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Objective The randomized phase 3 CORAIL trial evaluated whether lurbinectedin improved progression-free survival (PFS) compared to pegylated liposomal doxorubicin (PLD) or topotecan in patients with platinum-resistant ovarian cancer. Methods Patients were randomly assigned (1:1) to lurbinectedin 3.2 mg/m2 1-h i.v. infusion q3wk (experimental arm), versus PLD 50 mg/m2 1-h i.v. infusion q4wk or topotecan 1.50 mg/m2 30-min i.v. infusion Days 1–5 q3wk (control arm). Stratification factors were PS (0 vs. ≥1), prior PFI (1–3 months vs. >3 months), and prior chemotherapy lines (1–2 vs. 3). The primary endpoint was PFS by Independent Review Committee in all randomized patients. This study was registered with ClinicalTrials.gov , NCT02421588 . Results 442 patients were randomized: 221 in lurbinectedin arm and 221 in control arm (127 PLD and 94 topotecan). With a median follow-up of 25.6 months, median PFS was 3.5 months (95% CI, 2.1–3.7) in the lurbinectedin arm and 3.6 months (95% CI, 2.7–3.8) in the control arm (stratified log-rank p = 0.6294; HR = 1.057). Grade ≥ 3 treatment-related adverse events (AEs) were most frequent in the control arm: 64.8% vs. 47.9% (p = 0.0005), mainly due to hematological toxicities. The most common grade ≥ 3 AEs were: fatigue (7.3% of patients) and nausea (5.9%) with lurbinectedin; mucosal inflammation (8.5%) and fatigue (8.0%) in the control arm. Conclusions The primary endpoint of improvement in PFS was not met. Lurbinectedin showed similar antitumor efficacy and was better tolerated than current standard of care in patients with platinum-resistant ovarian cancer.

High blood pressure (BP) is a highly prevalent modifiable cause of cardiovascular disease, stroke, and death. Accurate BP measurement is critical, given that a 5-mmHg measurement error may lead to incorrect hypertension status classification in 84 million individuals worldwide. This position statement summarizes procedures for optimizing observer performance in clinic BP measurement, with special attention given to low-to-middle-income settings, where resource limitations, heavy workloads, time constraints, and lack of electrical power make measurement more challenging. Many measurement errors can be minimized by appropriate patient preparation and standardized techniques. Validated semi-automated/automated upper arm cuff devices should be used instead of auscultation to simplify measurement and prevent observer error. Task sharing, creating a dedicated measurement workstation, and using semi-automated or solar-charged devices may help. Ensuring observer training, and periodic re-training, is critical. Low-cost, easily accessible certification programs should be considered to facilitate best BP measurement practice.

