Obstetricians & Gynecologists, Oncology Specialist (cancer)
22 years of experience

Accepting new patients
University West
Cancer Research & Treatment Center
1201 Camino De Salud NE
Albuquerque, NM 87102
505-272-4946
Locations and availability (4)

Education ?

Medical School Score Rankings
University of Pennsylvania (1988)
Obstetrics & Gynecology
  • Currently 4 of 4 apples
Top 25%

Awards & Distinctions ?

Awards  
Patients' Choice Award (2012)
Associations
American Society of Clinical Oncology
Society of Gynecologic Oncology
American Board of Obstetrics and Gynecology

Affiliations ?

Dr. Muller is affiliated with 22 hospitals.

Hospital Affilations

Score

Rankings

  • Lovelace Medical Center
    Obstetrician & Gynecologist
    5400 Gibson Blvd SE, Albuquerque, NM 87108
    • Currently 4 of 4 crosses
    Top 25%
  • Espanola Hospital
    1010 Spruce St, Espanola, NM 87532
    • Currently 4 of 4 crosses
    Top 25%
  • West Mesa Medical Center
    10501 Golf Course Rd NW, Albuquerque, NM 87114
    • Currently 4 of 4 crosses
    Top 25%
  • Presbyterian Hospital
    Medical Oncology
    1100 Central Ave SE, Albuquerque, NM 87106
    • Currently 4 of 4 crosses
    Top 25%
  • Heart Hospital of New Mexico
    5150 Journal Center Blvd NE, Albuquerque, NM 87109
    • Currently 4 of 4 crosses
    Top 25%
  • University of New Mexico Hospital
    Medical Oncology
    2211 Lomas Blvd NE, Albuquerque, NM 87106
    • Currently 3 of 4 crosses
    Top 50%
  • Lovelace Womens Hospital
    4701 Montgomery Blvd NE, Albuquerque, NM 87109
    • Currently 3 of 4 crosses
    Top 50%
  • Kaseman Presby Hosp
    8300 Constitution Ave NE, Albuquerque, NM 87110
    • Currently 1 of 4 crosses
  • Parkland Health & Hospital System
    5201 Harry Hines Blvd, Dallas, TX 75235
    • Currently 1 of 4 crosses
  • UT Southwestern Zale Lipshy Hospital
  • Lovelace Sanvia Rehabilitation Hospital of New Mexico
    505 Elm St NE, Albuquerque, NM 87102
  • Parkland Memorial Hospital
  • Cancer Research & Treatment Center
    1 University Of New Mexico, Albuquerque, NM 87131
  • Children`s Medical Center of Dallas
  • University of New Mexico Mental Health Center
    2600 Marble Ave NE, Albuquerque, NM 87106
  • Parkland Health and Hospital System
  • University Hospital - St Paul
  • Zale - Lipshy University Hospital
  • University of New Mexico Health Sciences Center
  • UT Southwestern St Paul Hospital
  • Saint Joseph's Medical Center - Albuquerque
    601 Dr Martin Luther King Jr Ave NE, Albuquerque, NM 87102
  • UNM Medical Group
  • Publications & Research

    Dr. Muller has contributed to 45 publications.
    Title A Phase Ii Evaluation of Trabectedin in the Treatment of Advanced, Persistent, or Recurrent Uterine Leiomyosarcoma: a Gynecologic Oncology Group Study.
    Date January 2012
    Journal Gynecologic Oncology
    Excerpt

    To estimate activity and safety of trabectedin 1.5 mg/m2 IV over 24 hours every 3 weeks (1 cycle) in uterine leiomyosarcoma.

    Title Targeting the Egf Receptor for Ovarian Cancer Therapy.
    Date July 2011
    Journal Journal of Oncology
    Excerpt

    Ovarian carcinoma is the leading cause of death from gynecologic malignancy in the US. Factors such as the molecular heterogeneity of ovarian tumors and frequent diagnosis at advanced stages hamper effective disease treatment. There is growing emphasis on the identification and development of targeted therapies to disrupt molecular pathways in cancer. The epidermal growth factor (EGF) receptor is one such protein target with potential utility in the management of ovarian cancer. This paper will discuss contributions of EGF receptor activation to ovarian cancer pathogenesis and the status of EGF receptor inhibitors and EGF receptor targeted therapies in ovarian cancer treatment.

    Title Analysis of Genetic Copy Number Changes in Cervical Disease Progression.
    Date February 2011
    Journal Bmc Cancer
    Excerpt

    Cervical dysplasia and tumorigenesis have been linked with numerous chromosomal aberrations. The goal of this study was to evaluate 35 genomic regions associated with cervical disease and to select those which were found to have the highest frequency of aberration for use as probes in fluorescent in-situ hybridization.

    Title Pelvic Floor Disorders and Sexual Function in Gynecologic Cancer Survivors: a Cohort Study.
    Date December 2010
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    The purpose of this study was to assess the prevalence of pelvic floor disorders and sexual function in survivors of gynecologic cancer.

    Title Usa Hcg Reference Service, 10-year Report.
    Date October 2010
    Journal Clinical Biochemistry
    Excerpt

    The USA hCG Reference Service has been dealing with cases of persistent low levels of hCG and gestational trophoblastic diseases for 10years. Here we present the complete experience.

    Title Doctor, Should I Get This New Ovarian Cancer Test-ova1?
    Date August 2010
    Journal Obstetrics and Gynecology
    Title Normal Production of Human Chorionic Gonadotropin in Perimenopausal and Menopausal Women and After Oophorectomy.
    Date March 2010
    Journal International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society
    Excerpt

    The normal pituitary production of human chorionic gonadotropin (hCG)alongside luteinizing hormone, and its presence in women after bilateral oophorectomy, during perimenopause and menopause, as measured in serum and urine, has been known for 30 years and is described in numerous publications. Last year our group discussed this finding in a correspondence to the editor in the March 15th issue of New England Journal of Medicine, yet the misinterpretation of low-level hCG in these women seems to have increased in magnitude.

    Title Phase Ii Clinical Trial of Ixabepilone in Patients with Recurrent or Persistent Platinum- and Taxane-resistant Ovarian or Primary Peritoneal Cancer: a Gynecologic Oncology Group Study.
    Date January 2010
    Journal Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
    Excerpt

    PURPOSE Ixabepilone (BMS-247550) is a microtubule-stabilizing epothilone B analog with activity in taxane-resistant metastatic breast cancer. The Gynecologic Oncology Group conducted a phase II evaluation of the efficacy and safety of ixabepilone in patients with recurrent or persistent platinum- and taxane-resistant primary ovarian or peritoneal carcinoma. PATIENTS AND METHODS Patients with measurable platinum- and taxane-resistant ovarian or peritoneal carcinoma, defined as progression during or within 6 months of one prior course of treatment with each agent, received intravenous ixabepilone 20 mg/m(2) administered over 1 hour on days 1, 8, and 15 of a 28-day cycle. Results Of 51 patients entered, 49 were eligible. The objective response rate was 14.3% (95% CI, 5.9% to 27.2%), with three complete and four partial responses. Twenty patients (40.8%) had stable disease, whereas sixteen (32.7%) had increasing disease. The median time to progression was 4.4 months (95% CI, 0.8 to 32.6+ months); median survival was 14.8 months (95% CI, 0.8 to 50.0) months. Patients received a median of two treatment cycles (range, 1 to 29 cycles), and 18.4% of patients received > or = six cycles. Adverse effects included peripheral grade 2 (28.5%) and grade 3 (6.1%) neuropathy, grades 3 to 4 neutropenia (20.4%), grade 3 fatigue (14.3%), grade 3 nausea/emesis (22%), grade 3 diarrhea (10%), and grade 3 mucositis (4%). CONCLUSION Ixabepilone 20 mg/m(2) over 1 hour on days 1, 8, and 15 of a 28-day cycle demonstrates antitumor activity and acceptable safety in patients with platinum- and taxane-resistant recurrent or persistent ovarian or primary peritoneal carcinoma.

