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Obstetrician & Gynecologist (OB/GYN), Oncology Specialist (cancer)
14 years of experience
Video profile
Accepting new patients

Education ?

Medical School Score Rankings
East Carolina University (1996)
  • Currently 3 of 4 apples
Top 50%

Awards & Distinctions ?

Awards  
Best Doctors in North Carolina (2009)
Reproductive Scientist Development Program Scholar
Fellow (2006)
Best Doctors in North Carolina
Best in Category Research Award
North Carolinas Best Doctros
Best Doctors in America
James F. Nolan Award for best scientific presentat
Best Doctors in America (2009)
Reproductive Scientist Development Program Scholar (2006)
Best in Category Research Award (2007)
Patients' Choice Award (2008 - 2009, 2013)
Compassionate Doctor Recognition (2011 - 2013)
Top 10 Doctor - State (2014)
Texas
Gynecologic Oncologist
Associations
American Board of Obstetrics and Gynecology
Society of Gynecologic Oncology

Affiliations ?

Dr. Lea is affiliated with 8 hospitals.

Hospital Affilations

Score

Rankings

  • UT Southwestern University Hospital - Zale Lipshy
    5151 Harry Hines Blvd, Dallas, TX 75235
    • Currently 4 of 4 crosses
    Top 25%
  • Parkland Health & Hospital System
    5201 Harry Hines Blvd, Dallas, TX 75235
    • Currently 1 of 4 crosses
  • UT Southwestern University Hospital - St. Paul
    Medical Oncology
    5909 Harry Hines Blvd, Dallas, TX 75235
    • Currently 1 of 4 crosses
  • UT Southwestern St Paul Hospital
  • University Of Texas Southwestern Medical
  • UT Southwestern Zale Lipshy Hospital
  • Carolinas Medical Center MercyPineville
  • Univ TX Southwestern Med Ctr
    5323 Harry Hines Blvd, Dallas, TX 75390
  • Publications & Research

    Dr. Lea has contributed to 27 publications.
    Title Secondary Cytoreductive Surgery for Recurrent Platinum-sensitive Ovarian Cancer.
    Date April 2010
    Journal International Journal of Gynaecology and Obstetrics: the Official Organ of the International Federation of Gynaecology and Obstetrics
    Excerpt

    To determine the risks and benefits of secondary cytoreductive surgery for recurrent platinum-sensitive ovarian cancer.

    Title Secreted Protein Acidic and Rich in Cysteine As a Regulator of Murine Ovarian Cancer Growth and Chemosensitivity.
    Date February 2009
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Secreted protein acidic and rich in cysteine (SPARC) influences the growth of several solid tumors. Our objectives were to determine the effect of SPARC on the growth and response to cisplatin therapy of platinum-resistant ovarian cancer.

    Title Implications of Egfr Inhibition in Ovarian Cancer Cell Proliferation.
    Date June 2008
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVES: Epidermal Growth Factor Receptor (EGFR) is one of the four members of the Human Epidermal Receptor (HER) family and is over-expressed in multiple malignancies. EGFR over-expression in ovarian cancer has been associated with poor prognosis. Targeted inhibition of EGFR via its tyrosine kinase domain is a successful treatment in lung cancer. Our objective was to correlate EGFR over-expression and growth inhibition, by EGF receptor inhibitors, in ovarian cancer. MATERIALS AND METHODS: HER expression in nine epithelial ovarian cancer cell lines and one lung cancer cell line was determined by Western blot analysis. EGFR phosphorylation sites were analyzed and DNA sequencing was performed. Cell proliferation assays were performed in the presence of the tyrosine kinase inhibitor, gefitinib, and the EGFR monoclonal antibody, cetuximab. Inhibitory concentrations of 50% of these therapies were determined and compared across all cell lines. The lung cancer cell line, HCC827, was used as a control. RESULTS: Four of nine (44%) ovarian cancer cell lines and the control lung cancer cell line expressed EGFR. These same cell lines showed a common phosphorylated residue at position 992, while other residues were variably phosphorylated. All but one cell line expressed at least one HER family member. Mutational analysis of the ovarian cancer cell lines showed no mutations in EGFR exons 18-21. Cell proliferation assays using gefitinib and cetuximab showed minimal response in the ovarian cancer cell lines when compared to the control HCC827, but relative sensitivity compared to the one cell line that had no HER family expression. CONCLUSIONS: Ovarian cancer cell lines show variable expression of activated EGFR. EGFR inhibition alone, in ovarian tumors that lack a tyrosine kinase mutation or over-express EGFR is unlikely to result in clinical response.