Digital, The Lancet Commission on Hypertension identified that a key action to address the worldwide burden of high blood pressure (BP) was to improve the quality of BP measurements by using BP devices that have been validated for accuracy. Currently, there are over 3 000 commercially available BP devices, but many do not have published data on accuracy testing according to established scientific standards. This problem is enabled through weak or absent regulations that allow clearance of devices for commercial use without formal validation. In addition, new BP technologies have emerged (e.g. cuffless sensors) for which there is no scientific consensus regarding BP measurement accuracy standards. Altogether, these issues contribute to the widespread availability of clinic and home BP devices with limited or uncertain accuracy, leading to inappropriate hypertension diagnosis, management and drug treatment on a global scale. The most significant problems relating to the accuracy of BP devices can be resolved by the regulatory requirement for mandatory independent validation of BP devices according to the universally-accepted International Organization for Standardization Standard. This is a primary recommendation for which there is an urgent international need. Other key recommendations are development of validation standards specifically for new BP technologies and online lists of accurate devices that are accessible to consumers and health professionals. Recommendations are aligned with WHO policies on medical devices and universal healthcare. Adherence to recommendations would increase the global availability of accurate BP devices and result in better diagnosis and treatment of hypertension, thus decreasing the worldwide burden from high BP., La Comisión Lancet de Hipertensión determinó que una medida clave para responder a la carga mundial que representa la hipertensión arterial era mejorar la calidad de las mediciones de la presión arterial, mediante la utilización de dispositivos cuya exactitud haya sido validada. En la actualidad existen 3000 dispositivos comercializados, pero muchos no tienen datos publicados sobre pruebas de exactitud conformes a las normas científicas establecidas. La falta de regulación o su ineficiencia, que permiten la autorización de dispositivos para uso comercial sin una validación oficial, posibilitan este problema. Además, han surgido tecnologías nuevas de medición de la presión arterial (por ejemplo, los sensores sin brazalete) sobre las cuales no existe unanimidad en la comunidad científica con respecto a las normas de exactitud de la medición. En conjunto, estos aspectos contribuyen a la disponibilidad generalizada de tensiómetros de consultorio o domiciliarios que ofrecen una exactitud limitada o incierta, que llevan a diagnósticos, manejo y farmacoterapia inapropiados de la hipertensión a escala mundial. Los problemas más importantes relacionados con la exactitud de los dispositivos de medición de la presión arterial se pueden resolver mediante el requisito regulatorio de una validación independiente obligatoria de los dispositivos, en consonancia con la norma ISO universalmente aceptada. Esta es una recomendación básica y constituye una necesidad internacional acuciante. Otras recomendaciones clave son la elaboración de normas de validación específicas para las tecnologías nuevas de medición de la presión arterial y la publicación en línea de listas de los dispositivos nuevos exactos que están a la disposición de los usuarios y los profesionales de salud. Las recomendaciones están en consonancia con las políticas de la Organización Mundial de la Salud sobre los dispositivos médicos y la atención universal de la salud. El cumplimiento de las recomendaciones aumentará la disponibilidad mundial de dispositivos de medición de la presión arterial que sean exactos y tendrá como efecto un mejor diagnóstico y tratamiento, reduciendo así la carga mundial de la hipertensión., A Comissão Lancet sobre Hipertensão Arterial identificou que uma iniciativa central para enfrentar a carga mundial da hipertensão arterial seria a melhoria na qualidade da mensuração da pressão arterial pelo uso aparelhos de pressão arterial validados quanto à acurácia. Atualmente, existem mais de 3 000 aparelhos de pressão arterial disponíveis comercialmente; entretanto, muitos não têm dados publicados sobre testes de acurácia realizados de acordo com padrões científicos estabelecidos. Este problema resulta de regulamentação fraca ou inexistente, o que permite a aprovação para uso comercial de dispositivos sem validação formal. Além disso, surgiram novas tecnologias de mensuração da pressão arterial (por exemplo, sensores sem algemas) sem consenso científico quanto aos padrões de acurácia. No conjunto, essas questões contribuem para a oferta generalizada de dispositivos de pressão arterial clínica e domiciliar com acurácia limitada ou incerta, levando a diagnóstico, gerenciamento e tratamento inadequados da hipertensão em escala global. Os problemas mais significativos relacionados com a acurácia dos dispositivos de pressão arterial podem ser resolvidos por regulamentação que imponha a obrigatoriedade de validação independente dos aparelhos de pressão arterial, de acordo com a norma universalmente aceita pela Organização Internacional de Normalização. Esta é uma recomendação fundamental para a qual existe uma necessidade internacional urgente. Outras recomendações essenciais incluem o desenvolvimento de padrões de validação especificamente para novas tecnologias de mensuração da pressão arterial e listas on-line de aparelhos com acurácia adequada que sejam acessíveis aos consumidores e profissionais de saúde. As recomendações estão alinhadas com as políticas da Organização Mundial da Saúde (OMS) sobre dispositivos médicos e atenção universal à saúde. A adesão às recomendações aumentaria a oferta global de dispositivos de pressão arterial com acurácia adequada e resultaria em melhor diagnóstico e tratamento da hipertensão arterial, diminuindo assim a carga mundial dessa doença., Traducción oficial al español del artículo original en inglés efectuada por la Organización Panamericana de la Salud. En caso de discrepancia, prevalecerá la versión original en inglés. Wolters Kluwer Health, Inc. y sus sociedades no se hacen responsables de la exactitud de la traducción del original inglés ni de los eventuales errores que esta pueda contener. Cita del artículo original: Sharman JE, O'Brien E, Alpert B, Schutte AE, Delles C, Hecht Olsen M et al. Lancet commission on hypertension group position statement on the global improvement of accuracy standards for devices that measure blood pressure. J Hypertens. 2020:38:21-29.doi: https://doi. org/10.1097/HJH.0000000000002246, Ciencias Médicas y de la Salud

