the SN is a novel method of staging CRC. CK-IHC and RT-PCR identified occult micrometastases in 53% of patients whose SNs were negative by conventional staging techniques. These ultrasensitive assays of the SN can identify patients who may be at high risk for recurrence of CRC and therefore are more likely to benefit from systemic adjuvant therapy.

    Title Radiofrequency Ablation of Unresectable Hepatic Malignancies: Lessons Learned.
    Date March 2001
    Journal The Oncologist
    Excerpt

    Radiofrequency ablation (RFA) is increasingly used for the local destruction of unresectable hepatic malignancies. Relative contraindications include tumors in proximity to vital structures that may be injured by RFA and lesions whose size exceeds the ablation capabilities of the probe system employed. Given current technology, we believe that RFA should be cautiously utilized for lesions greater than 5 cm in diameter. Open (celiotomy) and laparoscopic approaches to RFA allow intraoperative ultrasonography, which may demonstrate occult hepatic disease. In addition, RFA performed via celiotomy can be accompanied by resection or cryosurgical ablation, and isolation of the liver from adjacent organs. Percutaneous RFA should be reserved for patients who cannot undergo general anesthesia, those with recurrent or progressive lesions, and those with smaller lesions sufficiently isolated from adjacent organs. Complications may be minimized when these approaches are selectively applied.

    Title Gastrointestinal Carcinoid Tumors and Second Primary Malignancies.
    Date January 2001
    Journal Journal of Surgical Oncology
    Excerpt

    The development of second primary malignancies (SPM) in patients with gastrointestinal carcinoid tumors is a well-described phenomenon, with reported rates as high as 55%. There is a predilection for gastrointestinal and genitourinary adenocarcinomas, but a variety of other malignancies have been reported as well. The etiology of this malignant predisposition may be rooted in the tumorigenic properties of the various neuroendocrine peptides elaborated and secreted by neuroendocrine cells. Peptides such as secretin, gastrin, bombesin, cholecystokinin (CCK), and vasoactive intestinal peptide (VIP) are believed to promote the growth of tumor cells. As many as 30 peptides and amines identified in neuroendocrine cells may have similar properties. This review of the literature on carcinoid-associated second primary malignancies is accompanied by a case report of metastatic carcinoid identified during surgical exploration for a perforating colon adenocarcinoma.

    Title Radiofrequency Ablation of 231 Unresectable Hepatic Tumors: Indications, Limitations, and Complications.
    Date January 2001
    Journal Annals of Surgical Oncology
    Excerpt

    BACKGROUND: Radiofrequency ablation (RFA) is increasingly used for the local destruction of unresectable hepatic malignancies. There is little information on its optimal approach or potential complications. METHODS: Since late 1997, we have undertaken 91 RFA procedures to ablate 231 unresectable primary or metastatic liver tumors in 84 patients. RFA was performed via celiotomy (n = 39), laparoscopy (n = 27), or a percutaneous approach (n = 25). Patients were followed with spiral computed tomographic (CT) scans at 1 to 2 weeks postprocedure and then every 3 months for 2 years. RESULTS: Intraoperative ultrasound (IOUS) detected intrahepatic disease not evident on the preoperative scans of 25 of 66 patients (38%) undergoing RFA via celiotomy or laparoscopy. In 38 of 84 patients (45%), RFA was combined with resection or cryosurgical ablation (CSA), or both. RFA was used to treat an average of 2.8 lesions per patient, and the median size of treated lesions was 2 cm (range, 0.3-9 cm). The average hospital stay was 3.6 days overall (1.8 days for percutaneous and laparoscopic cases). Ten patients underwent a second RFA procedure (sequential ablations) and, in one case, a third RFA procedure for large (one patient), progressive (seven patients), and/or recurrent (three patients) lesions. Seven (8%) patients had complications: one skin burn; one postoperative hemorrhage; two simple hepatic abscesses; one hepatic abscess associated with diaphragmatic heat necrosis following sequential percutaneous ablations of a large lesion; one postoperative myocardial infarction; and one liver failure. There were three deaths, one (1%) of which was directly related to the RFA procedure. Three of the complications, including one RFA-related death, occurred after percutaneous RFA. At a median follow-up of 9 months (range, 1-27 months), 15 patients (18%) had recurrences at an RFA site, and 36 patients (43%) remained clinically free of disease. CONCLUSIONS: Celiotomy or laparoscopic approaches are preferred for RFA because they allow IOUS, which may demonstrate occult hepatic disease. Operative RFA also allows concomitant resection, CSA, or placement of a hepatic artery infusion pump, and isolation of the liver from adjacent organs. Percutaneous RFA should be reserved for patients at high risk for anesthesia, those with recurrent or progressive lesions, and those with smaller lesions sufficiently isolated from adjacent organs. Complications may be minimized when these approaches are applied selectively.

    Title Focused Examination of Sentinel Lymph Nodes Upstages Early Colorectal Carcinoma.
    Date December 2000
    Journal The American Surgeon
    Excerpt

    Approximately 30 per cent of patients with early colorectal carcinoma (CRC) develop systemic disease. A subgroup of these patients may harbor occult micrometastatic disease and might benefit from adjuvant chemotherapy. We investigated sentinel lymph node (SLN) mapping and focused pathologic examination of the SLN as a means of detecting nodal micrometastases. Between 1996 and 2000 SLN mapping was performed in 50 consecutive patients undergoing colectomy for CRC. All lymph nodes in the resection specimen were examined via routine hematoxylin and eosin (H&E) staining. In addition multiple sections of each SLN were examined via both H&E and cytokeratin immunohistochemistry. At least one SLN was identified in 47 patients (94%). In seven patients (14%) SLN mapping identified aberrant drainage that altered the planned resection. The SLN(s) correctly predicted nodal basin status in 44 of 47 (94%) cases; there were three falsely negative SLNs. Sixteen cases had positive SLNs by conventional H&E staining. An additional 10 (20%) cases were upstaged by a focused examination of the SLNs. Micrometastases were identified in three cases by H&E staining of multiple sections of the SLN and in seven only by cytokeratin immunohistochemistry. In nine cases the SLN was the only node containing tumor cells. In this study, SLN mapping demonstrated aberrant nodal drainage patterns that altered the surgical resection in patients with CRC. Focused examination of SLNs may detect micrometastases missed by conventional techniques and thereby identify patients who might benefit from adjuvant therapy.

    Title Ta90-ic, a New Marker for Advanced Colon Cancer.
    Date October 2000
    Journal Annals of Surgical Oncology
    Excerpt

    BACKGROUND: Although carcinoembryonic antigen (CEA) is the most frequently used marker for colon cancer, it is elevated in only 70% of patients with advanced disease and in even fewer patients with earlier stages of disease. We previously identified a 90-kDa glycoprotein, TA90, which is present in serum in the form of circulating immune complexes. TA90 is found in a variety of solid neoplasms but rarely in healthy controls (3.2%). We hypothesized that this new tumor-associated antigen may be a useful marker for colon cancer. METHODS: Serum samples from 59 patients with known colon adenocarcinoma were analyzed for the presence of CEA and TA90. Fifty-one (86%) patients had distant metastases; the remaining patients had clinically localized primary colon cancer. A murine monoclonal antibody-based enzyme-linked immunosorbent assay was used to measure concentrations of TA90-specific circulating immune complexes (TA90-IC). A positive value was defined as an optical density of more than 0.410 at 405 nm. Forty-seven (80%) of the 59 patients had serum samples for TA90 and CEA drawn at the same time. RESULTS: TA90-IC concentrations were elevated more frequently than CEA concentrations (82.9% vs. 70.2%; P = .134). The combination of both markers identified more patients with colon carcinoma than did either marker alone (93.6%; P < .001). CONCLUSIONS: Concomitant use of TA90-IC and CEA identified 93.6% of patients with advanced colon cancer. The role of TA90-IC in screening and monitoring progression of earlier disease deserves further investigation.

    Title Lymphatic Mapping and Focused Analysis of Sentinel Lymph Nodes Upstage Gastrointestinal Neoplasms.
    Date August 2000
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    BACKGROUND: Lymph node analysis is essential for staging gastrointestinal (GI) neoplasms. Intraoperative lymphatic mapping and sentinel lymphadenectomy were originally described for melanoma but have not yet been investigated for most GI neoplasms. HYPOTHESES: (1) Lymphatic mapping and sentinel lymphadenectomy is feasible in GI neoplasms, (2) the sentinel node (SN) status reflects the regional node status, and (3) focused analysis of the SN improves staging accuracy. DESIGN: Prospective patient series. PATIENTS AND METHODS: Lymphatic mapping was performed in 65 patients with GI neoplasms by injecting 0.5 to 1 mL of isosulfan blue dye around the periphery of the neoplasm. Blue-stained SNs were analyzed by hematoxylin-eosin staining, multiple sectioning, and cytokeratin immunohistochemistry. RESULTS: Lymphatic mapping identified at least 1 SN in 62 patients (95%). Of the 36 cases with nodal metastasis, 32 (89%) had at least 1 positive SN and 15 (42%) had nodal metastasis only in the SN. In 11 cases, tumor deposits were identified by multiple sectioning (n = 2) or immunohistochemistry (n = 9) only. In 5 cases (8%), lymphatic mapping identified aberrant lymphatic drainage that altered the extent of the lymphadenectomy. CONCLUSIONS: Lymphatic mapping and sentinel lymphadenectomy are feasible in GI neoplasms and identify aberrant lymphatic drainage. The SN status accurately reflects the regional node status. Focused analysis of the SN increases the detection of micrometastases and may improve selection of patients for adjuvant treatment.

