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J T Wharton

Publications and source records attributed to J T Wharton.

At least 37 records · Page 2Linked to original sources
PubMed1998

Ovarian and breast cytotoxic T lymphocytes can recognize peptides from the amino enhancer of split protein of the Notch complex.

In this study we investigated recognition by ovarian tumor associated lymphocyte (OVTAL), and breast tumor associated lymphocytes (BRTAL), of peptides corresponding to the sequence 125-135 of the Aminoenhancer of split (AES) protein. Three of these peptides designated as G75:AES1/2 (128-135), G60: AES1/2 (127-137) and G61: AES1/2 (125-133) correspond to the wildtype AES sequence, while the fourth G76:GPLTPLPV, AES1/2 (128-135) corresponds to a variant sequence of the peptide G75 with the N-terminal Leu substituted to glycine. These sequences were chosen for study because mass-spectrometric analysis (MS) of a CTL active HPLC peptide fraction eluted from immunoaffinity precipitated HLA-A2 molecule, revealed: (a) the presence of an ion with a mass-to-charge ratio (m/z) of 793 which was more abundant than other ions of similar masses; (b) the tentatively reconstituted sequence of the ion 793 matched the sequence of peptide G76. We found that AES peptides G75 (128-135) and G76 (128-135) (L128G) reconstituted CTL recognition at concentrations ranging between 200-500 nM. These concentrations are lower than concentrations reported to activate effector function of CTL recognizing other epithelial tumor Ag. Furthermore, analysis with cloned CD8+ T cells indicated that G75 and G76 were not cross-reactive specificities, suggesting a key role for the N-terminal residues of the variant peptide in dictating specificities. Since the AES proteins are part of a set of transcriptional repressors encoded by the Enhancer of split [E(spl)] genes, and since these repressors are activated to suppress cell differentiation in response to Notch receptors signalling, the AES peptides may represent a novel class of self-antigens that deserve further consideration as tumor Ag in epithelial cancers.

Antigens, Neoplasm↗
PubMed1998

Growth and antigen recognition of tumor-infiltrating lymphocytes from human breast cancer.

In the present study, we isolated tumor-infiltrating lymphocytes (TIL) from 21 primary solid tumors and tumor-associated lymphocytes (TAL) from 9 malignant effusions, respectively, of breast cancer patients. Significant proliferation and expansion of T cells was observed in 23 of 30 distinct samples. TIL were isolated from primary tumors by either enzymatic digestion or mechanical disruption. The TIL cultures were initiated using OKT3 mAb in the presence of moderate concentrations (25-50 U/ml) of IL-2, followed by 100 U/ml of tumor necrosis factor (TNF)-alpha. TAL were not stimulated with OKT3 mAb, but all were successfully expanded in culture in the presence of IL-2 alone or together with TNF-alpha. Seven of nine distinct TAL grew in culture as predominantly CD4+ lines. In contrast, only 14 of 21 (66%) of primary breast TIL expanded in culture and were predominantly of CD8+ phenotype. Autologous tumor lysis was observed in seven of eight cases tested. Only one of the four TIL tested and one of the four TAL tested preferentially lysed autologous tumor. HER-2 peptide E75 (369-377) was recognized by two TIL lines of the five primary TIL tested and three of the four TAL tested. This suggests that E75 may be recognized by primary breast tumors. This may be of interest in developing vaccine strategies for therapeutic management of breast cancer.

Antigen-Antibody Reactions↗
PubMed1998

Phase I dose de-escalation trial of alpha-difluoromethylornithine in patients with grade 3 cervical intraepithelial neoplasia.