The Lancet Commission on Hypertension identified that a key action to address the worldwide burden of high blood pressure (BP) was to improve the quality of BP measurements by using BP devices that have been validated for accuracy. Currently, there are over 3 000 commercially available BP devices, but many do not have published data on accuracy testing according to established scientific standards. This problem is enabled through weak or absent regulations that allow clearance of devices for commercial use without formal validation. In addition, new BP technologies have emerged (e.g. cuffless sensors) for which there is no scientific consensus regarding BP measurement accuracy standards. Altogether, these issues contribute to the widespread availability of clinic and home BP devices with limited or uncertain accuracy, leading to inappropriate hypertension diagnosis, management and drug treatment on a global scale. The most significant problems relating to the accuracy of BP devices can be resolved by the regulatory requirement for mandatory independent validation of BP devices according to the universally-accepted International Organization for Standardization Standard. This is a primary recommendation for which there is an urgent international need. Other key recommendations are development of validation standards specifically for new BP technologies and online lists of accurate devices that are accessible to consumers and health professionals. Recommendations are aligned with WHO policies on medical devices and universal healthcare. Adherence to recommendations would increase the global availability of accurate BP devices and result in better diagnosis and treatment of hypertension, thus decreasing the worldwide burden from high BP.A Comissão Lancet sobre Hipertensão Arterial identificou que uma iniciativa central para enfrentar a carga mundial da hipertensão arterial seria a melhoria na qualidade da mensuração da pressão arterial pelo uso aparelhos de pressão arterial validados quanto à acurácia. Atualmente, existem mais de 3 000 aparelhos de pressão arterial disponíveis comercialmente; entretanto, muitos não têm dados publicados sobre testes de acurácia realizados de acordo com padrões científicos estabelecidos. Este problema resulta de regulamentação fraca ou inexistente, o que permite a aprovação para uso comercial de dispositivos sem validação formal. Além disso, surgiram novas tecnologias de mensuração da pressão arterial (por exemplo, sensores sem algemas) sem consenso científico quanto aos padrões de acurácia. No conjunto, essas questões contribuem para a oferta generalizada de dispositivos de pressão arterial clínica e domiciliar com acurácia limitada ou incerta, levando a diagnóstico, gerenciamento e tratamento inadequados da hipertensão em escala global. Os problemas mais significativos relacionados com a acurácia dos dispositivos de pressão arterial podem ser resolvidos por regulamentação que imponha a obrigatoriedade de validação independente dos aparelhos de pressão arterial, de acordo com a norma universalmente aceita pela Organização Internacional de Normalização. Esta é uma recomendação fundamental para a qual existe uma necessidade internacional urgente. Outras recomendações essenciais incluem o desenvolvimento de padrões de validação especificamente para novas tecnologias de mensuração da pressão arterial e listas

BACKGROUND: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. METHODS: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres) in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO) stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1) using a permuted block method (block size of six patients) to receive six cycles of paclitaxel (175 mg/m2) and carboplatin (area under the serum concentration-time curve 5 or 6) every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. FINDINGS: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7-34·2), 626 patients had progression-free survival events (405 [60%] of 678 in the trebananib group and 221 [66%] of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0-17·6]) and the placebo group (15·0 months [12·6-16·1]) groups (hazard ratio 0·93 [95% CI 0·79-1·09]; p=0·36). 512 (76%) of 675 patients in the trebananib group and 237 (71%) of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%] vs placebo 126 [38%]) anaemia (76 [11%] vs 40 [12%]), and leucopenia (81 [12%] vs 35 [10%]). 269 (40%) patients in the trebananib group and 104 (31%) in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. INTERPRETATION: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. FUNDING: Amgen. ispartof: LANCET ONCOLOGY vol:20 issue:6 pages:862-876 ispartof: location:England status: published