    Title Cryosurgical Ablation and Radiofrequency Ablation for Unresectable Hepatic Malignant Neoplasms: a Proposed Algorithm.
    Date July 2000
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    BACKGROUND: Thermal ablation of unresectable hepatic tumors can be achieved by cryosurgical ablation (CSA) or radiofrequency ablation (RFA). The relative advantages and disadvantages of each technique have not yet been determined. HYPOTHESIS: Radiofrequency ablation of malignant hepatic neoplasms can be performed safely, but is currently limited by size. Cryosurgical ablation, while associated with higher morbidity, is more effective for larger unresectable hepatic malignant neoplasms. DESIGN: Retrospective analysis of prospective patient database. PATIENTS AND METHODS: Between July 1992 and September 1999, 308 patients with liver tumors not amenable to curative surgical resection were treated with CSA and/or RFA (percutaneous, laparoscopic, celiotomy). No patient had preoperative evidence of extrahepatic disease. All patients underwent laparoscopy with intraoperative ultrasound if technically possible. Both RFA and CSA were performed under ultrasound guidance. Resection, as an adjunctive procedure, was combined with ablation in certain patients. RESULTS: Laparoscopy identified extrahepatic disease in 12% of patients, and intraoperative hepatic ultrasound identified additional lesions in 33% of patients, despite extensive preoperative imaging. Radiofrequency ablation alone or combined with resection or CSA resulted in reduced blood loss (P<.05), thrombocytopenia (P<.05), and shorter hospital stay compared with CSA alone (P<.05). Median ablation times for lesions greater than 3 cm were 60 minutes with RFA and 15 minutes with CSA (P<.001). Local recurrence rates for lesions greater than 3 cm were also greater with RFA (38% vs 17%). CONCLUSIONS: Laparoscopy and intraoperative ultrasound are essential in staging patients with hepatic malignant neoplasms. Radiofrequency ablation when combined with CSA reduces the morbidity of multiple freezes. Although RFA is safer than CSA and can be performed via different approaches (percutaneously, laparoscopically, or at celiotomy), it is limited by tumor size (<3 cm). Percutaneous RFA should be considered in high-risk patients or those with small local recurrences.

    Title Role of Na+-glucose Cotransport in Jejunal Meal-induced Absorption.
    Date March 2000
    Journal Digestive Diseases and Sciences
    Excerpt

    In awake dogs, meal ingestion stimulates the absorption of water and electrolytes from neurovascularly intact jejunal Thiry-Vella loops, even though these loops are isolated from the remainder of the gut. This study was designed to investigate the role of Na+-glucose cotransport in mediating this event. Meal ingestion enhanced absorption when the jejunal lumen was perfused with an isotonic solution containing D-glucose, D-galactose, or 3-O-methylglucose. This response was absent when the perfusate contained mannitol or when phlorizin was added to the D-glucose solution. Mucosa from the jejunal loops was serially biopsied and assayed for brush-border Na+-glucose cotransporter (SGLT1) mRNA and protein expression. Although no changes in SGLT1 mRNA levels were observed, protein levels significantly increased within 30 min following meal ingestion. The time course of SGLT1 protein expression corresponded with that of increased Na+ and water absorption. These results suggest that meal-stimulated jejunal absorption may be mediated through an induction of mucosal SGLT1.

    Title Radiofrequency Ablation: a Minimally Invasive Technique with Multiple Applications.
    Date December 1999
    Journal The Cancer Journal from Scientific American
    Excerpt

    PURPOSE: Radiofrequency ablation (RFA) of soft tissue, which has recently been approved by the United States Food and Drug Administration, destroys tumor cells by delivering an electrical current through a 15-gauge needle. This study evaluated RFA for patients with hepatic malignancies considered unresectable because of their distribution, their number, and/or the presence of liver dysfunction. PATIENTS AND METHODS: Between November 1997 and February 1999, 50 patients with 132 unresectable hepatic metastases underwent RFA of tumors from 0.5 to 9 cm in diameter. There were 41 colorectal metastases in 22 patients, 13 hepatomas in seven patients, 37 neuroendocrine metastases in six patients, and 41 noncolorectal metastases in 15 patients. Real-time ultrasonography was used to guide RFA, and lesions were ablated by applying temperatures of approximately 100 degrees C for 8 minutes. Overlapping ablations were used for larger lesions. In patients with multiple lesions, RFA was performed simultaneously with cryosurgery, resection, and/or hepatic arterial infusion. RESULTS: RFA was undertaken percutaneously on an outpatient basis in 13 patients (25 lesions). The remaining patients underwent RFA via laparoscopy (21 patients; 58 lesions) or celiotomy (16 patients; 49 lesions); mean hospital stay was 1 and 5 days, respectively. RFA was the sole therapy in 28 patients and was additional therapy in 22 patients. At a median follow-up of 6 months, 27 patients were free of disease, 17 were alive with disease, and six had died of their disease (three colon, three melanoma). Three patients whose disease recurred at a prior RFA site underwent successful percutaneous RFA. Overall, there was a significant postoperative reduction in levels of carcinoembryonic antigen, alpha-fetoprotein, serotonin, and 5-hydroxyindoleacetic acid. Intraoperative ultrasonography identified unrecognized hepatic lesions in 12 of 37 patients (32%); these lesions were successfully ablated. When performed with cryosurgery, RFA reduced the morbidity of multiple freezes. DISCUSSION: RFA is a safe and effective alternative for the ablation of unresectable hepatic malignancies and when used adjunctively can reduce the morbidity of cryosurgery. Percutaneous and laparoscopic RFA can be performed effectively with less than 24 hours of hospitalization. Intraoperative ultrasonography is essential for accurate staging.

    Title Radiofrequency Ablation: a Novel Primary and Adjunctive Ablative Technique for Hepatic Malignancies.
    Date November 1999
    Journal The American Surgeon
    Excerpt

    The majority of primary and metastatic tumors of the liver are not amenable to surgical resection at presentation. Radiofrequency ablation (RFA) is a new modality for local tumor destruction with minimal local and systemic complications. We prospectively reviewed the experience with RFA at a single institute as a primary or adjunctive ablative technique in the treatment of hepatic malignancies. Between November 1997 and December 1998, 30 patients with primary or metastatic hepatic lesions were treated with RFA at the John Wayne Cancer Institute and the Cancer Center at Century City Hospital. Pathology of the treated lesions included colorectal metastases (29 in 14 patients), neuroendocrine metastases (29 in 4 patients), noncolorectal metastases (29 in 9 patients), and hepatocellular carcinoma (6 in 3 patients). Twelve patients underwent RFA laparoscopically, 12 at celiotomy, and the remaining 6 patients had percutaneous ablation. RFA was the only procedure in 17 patients, whereas the remainder underwent a combination of RFA and other procedures including resection, cryosurgical ablation, and hepatic artery infusion pump placement. Median length of stay for all patients was 6 days (2 days for laparoscopic patients). A single complication of a delayed intrahepatic abscess was noted in this series (3%). There have been no deaths associated with RFA. At a median follow-up of 5 months, 16 patients remain disease free, and 10 are alive with disease. RFA is a safe and effective method of tumor ablation for hepatic malignancies. This technique can be performed laparoscopically, at celiotomy, or percutaneously and can be used as a primary technique or in conjunction with other interventional procedures.

    Title Universal Application of Intraoperative Lymphatic Mapping and Sentinel Lymphadenectomy in Solid Neoplasms.
    Date March 1999
    Journal The Cancer Journal from Scientific American
    Excerpt

    PURPOSE: Regional lymph node involvement is the most important prognostic indicator in patients with solid tumors. Conventional lymph node dissection has not been shown to affect survival and is often associated with considerable morbidity. Intraoperative lymphatic mapping and sentinel lymph node dissection were therefore designed as a minimally invasive alternative to routine elective lymph node dissection in patients with primary cutaneous melanoma. This study examined whether introperative lymphatic mapping and sentinel lymph node dissection were accurate in staging patients with other solid malignancies. PATIENTS AND METHODS: Between 1985 and 1998, 107 patients with breast cancer, 17 with thyroid tumors, 14 with gastrointestinal/gynecologic cancers, six with Merkel cell cancers, and five with squamous cell carcinomas of the head and neck have undergone mapping and sentinel lymph node dissection at the John Wayne Cancer Institute. RESULTS: The sentinel node was identified in 96% of patients (98% melanoma). In 36% of patients the sentinel node was the only tumor-positive node (71% melanoma). Eighteen percent of sentinel nodes were negative by hematoxylin and eosin staining but were positive by immunohistochemical staining (15% melanoma). CONCLUSION: These data suggest that many solid neoplasms have a primary lymphatic channel and lymph node to which it drains. Although sentinel lymph node dissection has been popularized in melanoma therapy, we have found it feasible for treatment of other solid malignancies. This technique may ultimately replace conventional dissection with more accurate staging.

