A randomized, double-blind, placebo-controlled phase 1b/2 study of ralimetinib, a p38 MAPK inhibitor, plus gemcitabine and carboplatin versus gemcitabine and carboplatin for women with recurrent platinum-sensitive ovarian cancer.

OBJECTIVE: This phase 1b/2 clinical trial (NCT01663857) evaluated the efficacy of ralimetinib in combination with gemcitabine (G) and carboplatin (C), followed by maintenance ralimetinib, for patients with recurrent platinum-sensitive epithelial ovarian cancer. METHODS: Phase 1b was to determine the recommended phase 2 dose (RP2D) of ralimetinib administered Q12H on Days 1-10 (q21d) in combination with G (1000 mg/m2, Days 3 and 10) and C (AUC 4, Day 3) for six cycles. In phase 2, patients were randomized double-blind 1:1 to ralimetinib (R)+GC or placebo (P)+GC, for six cycles, followed by ralimetinib 300 mg Q12H or placebo on Days 1-14, q28d. RESULTS: 118 patients received at least one dose of ralimetinib or placebo; eight in phase 1b and 110 in phase 2 (R+GC, N = 58; P+GC, N = 52). The RP2D for R+GC was 200 mg Q12H. The study met its primary objective of a statistically significant difference in PFS (median: R+GC, 10.3 mo vs. P+GC, 7.9 mo; hazard ratio [HR] = 0.773, P = 0.2464, against a two-sided false positive rate of 0.4). Secondary objectives were not statistically significant for median overall survival (R+GC, 29.2 mo vs. P+GC, 25.1 mo; HR = 0.827, P = 0.4686) or overall response rate (R+GC 46.6% vs. P+GC, 46.2%; P = 0.9667). The safety profile of R+GC therapy was mainly consistent with safety of the chemotherapy backbone alone. Grade 3/4 elevated alanine aminotransferase was more common in the ralimetinib arm. CONCLUSIONS: Addition of ralimetinib to GC resulted in a modest improvement in PFS.

Breast Cancer Screening, Mammography, and Other Modalities.

This article is an overview of the modalities available for breast cancer screening. The modalities discussed include digital mammography, digital breast tomosynthesis, breast ultrasonography, magnetic resonance imaging, and clinical breast examination. There is a review of pertinent randomized controlled trials, studies and meta-analyses which contributed to the evolution of screening guidelines. Ultimately, 5 major medical organizations formulated the current screening guidelines in the United States. The lack of consensus in these guidelines represents an ongoing controversy about the optimal timing and method for breast cancer screening in women. For mammography screening, the Breast Imaging Reporting and Data System lexicon is explained which corresponds with recommended clinical management. The presentation and discussion of the data in this article are designed to help the clinician individualize breast cancer screening for each patient.

Phase II evaluation of dasatinib in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group study.

OBJECTIVES: Preclinical data suggest an important role for the sarcoma proto-oncogene tyrosine kinase (SRC) in the oncogenesis of epithelial ovarian cancer (EOC) or primary peritoneal carcinoma (PPC). The Gynecologic Oncology Group (GOG) conducted a Phase II trial to evaluate the efficacy and safety of dasatinib, an oral SRC-family inhibitor in EOC/PPC, and explored biomarkers for possible association with clinical outcome. METHODS: Eligible women had measurable, recurrent or persistent EOC/PPC and had received one or two prior regimens which must have contained a platinum and a taxane. Patients were treated with 100mg orally daily of dasatinib continuously until progression of disease or adverse effects prevented further treatment. Primary endpoints were progression-free survival (PFS)≥6months and response rate. Serial plasma samples were assayed for multiple biomarkers. Circulating free DNA was quantified as were circulating tumor and endothelial cells. RESULTS: Thirty-five (35) patients were enrolled in a two-stage sequential design. Of the 34 eligible and evaluable patients, 20.6% (90% confidence interval: 10.1%, 35.2%) had a PFS≥6months; there were no objective responses. Grade 3-4 toxicities were gastrointestinal (mostly nausea and emesis; n=4), pulmonary (dyspnea and/or pleural effusion; n=4) and pain (n=5), and infrequent instances of anemia, malaise, insomnia, rash, and central nervous system hemorrhage. Lack of clinical activity limited any correlation of biomarkers with outcome. CONCLUSION: Dasatinib has minimal activity as a single-agent in patients with recurrent EOC/PPC.