    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 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 Adenocarcinoma of the Cervix.
    Date November 2004
    Journal Current Treatment Options in Oncology
    Excerpt

    Cervical adenocarcinomas are increasing in incidence each year, comprising up to 25% of all cervical cancers diagnosed in the United States. This increase largely reflects the inherent difficulty in detecting glandular precursor lesions using current screening practices. However, there also appears to be a recent shift in the epidemiology of the disease process with younger women being diagnosed more frequently. Fertility-sparing surgery is an option for selected patients with adenocarcinoma in situ or stage IA(1) cervical adenocarcinoma. Simple hysterectomy should be performed at the completion of childbearing or when preserving fertility is not an issue. The treatment of choice for most women with stage IA(2) to IB(1) disease is radical hysterectomy. Fewer than 20% of patients will need adjuvant therapy and the cure rate is excellent. Primary radiation with weekly cisplatin may be the best option for patients with stage IB(2) to IIA cervical adenocarcinoma. Patients treated initially by primary radical surgery will almost certainly require postoperative chemoradiation because of high-risk surgical-pathologic features. Patients with stage IIB to IVA disease should also receive primary radiation with weekly cisplatin. Management of recurrence should be individualized, depending on the location of disease and the type of previous therapy.

    Title P16 As a Molecular Biomarker of Cervical Adenocarcinoma.
    Date April 2004
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Cervical adenocarcinomas are increasing in incidence each year. The aim of this study was to identify a molecular biomarker to improve early detection. STUDY DESIGN: Fifty-five in situ and invasive cervical adenocarcinomas were compared with 5 normal endocervical controls by immunohistochemical analysis of p16, p21, p27, cyclin D1, cyclin E, p53, and Ki-67. Expression was scored from 0 to 8 by using an automated imaging system. Western blotting and polymerase chain reaction-based human papillomavirus (HPV) testing were performed on 16 of the invasive cases having fresh-frozen tissue. RESULTS: P16 exhibited a higher mean expression score for in situ (7.4; P<.0001) and invasive cervical adenocarcinoma (6.6; P<.0001) versus controls (2.0). A cutoff p16 expression score of 5 had a sensitivity of 94.5% and a specificity of 100%. Western blotting confirmed p16 protein expression. Fourteen (88%) of 16 invasive cervical adenocarcinomas were HPV-positive. CONCLUSION: P16 is a putative molecular biomarker of cervical adenocarcinoma. Overexpression appears to primarily reflect HPV-induced cell cycle dysregulation.

    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 Postconization Surveillance of Cervical Adenocarcinoma in Situ. A Prospective Trial.
    Date March 2004
    Journal The Journal of Reproductive Medicine
    Excerpt

    OBJECTIVE: To conduct a surveillance trial after conization to prospectively determine the outcome of conservative management of adenocarcinoma in situ (AIS). STUDY DESIGN: Women diagnosed with AIS were prospectively enrolled from September 2000 to September 2001. Eligibility criteria included patient age younger than 40 years, prior conization with negative margins and the desire to preserve fertility. Each cone biopsy specimen was secondarily reviewed. Postconization surveillance consisted of a liquid-based Pap test and endocervical curettage (ECC) every 4 months. Follow-up ended in September 2002. RESULTS: Ten women with a median age of 32 years (range, 26-37) were enrolled. Six were nulliparous and 2 primiparous. Seven patients were clinically free of disease after a median of 21 months (range, 5-24), 2 were lost to follow-up, and 1 was excluded when AIS could not be confirmed on the original specimen. Twenty-eight Pap smears and 18 ECCs were performed, but no additional surgical procedures were required due to abnormal cytopathology. CONCLUSION: This prospective trial on postconization surveillance demonstrated the safety of conservative management for AIS patients desiring to preserve fertility.