The Lancet Commission on Hypertension identified that a key action to address the worldwide burden of high blood pressure (BP) was to improve the quality of BP measurements by using BP devices that have been validated for accuracy. Currently, there are over 3 000 commercially available BP devices, but many do not have published data on accuracy testing according to established scientific standards. This problem is enabled through weak or absent regulations that allow clearance of devices for commercial use without formal validation. In addition, new BP technologies have emerged (e.g. cuffless sensors) for which there is no scientific consensus regarding BP measurement accuracy standards. Altogether, these issues contribute to the widespread availability of clinic and home BP devices with limited or uncertain accuracy, leading to inappropriate hypertension diagnosis, management and drug treatment on a global scale. The most significant problems relating to the accuracy of BP devices can be resolved by the regulatory requirement for mandatory independent validation of BP devices according to the universally-accepted International Organization for Standardization Standard. This is a primary recommendation for which there is an urgent international need. Other key recommendations are development of validation standards specifically for new BP technologies and online lists of accurate devices that are accessible to consumers and health professionals. Recommendations are aligned with WHO policies on medical devices and universal healthcare. Adherence to recommendations would increase the global availability of accurate BP devices and result in better diagnosis and treatment of hypertension, thus decreasing the worldwide burden from high BP.

Bevacizumab is the first antiangiogenic agent to have demonstrated benefit as first-line and maintenance therapy in epithelial ovarian cancer (EOC), with the Gynecologic Oncology Group 218 and ICON 7 phase III trials revealing significantly prolonged progression-free survival (PFS) for carboplatin/paclitaxel plus bevacizumab followed by bevacizumab maintenance versus carboplatin/paclitaxel alone. Results are forthcoming from several phase III maintenance trials of investigational antiangiogenic agents, each evaluating PFS as the primary endpoint: AGO-OVAR12/LUME-Ovar1 (nintedanib [BIBF 1120]), AGO-OVAR16 (pazopanib), and TRINOVA-1, -2, and -3 (AMG 386). Here we review available data and ongoing clinical trials of investigational antiangiogenic agents as maintenance therapy for EOC. Current controversies, including uncertainties regarding the (1) most appropriate clinical trial endpoints, (2) optimal dosing, duration, and timing of therapy (e.g., with first-line chemotherapy and/or as maintenance monotherapy), and (3) feasibility, tolerability, and cost of adding these agents to platinum/taxane regimens are also highlighted.

Trabectedin (ET-743, Yondelis®) is a novel marine antineoplastic alkaloid with a unique mechanism of action. The active substance trabectedin, a tetrahydroisoquinoline alkaloid, is a natural product originally isolated from the Caribbean sea squirt, Ecteinascidia turbinata and is currently manufactured by total synthesis. Trabectedin is licensed by the Spanish pharmaceutical drug company, PharmaMar and co-developed by Johnson & Johnson Pharmaceutical Research and Development, L.L.C., pursuant to a licensing agreement with PharmaMar. Trabectedin is the first anticancer marine-derived drug to be approved by the European Union. In 2007, trabectedin obtained marketing authorization from the European Commission and in many other countries worldwide for the treatment of patients with advanced soft tissue sarcoma (STS) after failure of anthracyclines and ifosfamide, or for those patients who are unsuitable to receive these agents. Based on the recently reported results of a large phase III study (OVA-301) comparing pegylated liposomal doxorubicin (PLD) alone with a combination of PLD and trabectedin in patients with recurrent ovarian cancer, in 2009 the European Commission granted marketing authorization for trabectedin combined with PLD for the treatment of patients with relapsed platinum-sensitive ovarian cancer. The results from OVA-301 showed that the combination of trabectedin and PLD improves progression-free survival and overall response rate over PLD alone with acceptable tolerance in the second-line treatment of recurrent ovarian cancer. In addition, an enhanced activity of trabectedin combined with PLD was observed in platinum sensitive patients, especially in those with a platinum-free interval ranging from 6 to 12 months. Overall, trabectedin-induced toxicities are mainly hematological and hepatic, with grade 3/4 neutropenia and thrombocytopenia observed in approximately 50% and 13% of patients, respectively, and grade 3/4 elevation of liver aminotransferases observed in 40-50% of patients treated with trabectedin. Current efforts are focused on the evaluation of the role of trabectedin in prolonging the platinum-free interval and the identification of predictive factors for patients treated with trabectedin as well as in the development of new trabectedin-based combinations.