    Title The Quagmire of Hcg and Hcg Testing in Gynecologic Oncology.
    Date March 2009
    Journal Gynecologic Oncology
    Excerpt

    Few molecules have created so much confusion as the hCG series of molecules. Here we present a comprehensive review of hCG as a tumor marker, of hCG and cancer and modern perspectives on the multiplicity of hCG, and its appropriate use in the management of gynecological malignancies and gestational trophoblastic diseases. The complexity of hCG is better understood. There is regular hCG produced by syncytiotrophoblast cells in pregnancy and by hydatidiform moles. This hormone functions to advance uterine angiogenesis and promote progesterone production by corpus luteal cells. Hyperglycosylated hCG is an independent molecule to regular hCG, it varies significantly from hCG in structure and is produced by cytotrophoblast cells. It is an autocrine or cytokine which functions to promote growth, invasion and malignancy. It is an absolute marker of invasive mole and invasive choriocarcinoma. Hyperglycosylated hCG is invaluable in the diagnosis and management of gestational trophoblastic diseases. The free beta-subunit of hCG is also an autocrine or cytokine and is produced in most gynecologic malignancies. Serum free beta-subunit or its urinary degradation product beta-core fragment is produced by 68% of ovarian, 51% of endometrial and 46% of cervical malignancies. Free beta-subunit enhances growth and invasion in all these malignancies leading to poor prognosis. Free beta-subunit and beta-core fragment are good tumor markers for these malignancies. There are few circumstances that create more confusion than the patient presenting with persistent low positive hCG results in the absence of pregnancy and absence of obvious malignancies. The series of hCG molecules as tumor markers will be reviewed to help the clinician best diagnose these often difficult clinical problems.

    Title Blood Test for Placental Site Trophoblastic Tumor and Nontrophoblastic Malignancy for Evaluating Patients with Low Positive Human Chorionic Gonadotropin Results.
    Date December 2008
    Journal The Journal of Reproductive Medicine
    Excerpt

    To examine utility of measurement of proportions of free beta-subunit of human chorionic gonadotropin (hCG) in diagnosis of placental site trophoblastic tumor (PSTT) and nontrophoblastic neoplasm in patients with persistent low hCG levels and patients with history of gestational trophoblastic diseases.

    Title Absence of Epidermal Growth Factor Receptor Mutations in Cervical Cancer.
    Date November 2008
    Journal International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society
    Excerpt

    Epidermal growth factor receptor (EGFR) is overexpressed in the majority of cervical cancers (CCs). Somatic mutations of EGFR have been associated with clinical response to tyrosine kinase inhibitors (TKIs) in lung cancer patients. This study was designed to establish the frequency of EGFR point mutations in patients diagnosed with high-grade squamous intraepithelial lesions (HSIL) and CC. Nine cell lines derived from CC were screened for EGFR mutations in exons 18 through 21. Eighty-nine patient samples derived from invasive CC (n = 80) and HSIL (n = 9) were analyzed for the presence of EGFR mutations in exons 19 and 21. We found no mutations affecting the EGFR kinase domain in exons 18 through 21 in all cell lines tested, and no EGFR mutations were detected in exons 19 and 21 in all 89 human neoplastic samples analyzed. These data indicate that mutations in the EGFR kinase domain are very rare in CC and HSIL. Our results suggest, therefore, that treatment of CC patients with TKIs may not have the same efficacy as seen in patients with lung cancer, and that targeting the EGFR with other inhibitors may be more appropriate.

    Title Detection of Perimenopause or Postmenopause Human Chorionic Gonadotropin: an Unnecessary Source of Alarm.
    Date April 2008
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    The normal pituitary production of human chorionic gonadotropin alongside luteinizing hormone, measurable in menopausal serum and urine was initially reported over 3 decades ago and has been described in numerous subsequent publications. Unfortunately, delays or cancellations of important medical procedures and use of needless chemotherapy still occurs because of the finding of human chorionic gonadotropin in perimenopausal and postmenopausal woman. We describe the problem and a concise approach to this management dilemma in menopausal women.

    Title Silencing of Hpv 18 Oncoproteins With Rna Interference Causes Growth Inhibition of Cervical Cancer Cells.
    Date September 2007
    Journal Reproductive Sciences (thousand Oaks, Calif.)
    Excerpt

    Silencing the expression of human papillomavirus (HPV) oncoproteins should have therapeutic benefits for cervical cancer. The authors' objective was to study RNA interference of the HPV 18 E6/E7 bicistronic mRNA with E6 small interfering RNA (siRNA) and E7 siRNA and determine the effect of each siRNA on oncoprotein expression, resultant cell growth, and downstream molecular effects. RNA interference was used to knockdown HPV 18 E6 and E7 oncoproteins on the HPV 18 positive cervical cancer cell lines HeLa and C4I. Western blotting was used to assay for each oncoprotein expression and select downstream molecular targets. Cell cycle analyses, cell viability assays, and colony formation assays were performed to determine the effect of treatment by both HPV 18 E6 siRNA and E7 siRNA. The transfection reagent oligofectamine and Tax siRNA were used as negative controls. Transfection with E6 siRNA caused complete loss of E6 but not E7 oncoprotein. However, E7 siRNA induced complete loss of both E6 and E7 oncoproteins. E6 siRNA mediated the reexpression of p53 protein and a moderate decrease in phosphorylated retinoblastoma protein expression (pRb), resulting in decreased colony formation. Transfection with E7 siRNA mediated a robust increase in p53 expression and complete loss of pRb, resulting in a marked decrease in colony formation compared to the E6 siRNA (P =.001). Flow cytometry revealed significantly increased apoptotic cells with E7 siRNA compared to E6 siRNA and control. RNA interference targeting the E7 portion of the bicistronic HPV 18 mRNA can silence both E6 and E7 oncoproteins and is most effective in cervical cancer growth inhibition.

    Title Normal Production of Human Chorionic Gonadotropin in Menopause.
    Date March 2007
    Journal The New England Journal of Medicine
    Title Gestational Trophoblastic Diseases: 2. Hyperglycosylated Hcg As a Reliable Marker of Active Neoplasia.
    Date August 2006
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVES: To determine whether circulating hyperglycosylated human chorionic gonadotropin (hCG-H), a promoter of choriocarcinoma growth and tumorigenesis, is a reliable marker of active gestational trophoblastic neoplasia (GTN) or choriocarcinoma, and whether hCG-H can consistently discriminate quiescent gestational trophoblastic disease (GTD) from neoplasia. METHODS: Patients were those referred to the USA hCG Reference Service for consultation. These included a total of 82 women with GTN, including 30 with histologic choriocarcinoma. They were compared with 26 patients with resolving hydatidiform mole and 69 with quiescent GTD (persistent positive low value of real hCG but no clinical evidence of disease). All were tested for total hCG and hCG-H. hCG-H was calculated as the percentage of total hCG (hCG-H(%)). RESULTS: We compared the utility of total hCG and hCG-H(%) in detecting active GTN and quiescent GTD. There was no significant difference when measuring total hCG (includes regular and hyperglycosylated hCG), between women with quiescent GTD and self-resolving hydatidiform mole compared to choriocarcinoma/GTN cases (P > 0.05 and P > 0.05). In contrast, hCG-H(%) was significantly higher in choriocarcinoma/GTN cases (P < 0.000001, and P < 0.000001). The usefulness of hCG and hCG-H(%) testing was assessed for discriminating between the 69 quiescent GTD cases, which required no therapy, and choriocarcinoma/GTN which need treatment. While hCG would detect 62% and 24% of malignancies at a 5% false positive rate, hCG-H(%) would detect 100% and 84% of malignancies at this same false positive rate. Follow-up data were received and repeat consultations were performed in 23 cases in which active disease was subsequently demonstrated. In 12 of 23 cases, hCG-H(%) results were able to first identify active disease 0.5 to 11 months prior to rapidly rising hCG or detection of clinically active neoplasia. In the remaining 11 cases, hCG-H(%) active disease appeared at the same time as rising hCG or demonstrable clinical tumor. DISCUSSION AND CONCLUSION: hCG-H(%) appears to reliably identify active trophoblastic malignancy. It is a 100% sensitive marker for discriminating quiescent GTD from active GTN/choriocarcinoma. It is also a marker for the early detection of new or recurrent GTN/choriocarcinoma. The data presented appear sufficient to encourage the adoption of hCG-H as a tumor marker in trophoblastic disease. Further studies are now urgently required to confirm and extend our findings.