    Title Cryosurgical Palliation of Metastatic Neuroendocrine Tumors Resistant to Conventional Therapy.
    Date January 1998
    Journal Surgery
    Excerpt

    BACKGROUND: Hepatic cryosurgery is a well-recognized modality for hepatic colon metastases. We examined its potential use for refractory neuroendocrine tumors causing progressive symptoms. METHODS: Between July 1992 and February 1997, 19 patients (with islet cell, 7; carcinoid, 8; vasoactive intestinal peptide, 1; gastrinoma, 3) underwent cryosurgery with ultrasonography. The number of lesions frozen ranged from 1 to 16 (median, 8), and their diameters ranged from 2 to 15 cm with an average of 4 cm. Patients underwent resection of the primary tumor either before (37%) or concurrent with (32%) cryosurgery, and half underwent excision of metastases with cryosurgery. Before cryosurgery, patients received chemotherapy (63%), somatostatin (47%), interferon (10%), hepatic artery ligation (5%), radiation (10%), and/or omeprazole (16%). RESULTS: The reduction in tumor markers reached 90% (5-hydroxyindoleacetic acid), 80% (vasoactive intestinal peptide), 90% (gastrin), 90% (pancreatic polypeptide), and 80% (serotonin). At a median follow-up of 17 months, the metastases had progressed in 11 patients (two underwent a second cryosurgical procedure that eliminated symptoms) and five had died. Subsequently an additional five patients received chemotherapy and three somatostatin. Median symptom-free and overall survival were 10 months and more than 49 months, respectively. CONCLUSIONS: Cryosurgery dramatically relieved symptoms with significant reduction in tumor markers. The reduced tumor burden may explain the subsequent response to systemic therapy. Cryosurgery is a useful adjuvant in symptomatic patients with refractory hepatic neuroendocrine metastases.

    Title Cryosurgery Causes a Profound Reduction in Tumor Markers in Hepatoma and Noncolorectal Hepatic Metastases.
    Date September 1997
    Journal The American Surgeon
    Excerpt

    Cryosurgical ablation of hepatic metastases from colon carcinoma has become a useful adjunct in the management of patients whose tumors are not amenable to surgical resection. We evaluated cryoablation of hepatoma and noncolorectal hepatic metastases by examining its effect on serum levels of tumor markers in 20 patients with primary liver cancer (N = 5) or liver metastases (N = 15) from breast cancer, neuroendocrine tumors, ovarian cancer, and thyroid cancer. All patients had failed conventional therapy and had no evidence of extrahepatic spread. After cryosurgery, 17 patients had a significant decrease in tumor marker levels (median 77%) and a significant improvement in symptoms. One patient died of nontumor causes, and five patients died of recurrent disease. Median interval to death or last follow-up was 28.3 months overall (range, 2-45 months), 17.9 months for nonsurvivors (range, 2-44 months), and 35.2 months for survivors (range, 26-45 months). Median survival was 32 months following curative surgery (range, 16-45 months) and 25 months following palliative surgery (range, 2-42 months). Cryosurgical ablation of noncolorectal hepatic metastases and primary hepatomas produces a profound reduction in serum levels of tumor markers. It is safe, provides excellent palliation of symptoms, and in selected patients can be performed with curative intent.

    Title Antisecretory Mechanisms of Peptide Yy in Rat Distal Colon.
    Date July 1997
    Journal Digestive Diseases and Sciences
    Excerpt

    Peptide YY (PYY) is a potent regulator of intestinal secretion. These studies investigated the role of Y1 and Y2 receptor subtypes in mediating the antisecretory effects of PYY on mucosa-submucosa preparations of rat distal colon. Addition of vasoactive intestinal peptide (VIP) to these tissues resulted in a 140 +/- 18% increase in basal short-circuit current (Isc) and the induction of Cl- secretion. VIP-stimulated increases in Isc were abolished by the addition of each of PYY, (Pro34)-PYY, a Y1 receptor-selective agonist, and PYY-(3-36), an endogenous Y2 receptor-selective ligand. However, when tissue neural transmission was blocked with tetrodotoxin, neither PYY nor its receptor subtype-selective analogs were able to inhibit VIP-stimulated increases in Isc. These results suggest that in the rat distal colon, the antisecretory actions of PYY are mediated through a combination of Y1 and Y2 receptor subtypes or through a novel receptor subtype that is unable to discriminate between (Pro34)-PYY and PYY-(3-36).

    Title Peptide Yy: a Potential Proabsorptive Hormone for the Treatment of Malabsorptive Disorders.
    Date May 1996
    Journal The American Surgeon
    Excerpt

    Peptide YY (PYY) is a 36 amino acid peptide that is released from the endocrine cells of the distal ileum, colon, and rectum following a meal. PYY is strongly proabsorptive in the small intestine. We studied the effects of intravenous PYY on colonic water and electrolyte transport in awake dogs. Dogs had 20 cm neurovascularly intact colon Thiry-Vella fistulas (TVS) surgically constructed. Colonic transport was studied in three experimental groups. Group 1 animals received a standard mixed meal. Group 2 animals were unfed and received intravenous PYY and 100 pmol/kg/hr for two hours. This dose of PYY has previously been shown to simulate the plasma levels of PYY normally seen after a meal. Group 3 received intravenous PYY at the same dose in addition to a mixed meal. Our study shows an increase in colonic water, Na+, and Cl- absorption after a meal (P < 0.05). Infusion of PYY at a 100 pmol/kg/hr was significantly proabsorptive beginning at 60 minutes (P < 0.01). Infusion of PYY in addition to a meal further increased absorption (P < 0.05). PYY is a potent proabsorptive agent in the colon of the conscious dog. PYY, or its analogs, may be useful clinical agents in intestinal malabsorptive disorders or after bowel resection.

    Title Na+/h+ Exchange Mediates Postprandial Ileal Water and Electrolyte Transport.
    Date May 1995
    Journal Digestive Diseases and Sciences
    Excerpt

    Feeding stimulates fluid and electrolyte absorption in the small intestine. Previous studies have suggested that Na+/glucose cotransport is important in initiating this response in the jejunum. The purpose of this study was to determine whether Na+/H+ exchange plays a role in meal-induced absorption. Exteriorized, neurovascularly intact jejunal and ileal loops (25 cm) were constructed in dogs. Following a two-week period of postoperative recovery, the loops of awake dogs were perfused with standard buffer alone or with increasing concentrations of amiloride, a Na+/H+ exchange inhibitor. Water, sodium, and chloride fluxes were calculated following a meal using [14C]PEG as a volume marker. The meal significantly increased absorption in both the jejunum (P < 0.001) and ileum (P < 0.01) in those animals perfused with buffer alone. More significantly, amiloride suppressed the increased absorption seen following a meal in the ileum (P < 0.001) but not the jejunum. The response in the ileum was dose dependent. These findings suggest that a major mediator of postprandial sodium and water absorption in the ileum is the Na+/H+ exchanger.

    Title Early Regional Expression and Secretion of Peptide Yy and Enteroglucagon After Massive Resection of Small Bowel.
    Date May 1995
    Journal Journal of the American College of Surgeons
    Excerpt

    BACKGROUND: Previous studies suggest that peptide YY (PYY) and enteroglucagon have an important role in intestinal adaptation after massive small bowel resection. This study was done to define the mechanisms, timing, and anatomic distribution of the PYY and enteroglucagon response. STUDY DESIGN: Lewis rats underwent resection of 70 percent of the small bowel (leaving equal segments of jejunum and ileum), transection, or laparotomy alone. Jejunum, ileum, and colon were compared in resected, transected, and control bowel six hours, 24 hours, one week, and two weeks postoperatively. RESULTS: Analysis of DNA, RNA, and protein per cm of bowel demonstrated hyperplastic changes. Radioimmunoassay revealed plasma PYY and enteroglucagon to be significantly elevated 24 hours after resection and they remained so through week two. In contrast, tissue PYY and enteroglucagon content decreased significantly in all tissues (p < 0.05) after resection. Reverse transcriptase polymerase chain reaction and Southern blot analysis demonstrated an immediate and sustained increase in PYY messenger RNA (mRNA) in both the ileum (fourfold) and in the colon (2.5-fold) at six hours (p < 0.05). A gradual increase in PYY mRNA was also demonstrated in the jejunum with significance at two weeks (p < 0.05). Proglucagon mRNA was significantly higher in the jejunum, compared with the ileum and colon, at 24 hours, one week, and two weeks postresection. CONCLUSIONS: Alterations in PYY and enteroglucagon synthesis occur early in the ileum and colon after massive small bowel resection. The residual jejunum, however, is primarily responsible for the adaptive hyperenteroglucagonemia. These findings suggest that although PYY and enteroglucagon are colocalized to the same cell type, there is a gene-specific response for these two peptides after resection.