    Title Management of Low-risk Gestational Trophoblastic Neoplasia in Indigent Women.
    Date March 2004
    Journal The Journal of Reproductive Medicine
    Excerpt

    OBJECTIVE: To identify the most effective dosing regimen for indigent patients with low-risk gestational trophoblastic neoplasia (GTN) at high risk of noncompliance. STUDY DESIGN: All women primarily treated for GTN at our public hospital between November 1990 and November 2001 were prospectively entered into a database. Patients were treated with either (1) methotrexate, 100 mg/m2, intravenous bolus, followed by a 12-hour infusion, 200 mg/m2 (regimen 1); (2) methotrexate, 0.4 mg/kg/m2 intramuscularly for 5 consecutive days on alternating weeks (regimen 2); or (3) methotrexate, 30-50 mg/m2 intramuscularly weekly (regimen 3). Medical records were reviewed to obtain clinical data, and statistical analysis was performed. RESULTS: Thirty-two women were treated for low-risk GTN. The median age at diagnosis was 22 years (range, 15-40). Patients receiving regimen 1 (5/5, 100%) and 2 (19/20, 95%) were more likely to achieve complete remission without switching to dactinomycin or combination chemotherapy than those receiving regimen 3 (3/7, 43%; P < .001). Regimen 1 required fewer median treatment cycles (1.0, P = .04) than regimens 2 (6.5 cycles) and 3 (8.0 cycles). Seventeen (52%) patients were noncompliant with the chemotherapy protocol and/or posttreatment surveillance. CONCLUSION: A 1-day methotrexate infusion is highly effective for treating indigent women with low-risk. GTN.

    Title Adenosquamous Histology Predicts Poor Outcome in Low-risk Stage Ib1 Cervical Adenocarcinoma.
    Date January 2004
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVE: The purpose of this study was to identify poor prognostic factors of low-risk stage IB1 cervical adenocarcinoma METHODS: .All women diagnosed with stage IB1 cervical adenocarcinoma between 1982 and 2002 were identified at our three institutions. Data were extracted from medical records. Patients were retrospectively assigned to a low- or intermediate/high-risk cohort based on the surgical-pathologic eligibility criteria of two randomized controlled trials of adjuvant therapy in early stage cervical cancer, Gynecologic Oncology Group protocols 92 and 109. Multivariate analysis was performed. RESULTS: Two hundred thirty women diagnosed with stage IB1 cervical adenocarcinoma had an overall 5-year survival of 89%. Adenosquamous cell type (P < 0.01) was the only independent risk factor of disease recurrence in the low-risk group (n = 178). The 5-year disease-free survival for low-risk adenosquamous patients was 79%, compared to 96% for other histologic subtypes (P < 0.01). Low-risk case subjects developed fewer disease recurrences than those in the intermediate/high-risk (n = 52) category (7% vs 46%; P < 0.01). The 5-year disease-free survival for intermediate/high-risk patients was 51% and no additional risk factors were identified. CONCLUSION: Adenosquamous histology is predictive of disease recurrence and decreased survival in low-risk stage IB1 cervical adenocarcinoma. This risk factor should be considered in future clinical trials of adjuvant therapy.

    Title Cervical Adenocarcinoma Survival Among Hispanic and White Women: a Multicenter Cohort Study.
    Date April 2003
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: We compared the clinical outcome of cervical adenocarcinoma in Hispanic and white women to determine whether race was an independent predictor of survival. STUDY DESIGN: All women who were diagnosed with cervical adenocarcinoma at three institutions between 1982 and 2000 were identified. Medical records were reviewed retrospectively. Hispanic and white cohorts were matched 1:2 for age, stage of disease, date of diagnosis, tumor size, histologic subtype, grade, and invasive depth. RESULTS: The 65 Hispanic patients were more likely to be treated at the public hospital (71% vs 14%; P <.001) than the 122 matched white patients. Most Hispanic patients (72%) and white patients (76%) presented with early (stage IA-IIA), not advanced (IIB-IVB), disease. Early (81% vs 81%, P =.65), advanced (37% vs 26%, P =.21), and overall 5-year survival rates (67% vs 68%, P =.57) were similar among Hispanic and white patients, respectively. The relative risk of race on recurrence was 1.22 (95% CI, 0.56-2.42) and on survival was 0.72 (95% CI, 0.36-1.44). CONCLUSION: Hispanic race is not an independent predictor of survival in cervical adenocarcinoma.