    Title Gestational Trophoblastic Diseases: 4. Presentation with Persistent Low Positive Human Chorionic Gonadotropin Test Results.
    Date August 2006
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVES: A high proportion of women with persistent low levels of hCG, in the absence of pregnancy or any evidence of tumor, have received chemotherapy and hysterectomy for assumed malignancy. Such chemotherapy and surgery were ineffective and unwarranted. This study identifies the causes of persistent low level of hCG and provides guidelines for the management of these patients, preventing unnecessary treatment in the future. METHODS: The USA hCG Reference Service has consulted on 170 women with low levels of hCG persisting for 3 months or longer. Serum total hCG was measured in the Diagnostic Products Corporation (DPC) Immulite assay and hyperglycosylated hCG in the Nichols Advantage test. RESULTS: Among these 170 patients, the average persistent hCG result was 102 +/- 152 mIU/ml, with a range of 6.1-900 mIU/ml. Thirteen (7.6%) of the 170 patients had true malignancy, 5 had placental site trophoblastic tumor, 3 had other gestational trophoblastic neoplasms (GTN), and 5 had non-trophoblastic malignancies. The remaining 157 patients had false-positive hCG, quiescent gestational trophoblastic disease (quiescent GTD), or pituitary hCG (hCG of pituitary origin). Of 71 patients with false-positive hCG, 47 patients received chemotherapy and 9 had surgery that had no effect on the level of hCG. Five of these patients with false-positive hCG were being monitored for hydatidiform mole or GTN. The majority of these cases were first investigated following an incidental pregnancy test. Of 69 patients who had quiescent GTD, 41 received chemotherapy and 9 underwent hysterectomy. All these therapies were unnecessary and ineffective. While 21 patients with quiescent GTD followed incidental pregnancy tests, the majority were discovered while monitoring patients after treatment for hydatidiform mole or GTN/choriocarcinoma (n = 48). Seventeen cases of pituitary hCG were found among those women who were peri- or post-menopause. Two patients also received chemotherapy for assumed malignancy which was not present. CONCLUSION: Clinicians frequently assume that an elevated hCG implies that a patient is pregnant or has GTD or recurrent GTN, even when apart from the pregnancy test, no clinical evidence was found to support such a diagnosis. In most of these cases of persistent low hCG etiologies, all therapies were found unnecessary and ineffective. Guidelines are proposed for managing these patients. It is essential to demonstrate a malignancy clinically and with readily available biochemical tests before initiating therapy. This applies whether the patient is identified by an incidental pregnancy test or is actively being monitored for gestational trophoblastic disease.

    Title Gestational Trophoblastic Diseases: 3. Human Chorionic Gonadotropin-free Beta-subunit, a Reliable Marker of Placental Site Trophoblastic Tumors.
    Date August 2006
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVES: Placental site trophoblastic tumor (PSTT) commonly presents with low and variable concentration of hCG immunoreactivity in serum which can be difficult to differentiate from early stage choriocarcinoma/gestational trophoblastic neoplasm (GTN) or quiescent gestational trophoblastic disease (quiescent GTD). Nontrophoblastic malignancies such as germ cell tumors or other tumors secreting low hCG must also be considered in the differential diagnosis. Because treatments for these conditions are different, a means of differentiating PSTT from other diagnoses is important. We investigate the usefulness of hCG-free beta-subunit to make this discrimination. METHODS: Data collected on cases referred to the USA hCG Reference Service for consultation served as a basis for this retrospective analysis. There were 13 cases with histology proven PSTT and 12 with nontrophoblastic malignancy. hCG-free beta-subunit was measured by immunoassay and reported as a proportion of total hCG (hCG-free beta-subunit(%)). hCG-free beta-subunit(%) results were determined for all histologically proven cases of PSTT and for the nontrophoblastic malignancies. Comparisons of hCG-free beta-subunit(%) were made and compared with those of the 82 choriocarcinoma/GTN cases and 69 quiescent GTD cases. The accuracy of hCG-free beta-subunit(%) to discriminate these malignancies was analyzed by investigating the areas under receiver-operating characteristics curve +/- standard error. RESULTS: hCG-free beta-subunit(%) was the predominant hCG form in cases of PSTT (mean +/- standard deviation, 60 +/- 19%) and nontrophoblastic malignancies (91 +/- 11%), thus discriminating these diagnoses from choriocarcinoma/GTN (9.3 +/- 9.2%) and from quiescent GTD (5.4 +/- 7.8%). The cutoff of >35% free beta-subunit is proposed. At this cutoff, 100% detection at 0% false-positive is achieved. The accuracy of hCG-free beta-subunit(%) for this discrimination is 100 +/- 0%. At a proposed cutoff of >80%, the free beta-subunit test will also distinguish PSTT from nontrophoblastic malignancy, with 77% detection at 23% false-positive or an accuracy of 92 +/- 3.2%. CONCLUSION: Measurement of the proportion hCG-free beta-subunit(%) was found to be useful in the diagnosis of PSTT using proposed cutoff values of >35% and >80%. While this finding needs to be confirmed by larger studies, it would be reasonable to measure hCG-free beta-subunit(%) whenever the diagnosis of PSTT is considered.

    Title Incidence and Survival Rates for Female Malignant Germ Cell Tumors.
    Date June 2006
    Journal Obstetrics and Gynecology
    Excerpt

    To evaluate 30-year, population-based trends in incidence and survival rates for malignant germ cell tumors originating within the female genital tract.

    Title A Case-control Study of Methylenetetrahydrofolate Reductase Polymorphisms in Cervical Carcinogenesis.
    Date June 2006
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVES: Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene are thought to be associated with a varying risk of cervical dysplasia. The purpose of this trial was to study the role of the two common functional MHTFR polymorphisms in a large multiracial population at risk for cervical dysplasia and cancer. METHODS: This is a nested case-control study of 376 subjects obtained from cohorts enrolled in an ongoing prospective cervical carcinogenesis protocol. Cases included invasive cancers (n = 51), and high (n = 50) and low (n = 50) grade dysplasia. There were 225 normal controls. Functional MTHFR 677C-->T and 1298A-->C genotypes were identified. Follow-up cytology data were reviewed for the control subjects from the time of study entry until August 2004. RESULTS: There is a significant racial difference in allele frequency of the 677C-->T polymorphism (P < 0.005). African-American women had an extremely low prevalence of the 677T allele (8%). There was no significant difference in the frequency of the 677T allele between cases and controls. There is no racial difference in allele frequency of the 1298A-->C polymorphism. Also, no significant difference was found between cases and controls. Of the 51 cancers, no case was homozygous for both aberrant polymorphisms (677T, 1298C), and only 3 cases were heterozygous for both. Follow-up data were available for 129 of 225 control subjects (57%). Only 15 (12%) have had a subsequent abnormal pap, and there was no association with the 677C-->T polymorphism. CONCLUSIONS: We confirm a significant difference in the 677T allele frequencies among racial groups. However, there is no association of either the 677C-->T or 1298A-->C polymorphisms in cervical carcinogenesis. There is no role of the combined polymorphism effect in cervical cancer or evidence of prediction for future Pap abnormalities.