Effectiveness of COVID-19 Convalescent Plasma Infusion Within 48 Hours of Hospitalization With SARS-CoV-2 Infection.

On January 30, 2020, the World Health Organization (WHO) declared the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic a worldwide emergency. Worldwide there have been 170 million cases of the resulting disease coronavirus 2019 (COVID-19), of those, 3.53 million have resulted in death. The Food and Drug Administration (FDA) with Mayo Clinic as the lead institution authorized COVID-19 convalescent plasma (CCP) for treatment of SARS-CoV-2 infection. Effective therapeutic window for CCP administration had yet to be defined. We addressed this gap by characterizing longitudinal biologic response and clinical outcomes of COVID-19 patients treated with CCP. Primary outcome was discharged to home/home health.

Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study.

PURPOSE: This study evaluated efficacy of single-agent trastuzumab against advanced or recurrent HER2-positive endometrial carcinoma (EC), and explored predictors for HER2 amplification. PATIENTS AND METHODS: Eligible patients had measurable stage III, IV, or recurrent EC. There was no limit on prior therapy although total prior doxorubicin dose was limited to 320 mg/m(2). Tumors were required to have HER2 overexpression (2+ or 3+ immunohistochemical staining) or HER2 amplification (FISH HER2/CEP 17 ratio >2.0). Trastuzumab was administered intravenously at a dose of 4 mg/kg in week 1, then 2 mg/kg weekly until disease progression. The primary endpoint was tumor response. RESULTS: Of the 286 tumors centrally screened by LabCorp, 33 (11.5%) were HER2-amplified. Three of 8 clear (38%) cell carcinomas and 7 of 25 serous carcinomas (28%) screened exhibited HER2 amplification compared with 7% (2/29) of endometrioid adenocarcinomas. HER2 overexpression was correlated with HER2 amplification (r=0.459; p<0.0001). Thirty-four women were enrolled; 1 was excluded (refused treatment); and 18 had tumors with known HER2 amplification. No major tumor responses were observed. Twelve women experienced stable disease, 18 had increasing disease, and 3 were indeterminate for tumor response. Neither HER2 overexpression nor HER2 amplification appeared to be associated with progression-free survival or overall survival. CONCLUSION: Trastuzumab as a single agent did not demonstrate activity against endometrial carcinomas with HER2 overexpression or HER2 amplification, although full planned accrual of women with HER2 amplified tumors was not achieved due to slow recruitment. Serous and clear cell endometrial carcinomas appear to be more likely to demonstrate HER2 amplification.

A Phase II evaluation of weekly topotecan as a single agent second line therapy in persistent or recurrent carcinoma of the cervix: a Gynecologic Oncology Group study.

PURPOSE: To estimate antitumor activity and toxicity of weekly topotecan hydrochloride in patients with persistent or recurrent cervical carcinoma who failed prior treatment. PATIENTS AND METHODS: Women entered on study had or failed one prior chemotherapy regimen in addition to radiosensitizing chemotherapy, performance status less than 3, and adequate hematologic, renal, hepatic, and neurological function. Topotecan was infused at 3.0 mg/m(2) on days 1, 8, and 15 every 28 days. RESULTS: Twenty-seven patients were enrolled onto this study with 25 evaluable. Twenty-two patients had received radiation and chemotherapy prior to study. A median of two and mean of three courses of chemotherapy was given (range, one to eight courses). The most frequently severe adverse events were grade 3 anemia (28%) and grade 4 (4%) along with grade 3 neutropenia (8%) and grade 4 (8%). Two patients had grade 4 thrombocytopenia. There were no complete or partial responders. Ten patients (40%) had stable disease, twelve (48%) had increasing disease, and response could not be assessed in three (12%). The median progression-free survival was 2.4 months for the patients with increasing disease and 6.2 months (3.5-8.8 months) for those with stable disease. Disease location was equally divided within and outside the irradiated field. The 12 patients with increasing disease were more likely to have disease outside the pelvic radiation field. CONCLUSION: There were no complete or partial responders to weekly topotecan among the 25 patients in this study.