    Title Endocervical Curettage at Conization to Predict Residual Cervical Adenocarcinoma in Situ.
    Date December 2002
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVE: To determine if performing an endocervical curettage (ECC) at the time of conization is a useful diagnostic tool for predicting residual cervical adenocarcinoma in situ (AIS) among women who might wish to preserve their fertility. METHODS: All patients diagnosed with AIS from 1995 to 2000 at four institutions were identified. Data were retrospectively extracted from clinical records. Women included in the statistical analysis were (1) younger than 40 years, (2) had an ECC performed at the time of the initial cone biopsy, (3) had a clearly demarcated surgical margin pathologically, and (4) underwent a second surgical procedure. RESULTS: Twenty-nine (24%) of 123 AIS patients met criteria for inclusion. The median age was 33 years (range, 17 to 39) and 13 (46%) were nulliparous. Initial surgery was a cold-knife conization (n = 17) or loop electrosurgical excision procedure (n = 12). Twelve (41%) ECCs and 15 (52%) cone margins were histologically positive. Sixteen patients underwent a repeat conization; 13 underwent hysterectomy. Thirteen (45%) patients had residual AIS at the time of their second surgical procedure. ECC had a superior positive predictive value (100% vs 47%; P < 0.01) and negative predictive value (94% vs 57%; P = 0.01) compared to cone margin in predicting residual AIS. None of the women undergoing fertility-sparing surgery developed recurrent AIS or adenocarcinoma. CONCLUSION: ECC performed at the time of conization may be a useful tool for predicting residual AIS in women considering fertility preservation.

    Title Early-stage Cervical Adenocarcinoma Treated by Surgical Intent: the Role of Para-aortic Lymph Node Dissection.
    Date March 2002
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVE: Previous reports suggest that cervical adenocarcinomas have a unique pattern of spread and are more apt to metastasize to para-aortic lymph nodes. The purpose of this study was to further define the node of para-aortic lymph node dissection in early-stage cervical adenocarcinoma treated by surgical intent. METHODS: Institutional review board approval was obtained to perform a computerized search of the data of all women diagnosed with cervical adenocarcinoma between 1982 and 2000. Hospital charts were retrospectively reviewed. Follow-up was obtained from the tumor registry, medical records, and correspondence with health care providers. RESULTS: Three hundred (87%) of 345 early-stage (FIGO IA(1)-IIA) cervical adenocarcinoma patients were primarily treated by surgical intent. Two hundred seventy-six underwent pelvic and para-aortic node dissection (n = 69) or pelvic node dissection only (n = 207); 24 had no lymph node dissection. The median number of lymph nodes removed was 13 pelvic (range, 1-58) and 3 para-aortic (range, 1-17). Three (4%) of 69 patients had para-aortic nodal metastases. Each had either grossly evident para-aortic adenopathy (n = 2) or an adnexal metastasis. Thirty-six of 40 women developing recurrent disease had at least some component of pelvic recurrence; 4 had only extrapelvic disease. Three patients undergoing para-aortic node dissection developed an isolated extrapelvic recurrence despite originally negative para-aortic nodes (n = 2) or treatment by extended-field radiation for para-aortic metastases. One woman undergoing only pelvic node dissection had an isolated extrapelvic recurrence despite originally negative nodes. CONCLUSIONS: Early-stage cervical adenocarcinoma primarily treated by surgical intent has a very low risk of para-aortic metastases. These were detected only when there was gross evidence of nodal or adnexal disease.