Objective Compared with every-3-week paclitaxel (q3T) plus carboplatin, dose-dense weekly paclitaxel (ddT) plus carboplatin improved the survival of ovarian cancer patients. We performed a cost analysis comparing these two regimens. Methods Using a Markov decision model, an acceptable incremental cost-effectiveness ratio (ICER) per progression-free life-year saved (PFLYS) was estimated. Cost of drugs, growth colony-stimulating factors, and transfusions were derived from Medicare reimbursement data. Survival and rates of complications were estimated based on the clinical trial. Results Using a body weight and surface area of an average woman age 63, the estimated cost per cycle of ddT was $107 vs. $80 for q3T. The costs per cycle of combination chemotherapy including treatment administration were $873 for ddT and $535 for q3T. With a median progression-free survival (PFS) of 28months with ddT vs. 17.2months with q3T, the ICER was $5809 per PFLYS for ddT compared with q3T arm. Using a maximum ICER of $100,000 per LYS as cost-effective threshold, the ddT regimen was cost-effective. The ICER was most sensitive to the hazard rate for difference in PFS between the two regimens. A 4-month difference in PFS resulted in a $1200 change of ICER per PFLYS. The ICER was also sensitive to overall survival difference, rate of hematological toxicity, and rate of discontinuation. Conclusions In this economic model, dose-dense weekly paclitaxel is a cost-effective treatment option for advanced ovarian cancer.

To investigate access to surgical care for endometrial cancer in Arizona.The Arizona HealthQuery (AZHQ) data warehouse with claims information on over 7 million patients in Arizona was searched using the International Classification of Disease (ICD-9) codes and Current Procedural Terminology (CPT) codes for endometrial cancer surgery from 2005 to 2008. Coordinates were gathered for patients and hospital to determine the distance traveled, race, insurance and annual caseload per hospital/surgeon were collected. Distance traveled was local (50 miles) or distant (≥ 50 miles) and served as the primary independent variable. Secondary variables included age, race, insurance, surgeon annual volume, and hospital annual volume. Logistic regression for distance traveled was performed for insurance coverage, race, hospital volume, and surgeon volume and expressed as an odds ratio.There were 1532 endometrial cancer surgeries performed at 67 hospitals by 242 surgeons in 15 counties. Most (61%) were performed by high-volume surgeons. Approximately 1 in 5 (19%) of patients traveled greater than 50 miles. Medicare insured patients were twice (OR=2.07, 95% CI=1.38-3.13) and Medicaid patients were three times (OR=3.41, 95% CI=1.89-6.15) as likely to travel over 50 miles. No significant difference was found between uninsured and privately insured patients (OR=0.87, 95% CI=0.45-1.68). Patients were more likely to travel to a high volume facility (OR 2.39, 95% CI=1.26-4.51). Hispanics (OR=2.72, 95% CI=1.72-4.32) and Native Americans (OR=8.60, 95% CI=3.43-21.52) were more likely to travel compared to Caucasians.In Arizona significantly different patterns of care are seen for endometrial cancer surgery based upon insurance coverage, race, surgeon and hospital. Patients travel farther to a high-volume hospital and high-volume surgeon. Hispanics or Native Americans travel farther for care when compared with Caucasians. Patients on government funded insurance plans travel farther for care than patients covered by private insurance or those lacking insurance.