    Title Immunohistochemical Evaluation of Heat Shock Proteins in Normal and Preinvasive Lesions of the Cervix.
    Date January 2006
    Journal Cancer Letters
    Excerpt

    Heat Shock Proteins (HSPs) are molecular chaperons with multiple functions relating to cellular homeostasis. Primary, HSPs are expressed in response to cellular stresses that may also include carcinogenesis. Patterns of expression have not been extensively evaluated in the multi-step carcinogenesis of cervical cancer (Normal --> HPV infection --> Cervical Precancer --> Cancer). We evaluated the expression of HSP40, HSP60, HSP70, and HSP90 in normal tissues (N=30), in cervical intraepithelial neoplasia grade 1 (CIN1)(synonymous with productive HPV infections) (N=32), and in CIN3 (cervical precancer)(N=25) by immunohistochemistry staining (graded 0-3) and compared the results to p16INK4a, a biomarker of oncogenic HPV infections and CIN3. We found strong patterns of increased HSP40, HSP60, and HSP70 immunostaining with increasing severity of the lesion in a manner similar to p16INK4a (P(Trend)<0.0005). No difference in staining intensity by grade of lesion was observed for HSP90 (P(Trend)=0.8). Tissue patterns in CIN3 of diffuse immunostaining for HSP40 and HSP70 were analogous to those observed for p16INK4a; HSP60 immunostaining appeared more punctate within cells than for other antigens although similar tissue patterns were observed. We conclude that HSP40, HSP60, and HSP70 expressions are up-regulated in response to the development of CIN3 akin to p16INK4a expression.

    Title Understanding the Mechanisms of Fhit Inactivation in Cervical Cancer for Biomarker Development.
    Date March 2005
    Journal Journal of the Society for Gynecologic Investigation
    Excerpt

    OBJECTIVE: Loss of the fragile histidine triad (Fhit) protein has been documented in cervical cancer and dysplasia. The goal of this study was to confirm the utility of homozygous deletions, aberrant methylation, and immunohistochemical evaluations of FHIT as functionally relevant determinants of FHIT expression. METHODS: We studied matched DNA, RNA, and protein from nine early-passage cervical cancer cell lines. DNA markers spanning FHIT were used to examine the extent of homozygous deletions for each cell line. 5 CpG island methylation of FHIT was investigated by methylation-specific polymerase chain reaction (PCR) assays. FHIT transcripts were characterized by reverse transcriptase (RT)-PCR. Western blot analysis and immunohistochemistry were performed to characterize Fhit protein expression. RESULTS: Homozygous deletions were found in six of nine cervical cancer cell lines, but only one had homozygous deletions involving an exon. All nine lines had both methylated and unmethylated alleles according to methylation-specific PCR. Loss of wild-type FHIT transcripts were found in five of nine lines. By western blot analysis, Fhit protein expression was lost in five of nine lines, producing an exact correlation with RT-PCR results. Immunohistochemical staining was concordant with Fhit protein expression by western blotting in eight of nine cell lines. CONCLUSION: A perfect correlation was found between FHIT mRNA expression and western blot analysis. Assays for Fhit protein expression and large FHIT homozygous deletions are representative biomarkers of Fhit expression. By contrast, the aberrant methylation assay is not concordant with FHIT gene expression, and we suggest caution in its use as a functionally relevant biomarker for cervical cancer.

    Title Brcapap: Feasibility of Clinical Brca Testing on Liquid-based Cervical Cytology: Implications for Biomarker Development.
    Date February 2005
    Journal Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology
    Excerpt

    OBJECTIVE: The study was designed to test the feasibility that lower genital tract cytology is a compatible medium for robust germ line genetic analyses. METHOD: BRCA1 and/or BRCA2 gene mutational analysis was done on DNA isolated from liquid-based cervical or vaginal cytology taken from 17 consenting women (age 29-65 years) who previously had genetic counseling followed by BRACAnalysis (Myriad Genetics, Salt Lake City, UT) blood analyses. Eleven women had known mutations in either BRCA1 or BRCA2 (cases) and six had no identified mutations (controls) on entry into the study. Anonymized cytology samples were sent to Myriad Genetics with a request for testing that was limited to the degree of genomic testing previously done on the blood samples. RESULTS: One cervicovaginal specimen from a test-positive woman had inadequate cellular content that precluded gene sequencing and therefore was excluded from this analysis. For the 16 women with adequate cytologic specimens, there was 100% concordance for BRCA mutation test results between blood and genital tract cytology (kappa = 1.0; 95% confidence interval, 0.51-1.0). CONCLUSION: We have shown the feasibility of using liquid-based genital tract cytology as an alternative biospecimen to blood for germ line genetic analysis using a clinical approved assay. It needs to be emphasized that any type of testing for BRCA1 or BRCA2 mutation genotype should only be done in the setting of pretest and posttest counseling.

    Title The Miracle of Life and Privilege of Death.
    Date July 2004
    Journal Obstetrics and Gynecology
    Title Ccnd1 Polymorphism and Age of Onset of Hepatoblastoma.
    Date June 2004
    Journal Oncogene
    Excerpt

    Cyclin D1, encoded by the gene CCND1, is a major regulator of the cell cycle transition from G1 phase to S phase. A CCND1 polymorphism (G to A) at codon 242, the boundary of exon 4 and intron 4, affects splicing such that exon 5 is not expressed in the A allele. Since exon 5 is involved in rapid turnover, the variant cyclin D1 corresponding to the A allele may have a longer half-life. A previous study demonstrated that in families with hereditary nonpolyposis colorectal cancer, the age of onset of colorectal cancer varied according to variation at this polymorphic site. We examined this CCND1polymorphism in a series hepatoblastoma, a childhood liver cancer that shares other molecular features with colon cancer. We determined in an analysis of 84 children with hepatoblastoma that the G/A exon 4 polymorphism in CCND1 is correlated with the age of onset of hepatoblastomas. The A/A genotype is associated with an earlier age of onset compared to the G/A or G/G genotype. The median age of patients with the G/G genotype was 22 months, compared to 17 months in patients with the G/A genotype and 11 months for the A/A genotype. These findings suggest that the CCND1 A polymorphism may contribute to tumor development in children with hepatoblastoma.

    Title Aberrant P16 Methylation is a Biomarker for Tobacco Exposure in Cervical Squamous Cell Carcinogenesis.
    Date April 2004
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: The purpose of this study was to determine the association between active tobacco exposure and aberrant p16 promoter methylation in primary cervical squamous cell cancer and high-grade squamous cervical dysplasia. STUDY DESIGN: p16 methylation-specific polymerase chain reaction was performed on DNA that was extracted from 60 cervical cancers, 30 high-grade dysplasia specimens, and 78 normal cervical cytologic specimens. Patient data were obtained by medical record review or were collected prospectively. RESULTS: Aberrant p16 methylation was significantly higher in squamous cell cervical cancers (61%) than in squamous high-grade dysplasia (20%) or normal cytologic specimens (7.5%). Approximately one half the women with squamous cancer and one half of the women with high-grade dysplasia were active smokers. Aberrant p16 methylation was associated with active tobacco use in patients with squamous carcinoma (odds ratio, 20.6; 95% CI, 3.6-118; P<.001) and high-grade dysplasia (odds ratio, 4.57; 95% CI, 1.63-12.78; P=.002). CONCLUSION: Aberrant p16 methylation is associated strongly with active tobacco use in squamous cell cervical cancers and high-grade dysplasia.