alpha-Difluoromethylornithine (DFMO) is a suicide inhibitor of ornithine decarboxylase and potent antiproliferative chemopreventive agent. We conducted a dose de-escalation Phase I trial of DFMO in patients with grade 3 cervical intraepithelial neoplasia to determine an optimal dose of DFMO using ornithine decarboxylase activity and polyamine modulation as surrogate biomarkers and to evaluate its toxicity. Thirty patients with biopsy-confirmed grade 3 cervical intraepithelial neoplasia were assigned sequentially to one of five DFMO doses (1.000, 0.500, 0.250, 0.125, or 0.060 g/m2) given daily for 31 days. One patient was excluded from analysis for protocol violation. Polyamine levels were assessed in cervical tissue, plasma, and RBCs. Tissue and blood samples were obtained before and after treatment with DFMO. All patients underwent loop excision of the cervix at the end of the study for complete histological evaluation and definitive treatment of the premalignant condition. No major clinical toxicity was observed at any DFMO dose. A reduction in tissue spermidine to spermine (SPD:SPM) ratio and an increase in plasma arginine levels were observed among patients receiving 1.000 g/m2/day (P < 0.05). A nonsignificant reduction in SPD:SPM ratio was also observed in the 0.500 g/m2/day dose group, and a nonsignificant increase in plasma arginine level was observed down to the 0.125 g/m2/day dose level. There was no evidence of modulation of other polyamines or precursors. Fifteen patients experienced a complete (5 patients) or partial (10 patients) histological response. In conclusion, DFMO was well tolerated and significantly modulated tissue SPD:SPM ratio and plasma arginine level at the dose of 1.000 g/m2/day. To clarify whether DFMO has activity at lower doses, these results will be tested in a three-armed double-blinded Phase II study using placebo and DFMO doses of 0.500 and 0.125 g/m2/day.

Administration, Oral↗
PubMed1998

Proliferative and cytokine responses to class II HER-2/neu-associated peptides in breast cancer patients.

Previous studies have characterized the reactivity of CD8+ CTLs with ovarian and breast cancer. There is little information about the antigens and epitopes recognized by CD4+ T cells in these patients. In this study, we analyzed the ability of T cells from peripheral blood mononuclear cells of breast cancer patients to recognize HER-2/neu (HER-2) peptides. We found that 13 of 18 patients responded by proliferation to at least one of the HER-2 peptides tested. Of these peptides, one designated G89 (HER-2: 777-789) was recognized by T cells from 10 patients. Seven of nine responding patients were HLA-DR4+, suggesting that this peptide is recognized preferentially in association with HLA-DR4. Analysis of the specificity and restriction of the cytokine responses to G89 by G89-stimulated T cells revealed that these cells secreted significantly higher levels of IFN-gamma than interleukin 4 and interleukin 10, suggesting priming for a Th0-T helper 1 response. The same pattern of cytokine responses was observed to the intracellular domain of HER-2 protein, suggesting that G89-stimulated T cells recognized epitopes of the HER-2 protein in association with HLA-DR4. Because HLA-DR4 is present in 25% of humans, characterization of MHC class II-restricted epitopes inducing Th0-T helper 1 responses may provide a basis for the development of multivalent HER-2-based vaccines against breast and ovarian cancer.

Amino Acid Sequence↗
PubMed1997

Identification of naturally processed human ovarian peptides recognized by tumor-associated CD8+ cytotoxic T lymphocytes.

Identification of naturally processed peptides recognized by tumorspecific CTLs may lead to epitope-specific tumor vaccines. Because these epitopes may be expressed differently on epithelial tumors and may differ in their ability to induce CTL in vivo, we have isolated the HLA-A2-peptide complexes by immunoaffinity from an established ovarian tumor line transfected with and expressing HLA-A2 gene. High-performance liquid chromatography-fractionated peptides were used to reconstitute epitopes recognized on HLA-A2 by three HLA-A2+ CD8+ CTL lines. These lines recognized at least three of the same groups of fractions (designated SKOV3.A, -B, and -C) but showed differences in the pattern of recognition of other fractions. To gain insight in the epitope distribution by freshly isolated ovarian tumors, we compared the recognition of peaks SKOV3.B and -C with the corresponding peaks from an ovarian tumor (OVA-6) that expressed similar levels of HLA-A2, using one of these lines (CTL-OVA-5) as indicator. CTL-OVA-5 recognized a large number of epitopes from peaks B and C rechromatographed on more resolving high-performance liquid chromatography gradient. Although a number of peaks appeared to be coincident on both SKOV3 and OVA-6, an even higher number appeared either not to overlap or to overlap only partially. These findings, which represent the first analysis of the epitopes presented by a patient tumor, suggest that the use of tumor line-derived peptides for vaccination may require selection of the epitopes corresponding to the ones presented by freshly isolated human tumors.