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.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.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 was17 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.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.

Background To determine the protein expression profile (PEP) of primary and recurrent ovarian cancer patients in order to predict therapeutic targets for chemotherapy. Methods Tissue samples were submitted for PEP in two formats, including formalin-fixed paraffin-embedded tissue for immunohistochemistry (IHC) and fresh frozen tissue for oligonucleotide microarray (MA) gene expression assays. Specimens were analyzed for 18 protein markers and 88 MA genes. A series of Generalized Linear Models (GLM) was used to predict the proportion of positive results by histology for each biomarker. Results Four hundred and twenty-eight specimens were analyzed for IHC and 67 specimens for MA analysis. The majority of specimens, 82%, were serous histology and 35.3% of specimens were poorly differentiated. Sixty percent of specimens were advanced stage, 62% were from a primary diagnosis, and 53% were obtained from a metastatic site. BCRP, ER, MGMT, and RRM1 proteins were overexpressed in 85%, 47%, 93%, and 47% of serous carcinomas, respectively. The MGMT and RRM1 biomarkers were significantly overexpressed in serous (p

Objective: The aim of this study was to determine the incidence of occult bilateral involvement in Stage I epithelial ovarian cancer. Methods. We retrospectively reviewed the records of all patients ( n = 135) with Stage I epithelial ovarian cancer treated at the University of Pennsylvania Cancer Center between 1985 and 1996. A study group of patients ( n = 118) who underwent a bilateral salpingo-oophorectomy as part of their staging laparotomy was identified. Operative notes, pathology reports, and discharge summaries were reviewed to document stage, grade, histology, intraoperative impression, gross pathological description, and microscopic diagnosis. Clinically occult bilateral involvement was defined as pathologically documented ovarian involvement by tumor in an ovary that appeared normal to the surgeon during staging laparotomy. Results. The study group consisted of mostly Stage IA (79/118, 67%), followed by Stage IC (35/118, 30%) and Stage IB (4/118, 3%), tumors. In 9/118 (7.6%) of these cases, bilateral disease was documented in the pathology report. In 3/118 (2.5%) of these cases, the bilateral involvement by tumor was clinically occult at the time of surgery. In only 1/118 (0.85%) of these cases did a clinically abnormal appearing ovary not contain tumor. Conclusion. Occult involvement by early ovarian cancer is uncommon at the time of staging laparotomy. In appropriately counseled patients strongly desiring to preserve fertility, a unilateral salpingo-oophorectomy may be considered as part of a staging procedure for apparent Stage IA epithelial ovarian cancer if the contralateral ovary appears normal to the surgeon. Consideration should be given to a wedge biopsy with intraoperative frozen section to help exclude occult disease in the normal appearing ovary.

Uterine leiomyoma is a benign smooth muscle tumor of the myometrium and is the most commonly encountered neoplasm in women of reproductive age. As for most benign tumors, the pathogenesis of leiomyoma remains obscure, especially at the molecular genetic level. The purpose of this study was to perform a genome-wide allelotype analysis to identify potential sites of tumor suppressor gene inactivation. Fifty-two cases of uterine leiomyoma were subjected to allelotype analysis by using matched pairs of tumor and blood DNA. Loss of heterozygosity (LOH) was assessed at 61 microsatellite markers distributed throughout the genome and representing all 41 chromosome arms. In general, LOH was very rare except on chromosome 7q, where LOH was observed in 34% of all informative tumors. Fine-deletion mapping with 25 microsatellite markers from the 7q22 region revealed a minimal deletion unit of approximately 4 cM, bounded by the markers D7S2453 proximally and D7S496 distally, that probably harbors a novel tumor suppressor gene involved in the etiology of this tumor.