Evaluation of a Streamlined Oncologist-Led BRCA Mutation Testing and Counseling Model for Patients With Ovarian Cancer.

Purpose There is a growing demand for BRCA1/ 2 mutation ( BRCAm) testing in patients with ovarian cancer; however, the limited number of genetic counselors presents a potential barrier. To facilitate more widespread BRCAm testing in ovarian cancer, pretest counseling by the oncology team could shorten testing turnaround times and ease the pressure on genetic counselors. Patients and Methods The prospective, observational Evaluating a Streamlined Onco-genetic BRCA Testing and Counseling Model Among Patients With Ovarian Cancer (ENGAGE) study evaluated a streamlined, oncologist-led BRCAm testing pathway. The analysis population comprised 700 patients with ovarian cancer at 26 sites in the United States, Italy, and Spain. The primary objectives were to assess turnaround time and, using questionnaires, to evaluate stakeholder satisfaction (patients, oncologists, and geneticists or genetic counselors) with the oncologist-led BRCAm testing pathway. Results The median overall turnaround time was 9.1 weeks (range, 0.9 to 37.1 weeks), with median turnaround times in the United States, Italy, and Spain of 4.1 weeks (range, 0.9 to 37.1 weeks), 20.4 weeks (range, 2.9 to 35.4 weeks), and 12.0 weeks (range, 2.0 to 36.7 weeks), respectively. Patient satisfaction with the oncologist-led BRCAm testing pathway was high, with > 99% of patients expressing satisfaction with pre- and post- BRCAm test counseling. Oncologist satisfaction with the BRCAm testing pathway was also high, with > 80% agreeing that the process for performing BRCAm testing worked well and that counseling patients on BRCAm testing was an efficient use of their time. Oncologists expressed higher levels of satisfaction with the BRCAm testing pathway than did geneticists or genetic counselors. Conclusion The results of the ENGAGE study demonstrate that an oncologist-led BRCAm testing process is feasible in ovarian cancer. Development of local BRCAm testing guidelines similar to the one used in this study could allow faster treatment decisions and better use of resources in the management of patients with ovarian cancer.

Thyroid cancer in pregnancy.

We report a case of papillary thyroid cancer in pregnancy and discuss the various diagnostic and therapeutic challenges inherent to this condition. Several case series are reviewed. In addition, we examine the effect of pregnancy on the development and progression of thyroid malignancy.

Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study.

PURPOSE: On the basis of reported activity of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or topotecan plus cisplatin in advanced cervix cancer, we undertook a randomized trial comparing these combinations versus cisplatin alone, to determine whether survival is improved with either combination compared with cisplatin alone, and to compare toxicities and quality of life (QOL) among the regimens. PATIENTS AND METHODS: Eligible patients were randomly allocated to receive cisplatin 50 mg/m(2) every 3 weeks (CPT); cisplatin 50 mg/m(2) day 1 plus topotecan 0.75 mg/m(2) days 1 to 3 every 3 weeks (CT); or methotrexate 30 mg/m(2) days 1, 15, and 22, vinblastine 3 mg/m(2) days 2, 15, and 22, doxorubicin 30 mg/m(2) day 2, and cisplatin 70 mg/m(2) day 2 every 4 weeks (MVAC). Survival was the primary end point; response rate and progression-free survival (PFS) were secondary end points. QOL data are reported separately. RESULTS: The MVAC arm was closed by the Data Safety Monitoring Board after four treatment-related deaths occurred among 63 patients, and is not included in this analysis. Two hundred ninety-four patients enrolled onto the remaining regimens: 146 to CPT and 147 to CT. Grade 3 to 4 hematologic toxicity was more common with CT. Patients receiving CT had statistically superior outcomes to those receiving CPT, with median overall survival of 9.4 and 6.5 months (P = .017), median PFS of 4.6 and 2.9 months (P = .014), and response rates of 27% and 13%, respectively. CONCLUSION: This is the first randomized phase III trial to demonstrate a survival advantage for combination chemotherapy over cisplatin alone in advanced cervix cancer.