    Title Adequacy of Oophorectomy at the Time of Gynecologic Surgery.
    Date July 2002
    Journal International Journal of Gynaecology and Obstetrics: the Official Organ of the International Federation of Gynaecology and Obstetrics
    Excerpt

    OBJECTIVES: To determine the incidence of incomplete ovarian removal during gynecologic surgery and correlate the risk of inadequate removal with the procedure chosen. METHODS: This is a prospective observational study. Ovaries received during a 4-month period in the participating institutions were independently histologically evaluated. Gross inspection of the ovarian capsule, infundibulopelvic ligament, hilum and utero-ovarian ligament was assessed. Grossly close margins were confirmed histopathologically. Any margin with histologically confirmed ovarian tissue at the margin was interpreted as incompletely removed. Details of each surgical procedure were recorded for comparison. RESULTS: Ovaries (n=174) from 94 patients were collected and 155 were evaluable. The overall incidence of incomplete ovarian removal was 6.5%. Of the 125 ovaries removed abdominally, 23 were laparoscopically assisted and 7 were vaginal; inadequate removal was documented in 5%, 9% and 29%, respectively (P=0.04). There was no relationship of inadequate resection by underlying pathologic diagnosis (P=0.25) or by institution (4.6% university hospital vs. 8.8% community hospital; P=0.29). CONCLUSIONS: Incomplete ovarian removal occurs and is related to surgical approach. A larger study is warranted to evaluate the role of pelvic pathology or surgeon experience as a risk for incomplete oophorectomy.

    Title Germline Brca1-2 Mutations in Non-ashkenazi Families with Double Primary Breast and Ovarian Cancer.
    Date December 2001
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVE: Ashkenazi women with double primary breast and ovarian cancer have a high prevalence (57%) of germline Jewish founder mutations in the BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT) genes. The purpose of this study was to determine the frequency and type of BRCA1-2 mutations in non-Ashkenazi families with at least one member having double primary breast and ovarian cancer. METHODS: Women at increased risk for cancer based upon their family history were enrolled at the University of Texas Southwestern Familial Cancer Registry between 1992 and 2000. Blood samples from patients desiring genetic testing were sent for complete DNA sequencing of the BRCA1 and BRCA2 genes. Families with a member having both breast and ovarian cancer were identified and clinical data were obtained. RESULTS: Sixty-two (7%) of 900 enrolled families were non-Ashkenazi and had at least one member with double primary breast and ovarian cancer. Twenty-one families had members who underwent genetic testing; 41 did not. Thirteen (62%) families had a germline BRCA1 (n = 11) or BRCA2 (n = 2) mutation; only one Jewish founder mutation (185delAG) was detected. Eight (38%) families tested negative. Six (86%) of seven women undergoing genetic testing who themselves had double primary breast and ovarian cancer were BRCA1-2 mutation carriers. CONCLUSIONS: Germline BRCA1-2 mutations are common in non-Ashkenazi families with a member having double primary breast and ovarian cancer. These mutations occurred throughout both genes, emphasizing the need for comprehensive sequencing. One family had the BRCA2 6985delCT mutation, which lies beyond the "ovarian cancer cluster" region.

    Title Searching for Microsatellite Mutations in Coding Regions in Lung, Breast, Ovarian and Colorectal Cancers.
    Date May 2001
    Journal Oncogene
    Excerpt

    RepX represents a new informatics approach to probe the UniGene database for potentially polymorphic repeat sequences in the open reading frame (ORF) of genes, 56% of which were found to be actually polymorphic. We now have performed mutational analysis of 17 such sites in genes not found to be polymorphic (<0.03 frequency) in a large panel of human cancer genomic DNAs derived from 31 lung, 21 breast, seven ovarian, 21 (13 microsatellite instability (MSI)+ and eight MSI-) colorectal cancer cell lines. In the lung, breast and ovarian tumor DNAs we found no mutations (<0.03-0.04 rate of tumor associated open reading frame mutations) in these sequences. By contrast, 18 MSI+ colorectal cancers (13 cancer cell lines and five primary tumors) with mismatch repair defects exhibited six mutations in three of the 17 genes (SREBP-2, TAN-1, GR6) (P<0.000003 compared to all other cancers tested). We conclude that coding region microsatellite alterations are rare in lung, breast, ovarian carcinomas and MSI (-) colorectal cancers, but are relatively frequent in MSI (+) colorectal cancers with mismatch repair deficits.

    Title Intraoperative Lymphatic Mapping in Cervix Cancer Patients Undergoing Radical Hysterectomy: A Pilot Study.
    Date November 2000
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVE: Intraoperative lymphatic mapping and sentinel lymph node identification (SLN) have been increasingly evaluated in the treatment of a variety of solid tumors, particularly breast cancer and melanoma. We sought to evaluate the feasibility of these procedures in patients undergoing radical hysterectomy with pelvic lymphadenectomy for treatment of early cervical cancer. METHODS: Twenty patients with normal-appearing lymph nodes underwent intracervical injection of isosulfan blue dye (lymphazurin 1%) at the time of planned radical hysterectomy and bilateral pelvic/low paraortic lymphadenectomy (40 nodal basins). Regional lymphatic tissue was inspected for dye uptake into lymphatic channels and lymph nodes. Tumor characteristics, surgical findings, and specific locations of lymphatic dye uptake were recorded and correlated with final pathology results. RESULTS: Sentinel lymph nodes were identified in 12 of 20 (60%) patients. A total of 23 sentinel nodes were identified in 17 of 40 (43%) nodal basins dissected (range: 0-2 per basin). Successful SLN identification was less likely in patients with tumors >4 cm compared with those with tumors </=4 cm (P = 0.035). Of 4 patients with metastatic nodal disease, 3 had tumor involving a SLN; the fourth had no identifiable SLN (inadequate study). In all, 3 of 8 lymph nodes with confirmed metastatic disease were identified using this technique. CONCLUSION: SLN identification and intraoperative lymphatic mapping are feasible and safe. Lymphatic dye uptake appears to be less reliable in patients with larger tumors. Although sentinel node pathology was representative of the lymphatic basin sampled in all cases, the rate of SLN identification was low with this technique. Lymphatic mapping procedures should be further investigated in the treatment of early cervix cancer.

    Title Chromosome 4 Deletions Are Frequent in Invasive Cervical Cancer and Differ Between Histologic Variants.
    Date October 2000
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVE: Patterns of discontinuous deletion of chromosome 4 have been described in histologic variants of lung carcinomas and may represent different "hotspot" targets for gene-environment interactions. Since similar environmental risks exist for cervical cancer, we investigated patterns of discontinuous deletion in two major histologic variants. METHODS: Thirteen archival cases of squamous cell cancer (SCCA) and 11 cases of adenocarcinoma (AC) were precisely microdissected. Matched normal and tumor DNA were used for polymerase chain reaction (PCR) based loss of heterozygosity (LOH) analyses using 19 polymorphic markers spanning chromosome 4. Human papillomavirus (HPV) detection was determined by PCR using general and type-specific primers (HPV 16, 18). Differences in LOH between histologic tumor types and chromosomal regions were determined using Fisher's exact test. RESULTS: Loss at any chromosome 4 locus occurred in 92% of all tumors studied, with the majority of deletions occurring on the long arm of the chromosome. Four discrete minimal regions of discontinuous deletion (R) were identified. For these regions, LOH frequencies were 76% (R1, 4q34-q35), 48% (R2, 4q25-q26), 36% (R3, 4p15.1-p15.3), and 26% (R4, 4p16). Loss in SCCA predominated at 4q (4q34-q35; 83%) and in AC at 4p (4p15.3; 50%). Overall LOH on the p arm was significant in AC (82%) compared to SCCA (31%) (P = 0.02). HPV detection was similar in SCCA (85%) and AC (73%), and HPV 16/18 subtypes were similarly represented in both histologies. CONCLUSIONS: Chromosome 4 deletions are frequent in cervical carcinomas. Different patterns of deletion between SCCA and AC may represent gene regions targeted by different gene-environment interactions in these tumor subtypes.