Antigens, Neoplasm↗
PubMed1997

Prognostic significance of residual disease in patients with stage IV epithelial ovarian cancer.

PURPOSE: To evaluate the role of surgical debulking in patients with stage IV ovarian cancer. METHODS: We conducted a retrospective review of patients with advanced epithelial ovarian cancer treated at M. D. Anderson Cancer Center. Eligible patients included women with stage IV disease treated with platinum-based chemotherapy. Surgical debulking was considered optimal if the diameter of the largest residual tumor was 2 cm or less. Survival analysis and comparisons were performed using the Kaplan-Meier method and the log-rank test. RESULTS: One hundred eight women with stage IV ovarian cancer were identified. The extraperitoneal metastatic sites were the liver parenchyma in 16 patients, the pleura in 54 patients, a variety of other organs in 22, and two or more sites in the remaining 16. Median age of the patient population was 58 years (range 35-81 years). Surgery to reduce the primary tumor was performed in 100 patients. The procedures included salpingo-oophorectomy with or without hysterectomy in 94 patients, omentectomy in 90, small bowel resection in 4, large bowel resection in 23, and splenectomy in 2. At the completion of surgery, tumor reduction was considered optimal in 31 patients, suboptimal in 61, and undetermined in 8. The overall median survival for optimally debulked patients was 25 months compared to 15 months for suboptimally debulked patients (P < 0.02). The progression-free survival, on the other hand, was not statistically different between the two groups. CONCLUSION: Residual tumor seems to be an important prognostic factor in patients with stage IV ovarian cancer. Surgical debulking may play a significant role in the treatment of these patients.

Adult↗
PubMed1997

Polyamine measurements in the uterine cervix.

Cervical cancer remains a significant health problem. New strategies based on the molecular aspects of cervical carcinogenesis are needed. Chemoprevention represents a novel strategy for cervical cancer prevention. Our group plans phase I and II trials using alpha-difluoromethylornithine, a suicide inhibitor of ornithine decarboxylase and potent antiproliferative chemopreventive agent. We conducted a study to identify which polyamines in tissue could best serve as surrogate endpoint biomarkers for future trials. Thirty patients with biopsy-proven cervical intraepithelial neoplasia grade 3 underwent colposcopically directed biopsies of normal and abnormal areas of the uterine cervix for analysis of polyamine synthesis biomarkers. Statistically significant differences were found in the ornithine decarboxylase value and the spermidine:spermine ratio between normal and abnormal areas of the cervix. In general, the ranges in measurements varied widely. Differences in polyamine synthesis biomarkers between colposcopically normal and abnormal areas can be demonstrated. However, studies using polyamine synthesis biomarkers in the cervix would require large numbers of patients to achieve significance.

Cervix Uteri↗
PubMed1996

Sexual adjustment of patients undergoing gracilis myocutaneous flap vaginal reconstruction in conjunction with pelvic exenteration.

BACKGROUND: Although the technique for gracilis myocutaneous vaginal reconstruction was first described in the mid-1970s and has been used in conjunction with pelvic exenteration since that time, there is little available information regarding sexual adjustment after such a procedure. The purpose of this study was to assess the sexual adjustment of women who underwent pelvic exenteration and gracilis myocutaneous vaginal reconstruction at the study institution. METHODS: In a prospective study design, 95 patients were identified who underwent pelvic exenteration and gracilis myocutaneous vaginal reconstruction at the study institution from 1977 through 1989 and a convenience sample was selected of 44 patients who completed a modified version of the Sexual Adjustment Questionnaire (SAQ) when they returned to the gynecologic oncology outpatient clinic for routine follow-up care. A vaginal assessment was also performed by the attending physician. RESULTS: Twenty-one of 40 patients (52.5%) completing the questionnaire reported not resuming sexual activity after surgery; 19 patients reported sexual activity between 1.5 months to 12 years postoperatively. Of the patients who resumed sexual activity, 84% did so within 1 year of surgery. The most common problems noted by patients in adjusting to sexual activity after surgery were self-consciousness about the urostomy or colostomy and being seen in the nude by their partner, vaginal dryness, and vaginal discharge. The mean rank of preexenteration SAQ scores was 66.4, and the mean rank of postexenteration scores was 48.7 (P < 0.0001), demonstrating that sexual adjustment after exenteration was significantly poorer than before the surgery. On the basis of data gathered from a vaginal assessment form, 31 of 44 patients (70.4%) were judged to have a potentially functional neovagina. CONCLUSIONS: Based on the findings of this questionnaire study, sexual adjustment is often significantly impaired in women after pelvic exenteration and gracilis myocutaneous vaginal reconstruction. Future modifications in surgical technique, more realistic patient counseling and aggressive postoperative support will hopefully minimize such problems.