Utilization of diagnostic studies in the pretreatment evaluation of invasive cervical cancer in the United States: results of intergroup protocol ACRIN 6651/GOG 183.

PURPOSE: To review the current utilization of diagnostic tests prescribed by the International Federation of Gynecology and Obstetrics (FIGO) clinical staging guidelines in the pretreatment work-up of invasive cervical cancer, and to compare the data with those of previous patterns of care studies. PATIENTS AND METHODS: This interdisciplinary American College of Radiology Imaging Network/Gynecologic Oncology Group prospective clinical trial was conducted between March 1, 2000, and November 11, 2002. Twenty-five participating institutions, all from the United States, enrolled a total of 208 patients. Only patients scheduled for surgery with biopsy-confirmed cervical cancer of clinical FIGO stage IB or higher were eligible. The patterns of care data analysis was based on 197 patients who met all inclusion criteria. The conventional FIGO-recommended tests used for pre-enrollment FIGO clinical stage classification were at the discretion of the treating physician; overall frequency of use was tabulated for each test. RESULTS: Use of cystoscopy (8.1%) and sigmoidoscopy or proctoscopy (8.6%) was significantly lower than in 1988 to 1989 (P < .0001 in each instance). Intravenous urography was used in only 1% of patients as compared with 42% in 1988 to 1989 and 91% in 1983. No patient included in the data analysis had barium enema or lymphangiography. Only 26.9% of patients had examination under anesthesia for FIGO clinical staging. CONCLUSION: There is a large discrepancy between the diagnostic tests recommended by FIGO and the actual tests used for cervical cancer staging, suggesting a need to reassess the relevance of the FIGO guidelines to current clinical practice in the United States.

Role of imaging in pretreatment evaluation of early invasive cervical cancer: results of the intergroup study American College of Radiology Imaging Network 6651-Gynecologic Oncology Group 183.

PURPOSE: To compare magnetic resonance imaging (MRI) and computed tomography (CT) with each other and to International Federation of Gynecology and Obstetrics (FIGO) clinical staging in the pretreatment evaluation of early invasive cervical cancer, using surgicopathologic findings as the reference standard. PATIENTS AND METHODS: This prospective multicenter clinical study was conducted by the American College of Radiology Imaging Network and the Gynecologic Oncology Group from March 2000 to November 2002; 25 United States health centers enrolled 208 consecutive patients with biopsy-confirmed cervical cancer of FIGO stage > or = IB who were scheduled for surgery based on clinical assessment. Patients underwent FIGO clinical staging, helical CT, and MRI. Surgicopathologic findings constituted the reference standard for statistical analysis. RESULTS: Complete data were available for 172 patients; surgicopathologic findings were consistent with FIGO stages IA to IIA in 76% and stage > or = IIB in 21%. For the detection of advanced stage (> or = IIB), sensitivity was poor for FIGO clinical staging (29%), CT (42%), and MRI (53%); specificity was 99% for FIGO clinical staging, 82% for CT, and 74% for MRI; and negative predictive value was 84% for FIGO clinical staging, 84% for CT, and 85% for MRI. MRI (area under the receiver operating characteristic curve [AUC], 0.88) was significantly better than CT (AUC, 0.73) for detecting cervical tumors (P = .014). For 85% of patients, FIGO clinical staging forms were submitted after MRI and/or CT was performed. CONCLUSION: CT and MRI performed similarly; both had lower staging accuracy than in prior single-institution studies. Accuracy of FIGO clinical staging was higher than previously reported. The temporal data suggest that FIGO clinical staging was influenced by CT and MRI findings.