    Title Amino Acids Mediate Postprandial Jejunal Proabsorption.
    Date February 1995
    Journal The Journal of Surgical Research
    Excerpt

    Ingestion of a meal stimulates small intestinal ion and water transport. Current evidence suggests that this response, termed proabsorption, is primarily mediated by the apical Na+/glucose cotransporter. Like glucose, the majority of amino acid absorption occurs by Na(+)-dependent, secondary active transport. The purpose of this study was to determine the role of amino acid transport in meal-induced jejunal ion and water absorption in vivo. Exteriorized, neurovascularly intact jejunal loops measuring 25 cm were created in six female mongrel dogs, and the dogs were allowed to recover for 2 weeks. After an overnight fast, the loops were perfused with a standard buffer containing 10 mM aspartate, leucine, glycine, or lysine. Net water and electrolyte absorption before and after a mixed meal was calculated using [14C]polyethylene glycol as a volume marker. Aspartic acid, leucine, glycine, and lysine are each transported by a separate transporter system. Except for lysine, each amino acid significantly (P < 0.05) potentiated sodium and water absorption after a meal. In addition, this effect was at least as great as that seen with 10 mM glucose. These results demonstrate that amino acid transporter, like the Na+/glucose cotransporter, mediates meal-induced jejunal sodium and water absorption and may be as important in the proabsorptive response.

    Title Peptide Yy Immunoneutralization Inhibits Meal-induced Absorption in Vivo.
    Date January 1995
    Journal Surgery
    Excerpt

    BACKGROUND. Plasma peptide YY (PYY) levels rise after a meal and have recently been shown to increase small bowel-absorption. The purpose of this study was to determine whether immunoneutralization of PYY would block postprandial absorption in vivo. METHODS. Exteriorized, neurovascularly intact jejunal and ileal segments (25 cm) were created in six mongrel dogs. After a 2-week recovery luminal perfusion with an isotonic buffer, containing [14C]-polyethylene glycol as a volume marker, was used to analyze water and sodium flux after an oral meal. Each meal was accompanied by either intravenous anti-PYY (0.5 mg.kg-1.h-1) or nonspecific immunoglobulin IG (control). PYY antibody binding was determined by radioimmunoassay. RESULTS. Displacement studies showed complete PYY neutralization. In control experiments feeding increased absorption of sodium and water in both segments. PYY immunoneutralization had no effect on jejunal absorption but significantly diminished ileal absorption (p < 0.05). CONCLUSIONS. These results suggest that PYY acts selectively in the ileum to increase postprandial fluid and electrolyte absorption after a meal. Agents directed at PYY-stimulated absorption may prove to be of therapeutic benefit in patients with malabsorptive conditions.

    Title Up-regulation of Na+,k+ Adenosine Triphosphatase After Massive Intestinal Resection.
    Date August 1994
    Journal Surgery
    Excerpt

    BACKGROUND. The mechanisms of intestinal adaptation after resection are not completely defined. The purpose of this study was to examine the changes after resection in the enterocyte basolateral Na+,K+ adenosine triphosphatase (ATPase) known to play a critical role in epithelial transport and homeostasis. METHODS. Lewis rats underwent 70% small bowel resection or transection. At 6 hours, 24 hours, 1 week, and 2 weeks, jejunum and ileum were harvested for analysis of Na+,K+ ATPase activity, kinetic analysis, and alpha 1-ATPase messenger RNA and protein levels. RESULTS. Na+,K+ ATPase activity increased (p < 0.05) in both the jejunum and ileum by 2 weeks after resection. This rise in activity correlated with an increase in the maximal activity of ATPase, from 20.8 to 101.01 mumol inorganic phosphate.mg-1.hr-1. ATPase messenger RNA levels increased sixfold in the jejunum and tenfold in the ileum by 2 weeks after resection (p < 0.05). Protein levels rose at 6 hours and remained elevated in both tissues. CONCLUSIONS. After intestinal resection, enterocyte Na+,K+ ATPase activity rises as a result of an increase in the number of transporters per cell. This occurs through both transcriptional and translational mechanisms. It appears that intestinal adaptation after resection involves not only an increase in absorptive surface area but also functional adaptation by the individual enterocyte.

    Title Adaptation of the Na+/glucose Cotransporter Following Intestinal Resection.
    Date August 1994
    Journal The Journal of Surgical Research
    Excerpt

    Following massive small bowel resection, the remaining intestine adapts to compensate for lost absorptive capacity. Although the Na+/glucose cotransporter plays a critical role in nutrient, fluid, and electrolyte transport in the small intestine, its role in adaptation following resection has not been defined. To examine this, we sought to determine whether there were changes in the expression of the Na+/glucose cotransporter, SGTL1, at the messenger RNA level. Lewis rats underwent either transection or 70% small bowel resection and reanastomosis. The animals were sacrificed at intervals following operation. Jejunum proximal to the anastomosis and ileum and colon distal to the anastomosis were harvested and analyzed for Na+/glucose mRNA by reverse transcriptase-polymerase chain reaction and Southern blot. Blots were semiquantitated by 32P labeling and standardized to beta-actin. Histologic sections and analysis of DNA, RNA, and protein content revealed hyperplastic changes. Following resection, mRNA for the Na+/glucose cotransporter in the jejunum increased significantly (P < 0.05) by 1 week and remained elevated. In the ileum, an almost fivefold increase occurred at 6 hr and persisted throughout the study (P < 0.05). The early response was greater in the ileum, distal to the reanastomosis, than that in the jejunum (P < 0.05). In contrast, there was no change in the small amount of transporter mRNA detected in the colon. These results suggest that, in addition to mucosal hyperplasia, the intestinal response to resection involves upregulation of transporter mRNA by the individual enterocyte. This transcriptional increase in the Na+/glucose cotransporter appears to be an early response by the intestine and may be important in maintaining overall intestinal transport capacity following resection.

    Title Effects of Raw Soya Diet and Cholecystokinin Receptor Blockade on Pancreatic Growth and Tumor Initiation in the Hamster.
    Date August 1994
    Journal Cancer Letters
    Excerpt

    Raw soya diet in the hamster had short-term trophic effects on the pancreas, causing significant increases in pancreatic weight, DNA, RNA, and protein. These changes appear to be mediated by cholecystokinin (CCK) because the increases were blocked by infusion of the CCKA receptor antagonist, MK329. Raw soya diet significantly increased plasma levels of CCK in both the short-term and long-term studies. However, raw soya did not potentiate pancreatic cancer in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Infusion of MK329 during the initiation period of carcinogenesis did not change tumor incidence or yield, suggesting that endogenous CCK does not influence tumor induction during the initiation period in the hamster.

    Title Peptide Yy Augments Postprandial Small Intestinal Absorption in the Conscious Dog.
    Date July 1994
    Journal American Journal of Surgery
    Excerpt

    Since feeding increases intestinal fluid and electrolyte losses in short bowel syndrome, an agent increasing postprandial small bowel absorption might have a therapeutic role. Peptide YY (PYY) has recently been shown to increase net small bowel absorption under basal conditions. The aim of this study was to determine whether PYY can also augment postprandial absorption. Exteriorized, neurovascularly intact jejunal and ileal segments (25 cm Thiry-Vella loops) were created in dogs (n = 6) and gastrointestinal continuity was restored. Luminal perfusion with [14C]polyethylene glycol was used to calculate the change in water (H2O) and sodium (Na+) and chlorine (Cl-) ion fluxes after an oral meal. Changes in fluxes were also determined after a 2-hour infusion of a physiological dose of PYY (100 pmol/kg per hour). In a third series of experiments, fluxes were measured after a meal, during PYY infusion. Feeding increased small bowel absorption of fluid and electrolytes independent of the luminal content. This effect persisted for 2 hours after the meal. PYY infusion significantly augmented this proabsorptive response in both jejunum and ileum. These results suggest that PYY-agonists may have a therapeutic role in conditions such as short bowel syndrome where postprandial absorption is reduced.