Adaptation, Psychological↗
PubMed1996

Definitive radiotherapy for carcinoma of the vagina: outcome and prognostic factors.

PURPOSE: Primary carcinoma of the vagina is an uncommon tumor. Because of the long-standing interest in this disease at our institution a substantial number of patients with this disease has been accumulated, and this retrospective review was performed to define disease outcome, to delineate significant prognostic factors, and to provide treatment guidelines. METHODS AND MATERIALS: This was a retrospective review of 301 patients with vaginal carcinoma (271 with squamous cell and 30 with adenocarcinoma) who received definitive radiotherapy between 1953 and 1991. Prognostic factors for outcome (local control, pelvic control, metastatic relapse, survival, and complications) were evaluated using univariate and multivariate techniques. RESULTS: Patients disease was staged using the International Federation of Gynecology and Obstetrics (FIGO) system, and stages were distributed as follows: 0, 37 (12%); I, 65 (22%); II, 122 (40%); III, 60 (20%); and, IVA, 17 (6%). Treatment varied according to stage, with brachytherapy predominating for early disease but external beam playing a prominent role for more advanced disease. Patients with in situ disease received brachytherapy alone or transvaginal orthovoltage irradiation. For Stage I, brachytherapy alone was used in 25, external beam and brachytherapy in 38, and transvaginal alone in 2. For Stage II, brachytherapy alone was used in 20, external and brachytherapy in 66, and external irradiation alone in 36. For Stage III, external and brachytherapy was used in 15, and external alone in 45. Two patients with Stage IVA received brachytherapy alone, 10 received a combination of external and brachytherapy, and 6 received external irradiation alone. Total doses ranged from 10 to 154 Gy (mean 74.7 Gy, median 70.0 Gy), but only 18 (6%) received less than 55 Gy. At a median follow-up of 13 years, the 5-, 10-, 15-, 20-, and 25-year survival rates were 60%, 49%, 38%, 29%, and 23%, respectively. Beyond 5 years the survival rates relative to those for age-matched females in the general population were between 50 and 65%. Actuarial local recurrence rates were 23%, 26%, and 26% at 5, 10, and 15 years. Actuarial pelvic relapse rates were 26%, 30%, and 31% at 5, 10, and 15 years, and metastatic rates at those times were 15%, 18%, and 18%. Adenocarcinoma (nonclear cell) was a significantly worse disease than squamous cell carcinoma. The major determinants of local control for squamous carcinoma were tumor bulk (specified by size in centimeters, or by FIGO stage), tumor site (upper lesions faring better than others), and tumor circumferential location (lesions involving the posterior wall faring worse). Tumor bulk was an important determinant of metastatic relapse, but failure to achieve local control was also an independently significant determinant of metastases. Salvage after first relapse was uncommon and the survival rate at 5 years after relapse was only 12%. Serious complications occurred in 39 patients with an actuarial incidence of 19% at 20 years. CONCLUSION: Vaginal carcinoma poses a formidable therapeutic challenge. The disease is heterogeneous with respect to its prognostic factors. Nonclear cell adenocarcinoma has an extremely poor prognosis and should be distinguished from squamous carcinoma. Both external beam and brachytherapy play crucial roles in management and most patients with disease beyond in situ should receive a significant component of external irradiation prior to brachytherapy.

Adenocarcinoma↗
PubMed1996

Molecular genetic analysis of clear cell adenocarcinomas of the vagina and cervix associated and unassociated with diethylstilbestrol exposure in utero.