    Title Stage Iib-ivb Cervical Adenocarcinoma: Prognostic Factors and Survival.
    Date January 2002
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVE: The incidence of cervical adenocarcinoma is increasing relative to squamous cell carcinoma and all cervical cancers. Few reports have described the outcome of patients with advanced cervical adenocarcinoma. The purpose of this study was to determine the prognostic factors and survival for patients with stage IIB-IVB disease. METHODS: Institutional Review Board approval was obtained to perform a computerized search of all women diagnosed with cervical adenocarcinoma at our three institutions between 1982 and 2000. Medical records were retrospectively reviewed. Clinical follow-up was obtained from the SGO database and tumor registry and via correspondence with health care providers. Statistical analysis was performed using logistic regression for clinical variables and the log-rank test to compare Kaplan-Meier survival estimates. RESULTS: Eighty-three women with FIGO stage IIB-IVB cervical adenocarcinoma were identified. The median patient age was 53 years (range, 22-88). The median follow-up of 17 (20%) surviving patients was 33 months (range, 6-147); 66 (80%) died during the study interval. Stage IIB disease, young patient age, and grade 1 histology were independent variables having a favorable impact on survival (each P < 0.02). Stage IIB patients (n = 41) were more likely to be alive at 2 (64% vs 8%) and 5 years (30% vs 0%) than women with stage IIIA-IVB disease (n = 42; P < 0.01). CONCLUSIONS: Women diagnosed with advanced stage cervical adenocarcinoma have a poor prognosis. Prospective, multicenter trials of platinum-based chemoradiation or other novel therapies are urgently needed in the treatment of this highly lethal disease.

    Title Optimum Screening Interventions for Gynecologic Malignancies.
    Date March 2001
    Journal Texas Medicine
    Excerpt

    The availability of screening modalities and improvements in prevention have reduced the risk of developing some cancers over the last few decades. Methods for optimal screening of gynecologic cancers are still being investigated. Cervical cancer is the only gynecologic malignancy for which a screening modality is widely accepted and recommended to all women. Annual screening of cervical cells has been shown to reduce the incidence of cervical cancer by 78%. Unfortunately, more than 50% of cervical cancers occur in women who have not been screened optimally. In the year 2000, an estimated 12,800 women developed cervical cancer. Of these women, 89% were seen by a physician but not screened. Vaginal cancer is associated with a similar etiology, pathobiology, and symptomatology as is cervical cancer. Vaginal dysplasia and cancer can also be detected by the Pap test, but the prevalence of the disease is low. Endometrial carcinoma is the most common gynecologic cancer. The widespread availability of outpatient biopsy devices has been the most significant advance in the early diagnosis of corpus cancers. Ovarian cancer is the gynecologic malignancy associated with the highest death rate. No modality has been shown as an effective screening method for this cancer. Women with a family history of ovarian cancer may benefit from combined modality screening; prophylactic oophorectomy should be offered to those with hereditary ovarian cancer syndromes. A complete physical examination by the physician offers the best method for early detection of vulvar cancer. Awareness and implementation of recommended screening guidelines for gynecologic cancers by primary care and specialty physicians can decrease the incidence and mortality of cervical cancer. Including the genital tract in the complete examination of the female patient could decrease markedly the mortality from the other gynecologic cancers.

    Title Complete Groin Lymphadenectomy with Preservation of the Fascia Lata in the Treatment of Vulvar Carcinoma.
    Date June 2000
    Journal Gynecologic Oncology
    Excerpt

    OBJECTIVE: The goal of this study was to assess the local groin recurrence of vulvar carcinoma in patients treated by complete groin node dissection with preservation of the fascia lata (GNDPFL). METHODS: This study is a retrospective chart review of 60 patients with Stage I-IV vulvar carcinoma who underwent radical vulvectomy and GNDPFL between 1990 and 1998. All superficial inguinal nodes and the deep femoral nodes on the anterior and medial surfaces of the femoral vein within the fossa ovalis were removed en bloc while sparing the fascia lata and the cribriform fascia over the femoral artery. RESULTS: Of the 60 study patients, 14 patients had Stage I disease, 20 Stage II, 21 Stage III, and 5 Stage IV. The mean number of nodes removed was 10 per groin. Thirty-nine patients had benign nodes on groin dissection. None of these 39 patients developed cancer recurrence in the dissected groins. Twenty-one of the sixty study patients (34%) had malignant nodes on groin dissection. Of these 21 patients, 2 experienced cancer recurrence in the groins. Our study describes a groin recurrence rate of 7.6% in patients with fewer than three malignant unilateral groin nodes. Postoperatively, 13% of patients developed lymphedema and 15% formed lymphoceles. CONCLUSIONS: The zero groin recurrence rate in patients with negative nodes and the low rate of recurrence in patients with positive nodes indicate that groin lymphadenectomy with preservation of fascia lata is complete, therapeutic, and comparable to radical techniques of lymphadenectomy involving skeletonization of femoral vessels, resection of fascia lata, and muscle transposition.