    Title Molecular Papanicolaou Tests in the Twenty-first Century: Molecular Analyses with Fluid-based Papanicolaou Technology.
    Date August 2000
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: This study was undertaken to demonstrate the feasibility of performing molecular analyses at the deoxyribonucleic acid, ribonucleic acid and protein levels of cervical cytologic examination with a methanol fluid-based Papanicolaou specimen collection system. STUDY DESIGN: Genomic deoxyribonucleic acid and total ribonucleic acid were extracted from cell pellets obtained from the residual fluid-based Papanicolaou specimen collection buffer after clinical processing. Genomic and human papillomavirus deoxyribonucleic acid polymerase chain reaction and reverse transcriptase-polymerase chain reaction were performed. Messenger ribonucleic acid transcript analysis and human papillomavirus 16 E6 mutational analysis were also performed. Methylation-specific polymerase chain reaction was used to evaluate hypermethylation status of the p16 gene and the gene for E-cadherin. Immunohistochemical staining for protein expression was performed on the processed monolayer slides. RESULTS: Cell pellets from the residual fluid-based cytologic specimen yielded good quality deoxyribonucleic acid and ribonucleic acid. Molecular analyses of genomic deoxyribonucleic acid were successful for the identification of human papillomavirus E6 and p53 polymorphism status by means of restriction enzyme digestion and direct sequencing. Methylation status of the promotor regions of the p16 tumor suppressor gene and the gene for E-cadherin were also successfully identified. Ribonucleic acid was used as the template for transcript analysis and mutational analysis of the corresponding complementary deoxyribonucleic acid of the p53 gene. Protein expression analysis was demonstrated by immunohistochemical staining for carcinoembryonic antigen. CONCLUSION: It is feasible to conduct multiple molecular analyses at the deoxyribonucleic acid, ribonucleic acid, and protein levels of the cervicovaginal cell pellets from the residual fluid-based Papanicolaou cytologic specimen. This relatively simple and widely used collection system will allow significant advances in molecular epidemiology and eventual development of a molecular Papanicolaou test.

    Title Allelic Loss and Microsatellite Alterations of Chromosome 3p14.2 Are More Frequent in Recurrent Cervical Dysplasias.
    Date August 2000
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    Epidemiological studies have documented the unpredictable clinical progression or recurrence of cervical dysplasia. Recent studies have shown several molecular changes in cervical cancers and their associated dysplasia. We conducted molecular analyses on a retrospectively ascertained cohort of recurrent and nonrecurrent cervical dysplasia cases in an attempt to define molecular biomarkers to predict progressive or recurrent disease. Cases were chosen if long-term follow-up (3-5 years after conization) and biopsy confirmation were available. Paraffin-embedded, postconization cervical tissues from 19 recurrent and 18 nonrecurrent dysplasias were analyzed. Human papillomavirus (HPV) was identified by PCR for general and type-specific (HPV-16 and HPV-18) primers. Allelotyping analysis was performed by multiplex PCR using a panel of 16 microsatellite markers targeting putative tumor suppressor gene regions on chromosomes 3p, 5p, 6p, 9p, 11q, and 17p. The overall rate of HPV infection was similar in both groups. In the allelotyping analysis, loss of heterozygosity at the fragile histidine triad region in 3p14.2 was significantly higher in the recurrent group than in the nonrecurrent group (P = 0.005). Furthermore, microsatellite alterations (MAs) were more frequent in the recurrent group (mean MA index, 0.254) as compared with the nonrecurrent group (mean MA index, 0.085; P = 0.0025). These findings suggest that HPV status alone does not predict recurrence and that loss of heterozygos. ity at the fragile histidine triad region may represent a potential biomarker in predicting recurrence. Frequent MAs in the recurrent group may represent an underlying genomic instability that creates susceptibility for allelic loss, thus increasing the risk for recurrence or progression.

    Title Laparoscopy in Patients Following Transverse Rectus Abdominis Myocutaneous Flap Reconstruction.
    Date August 2000
    Journal Obstetrics and Gynecology
    Excerpt

    We report our technique and experience performing laparoscopic pelvic surgery on four women after transverse abdominus rectus myocutaneous flap (TRAM).

    Title Ectopic Production and Localization of Beta-human Chorionic Gonadotropin in Lymphoepithelioma-like Carcinoma of the Cervix: a Case Report.
    Date June 2000
    Journal International Journal of Gynecological Pathology : Official Journal of the International Society of Gynecological Pathologists
    Excerpt

    A 32-year-old woman underwent a suction curettage for missed abortion. The initial serum human chorionic gonadotropin (beta-hCG) level was 40 IU/ml. The histologic examination of the uterine curettage specimen showed scant strips of a poorly differentiated malignant neoplasm and no chorionic villi. The tumor showed strong immunoreactivity for cytokeratin (AE1/AE3) and beta-hCG but no reactivity for human placental lactogen. The combination of histologic appearance, beta-hCG immunoreactivity, and elevation of serum beta-hCG raised a strong suspicion for epithelioid trophoblastic tumor (ETT). Postcurettage serial serum beta-hCG levels remained in the range of 20 to 45 micrograms/ml. Computerized tomographic scan showed a 1.0-cm circumscribed mass in the upper endocervix. A radical hysterectomy and pelvic lymphadenectomy were performed. Gross examination of the hysterectomy specimen likewise showed a well-circumscribed mass in the upper endocervix. Histologic examination revealed an undifferentiated carcinoma accompanied by intense lymphoplasmacytic infiltrate. A final diagnosis of lymphoepithelioma-like carcinoma (LELC) was rendered. LELC with elevated serum beta-hCG level and immunoreactivity to beta-hCG should be distinguished from ETT in a small endocervical curettage sample.

    Title Role of Tsg101 in Uterine Cervix Cancer.
    Date January 2000
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVE: TSG101 was first described as a possible tumor suppressor gene in breast cancer. To determine whether TSG101 might play a role in cervical carcinogenesis, we examined a panel of cervical cancer cell lines and primary tumor specimens for transcript abnormalities and mutations in TSG101. METHODS: Total RNA was derived from cell line cultures or primary tumor specimens. We performed nested reverse transcription polymerase chain reaction (RT-PCR) with eight overlapping primer sets, followed by single-strand conformational polymorphism (SSCP) analysis, to screen for mutations in the TSG101 open reading frame. Representative normal and shifted SSCP bands were sequenced. To identify abnormal-sized transcripts, we performed RT-PCR with primers flanking the open reading frame followed by gel electrophoresis. RESULTS: Mutational analysis was performed on cDNAs from 20 primary cervical tumors and 8 cervical carcinoma cell lines. Two polymorphisms were identified, neither of which resulted in an altered amino acid sequence. Transcript analysis was performed on a subset of 16 primary cervix tumors and 6 cervix carcinoma cell lines. The wild-type transcript (1228 bp) was the dominant transcript expressed in all samples. A transcript measuring 330 bp was detected in 5 of 6 cell lines and 11 of 16 primary tumor specimens. CONCLUSION: Our results suggest that mutations in TSG101 rarely occur in carcinomas of the uterine cervix. However, the presence of minor aberrant TSG101 transcripts is a common feature. The relationship between aberrant transcription and carcinogenesis should be further investigated.