    Title Cyclic Amp-mediated Release of Peptide Yy (pyy) from the Isolated Perfused Rabbit Distal Colon.
    Date December 1993
    Journal Regulatory Peptides
    Excerpt

    We have investigated the role of the colonic nervous system in regulating the release of peptide YY (PYY) from the isolated perfused rabbit distal colon. In addition, we have studied the role of cAMP- and Ca(2+)-dependent mechanisms in mediating the release of PYY. We investigated three agents which stimulate increases in intracellular cAMP (vasoactive intestinal polypeptide (VIP), cholera toxin, and forskolin) and three agents which raise intracellular Ca2+ concentrations (substance P, carbachol, and the calcium ionophore A23187). The three cAMP-dependent agents, VIP (10(-7) M and 3 x 10(-7) M), cholera toxin (100 micrograms), and forskolin (10(-6) M and 10(-5) M) significantly stimulated release of PYY (P < 0.05). Tetrodotoxin (3 x 10(-6) M) did not alter forskolin (10(-5) M) stimulated release of PYY. Substance P (10(-9) M and 10(-8) M), carbachol (10(-5) M), and A23187 (10(-6) M) failed to stimulate the release of PYY. These results suggest that the colonic neurotransmitter VIP participates in the modulation of PYY release from rabbit distal colons. Further, these studies suggest that release of PYY is mediated by cAMP-dependent pathways.

    Title Peptide Yy is a Physiological Regulator of Water and Electrolyte Absorption in the Canine Small Bowel in Vivo.
    Date November 1993
    Journal Gastroenterology
    Excerpt

    BACKGROUND: Peptide YY (PYY), a hormone released following a meal, is one potential mediator of intestinal absorption. Although PYY inhibits 5'-cyclic adenosine monophosphate (cAMP)-stimulated small intestinal secretion in vitro, its effects on fluid and electrolyte transport in vivo are unknown. METHODS: This study examines the effects of physiological doses of PYY in dogs (n = 6) with jejunal and ileal exteriorized, neurovascularly intact intestinal loops (Thiry-Vella fistulas). RESULTS: Plasma PYY levels increased after a meal from 155 +/- 15 to 324 +/- 26 pmol/L at 30 minutes and remained elevated for 2 hours. PYY infused intravenously in unfed animals at 25, 50, 100, and 200 pmol.kg-1.h-1, produced a dose-dependent increase in plasma PYY levels. At 100 pmol.kg-1.h-1, PYY plasma concentrations were similar to those of fed animals (317 +/- 39 pmol/L). PYY infusion resulted in a dose-dependent increase in water and electrolyte absorption at all doses in both the jejunum and ileum. Although the relative increase in absorption was similar, the magnitude was greater in the ileum. CONCLUSIONS: Physiological concentrations of PYY produced an increase in small bowel absorption of water and electrolytes in vivo. The postprandial release of PYY may mediate the increase in absorption following a meal. Such a proabsorptive agent may have considerable potential for clinical use in malabsorptive states.

    Title Deoxycholate is an Important Releaser of Peptide Yy and Enteroglucagon from the Human Colon.
    Date November 1993
    Journal Gut
    Excerpt

    Peptide YY (PYY) and enteroglucagon are hormonal peptides found in endocrine cells of the distal intestinal mucosa. Although it is known that plasma concentrations of both peptides increase in response to feeding, the mechanism by which ingested food causes release of colonic hormones is not understood. The release of PYY and enteroglucagon was measured in response to intraluminal stimuli in 176 patients having investigative colonoscopy. Introduction of air, saline (isotonic and hypertonic), glucose (isotonic and hypertonic), oleic acid (without bile salts), and casein hydrolysate all failed to release PYY but glucose caused a small but significant increase in enteroglucagon concentrations. In contrast with the lack of effect of nutrients, infusion of deoxycholic acid produced a rapid and marked dose responsive increase in plasma PYY concentrations when introduced into the sigmoid colon. PYY release was statistically significant at doses between 3.3 mM to 30 mM; for example 10 mM deoxycholate caused a sixfold increase in plasma PYY concentrations. Infusion of 10 mM deoxycholate into the transverse colon or caecum produced an increase of PYY that was similar to the responses in the sigmoid colon. There was also a significant release of enteroglucagon in response to infusion of this bile salt into the sigmoid colon at doses between 3.3 mM and 30 mM. The enteroglucagon response to 10 mM deoxycholate was similar in all three colonic regions. When oleic acid was added to deoxycholate as an emulsion, the release of PYY and enteroglucagon was similar to that seen with the bile salt alone. These findings suggest that bile salts may play an important part in the control of colonic endocrine function and may explain the increased circulating concentrations of colonic regulatory peptides that are seen in malabsorption states and after small bowel resection in humans.

    Title Effects of High Fat Diet and Cholecystokinin Receptor Blockade on Pancreatic Growth and Tumor Initiation in the Hamster.
    Date July 1993
    Journal Carcinogenesis
    Excerpt

    The mechanism by which high-fat diet potentiates pancreatic cancer is not known, but trophic hormones may be involved. In preliminary growth studies, hamsters fed a high fat diet (17.5% lard, 17.5% corn oil) for 14 days showed a 16.3% increase (P < 0.01) in pancreatic weight compared to controls on low fat diet (2.5% lard, 2.5% corn oil). A significant increase was also seen at 28 days. Similar increases were seen in pancreatic DNA (29%, P < 0.01) and pancreatic RNA (22%, P < 0.05) at 14 days. Plasma cholecystokinin (CCK) levels at 14 days were 2.5 fold higher in the animals fed high fat (P < 0.01). Infusion of the CCK antagonist MK329 (25 nmol/kg/h) completely abolished the increase in pancreatic weight, pancreatic DNA and pancreatic RNA. The effect of CCK receptor blockade during the initiation period of carcinogenesis was investigated in hamsters fed the same diets used in the growth studies. One hundred animals received a single injection of N-nitrosobis(2-oxopropyl)amine, (BOP, 20 mg/kg). Half of the hamsters in each diet group received a 2 week infusion of MK329 (25 nmol/kg/h), beginning 8 days before carcinogen administration. At the time of death, 55 weeks after carcinogen administration, non-fasting plasma CCK levels were 31% higher in the high fat fed hamsters than in the low fat fed animals (P < 0.01). The high-fat diet group had a 3-fold increase in total cancer incidence and a 5-fold increase in advanced lesions (adenocarcinomas). Tumor incidence and yield were not changed in either diet group by CCK-receptor blockade during the initiation period. Cholecystokinin appears to mediate the short-term trophic effect that high-fat feeding has on the pancreas. However, potentiation of pancreatic cancer by high-fat diet in the hamster cancer model does not appear to be influenced by endogenous cholecystokinin at the time of tumor induction.

    Title Management of Unresectable Malignant Endocrine Tumors of the Pancreas.
    Date May 1993
    Journal Surgery, Gynecology & Obstetrics
    Excerpt

    Malignant endocrine tumors of the pancreas are a heterogenous group of tumors with a multipotential secretory capacity. The lesions are generally slow growing with a relatively long life expectancy from the time of diagnosis. Death results from a combination of local and metastatic disease and the sequelae of excess hormone secretion. While potentially successful curative resections are rare, long term survival is frequently possible based on the rate of growth and the inhibition of the bioactive effects of the secretory products of the tumor. Regional control with palliative surgical debulking and transcatheter arterial embolization of hepatic metastases has an important role in terms of symptomatic relief and long term survival. These tumors respond frequently to chemotherapy. Combination chemotherapy is more effective than single agent treatment. Preliminary information suggests that leukocyte interferon is useful in treatment, but this agent still requires careful prospective evaluation. While current data do not support the use of octreotide for an antitumor effect, it is capable of producing prompt and substantial symptomatic relief with minimal side effects in a large proportion of patients with functional malignant endocrine tumors of the pancreas. Many advances have been made in the recognition, diagnosis and management of patients with malignant endocrine tumors of the pancreas. Additional basic cellular research is necessary to define the molecular and cell biologic factors of these tumor cells. Particular facets that require further understanding include their basic cytogenetic abnormality, regulation of peptide production and the role of peptides and other growth factors in endocrine, paracrine and autocrine regulatory relationships. The answers to these questions will hopefully promulgate the discovery of improved cytotoxic agents, better peptide pharmacotherapeutic agents and improve the overall management of patients with unresectable malignant endocrine tumors of the pancreas.

    Title Influence of Chloroquine on Diet-induced Pancreatitis.
    Date February 1993
    Journal Pancreas
    Excerpt

    Recent investigations have suggested that digestive zymogens may become activated within the acinar cell during acute pancreatitis. While the molecular events responsible for intracellular zymogen activation remain unknown, several potential enzymatic pathways require an acidic pH to optimally proceed. We therefore proposed that manipulation of subcellular pH might alter the course of experimental pancreatitis. Chloroquine, a weak base that raises the pH of acidic subcellular compartments, was administered to young female mice in which pancreatitis was induced by a choline-deficient, ethionine-supplemented (CDE) diet. Control animals were maintained on regular laboratory chow. Examination of isolated pancreatic acini using acridine orange cytofluorescence demonstrated expansion of acidic subcellular compartments in animals fed the CDE diet. These compartments were effectively neutralized in animals receiving chloroquine. Animals receiving continuous infusions of high-dose chloroquine demonstrated a significant (p < 0.05) decrease in free pancreatic tryptic activity as well as improved survival. These changes were also associated with decreased trypsinogen content in animals treated with high-dose chloroquine, suggesting an additional potential effect of chloroquine on zymogen synthesis and accumulation. One explanation of these findings is that a low-pH compartment may be important in the pathogenesis of diet-induced pancreatitis.