Subcutaneous management of vertical incisions with 3 or more centimeters of subcutaneous fat.

OBJECTIVE: This study was undertaken to determine the most appropriate management of the subcutaneous tissue of midline vertical incisions with 3 cm or more of subcutaneous fat. STUDY DESIGN: Patients undergoing surgery within the Division of Gynecologic Oncology at University of South Florida and East Tennessee State University with 3 cm or more of subcutaneous fat were randomly assigned to 1 of 3 groups: suture approximation of Camper's fascia, closed suction drainage of the subcutaneous space, or no intervention as a control group. Participants were evaluated daily during postoperative hospitalization and at 2 and 6 weeks postoperatively as an outpatient. Demographic information, perioperative data, and wound complications were recorded and then analyzed with chi2, t test, analysis of variance, and logistic regression where appropriate. RESULTS: Two hundred twenty-five patients were enrolled with 222 eligible for evaluation. Wound complications were observed in 34 (15.3%) patients, and 25 of these women also had wound disruption. Overall wound complication and wound disruption rates were not significantly different between groups: suture (12.8%, 7.7%), drain (17.9%, 14.9%), control (15.6%, 11.7%); P = .70 and P = .39, respectively. CONCLUSION: Suture approximation or drainage of the subcutaneous tissues of women with 3 cm or more subcutaneous fat measured in midline vertical incisions resulted in no significant change in the incidence of overall wound complications or superficial wound disruption.

Activation and overexpression of centrosome kinase BTAK/Aurora-A in human ovarian cancer.

Previous studies have demonstrated amplification of the centrosome serine/threonine kinase BTAK/Aurora-A in 10-25% of ovarian cancers. However, alterations of BTAK/Aurora-A at kinase and protein levels and its role in ovarian cancer progression have not been well documented. In this study, we examined the kinase activity and protein levels of BTAK/Aurora-A in 92 patients with primary ovarian tumors. In vitro kinase analyses revealed elevated BTAK/Aurora-A kinase activity in 44 cases (48%). Increased BTAK/Aurora-A protein levels were detected in 52 (57%) specimens. High protein levels of BTAK/Aurora-A correlated well with elevated kinase activity. Activation and overexpression of BTAK/Aurora-A were more frequently detected in early stage/low-grade ovarian tumors, although there was no statistic significance at the kinase level between early stage/low-grade and late stage/high-grade tumors. Moreover, BTAK/Aurora-A was preferentially expressed in noninvasive tumors, as revealed by immunohistochemical staining, suggesting that alterations of BTAK/Aurora-A could be an early event in human ovarian oncogenesis. To our knowledge, this is the first demonstration of recurrent activation and overexpression of BTAK/Aurora-A in human ovarian cancer, which may play a critical role in development of this malignancy.

Lysophospholipids are potential biomarkers of ovarian cancer.

OBJECTIVE: To determine whether lysophosphatidic acid (LPA) and other lysophospholipids (LPL) are useful markers for diagnosis and/or prognosis of ovarian cancer in a controlled setting. METHOD: Plasma samples were collected from ovarian cancer patients and healthy control women in Hillsborough and Pinellas counties, Florida, and processed at the University of South Florida H. Lee Moffitt Cancer Center and Research Institute (Moffitt). Case patients with epithelial ovarian cancer (n = 117) and healthy control subjects (n = 27) participated in the study. Blinded LPL analysis, including 23 individual LPL species, was performed at the Cleveland Clinic Foundation using an electrospray ionization mass spectrometry-based method. LPL levels were transmitted to Moffitt, where clinical data were reviewed and statistical analyses were performed. RESULTS: There were statistically significant differences between preoperative case samples (n = 45) and control samples (n = 27) in the mean levels of total LPA, total lysophosphatidylinositol (LPI), sphingosine-1-phosphate (S1P), and individual LPA species as well as the combination of several LPL species. The combination of 16:0-LPA and 20:4-LPA yielded the best discrimination between preoperative case samples and control samples, with 93.1% correct classification, 91.1% sensitivity, and 96.3% specificity. In 22 cases with both preoperative and postoperative samples, the postoperative levels of several LPL, including S1P, total LPA, and lysophosphatidylcholine (LPC) levels and some individual species of LPA and LPC, were significantly different from preoperative levels. CONCLUSION: LPA, LPI, LPC, and S1P appear useful as diagnostic and prognostic biomarkers of ovarian cancer.