    Title Frequent Expression of Beta-human Chorionic Gonadotropin (beta-hcg) in Squamous Cell Carcinoma of the Cervix.
    Date December 1999
    Journal International Journal of Gynecological Pathology : Official Journal of the International Society of Gynecological Pathologists
    Excerpt

    Human chorionic gonadotropin (beta-hCG) has been detected within tissue homogenates, culture fluid, and sera of patients with squamous cell carcinoma of the cervix. Studies regarding in vivo localization of beta-hCG in squamous cell carcinoma of the cervix are scant and conflicting. Cervical samplings (biopsy and/or curettage specimens) of 63 cases of poorly differentiated invasive squamous cell carcinoma of the cervix were initially stained by the immunoperoxidase technique for the presence of beta-hCG and human placental lactogen (hPL). Based on beta-hCG reactivity, patients were divided into beta-hCG-positive and beta-hCG-negative groups. Thirty-three of the 63 (52%) cases showed localization of beta-hCG in tumor cells. Subsequent specimens of patients, who underwent surgical treatment, were likewise examined for beta-hCG reactivity. These surgical specimens showed focal beta-hCG reactivity in the beta-hCG-positive group only. The beta-hCG reactivity was seen in both high-grade SIL (CIN III), invasive squamous cell carcinoma, and its metastases. The focal beta-hCG reactivity was predominantly confined to the peripheral tumor cells at the stromal-epithelial interface in noninvasive and invasive lesions. Intensity of immunostaining was moderate to strong. The beta-hCG staining was observed in different cancer stages and in various age groups. No hPL reactivity was seen in any cases. Poorly differentiated squamous cell carcinoma of uterine cervix showing immunoreactivity for beta-hCG should be distinguished from choriocarcinoma and other trophoblastic tumors.

    Title Genetic Changes During the Multistage Pathogenesis of Human Papillomavirus Positive and Negative Vulvar Carcinomas.
    Date October 1999
    Journal Journal of the Society for Gynecologic Investigation
    Excerpt

    OBJECTIVE: To identify the molecular alterations found in 30 human papillomavirus (HPV) positive (n = 15) and negative (n = 15) vulvar carcinomas (VC) and their associated preinvasive lesions (VIN [vulvar intraepithelial neoplasia]) and normal epithelium to determine a common molecular pathogenesis of HPV positive and negative VC. METHODS: Loss of heterozygosity (LOH) at seven 3p chromosomal regions (3p12, 3p14.2, 3p14.3-21.1, 3p21.3, 3p22-24, 3p24.3, 3p25), 13q14 (RB) and 17p13.1 (p53) loci, and TP53 gene mutations in microdissected archival tissues were investigated. RESULTS: Fourteen of fifteen HPV positive VC had HPV 16 DNA sequences. The fractional regional loss index (FRL), an index of total allelic loss at all chromosomal regions analyzed, was greater in the HPV negative VCs than in the HPV positive tumors (FRL = 0.55 versus 0.32; P = .048) and was also greater in the HPV negative high-grade VINs as compared with the HPV positive lesions (0.29 versus 0.02; P = .002). Overall, LOH at any 3p region was frequent (80%) in both groups of cancers and in their associated VIN lesions. Although TP53 gene mutations were present in a minority of VCs (20%), allelic losses at the TP53 locus were frequently present, especially in HPV negative VCs, as compared with the HPV positive tumors (62% versus 15%; P = .02). CONCLUSION: A greater number of molecular alterations are found in HPV negative VCs compared with HPV positive tumors. Allelic losses at 3p are common early events in vulvar carcinogenesis in HPV negative cancers detected at a high rate in the corresponding high-grade precursor lesions (VIN II/III). TP53 gene mutations with associated 17p13.1 LOH are more common in HPV negative cancers.

    Title Comparison of Molecular Changes in Cervical Intraepithelial Neoplasia in Hiv-positive and Hiv-indeterminate Subjects.
    Date October 1999
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVE: HIV infection is associated with an increased incidence of cervical malignancy and its precursor lesions (CIN, cervical intraepithelial neoplasia) compared with the general population. We studied the molecular abnormalities in the development of HIV-associated CIN and compared them with those present in CINs arising in HIV-indeterminate subjects ("sporadic CIN"). METHODS: We investigated the presence of human papilloma virus (HPV) sequences, loss of heterozygosity (LOH), and microsatellite alterations (MAs) at five 3p chromosomal regions using 17 polymorphic markers in precisely microdissected archival tissues from 16 HIV-positive CINs and compared them with those present in 39 sporadic CINs. RESULTS: HPV sequences were detected in 36 of 55 (66%) CIN lesions, and high-risk oncogenic strains (HPV 16 and 18) accounted for 15 of them. No differences in the HPV frequencies were found between HIV-associated and sporadic CINs. Allelic losses at one or more chromosome 3p regions were frequently detected in CIN lesions (49%). The overall frequency of 3p LOH and the frequencies at all individual regions were similar in HIV-associated and sporadic CINs. The frequency of MA present in the HIV-associated CIN cases (0.093) was sixfold greater than in sporadic CINs (0.014; P = 0.0001). At least 1 MA was present in 11 (69%) of 16 HIV-associated vs. 5 of 39 (13%) sporadic CIN (P = 0.0006). Molecular changes were independent of the presence of HPV sequences. CONCLUSION: Chromosome 3p deletions are frequently detected in the precursor lesions of cervical carcinoma (CIN) and there are no differences in the 3p LOH frequencies between HIV-associated and sporadic CIN lesions. Microsatellite alterations, which reflect widespread genomic instability, occur at greatly increased frequency in HIV-associated CIN. Although the mechanism underlying the development of increased MAs is unknown, it may play a crucial role in the development of many HIV-associated neoplasias.

    Title Loss of Heterozygosity and Mutational Analysis of the Pten/mmac1 Gene in Synchronous Endometrial and Ovarian Carcinomas.
    Date February 1999
    Journal Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
    Excerpt

    Mutations of the human putative protein tyrosine phosphatase (PTEN/MMAC1) gene at chromosome 10q23 have been found frequently in type I endometrial carcinomas. Endometrioid adenocarcinoma is the most frequent histology seen in patients with clinically determined synchronous endometrial and ovarian carcinomas. We report a high incidence of PTEN/MMAC1 mutations and 10q23 loss of heterozygosity (LOH) in patients with synchronous endometrial and ovarian carcinomas. Paraffin-embedded precision microdissected tumors were analyzed for 10 matched synchronous endometrial and ovarian cancers and 11 matched control metastatic endometrial cancers. Single-stranded conformation polymorphism analysis was used to screen for mutations in all tumors and corresponding normal lymphocyte DNA. LOH was determined using a panel of four microsatellite markers within the PTEN/MMAC1 locus. PTEN/MMAC1 mutations were found in 43% (9 of 21) of the endometrial cancers studied, similarly represented in the clinically synchronous group (5 of 10 or 50%) and the advanced metastatic group (4 of 11; 36%; P = 0.53). In two of the five cases of clinically synchronous cancers, identical or progressive PTEN mutations were found in both the endometrial and ovarian cancers, suggesting that the ovarian tumor is a metastasis from the endometrial primary. PTEN/MMAC1 mutations in the advanced endometrial cancers were similar in the corresponding metastases. In one case, the mutation was seen in only one of two metastatic lymph nodes. The LOH analysis demonstrated 55% LOH in at least one PTEN/MMAC1 marker. These findings suggest that the putative tumor suppressor gene PTEN/MMAC1 may be a viable molecular marker to differentiate synchronous versus metastatic disease in a subset of clinically synchronous endometrial and ovarian carcinomas.