    Title Contrasting Cytotoxic Mechanisms of Similar Antitumour Diaziridinylbenzoquinones.
    Date July 1990
    Journal Free Radical Research Communications
    Excerpt

    The mechanisms of cytotoxicity of the antitumour diaziridinylbenzoquinones, AZQ and BZQ, have been investigated. HPLC analysis has been used to study the products as well as the rate of decomposition of acid-assisted ring-opening in aqueous medium as a function of pH. Microconcentrators with a molecular weight cutoff of 30 kDa were utilised to study the covalent binding of both compounds to calf thymus DNA. Radical production of both compounds in K562 cell incubations was followed using ESR and their uptake into K562 cells was monitored using radiolabelled compounds. The results show that these two diaziridinylbenzoquinones, although very similar in structure, have diverse mechanisms of cytotoxicity. The implications of these findings are discussed in the light of antitumor action.

    Title The Reductive Deglycosylation of Adriamycin in Aqueous Medium: a Pulse Radiolysis Study.
    Date July 1990
    Journal Free Radical Research Communications
    Excerpt

    The free radical (II) produced by one-electron reduction of adriamycin (I) exists in aqueous solution at pH 7.0 in equilibrium with the parent and the two-electron reduced form (III). Over some hundreds of milliseconds deglycosylation takes place yielding an aglycone (IV) which subsequently rearranges to form a more stable aglycone, 7-deoxyadriamycinone (V). The changes in the optical absorption spectrum accompanying these processes are reported. The rate constant for III----IV is 1.1 s-1 and for IV----V is 1.5 x 10(-2) s-1. At pH 4.0 the two electron reduced form of adriamycin exists predominantly in a different tautomeric form (VII). It is suggested that this deglycosylates via a free radical mechanism involving the acidic form of the semiquinone free radical (VI).

    Title Comparison of the Structural and Cytotoxic Activity of Novel 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone Analogues.
    Date April 1990
    Journal Cancer Research
    Excerpt

    Eight analogues of 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone have been synthesized and tested for cytotoxicity against four different leukemic and lymphomic cell lines. For K562 and BSM cells, the toxicity could be correlated with the ease of reduction of the compounds as determined by the one-electron reduction potentials and the electron spin resonance detection of the reduced compounds produced by the cells. The cell toxicity could also be correlated with the efficiency of the compounds to form cross-links in DNA. However, no such correlations could be observed for the L1210 and Raji cells, although the activity of the NADPH dependent reducing enzymes in these cells was similar to that in the others. It is believed that for the L1210 and Raji cells, the influx/efflux of the different compounds may be more important to the cytotoxicity than their reduction or alkylation.

    Title The Esr Detection of Irradiated Food.
    Date March 1990
    Journal International Journal of Radiation Applications and Instrumentation. Part A, Applied Radiation and Isotopes
    Excerpt

    Previous work has shown that the calcified tissues in several foods give rise to characteristic ESR spectra on irradiation. Further foods have now been examined. Mussel and crab shells give large signals, compared with bones of poultry, beef or frog, while prawn cuticle gives a smaller signal. The limits of detection of irradiation vary between species but are below the doses likely to be used commercially. Quantitative estimation of dose can be achieved by re-irradiation and extrapolation to zero signal.

    Title A Comparison of the Free Radical Properties of Several Anthracycline Anti-tumour Drugs and Some of Their Analogues.
    Date May 1989
    Journal Free Radical Research Communications
    Excerpt

    NADPH consumption and esr spectroscopy have been used to study the rate of formation and signal intensity of free radicals produced by various anthracycline anti-tumour drugs in rat liver microsomal extract. The drugs investigated were Adriamycin, 4'Deoxyadriamycin, Daunorubicin, 4 Demethoxydaunorubicin and Carminomycin. Pulse radiolysis was also used to determine the case of reduction of each of the analogues to its semiquinone radical and some kinetic properties of the radicals produced. It is believed that the occurrence of reactions other than dismutation could be responsible for the shortened lifetimes of the semiquinone radicals observed in biological systems.