Objective.To report a case of stage IIIc poorly differentiated endometrial adenocarcinoma with trophoblastic differentiation and to review previously reported cases. Methods.The clinical course and histopathology of the case were reviewed, and a literature search for other reported cases was performed. Results.The tumor contained syncytiotrophoblast-like giant cells that stained positively for the beta subunit of human chorionic gonadotropin (β-hCG), and the patient's serum β-hCG level was elevated (95 mIU/ml), but became undetectable after treatment. β-hCG was used as a tumor marker during further therapy. At 16 months' survival, she remains without evidence of disease and with a β-hCG (level

Objective. The objective was to determine the toxicity and surgically documented response rate of sequential high-dose chemotherapy with peripheral stem cell support in patients with persistent or recurrent cisplatin-sensitive ovarian cancer. Methods. Fourteen patients (average age, 45 years) were treated with cyclophosphamide (4.5 g/m 2 ), followed by granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral stem cell harvests. The subsequent regimen prescribed three courses of carboplatin (1 g/m 2 ) and cyclophosphamide (1.5 g/m 2 with 2-mercaptoethanesulfonate) every 2 weeks with stem cell support. This was followed by three courses of paclitaxel at 250 mg/m 2 every 2 weeks with G-CSF support only. Six patients were entered on the basis of a positive second-look laparotomy and 8 patients had a first recurrence after at least a 6-month disease-free interval. Results. Fourteen patients were entered and 12 patients completed all planned courses of therapy (mean time, 13 weeks). Normal hematopoiesis was reestablished after each cycle. Hospitalization for neutropenic fever occurred in 11/93 cycles (11.8%). Thirteen patients required blood transfusions and in 12 patients platelet transfusions were given. One patient had grade 3 neurotoxicity. An initial elevated CA 125 returned to normal in 7/8 patients (88%) and 71% of patients with measurable disease responded to therapy. There were 2 pathologic complete responders (PCR), making the PCR rate 2/14 or 14% (0–35%). Conclusion. Although this regimen was well tolerated and clinical response rates were high, the surgically documented response rate was not clearly superior to conventional salvage regimens in platinum-sensitive patients.

To determine characteristics predictive of persistent ectopic pregnancy (EP).Retrospective cohort study.Tertiary care, university hospital.All women treated surgically for an EP whose postoperative hCG levels were followed until complete resolution or determination of a persistent EP over a 54-month period.Final outcome defined as successful treatment or persistent EP.Twenty-six (17.7%) of 147 patients were diagnosed with a persistent EP. An inverse relationship was noted between the percent decrease in hCG at postoperative day 1 and the incidence of persistent EP. A significantly greater percentage of persistent EPs were noted when the postoperative day 1 hCG fell50% from the initial preoperative hCG level (relative risk = 3.51 [1.25 to 6.68]). No case of persistent EP was noted if the postoperative day 1 hCG declined byor = 77%. Surgical time differed significantly (129 minutes versus 101 minutes) between cases treated successfully as compared with cases in which conservative treatment failed. No other preoperative or intraoperative variables were found to be significantly different.Although no single postoperative hCG value is predictive of conservative surgical treatment for EP, a day-1 postoperative hCG value may be used as a predictor of persistent EP.

We tested the hypothesis that ovarian cancers associated with germ-line mutations of BRCA1 have distinct clinical and pathological features as compared with sporadic ovarian cancers.We reviewed clinical and pathological data on patients with primary epithelial ovarian cancer found to have germ-line mutations of BRCA1. Survival among patients with advanced-stage cancer and such mutations was compared with that in control patients matched stage, grade, and histologic subtype of the tumors. A combination of single-strand conformation and sequencing analyses was used to examine the 22 coding exons and intronic splice-donor and splice-acceptor regions of BRCA1 for mutations in pathological specimens. Alternatively, some patients were known to be obligate carriers of the mutant BRCA1 gene because of their parental relationships with documented mutant-gene carriers.We identified 53 patients with germ-line mutations of BRCA1. The average age at diagnosis was 48 years (range, 28 to 78). Histologic examination in 43 of the 53 patients showed serous adenocarcinoma. Thirty-seven tumors were of grade 3, 11 were of grade 2, 2 were of grade 1, and 3 were of low malignant potential. In 38 patients, the tumors were of stage III; 9 patients (including those with tumors of low malignant potential) had stage I disease, 5 had stage IV, and 1 had stage II. As of June 1996, with a median follow-up among survivors of 71 months from diagnosis, 20 patients had died of ovarian cancer, 27 had no evidence of the disease, 4 were alive with the disease, and 2 had died of other diseases. Actuarial median survival for the 43 patients with and advanced-stage disease was 77 months, as compared with 29 months for the matched controls (P0.001).As compared with sporadic ovarian cancers, cancers associated with BRCA1 mutation appear to have a significantly more favorable clinical course.