In vitro chemoresponse in metachronous pairs of gyneclologic cancers.

BACKGROUND: While most gynecologic cancers respond to first-line cytotoxic chemotherapy, treatment of recurrent disease is frequently associated with acquired drug resistance. In order to find an in vitro surrogate of this clinical phenomenon, a tumor chemoresponse assay was studied. METHODS/MATERIALS: Patients who had tissue submitted for repeated chemoresponse testing were identified through a retrospective search. Sixty-three patients met inclusion criteria (chemoresponse testing completed at primary diagnosis and upon recurrence of disease and assays completed ≥90 days apart). The Wilcoxon signed-rank test was used to compare chemoresponse, represented as a response index (RI), between primary and recurrent measurements. In a secondary analysis, response was categorized and coded as Responsive = 3, Intermediately Responsive = 2 and Non-Responsive = 1, and the paired t-test was used to compare chemoresponse between primary and recurrent measurement. RESULTS: Median time between primary and recurrent tumor testing was 309 days (IQR 208-422). Drugs tested included carboplatin, cisplatin, docetaxel, doxorubicin, gemcitabine, paclitaxel, topotecan, and combination carboplatin/gemcitabine and carboplatin/paclitaxel. There were no differences in chemoresponse between primary and recurrent measurement when chemoresponse was represented by RI scores; although a trend toward increased resistance to paclitaxel upon recurrence was noted. When chemoresponse was analyzed as a continuous variable corresponding to categorized response, a significant shift toward increased resistance to paclitaxel at recurrence, and a marginally significant trend toward increased resistance to carboplatin at recurrence, were observed. CONCLUSIONS: We observed a trend toward increased chemoresistance at recurrence for paclitaxel, and a marginally significant trend toward increased chemoresistance to carboplatin, but no change in chemoresponsiveness between primary diagnosis and recurrence of disease for other common chemotherapy drugs, including common second-line agents such as doxorubicin, gemcitabine, and topotecan.

In vitro chemoresponse in metachronous pairs of ovarian cancers.

BACKGROUND/AIM: An in vitro chemoresponse assay may aid effective therapy selection in epithelial ovarian cancer (EOC). This study explores changes in chemoresponse between paired primary and recurrent EOC tumors. PATIENTS AND METHODS: RESULTS from metachronous tumors were examined in 242 patients. Changes in in vitro chemoresponse, measured by the area under the dose response curve (AUC) between paired tumors were assessed. RESULTS: A significant increase in AUC was identified in most first-line therapies over time. No significant difference was observed in most recurrent therapies. When the elapsed time between occurrences was <17 months, no difference was observed for any recurrent therapies, and half of first-line therapies exhibited significant increases in AUC. When ≥17 months, all 7 therapies showed significant increases. CONCLUSION: These results suggest an increase in chemoresistance over time, which is more pronounced for first-line therapies. This is consistent with clinical observations and suggests the biologic concordance between assay results and response to chemotherapy.

Clinical results and quality of life analysis for the MVAC combination (methotrexate, vinblastine, doxorubicin, and cisplatin) in carcinoma of the uterine cervix: A Gynecologic Oncology Group study.