    Title Esr Detection of Irradiated Food.
    Date September 1988
    Journal Nature
    Title The Lack of Correlation Between Toxicity and Free Radical Formation of Two Diaziridinyl Benzoquinones.
    Date June 1988
    Journal Biochemical Pharmacology
    Excerpt

    L1210 and K562 leukaemic cells have been used to study the relationship between cytotoxicity and free radical production by two aziridinyl benzoquinones, 2,5-bis(carboethoxyamino)3,6-diaziridinyl-1,4-benzoquinone (AZQ) and 2,5-bis(2-hydroxyethylamino)-3,6-diaziridinyl-1,4-benzoquinone (BZQ). BZQ showed a high level of toxicity in both cell lines, but no ESR signal was detectable, while AZQ readily produced an ESR signal but much lower cytotoxicity was observed, particularly in L1210 cells. The rate of superoxide formation was measured for each drug. The results demonstrate that cell killing and free radical production do not necessarily concur.

    Title Structure and Mobility of Electron Gain and Loss Centres in Proteins.
    Date February 1988
    Journal Nature
    Excerpt

    Radiation damage to proteins is a topic of intense interest to those involved in radiation effects in biology, and also to those involved in radiotherapy. Although it has been widely studied, fundamental processes in protein damage are very hard to specify because of the complexity of the final damage products. But the non-invasive technique of electron-spin resonance is ideally suited to the task of detecting and identifying the primary and secondary products as these are expected to contains unpaired electrons (that is, free-radicals) and such species are uniquely detected by this sensitive form of spectroscopy. Our present study shows that a major radical species formed by electron loss in a range of proteins is the backbone amido radical, -N.(CO)-, characterized by hyperfine coupling to one 14N nucleus. These centres are efficiently trapped in proteins at low temperatures. In contrast, the expected backbone electron-capture centres, -NH(CO.-)-, are not readily trapped and electron transfer occurs until the ejected electron is trapped by some electrophilic centre. Such electron mobility was in fact established in our previous work on oxyhaemoglobin (FeO2----FeO2-), superoxide dismutase (Cu(II)----Cu(I] haemocyanin (Cu(II)O2Cu(I)----Cu(I)O2Cu(II] and various proteins containing S-S bonds (-S-S-)----(-S.-S-) (refs 1-4 respectively). This is strongly supported by our observation that such electrons are captured by DNA molecules, giving T.- centres, when nucleohistones are irradiated, and that Fe(CN)3-(6) ions readily scavenge such electrons from proteins which are devoid of highly electrophilic centres.

    Title Electron Transfer from Protein to Dna in Irradiated Chromatin.
    Date February 1988
    Journal Nature
    Excerpt

    Irradiation of dry or fully hydrated frozen DNA systems (conditions of direct damage) has been shown by electron-spin resonance spectroscopy to give rise to electron-gain centres localized on thymine (T.-) and electron loss centres ('holes') localized on guanine (G.+) with approximately equal yields. Our parallel studies on the development of both single- and double-strand breaks under comparable conditions provide good evidence that these radical centres are the precursors to such damage, and we and others have argued that this may be of relevance to the damage pathways in vivo. We now report evidence that when DNA is complexed to proteins as it is in the nuclei of eukaryotes, electron transfer from the histone to DNA is facile, leading to a significant increase in the yield of electron-gain centres in DNA as judged from their electron-spin resonance spectra. In contrast 'holes' generated in the protein are trapped and do not lead to any detectable increase in the yields of G.+.

    Title The Reduction of Anti-tumour Diaziridinyl Benzoquinones.
    Date September 1987
    Journal Biochimica Et Biophysica Acta
    Excerpt

    The properties of the semiquinone radicals produced for 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone (AZQ) and 2,5-bis(2-hydroxyethylamino)-3,6-diaziridinyl-1,4-benzoquinone (BZQ), have been investigated. AZQ semiquinone radicals can be produced from the reduction of AZQ by superoxide radicals, whereas BZQ semiquinone radicals are unstable in the presence of oxygen. The one-electron reduction potentials of the couples Q/Q-. at pH 7.0 were determined as -70 +/- 10 mV for AZQ and -376 +/- 15 mV for BZQ. The difference in these potentials is explained. As a consequence of ESR studies on the enzymatically produced radicals, we have considered the factors which determine the detection of ESR signals for reduced quinones produced in a biological system.

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