BACKGROUND: Prenatal exposure to the synthetic estrogen diethylstilbestrol (DES) is associated with the subsequent development of clear cell adenocarcinoma of the lower reproductive tract in young women, and data concerning the molecular genetic alterations involved in the etiology of this tumor type have not previously been reported. Such knowledge would be of potential value by providing insight into the molecular mechanisms of hormonal carcinogenesis in general, as well as by suggesting molecular markers for risk assessment in the estrogen-exposed population. METHODS: A total of 24 samples of clear cell adenocarcinoma of the vagina or cervix, 16 associated with exposure in utero to DES and 8 with no history of DES exposure, were obtained as archival fixed and embedded tissue specimens. DNA was purified from these tissues and used to examine a number of biologically plausible molecular genetic endpoints for tumor specific alterations. RESULTS: No evidence was found for mutations in the K-ras or H-ras protooncogenes, the Wilms' tumor (WT1) tumor suppressor gene, or the estrogen receptor gene. Sporadic overexpression of the p53 tumor suppressor gene was detected in some tumor cell nuclei by immunohistochemistry, but in the absence of detectable p53 gene mutation. Genetic instability as manifested by somatic mutation of microsatellite repeats was widespread in these tumors, with evidence of microsatellite instability in all DES-associated tumors examined, and in 50% of those tumors not associated with DES exposure. CONCLUSIONS: These data are consistent with the hypothesis that the induction of genomic instability may be an important mechanism of DES-induced carcinogenesis.

Adenocarcinoma, Clear Cell↗
PubMed1996

Groin dissection practices among gynecologic oncologists treating early vulvar cancer.

OBJECTIVE: To survey the surgical practice of gynecologic oncologists regarding the extent of groin dissection for early vulvar cancer. METHODS: A 14-item questionnaire was developed and presented to the Annual Meeting of the Felix Rutledge Society. Gynecologic oncologists were asked to describe in descriptive, categorical, and visual terms the groin procedure that they perform as part of management of early vulvar cancers. Three ink-line drawings were created by a medical illustrator for the purpose. Fifty returned surveys were evaluable. RESULTS: The most commonly performed procedures were removal of the lymph nodes above the cribriform fascia and those medial to the femoral vein (40%), removal of lymph nodes above the cribriform fascia (34%), and removal of all nodes above and below the cribriform fascia (22%). Respondents performing the first procedure termed it "superficial inguinal lymphadenectomy" (40%), "inguinal femoral lymphadenectomy" (25%) and a variety of other names (35%). Respondents performing the second two procedures were much more consistent in the figure and name that they matched with their description of the nodes removed. When respondents were asked to match the figures with categorical definitions based on their understanding of the literature, the figure depicting Scarpa's triangle following removal of the superficial inguinal and medial femoral nodes was named superficial inguinal lymphadenectomy by 24% despite the fact that the femoral vein was clearly visible and labeled. CONCLUSIONS: We conclude that (1) among this group of gynecologic oncologists superficial inguinal and medial femoral lymphadenectomy is the most commonly performed procedure for women with early vulvar cancer and that the procedure is frequently called superficial inguinal lymphadenectomy; (2) publications and protocols on this topic must provide complete descriptions of procedures performed, and investigators must assure that individual surgeons are performing the same procedure; and (3) treatment results with superficial inguinal and medial femoral lymphadenectomy are poorly described and a fertile area for further study.

Female↗
PubMed1996

Intraabdominal lymphatic mapping to direct selective pelvic and paraaortic lymphadenectomy in women with high-risk endometrial cancer: results of a pilot study.