    Title Plasma and Tissue Alterations of Peptide Yy and Enteroglucagon in Rats After Colectomy.
    Date September 1992
    Journal The Yale Journal of Biology and Medicine
    Excerpt

    Peptide YY (PYY) and enteroglucagon are produced by endocrine cells of the colonic mucosa. PYY inhibits upper gastrointestinal motility, and enteroglucagon is trophic for small bowel mucosa. Adaptive increase in the production and release of these peptides may improve functional results after colorectal resections. We hypothesized that if segments of the colon were resected, then production and release of PYY and enteroglucagon would increase in the remaining segments of bowel. Animals which underwent colonic transections and partial resections had transient elevations of PYY up to 250 +/- 80 pmol/L, which dropped to control group levels in the second week following surgery. Rats with an abdominal colectomy had significantly greater PYY levels than all other groups from the third (208 +/- 30 pmol/L) to the thirty-eighth (100 +/- 16 pmol/L) week of the study. Circulating levels of enteroglucagon were elevated to 156 +/- 35 pmol/L in rats with a right hemicolectomy during the first week following surgery. Enteroglucagon levels did not significantly vary in the other groups studied. Both tissue PYY (413 +/- 33 pmol/gram) and tissue enteroglucagon (171 +/- 17 pmol/gram) were significantly elevated in the rectums of the rats with an abdominal colectomy, as compared to all other groups. The elevated tissue levels may thus account for the ability to maintain elevated plasma PYY. Double immunogold labeling of endocrine cells in the colorectal tissue for PYY and enteroglucagon revealed both peptides within the same endocrine cells and secretory granules. These studies support the hypothesis that circulating levels of PYY are elevated after major colonic resections and suggest that L-type endocrine cells may participate in adaptive responses which improve intestinal function following colonic surgery.

    Title Distribution and Immunocytochemical Colocalization of Peptide Yy and Enteroglucagon in Endocrine Cells of the Rabbit Colon.
    Date July 1991
    Journal Endocrinology
    Excerpt

    Peptide YY (PYY) is 36 amino acid peptide hormone present in high concentrations in the colon where it is colocalized with enteroglucagon in L cells. A selective release of PYY and enteroglucagon from the rabbit colon has been described, raising the question of the exact localization of the two hormones in the rabbit colon. We have therefore examined the distribution of PYY and enteroglucagon as well as somatostatin in the rabbit colon using RIA and electron microscopic immunocytochemistry. PYY and enteroglucagon were present in high concentrations in the colorectal mucosa with peak concentrations in the left colon (PYY 544 +/- 87 pmol/g, enteroglucagon 152 +/- 10 pmol/g). Electron microscopic examination of the colonic mucosa demonstrated a large population (65%) of EC cells, a moderate population (30%) of L cells, and a small population (5%) of D cells. By immunogold labeling serotonin was localized to EC cells, PYY and enteroglucagon to L cells, and somatostatin to the D cell. Double immunogold labeling revealed PYY and enteroglucagon in all L cells examined (93 cells). A majority of the secretory granules (83%) were labeled by both PYY and glucagon antibodies, whereas a significant portion of granules (15%) was labeled by the PYY antibodies alone. The results demonstrate that L cells are the sole source of PYY and enteroglucagon in the rabbit colon and that L cells contain different populations of secretory granules. The existence of different secretory granules in L cells may explain the selective release of PYY and enteroglucagon observed in the rabbit colon.

    Title Short-chain Fatty Acid Release of Peptide Yy in the Isolated Rabbit Distal Colon.
    Date June 1991
    Journal Scandinavian Journal of Gastroenterology
    Excerpt

    Short-chain fatty acids (SCFAs) form the major ionic fraction of stool, provide the major metabolic substrate for colonic epithelium, and promote mucosal ion transport. Despite this prominent role of SCFAs in metabolism of the colon, their effect on colonic endocrine cell function has not been studied. Consequently, we hypothesized that SCFAs might modulate release of peptide YY (PYY) from colonic type-L endocrine cells. The specific aims of this study were to measure release of PYY from the isolated perfused rabbit distal colon stimulated by intraluminal infusion of 0.9% saline, acetate (10 mM), acetoacetate (10 mM), n-butyrate (1, 3.3, 10, 100 mM), and pyruvate (10 mM). PYY levels were measured by radioimmunoassay in the venous effluent of the rabbit colon. All four SCFAs (10 mM) caused at least a twofold increase in integrated release of PYY from the isolated perfused rabbit colon. Graded concentrations of n-butyrate caused a stepwise release of PYY. This study suggests that SCFAs may modulate the release of colonic PYY in rabbits.

    Title Adaptive Increase in Peptide Yy and Enteroglucagon After Proctocolectomy and Pelvic Ileal Reservoir Construction.
    Date March 1991
    Journal Diseases of the Colon and Rectum
    Excerpt

    Functional results improve with time after proctocolectomy and pelvic ileal reservoir construction. We hypothesized that adaptive increases of circulating and tissue levels of the gut hormones peptide YY (PYY) and enteroglucagon may contribute to this improvement by slowing small bowel transit and increasing small bowel absorption. The specific aim of this study was to measure plasma and ileal mucosal concentrations of PYY and enteroglucagon in dogs 1 year after proctocolectomy and ileal reservoir-anal anastomosis. In the ileal reservoir dogs, postprandial PYY levels reached 238 +/- 31 pmol/liter compared with 93 +/- 33 pmol/liter in sham operated controls (P less than 0.001). Postprandial plasma enteroglucagon levels reached 199 +/- 53 pmol/liter in reservoir animals and 52 +/- 4 pmol/liter in controls (P less than 0.05). Tissue levels of PYY in the mucosa of the ileal reservoirs were 419 +/- 43 pmol/g compared with 133 +/- 23 pmol/g in normal terminal ileum (P less than 0.0001). Enteroglucagon levels were also elevated in reservoir mucosa (193 +/- 21 pmol/g vs. 113 +/- 9 pmol/g in controls, P less than 0.05). These data demonstrate that postprandial and tissue levels of PYY and enteroglucagon increase in dogs 1 year after construction of ileal reservoirs. The adaptive increase in PYY would slow small bowel transit and the increase in enteroglucagon would promote mucosal growth, each contributing to the improved functional results.

    Title Amelioration of Cholinergic-induced Pancreatitis with a Selective Cholecystokinin Receptor Antagonist.
    Date January 1991
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    Acute edematous pancreatitis follows excessive cholinergic stimulation in patients exposed to anticholinesterase-containing insecticides. We describe the role of cholecystokinin and the benefits of cholecystokinin receptor blockade in this form of pancreatitis. A cholinergic mimetic (carbachol) was administered to rats weighing 300 to 350 g and produced a form of edematous pancreatitis that mimics that seen in humans. Animals received carbachol intraperitoneally, either alone (250 micrograms/kg of body weight) or with cholecystokinin-receptor antagonist devazepide (3 mg/kg of body weight) and were killed 4 hours later. Carbachol administration resulted in a 19% increase in pancreatic weight, a fourfold increase in serum amylase levels, and a 14-fold increase in serum lipase levels. Plasma cholecystokinin levels, however, were not altered. Devazepide administered prior to cholinergic hyperstimulation blocked pancreatic weight increase and reduced elevations in serum amylase levels twofold and lipase levels fourfold. Although cholecystokinin levels are not elevated in this model of pancreatitis, blockade of even low, background concentrations of this regulatory peptide is beneficial.