OBJECTIVES: The Gynecologic Oncology Group (GOG) compared methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) with topotecan and cisplatin (TC) or cisplatin alone (C) in advanced cervical cancer. The primary endpoint was overall survival (OS), with response rate, progression-free survival (PFS), and quality of life (QOL) as secondary objectives. METHODS: Eligible patients were randomly allocated to receive either cisplatin 50 mg/m2 q 3 weeks (C) or cisplatin 50 mg/m2 day 1 and topotecan 0.75 mg/m2 days 1-3 q 3 weeks (TC) or methotrexate 30 mg/m2 days 1, 15, and 22, vinblastine 3 mg/m2 days 2, 15, and 22, doxorubicin 30 mg/m2 day 2, and cisplatin 70 mg/m2 day 2 q 4 weeks (MVAC). QOL was assessed at four time points using the Functional Assessment of Cancer Therapy-Cervix (FACT-Cx), Neurotoxicity Subscale (FACT/GOG-NTX subscale), and Brief Pain Inventory (BPI). RESULTS: One hundred eighty-six patients (C = 60; TC = 63; MVAC = 63) were enrolled before MVAC was closed by the GOG Data Safety Monitoring Board after four treatment-related deaths occurred on that arm. MVAC produced a 22% overall response rate (95% CI: 0.13 to 0.34) and median PFS and OS of 4.4 months and 9.4 months, respectively. Compared with C and TC, there was more hematologic toxicity with MVAC. There were no appreciable differences in QOL scores after controlling for baseline scores. CONCLUSIONS: MVAC's clinical activity tended to be similar to that of TC but with an unacceptable risk of death from sepsis at this dose and schedule. Nevertheless, QOL, as measured by these instruments, was not substantially impaired by this regimen.

Upper vaginectomy for the treatment of vaginal intraepithelial neoplasia.

OBJECTIVE: The purpose of this study was to evaluate the use of upper vaginectomy for the treatment of vaginal intraepithelial neoplasia (VAIN). STUDY DESIGN: We conducted a retrospective review. Between August 1, 1985 and April 30, 2004, 105 patients were identified who had undergone upper vaginectomy for VAIN. RESULTS: Thirty-six patients had previously been treated for VAIN. Mean operative time and estimated blood loss were 55 minutes and 113 mL, respectively. Ten percent had intraoperative complications. Twenty-three (22%) patients had negative findings on final pathologic examination, and invasive cancer was found in 13 (12%) patients. Four patients had postoperative complications. Follow-up was available in 52 patients; 46 (88%) remain without recurrence at a mean follow-up of 25 months. CONCLUSION: In our patients, upper vaginectomy was efficacious for the treatment of VAIN. The procedure led to the diagnosis of occult invasive cancer in 12% of these women.

Hormone replacement therapy and breast cancer risk in California.

Numerous studies have documented increased breast cancer risks with hormone replacement therapy (HRT), but these do not give a woman her specific absolute risk for the remainder of her life. This article estimates the magnitude of the effect of HRT on breast cancer incidence in California and calculates a woman's cumulative risk of breast cancer with different formulations and durations of HRT use. The effects of HRT on the underlying breast cancer incidence were estimated using the attributable fraction method, applying HRT prevalence data from the 2001 California Health Interview Survey and published rates of higher relative risk (RR) from HRT use from the Women's Health Initiative (WHI) study and Million Women's Survey (MWS). The annual number of breast cancers potentially attributable to HRT in California was estimated, along with individual cumulative risk of breast cancer for various ages to 79 years according to HRT use, duration, and formulation. Using the WHI data, 829 of 19,000 breast cancers (4.3%) in California may be attributable to HRT. This figure increases to 3401 (17.4%) when the MWS RRs are applied. Use of estrogen-only HRT or short-term (approximately 5 years) use of combined HRT has a minimal effect on the cumulative risk calculated to the age of 79 years; application of the MWS data to a Californian woman commencing HRT at the age of 50 years (no HRT, 8.5%; estrogen only, 8.6%; combined, 9.1%). Prolonged (approximately 10 years) use of combined HRT increases the cumulative risk to 10.3%. This article demonstrates that HRT will generate a small additional risk of breast cancer in an individual. The reduction in perimenopausal symptoms may be considered sufficient to warrant this extra risk. However, this view needs to be balanced because the small increases in individual risk will be magnified, producing a noticeable change in population cancer caseload where HRT use is high.