OBJECTIVE: To determine the feasibility of intraperitoneal lymphatic mapping of the uterine fundus as a means of identifying target sites for lymph node biopsy during staging laparotomy and to develop preliminary experience with the technique. METHODS: Fifteen women with high-risk endometrial tumors were entered on this Institutional Review Board-approved pilot study. At laparotomy, isosulfan blue dye (1.0 ml) was injected into the subserosal myometrium at three sites: the superior midpoint of the fundus, 2 cm inferiorly on the anterior wall, and 2 cm inferiorly on the posterior wall. Dye uptake into lymphatic channels was observed for 10 min. The retroperitoneal spaces were opened. Blue lymphatic channels and nodes within the pelvic and paraaortic regions were identified. Nodes demonstrating dye uptake were biopsied as separate specimens: the locations of these nodes were carefully recorded. Hysterectomy and selective lymphadenectomy were then performed as usual. RESULTS: Lymphatic channels coursing into the broad ligament and along the ovarian vessels were identified from all uteri injected. Deposition of dye into grossly identifiable lymph nodes was seen in 10 of 15 cases (67%). A total of 31 nodes demonstrated dye uptake. The locations of these nodes included paraaortic sites in 12, common iliac in 6, and pelvic in 13. No dye-containing paraaortic nodes were seen below the origin of the inferior mesenteric artery. Lymphatic channels coursing above the renal vessels were seen routinely. Microscopic nodal metastases to sentinel nodes were identified in 2 of 4 women with proven lymphatic spread. CONCLUSIONS: Lymphatic mapping of the uterine fundus is feasible and can identify targets for selective nodal biopsy in some women. Preliminary observations confirm that the lymphatic network draining the uterus is complex and involves both pelvic and paraaortic nodes. Lymphatic channels that parallel the ovarian vessels were not observed to enter nodes until reaching the level of the midabdomen. Further experience and refinement of techniques may lead to the development of a selective lymphadenectomy based upon direct visualization of the lymphatic drainage of the uterus rather than the current random sampling.

Aorta↗
PubMed1996

Arterial occlusion complicating treatment of gynecologic cancer: a case series.

The objective in this paper is to describe the severity and outcome of arterial occlusion complicating treatment of women with gynecologic cancer. A series of six patients who underwent amputation were identified. Acute arterial occlusions were seen in three patients. One patient suffered extensive thrombosis of the hand and wrist resulting in amputation 3 weeks after cytoreductive surgery and chemotherapy for Fallopian tube cancer. She had a history of pulmonary embolism and deep-vein thrombosis. This patient was thought to have thrombophilia. One elderly patient with known arteriosclerosis developed sepsis following radical deep excision and groin dissection for vulvar cancer and lost two digits presumably due to microemboli. One patient developed thrombosis of the femoral artery on the second day following cytoreductive surgery for ovarian cancer. She responded to anticoagulation therapy; however, necrosis remained in portions of the heel and toes. Three patients underwent amputation of a lower extremity when they developed chronic arterial insufficiency after pelvic radiotherapy. The patients were irradiated at the ages of 28, 30, and 35 years for cervix cancer in two patients and a low-grade retroperitoneal sarcoma in one patient. Two received neutron beam therapy and one received conventional photon beam therapy. All three had extensive late radiation morbidity to the bladder and rectum and had multiple prior surgeries. The amputations occurred at the ages of 48, 48, and 55 due to accelerated arteriosclerosis. Two patients died as a result of this complication. Acute and chronic arterial occlusions are rare yet dramatic complications of therapy for gynecologic cancer. This series illustrates the predisposing factors, presentation, and management of these unusual events.

Adult↗
PubMed1996

Treatment of poor-prognosis sex cord-stromal tumors of the ovary with the combination of bleomycin, etoposide, and cisplatin.

OBJECTIVE: To investigate the clinical activity of the combination of bleomycin, etoposide, and cisplatin for metastatic ovarian sex cord-stromal tumors of all types and poorly differentiated Sertoli-Leydig cell tumors confined to the ovary. METHODS: The regimen was administered as follows: bleomycin 10-15 mg/day by continuous intravenous (IV) infusion on days 1-3; etoposide 100 mg/m2 IV per day on days 1-3; cisplatin 100 mg/m2 IV on day 1. End points for analysis included response, progression-free survival, and survival. RESULTS: Nine patients were entered in this trial. The median age was 37 years (range 12-69). Histologic types included adult granulosa cell tumor in five patients, juvenile granulosa cell tumor in one, poorly differentiated Sertoli-Leydig cell tumor in two, and mixed tumor in one. Stage distribution was as follows: stage Ia, two; stage IIc, one; stage IIIc, one; recurrent, five. Of the six patients with measurable disease, two (33%) had a complete response (one surgical and one clinical), and three (50%) had a partial response, for an overall response rate of 83%; one patient had no response. Toxicity was acceptable; two patients had mild bleomycin pulmonary toxicity. Of the three patients with nonmeasurable disease, one relapsed, one developed progressive disease, and one remains in remission. Of the seven patients with metastatic disease, only one (14%) had a durable remission. Median progression-free survival was 14 months. Median survival time was 28 months. At the time of analysis, two patients were alive disease-free, three were alive with disease, and four were dead of disease. CONCLUSION: Although the overall response rate to the combination of bleomycin, etoposide, and cisplatin was high, the regimen apparently lacks durable activity in this group of tumors. More active drugs and modalities should continue to be investigated.