    Title In Vivo Studies of Adenovirus-based P53 Gene Therapy for Ovarian Cancer.
    Date July 1998
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVES: To test the safety, efficacy, and toxicity of gene therapy using wild-type p53-expressing adenovirus (Ad-CMV-p53) in a nude mouse model with intraperitoneal (i.p.) 2774 human ovarian cancer cell line that contains a p53 mutation. STUDY DESIGN: An initial study of adenovirus tolerance was determined in nude mice by a single i.p. injection of increasing doses of Ad-CMV-p53. Nude mice were implanted with an LD100 dose of 1 x 10(7) cells. To study the efficacy and specificity of Ad-CMV-p53 treatment, the mice received treatment with different adenovirus constructs. One group received Ad-CMV-p53 and another group received a control adenovirus construct, Ad-CMV-beta gal. To study the treatment response to Ad-CMV-p53, the mice were divided into groups and received various treatment schedules of 1 x 10(8) pfu of Ad-CMV-p53. RESULTS: The mice tolerated Ad-CMV-p53 without adverse effects at doses of 1 x 10(8) pfu. The response to Ad-CMV-p53 showed significant survival duration in each dose regimen, with a survival time greater than that of untreated animals (P = 0.0173). However, no statistically significant survival advantage was observed between Ad-CMV-p53- and Ad-CMV-beta gal-treated mice. CONCLUSIONS: These studies show that at the adenovirus dose and administration regimen used, there is effective but not specific 2774 tumor growth inhibition in vivo. Efficient introduction of biologically active genes into tumor cells would greatly facilitate cancer therapy. Thus, although promising, these results caution that much effort will be required to realize the potential for clinical application of adenovirus-based ovarian cancer gene therapy.

    Title Abnormalities of Fragile Histidine Triad Genomic and Complementary Dnas in Cervical Cancer: Association with Human Papillomavirus Type.
    Date March 1998
    Journal Journal of the National Cancer Institute
    Excerpt

    BACKGROUND: Chromosome 3p14.2 contains FRA3B, the most active chromosome breakage site in the human genome. The fragile histidine triad (FHIT) gene, a putative tumor suppressor gene, overlaps FRA3B. Human papillomavirus (HPV), a known cofactor in cervical carcinogenesis, can integrate into FRA3B. We examined abnormalities in FHIT and its RNA transcripts in cervical cancer cell lines and tumors. We also investigated the relationship between loss of heterozygosity (LOH) in FHIT/FRA3B and the presence of oncogenic HPV types. METHODS: Eleven cell lines, 40 tumors (20 fresh and 20 archival), and 10 normal cervical epithelia were examined. Two intragenic polymorphic markers (D3S1300 and D3S4103) and the polymerase chain reaction (PCR) were used to examine FHIT LOH. Reverse transcription-PCR (RT-PCR) analysis and single-strand conformation polymorphism analysis of RT-PCR products were used to characterize FHIT transcripts. Oncogenic HPV types were identified by PCR, using general and type-specific primers. RESULTS: All normal epithelia, 19 of 20 fresh tumors and nine of 11 cell lines expressed wild-type and, occasionally, exon 8-deleted FHIT transcripts. Additional aberrant FHIT transcripts were seen in nine of 20 fresh tumors and in seven of 11 cell lines. DNA sequencing of the aberrant transcripts revealed a variety of insertions and deletions but no point mutations. Three cell lines also had homozygous FHIT deletions. Oncogenic HPV types (i.e., 16, 18, 31, and 33) were detected in 18 of 20 archival tumors, and, in these tumors, LOH within FHIT was identified in nine of 16 informative cases. HPV 16 was found to be associated with LOH in the FHIT/FRA3B region (P = .041). CONCLUSION: FHIT/FRA3B is frequently altered in cervical cancer, demonstrating LOH, occasional homozygous deletions, and frequent aberrant transcripts not found in normal epithelia. However, the presence of wild-type transcripts and the lack of protein-altering point mutations raise questions about FHIT's function as a classic tumor suppressor gene in cervical tissue.

    Title Mutations in the Brca1-associated Ring Domain (bard1) Gene in Primary Breast, Ovarian and Uterine Cancers.
    Date March 1998
    Journal Human Molecular Genetics
    Excerpt

    Germline alterations of BRCA1 result in susceptibility to breast and ovarian cancer. The protein encoded by BRCA1 interacts in vivo with the BRCA1-associated RING domain (BARD1) protein. Accordingly, BARD1 is likely to be a critical factor in BRCA1-mediated tumor suppression and may also serve as a target for tumorigenic lesions in some human cancers. We have now determined the genomic structure of BARD1 and performed a mutational analysis of 58 ovarian tumors, 50 breast tumors and 60 uterine tumors. Seven polymorphisms were detected within the 2.34 kb coding sequence of BARD1 . Somatically acquired missense mutations were observed in one breast carcinoma and one endometrial tumor; in at least one of these cases, tumor formation was accompanied by loss of the wild-type BARD1 allele, following the paradigm for known tumor suppressor genes. In addition, a germline alteration of BARD1 was identified in a clear cell ovarian tumor (Gln564His); again, loss of the wild-type BARD1 allele was observed in the malignant cells of this patient. The Gln564His patient was also diagnosed with two other primary cancers: a synchronous lobular breast carcinoma and a stage IA clear cell endometrioid cancer confined to an endometrial polyp 6 years earlier. These findings suggest an occasional role for BARD1 mutations in the development of sporadic and hereditary tumors.

    Title Adenovirus-based P53 Gene Therapy in Ovarian Cancer.
    Date December 1995
    Journal Gynecologic Oncology
    Excerpt

    Mutations of the p53 tumor suppressor gene are the most common molecular genetic abnormality to be described in ovarian cancer. To determine the feasibility of mutant p53 as a molecular target for gene therapy in ovarian cancer, we constructed an adenovirus vector containing the wild-type p53 gene. The ability of this adenovirus construct (Ad-CMV-p53) to express p53 protein was examined by Western blot analysis in the H358 lung cancer cell line, which has a homozygous deletion of the p53 gene. The ability of the adenovirus vector system to infect ovarian cancer cells was tested using an adenovirus containing the beta-galactosidase reporter gene under the control of the CMV promoter (Ad-CMV-beta gal). The ovarian cancer cell line 2774, which contains an Arg273His p53 mutation, was infected with Ad-CMV-beta gal, and the infected cells were assayed for beta-galactosidase activity after 24 hr. To test the ability of wild-type p53 to inhibit cell growth, the 2774 cell line was infected with Ad-CMV-p53 or Ad-CMV-beta gal, and the effect of these agents on the growth of 2774 cells was determined using an in vitro growth inhibition assay. Western blot analysis of lysates from H358 cells infected with Ad-CMV-p53 showed expression of wild-type p53 protein. When 2774 cells were infected with Ad-CMV-beta gal at a multiplicity of infection (m.o.i.) of 10 PFU/cell, > 90% of cells showed beta-galactosidase activity, demonstrating that these cells are capable of efficient infection by the adenovirus vector. Growth of 2774 cells infected with Ad-CMV-p53 was inhibited by > 90% compared to noninfected cells. The ability of the adenovirus vector to mediate high-level expression of infected genes and the inhibitory effect of Ad-CMV-p53 on the 2774 cell line suggests that the Ad-CMV-p53 could be further developed into a therapeutic agent for ovarian cancer.

    Title Pelvic Masses.
    Date
    Journal The Medical Clinics of North America
    Excerpt

    Pelvic masses develop commonly in women of all ages and states of health. Despite the variety of masses that exist, general guidelines for diagnosis and management allow most masses to be treated in a generalist setting. This article is intended to guide non-obstetric and non-gynecologic physicians through diagnosis and treatment of nonmalignant pelvic masses. It includes information on physical examination, appropriate imaging techniques, laboratory tests, and variations in treatment for adolescents and pre- and postmenopausal women. It also addresses referral guidelines for suspected malignant masses.

    Title Phase Ib Study of the Combination of Docetaxel, Gemcitabine, and Bevacizumab in Patients with Advanced or Recurrent Soft Tissue Sarcoma: the Axtell Regimen.
    Date
    Journal Annals of Oncology : Official Journal of the European Society for Medical Oncology / Esmo
    Excerpt

    To assess the response of patients with soft tissue sarcoma (STS) to the combination of docetaxel, bevacizumab, and gemcitabine. Vascular endothelial growth factor (VEGF)-A levels and expression of VEGF-A and VEGF receptors 1 and 2 were evaluated.


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