    Title A Novel Micromethod for Pancreatic Acinar Secretion. Time Course of Cck Stimulation and Its Inhibition by L-364,718.
    Date December 1990
    Journal International Journal of Pancreatology : Official Journal of the International Association of Pancreatology
    Excerpt

    Dispersed acini have proven to be particularly valuable in the study of pancreatic enzyme secretion. Complex time course studies or experiments requiring large numbers of replicates have proven difficult, however, with currently available techniques. Using a custom-designed incubation chamber, a miniaturized incubation method has been devised, which allows for continuous oxygenation of acini in 96-well microtiter plates and rapid separation of medium from acini by vacuum filtration. The filtrates from individual wells are collected into the wells of a second microtiter plate for pancreatic enzyme measurement. Using the above method, the dose response and time course of cholecystokinin (CCK-8)-stimulated amylase secretion was investigated. During a 1-h incubation, unstimulated amylase secretion was 4.1 +/- 0.3% of total acini content. Response to CCK was very sensitive, being detected at 10(-13) M (p less than 0.05), half-maximal at 10(-11) M CCK (14.0 +/- 0.6%, p less than 0.001) and maximal at 10(-9) M CCK (24.8 +/- 1.0%, p less than 0.001). In the time course experiments, an increase in amylase secretion was detected by 2.5 min and continued to increase steadily to a plateau at 40 min, with both submaximal (10(-11) M) and maximal (10(-9) M) CCK concentrations. The potent and specific CCK-receptor antagonist, L-364,718, caused a dose-dependent decrease in CCK-stimulated amylase secretion, with a half-maximal effect at 10(-10) M. The receptor antagonist, L-364,718, at 10(-8) M completely abolished CCK-stimulated amylase secretion. This microtechnique provides a simple, reliable, and reproducible method for the study of dispersed pancreatic acini.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Experimental Models of Acute Pancreatitis.
    Date August 1990
    Journal The Journal of Surgical Research
    Excerpt

    Acute pancreatitis remains a disease of uncertain pathogenesis and nonspecific therapy. Because of the practical problems plaguing investigation of pancreatitis in man, investigators have developed various experimental animal models of pancreatitis in order to develop rationale concepts regarding pathogenesis and therapy. Despite numerous investigations over the past century, the events involved in the initiation and progression of pancreatitis remain obscure. Indeed, identification of the cellular mechanisms responsible for the initiation of this disease may allow for significant advances in therapy. Previous studies have largely focused on the mechanism of pancreatitis at the organ level. It is now apparent that the early initiating events in acute pancreatitis probably occur at a membrane or intracellular level. The resolution of the cellular events which underlie the development of pancreatitis in combination with the introduction of new therapeutic agents may enable a rational and safe protocol to be developed for the support of patients with pancreatitis. In this review different experimental models of acute pancreatitis are discussed. Emphasis is placed on the relevance of various models to clinical pancreatitis.

    Title Intra-ocular Transplantation of Carcinoid Tumours from Mastomys and Humans.
    Date July 1990
    Journal The Journal of Pathology
    Excerpt

    Carcinoid tumours from man and Mastomys (Praomys) natalensis produce a variety of peptide hormones. The study of these peptide-secreting tumours has been difficult because of the small amount of tissue available and because of limitations with present cell culture systems. The aim of this study was to establish an experimental model where carcinoid tumours could be maintained and their hormone secretion studied. The intra-ocular transplantation technique was chosen for its simplicity and high rate of success. Gastric carcinoid tumours from mastomys (n = 4) and human carcinoids (n = 2) (one bronchial and one ileal) were transplanted to the anterior eye chamber of Sprague-Dawley rats. Pieces of fresh tumour tissue were injected into the anterior eye chamber of rats and allowed to grow for 4-8 weeks. Rats transplanted with human tissue were immunosuppressed by daily injections with cyclosporin A (20 mg/kg). Eye chambers were inspected regularly and plasma from transplanted rats was collected for assay of peptide YY (PYY) and glucagon. Vascularization of transplants occurred within 1-2 days after transplantation in 70-80 per cent of all experiments. Microscopic analysis of transplants demonstrated a rich supply of blood vessels to tumour cells which contained characteristic neurosecretory granules. Transplanted rats had significantly (P less than 0.05) elevated levels of PYY (44-165 pmol/l) and glucagon (67-162 pmol/l) in plasma as compared with sham-operated rats (PYY 28-40 pmol/l, glucagon 33-40 pmol/l), indicating that hormone secretion by tumour cells in oculo was maintained.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Significance of Gastric Endocrine Tumor and Age-related Gut Peptide Alterations in Mastomys.
    Date May 1990
    Journal Regulatory Peptides
    Excerpt

    The Mastomys (Praomys natalensis) species are a unique natural model in which the bioactivity of gastric carcinoids may be studied. Several investigators have previously demonstrated that these tumors contain large amounts of histamine. In this study we investigated the presence of peptides associated with the neoplasm. The levels and location of gastrin, gastric inhibitory peptide (GIP), neurotensin, peptide YY (PYY), pancreatic polypeptide (PP), glucagon, bombesin, vasoactive intestinal peptide (VIP) and somatostatin (SRIF) were investigated by radioimmunoassay and immunocytochemistry. In addition the distribution of these peptides were evaluated in the gastrointestinal tract of young and old animals to investigate possible age-related changes. PYY and enteroglucagon (EG) were significantly (P less than 0.001) elevated in both tumor tissue (676 +/- 152, 551 +/- 164 pmol/g) and plasma (620 +/- 160, 500 +/- 147 pmol/l) of tumor-bearing animals. Immunocytochemistry revealed PYY- and EG-like immunoreactivity in 20-30% of tumor cells. A significant decrease (P less than 0.05) in bombesin was noted in older animals, but no changes in gastric tissue content of PYY or EG could be detected between young and old animals. Gastrin was not detected in tumors and there were no significant changes in tissue or plasma levels with age. Small bowel concentrations of VIP and PYY were higher in the older mastomys (P less than 0.05). In contrast, colonic levels of bombesin, VIP, somatostatin and PYY were significantly lower (P less than 0.05) in older mastomys compared with young. The age-related changes in several peptides may reflect an adaptive response to acid hypersecretion. The multi-hormonal character of these neoplasms suggests that these tumors develop from a pluripotential stem cell.

    Title Deoxycholate-stimulated Release of Peptide Yy from the Isolated Perfused Rabbit Left Colon.
    Date January 1990
    Journal The American Journal of Physiology
    Excerpt

    The purpose of this study was 1) to measure the effect of graded concentrations of oleic acid and deoxycholic acid (DCA) on the release of peptide YY (PYY) and enteroglucagon and 2) to test whether DCA-stimulated release of PYY was neurally mediated by blocking neuronal conduction with tetrodotoxin. Studies were performed in isolated left colons from New Zealand White rabbits. Oleic acid in concentrations from 0.22 to 22 mM suspended in 10 mM DCA significantly stimulated release of PYY (P less than 0.01) but resulted in no graded response (Bartlett's test, P = 0.15). Similarly, oleic acid (2.2 mM) suspended with ursodeoxycholic acid (10 mM) produced no increased release of PYY above that achieved by ursodeoxycholic acid alone. In contrast, oleic acid (2.2 and 22 mM suspended with 10 mM DCA) produced a graded release of enteroglucagon during the stimulated period. Deoxycholic acid caused a concentration-dependent release of PYY (1, 3.3, 10, and 25 mM) during the stimulated period. Deoxycholic acid (1 and 10 mM) did not significantly increase enteroglucagon release. Tetrodotoxin blockade had no effect on release of PYY stimulated by 10 mM DCA. Because PYY and enteroglucagon are both found in colonic endocrine cells, these results suggest that the release of PYY and enteroglucagon are mediated by specific secretagogues and not simply caused by noxious effects of the agonists. Also, this study has demonstrated that DCA-stimulated release of PYY is not dependent on neuronally mediated mechanisms.

    Title H2-receptor Blockade Induces Peptide Yy and Enteroglucagon-secreting Gastric Carcinoids in Mastomys.
    Date January 1990
    Journal Surgery
    Excerpt

    Gastric carcinoid tumor formation has been reported with prolonged achlorhydria in both animals and human beings. The hypothesis in this study was that the ablation of parietal cell function in an animal (mastomys) genetically predisposed to gastric neuroendocrine neoplasia would promote and accelerate tumor formation. Loxtidine, an irreversible H2-receptor blocker, was administered at 1 mg/kg/day in drinking water for 4 months to young mastomys (n = 16). After 4 months of treatment, 14 of 16 animals had gastric carcinoids compared with 0 of 16 young control animals and 4 of 16 older control animals. Ultrastructurally, these tumors were characterized by the presence of neurosecretory granules. Serum gastrin levels were elevated (230 +/- 40 pmol/L) in loxtidine-treated animals compared with control animals (26 +/- 8 pmol/L) (p less than 0.05). In addition, both peptide YY (620 +/- 160 pmol/L) and enteroglucagon (500 +/- 147 pmol/L) were significantly elevated compared with control groups (p less than 0.05). Similarly, in tumor tissue, peptide YY (676 +/- 152 pmol/gm) and enteroglucagon (551 +/- 164 pmol/gm) were found in large quantities, whereas gastrin was undetectable. These observations provide substantial support for the possible pathophysiologic role of gut peptides, particularly gastrin, in the generation of endocrine neoplasia. The advent of endocrine tumors after inhibition of a gut secretory cell (parietal) may be of considerable significance in understanding the genesis of endocrine neoplasia. Whether the drug acts as a neoplastic promoter of enterochromaffin-like cells or the tumor development is related to elevation of peptides such as gastrin cannot be established in this study. Long-term H2-receptor blockade with new potent, irreversible agents as an alternative to surgery may have potential grave implications that require careful consideration.