Adolescent↗
PubMed1996

Transgene expression in the rhesus cervix mediated by an adenovirus expressing beta-galactosidase.

OBJECTIVES: More than 90% of cervical cancers are positive for human papillomavirus, which functionally represses p53 and pRb. The remainder have been found to contain p53 mutations. Gene therapy involves insertion of a functioning gene into a patient to correct a genetic abnormality. STUDY DESIGN: The ability of a beta-galactosidase adenovirus to mediate transgene expression in the rhesus cervix was evaluated. Three different doses and two different entry techniques of virus were investigated. RESULTS: The ideal dose determined by X-galactosidase staining was 2 x 10(10) plaque-forming units, and the injection method yielded better staining than did abrasion with topical application. Increased adenoviral-specific immunoglobulin G antibody response in the injected monkeys confirmed the results. CONCLUSION: High transduction efficiency by use of adenoviral vectors can be achieved in the cervix. Reversing the effects of human papillomavirus and p53 mutations with gene therapy may become a novel therapy for invasive and preinvasive cervical cancer.

Adenoviridae↗
PubMed1996

Vaginal intraepithelial neoplasia and vaginal cancer.

Vaginal cancer is infrequent, but the morbidity associated with treatment is high. Delays in diagnosis account for presentations in advanced stages. Screening is probably not warranted given the low incidence, but inspection of the vagina should be performed at the time of Pap smear screening. No molecular markers are currently promising. Chemoprevention with retinoids may be feasible.

Carcinoma in Situ↗
PubMed1995

Chemoprevention trials and surrogate end point biomarkers in the cervix.

Cervical cancer is the second most common malignancy in women worldwide and remains a significant health problem for women, especially minority and underserved women. Despite an understanding of the epidemiologic risks, the screening Papanicolaou smear, and morbid and costly treatment, overall survival remains 40%. New strategies, based on the clinical and molecular aspects of cervical carcinogenesis, are desperately needed. Chemoprevention refers to the use of chemical agents to prevent or delay the development of cancer in healthy populations. Chemoprevention studies have several unique features that distinguish them from classic chemotherapeutic trials; these features touch on several disciplines and weave knowledge of the biology of carcinogenesis into the trial design. In the design of chemoprevention trials, four factors are important: high risk cohorts must be identified; suitable medications must be selected; study designs should include Phases I, II, and III; and studies should include the use of surrogate end point biomarkers. Surrogate end point biomarkers are sought because the cancer develops over a long period of time, and studies of chemopreventives would require a huge number of subjects followed for many years. Surrogate end point biomarkers serve as alternative end points for examination of the efficacy of chemopreventives in tissue. High risk cohorts include women with cervical intraepithelial neoplasia (CIN) or squamous intraepithelial lesions (SIL). Nutritional studies have helped define micronutrients of interest (folate, carotenoids, vitamin C, vitamin E). Other medications of interest include retinoids (4-hydroxyphenylretinamide [4-HPR], retinyl acetate gel, topical all-trans-retinoic acid), polyamine synthesis inhibitors (alpha-difluoromethylornithine [DFMO]), and nonsteroidal anti-inflammatory drugs (ibuprofen). Phase I chemoprevention studies of the cervix have tested retinyl acetate gel and all-trans-retinoic acid. Phase II trials of all-trans-retinoic acid, beta-carotene, and folic acid have been and are being carried out, whereas Phase III trials of all-trans-retinoic acid have been completed and have shown significant regression of CIN 2 but not CIN 3. Phase I studies of DFMO and Phase II studies of DFMO and 4-HPR are underway. Surrogate end point biomarkers under study include (1) quantitative cytology and histopathology; (2) human papillomavirus type testing; (3) biologic measures of proliferation, regulation, differentiation, and genomic instability; and 4) fluorescence spectroscopic emission. Clinical trials with biologic end points will contribute to our understanding of the neoplastic process and hence aid us in developing new preventive and therapeutic strategies.

Aneuploidy↗