    Title Prostaglandin E Analogue Inhibition of Pancreatic Enzyme Secretion.
    Date December 1989
    Journal Pancreas
    Excerpt

    The effect of native prostaglandins and their methylated analogues on pancreatic enzyme secretion remains unclear, with previous studies reporting inconsistent results. To determine whether the E series prostaglandins directly influence pancreatic secretion, we studied the effect of rioprostil, a prostaglandin E1 analogue, and 16,16-dimethyl prostaglandin E2 (DMPGE2), a prostaglandin E2 analogue, on enzyme release from dispersed guinea pig pancreatic acini. Basal amylase release (4.3 +/- 0.6% of total acinar content) was not altered by either analogue (10(-10)-10(-5) M). A 50% inhibition of maximal cholecystokinin stimulation (10(-9) M; 28.8 +/- 1.2%) was seen with rioprostil (10(-7) M; 14.6 +/- 1.3%) and DMPGE2 (10(-6) M; 15.9 +/- 0.7%) (both p less than 0.005). Prostaglandin inhibition of carbachol-stimulated amylase was less pronounced. The most effective inhibitory dosage with maximal carbachol (10(-5) M; 30.2 +/- 1.9%) was 10(-6) M for both rioprostil (19.2 +/- 1.6%) and DMPGE2 (22.4 +/- 1.7%) (both p less than 0.005). Incubation of acini with A23187, phorbol ester, and 1-oleoyl-2-acetyl-glycerol resulted in a dose-dependent increase in amylase release that was not altered by maximal concentrations of either prostaglandin analogue. Our results indicate that rioprostil and DMPGE2 can directly inhibit pancreatic acinar secretion. This effect appears to occur before activation of the inositol phospholipid system.

    Title Effects of the Cck Receptor Antagonist L364,718 on Pancreatic Growth in Adult and Developing Animals.
    Date November 1989
    Journal The American Journal of Physiology
    Excerpt

    Although exogenous administration of cholecystokinin (CCK) or dietary manipulation to increase circulating CCK have previously been shown to promote pancreatic growth, the role of CCK in controlling normal pancreatic development remains unclear. A potent CCK receptor antagonist, L364,718, was administered to rats, guinea pigs, and hamsters to block the effect of endogenous CCK. Animals were given continuous infusions of L364,718 (25 nmol.kg-1.h-1), CCK octapeptide [(CCK-8) 200 pmol.kg-1.h-1], or both CCK-8 and L364,718 for 14 and 28 days. Adult (4-mo-old) and young (4-wk-old) animals were used. CCK-8 and L364,718 were administered via separate, subcutaneously implanted mini-osmotic pumps. Infusions of CCK-8 alone for 28 days resulted in a 21.7% increase in wet pancreatic weight in 4-wk-old rats and a 22.7% increase in 4-wk-old guinea pigs (both P less than 0.001 compared with controls). Similar increases were found in DNA, RNA, and total protein contents. Coadministration of L364,718 totally blocked the trophic effects of exogenously infused CCK-8 in rats and guinea pigs. Administration of L364,718 alone in hamsters, guinea pigs, and rats for 14 and 28 days failed to alter the normal growth of the pancreas gland as measured by these parameters. Although elevated levels of CCK appear to promote a potent trophic response in the growing pancreas, this regulatory peptide does not appear to be an essential trophic factor for the normal growth of the exocrine pancreas in these animals.

    Title Cholecystokinin Augmentation of 'surgical' Pancreatitis. Benefits of Receptor Blockade.
    Date June 1989
    Journal Archives of Surgery (chicago, Ill. : 1960)
    Excerpt

    The management of acute pancreatitis has not changed appreciably throughout several decades. Recent evidence has suggested that cholecystokinin (CCK) may play an important role in pancreatic disease. Investigations into the precise role of CCK in acute pancreatitis have been hampered by the lack of a specific CCK receptor antagonist. Using a newly described, highly potent and specific CCK receptor antagonist, L-364,718, the effect of CCK in two models of acute "surgical" pancreatitis was examined: (1) the bile salt ductal perfusion model in the rat and (2) a traumatic model in the guinea pig. At a suboptimal dose for pancreatic enzyme secretion (25 pmol/kg/h), CCK was found to potentiate the severity of the ensuing pancreatitis in both models. Continuous CCK receptor blockade with L-364,718 (25 nmol/kg/h) improved biochemical, morphologic, and survival indexes. This study suggests that physiologic levels of CCK play an important permissive role in the evolution of acute pancreatitis. The use of L-364,718 as an investigative probe or therapeutic tool for acute pancreatitis is worthy of further consideration.

    Title Malignant Diathesis from Jejunal-ileal Carcinoids.
    Date March 1989
    Journal The American Journal of Gastroenterology
    Excerpt

    A facet of carcinoid tumors often not recognized is their close association with other, noncarcinoid malignancies. The clinical course of two patients with multiple ileal-jejunal carcinoids and multiple other noncarcinoid malignancies is described. These patients were found to have elevated circulating levels of gastrin, bombesin, glucagon, enteroglucagon, pancreatic polypeptide, and peptide tyrosine tyrosine. These regulatory peptides have been demonstrated to promote trophic effects on the gastrointestinal tract as well as malignant tumors. We propose that the release of these bioactive hormones into the portal and systemic circulation by carcinoid tumors may play some role in their association with these multiple second tumors.

    Title Does Vasoactive Intestinal Polypeptide Mediate the Pathophysiology of Bowel Obstruction?
    Date February 1989
    Journal American Journal of Surgery
    Excerpt

    We hypothesized that bioactive peptides might be released into the portal circulation and mediate pathophysiologic alterations accompanying small bowel obstruction. We studied this question in a subacute canine small bowel obstruction model using 50 percent diameter occlusion. Control animals underwent sham laparotomy. Vasoactive intestinal peptide (VIP), peptide YY, and gastrin were measured in portal and systemic plasma by specific radioimmunoassays at 24-hour intervals as the obstruction progressed to completion over 5 days. All peptides in both groups demonstrated portal and peripheral gradients. In control dogs, peptide concentrations did not change postoperatively but VIP increased markedly in obstructed dogs, demonstrating a median portal level of 95 pmol/liter at 96 hours compared with 31.5 pmol/liter in control animals. These portal VIP levels are known to cause hypersecretion and splanchnic vasodilation in experimental models. The release of vasoactive compounds such as VIP may mediate local pathophysiology in human small bowel obstruction. A similar explanation of the systemic effects is consistent with the known cardiopulmonary bioactivity of VIP.

    Title Advanced Rectal Cancer. What is the Best Palliation?
    Date December 1988
    Journal Diseases of the Colon and Rectum
    Excerpt

    The best treatment of advanced rectal cancer remains uncertain. The aim of this study was to determine the outcome after palliative procedures in patients with advanced rectal cancer. One hundred and three patients treated over a seven-year period were identified, including 30 with local invasion, 18 with local metastases, and 55 with distant metastases. Patients were grouped into two groups: those who underwent palliative resection (68) and those who were treated without rectal resection (55). The nonresected group included patients who underwent diverting colostomies (28) and those who received multimodality therapy without surgery (7). The average age of all patients was 63.1 years. Patients in the nonresected group had more distant disease (68 percent) than the resected group (46 percent). Significant pelvic pain was a more common problem in the nonresected group (15 percent) than in the resected group (4 percent). Similarly, pelvic sepsis was more common in the nonresected group (14 percent) than in the resected group (9 percent). Postoperative mortality was 4.3 percent after palliative resection and 3.8 percent after diverting colostomy. Survival of the resected group at one year was 65 percent and at two years 20 percent. Survival of the nonresected group at one year was 20 percent and at two years 0 percent. Survival in the resected group was significantly (P less than .01) better than the nonresected group but probably can be attributed to the more extensive disease generally present in the patients who did not undergo resection. These results suggest that patients with advanced rectal cancers should undergo palliative resection whenever possible because resection decreases pelvic complications and may improve quality of life.

    Title Urgent Need for a New Staging System in Advanced Colorectal Cancer.
    Date
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    Despite recent advances in the medical treatment of metastatic colorectal cancer (mCRC), which include irinotecan- and oxaliplatin-based first-line regimens, the concept of planned sequential therapy involving three active agents during the course of a patient's treatment and the increasing use of targeted monoclonal antibodies, 5-year survival rates for patients with advanced CRC remain unacceptably low. For patients with CRC liver metastases, liver resection remains the only chance of cure, with 5-year survival rates ranging from 25% to 40%. However, 80% to 85% of patients with stage IV CRC have liver disease which is considered unresectable at presentation. The rapid expansion in the use of improved combination chemotherapy regimens plus or minus biologics, to render initially unresectable metastases resectable has increased the percentage of patients eligible for potentially curative surgery. However, the current staging criteria for CRC patients with metastatic disease do not reflect these recent changes or the fact that there is also a large variation in the survival of patients with stage IV CRC. For example the survival for a patient with a solitary, resectable liver metastasis is better than that for a patient with stage III disease. A new staging system is therefore needed that acknowledges both the improvements that have been made in surgical techniques for resectable metastases and the impact of modern chemotherapy on rendering initially unresectable CRC liver metastases resectable, while at the same time distinguishing between patients with a chance of cure at presentation and those for whom only palliative treatment is possible.

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