OBJECTIVE: This study evaluates overexpression of the p53 protein and point mutation in the p53 gene in a group of patients with stage IB and IIA cervical cancer. STUDY DESIGN: We reviewed the medical records of all patients who underwent radical hysterectomy for the treatment of stage IB and IIA cervical cancer between 1980 and 1985 at Memorial Sloan-Kettering Cancer Center. Overexpression of p53 protein was determined with the use of immunohistochemistry on fixed and paraffin-embedded tissue. Two blocks were selected for each tumor, and tissue sections from each block were tested with both monoclonal (Ab-6) and polyclonal (CM-1) anti-p53 antibodies. Molecular analysis for determination of specific p53 gene mutations was performed with single-strand conformation polymorphism analysis. A group of 132 patients was identified for inclusion in the study. RESULTS: Fifty-eight of 132 tumors (44%) showed overexpression of the p53 protein and were subjected to molecular analysis. Discrepancy between pairs of blocks (7/132, 5.3%) and between antibodies for the same block (5/264, 1.9%) was uncommon. High-level overexpression was rare (5/132, 3.8%). No difference in survival was found on the basis of overexpression of p53 protein. Only one of the 58 cases (1/58, 1.7%) that showed overexpression of the p53 protein exhibited a point mutation (exon 8) in p53 by single-strand conformation polymorphism. This case had a low level of overexpression of p53 protein on immunohistochemistry. CONCLUSIONS: Low levels of overexpression of p53 were frequently seen in early cervical cancers (40/132, 30%). However, mutation of the p53 gene was rarely seen in these tumors. Overexpression of p53 protein as detected by immunohistochemistry is not predictive of a somatic mutation in the p53 gene in cervical cancer. Molecular analysis is required for confirmation of p53 mutations in these tumors. (Am J Obstet Gynecol 1996;175:1266-71.)

Our purpose was to test the feasibility of adenovirus-mediated gene therapy of ovarian cancer.Ovarian cancer cell lines were exposed to an adenovirus vector expressing a reporter gene (lacZ) and to the same vector bearing the herpes simplex virus thymidine kinase gene (Ad.RSVtk) followed by ganciclovir. lacZ expression and growth inhibition were quantitated. Immunodeficient mice were injected intraperitoneally and subcutaneously with human ovarian cancer cells and treated with Ad.RSVtk and ganciclovir. Statistical analyses included one-way analysis of variance and t tests.Staining for lacZ demonstrated viral transduction in vitro. After exposure to Ad.RSVtk all cell lines showed significant (p0.0001, analysis of variance) cytotoxicity to ganciclovir. Human ovarian tumor cells established subcutaneously or intraperitoneally in immunodeficient mice responded to therapy with Ad.RSVtk followed by ganciclovir. Treated mice had a 10- to 20-fold lower subcutaneous tumor burden than did control mice. Additionally, no intraperitoneal tumors were observed in treated mice.Ovarian cancer cells are readily transduced with recombinant adenovirus and become sensitive to ganciclovir after transduction with Ad.RSVtk. These data support the development of this method for human clinical trials.

The Internet is a computer network accessible to over 30 million computer users worldwide. By default, it has become the “information superhighway” that is growing at an explosive rate of between 1 and 2 million new users per month. Internet contains thousands of information servers covering a bewildering array of topics. Many provide information of interest to cancer patients and healthcare professionals. Identifying the outstanding “golden” resources from the chaos is difficult. To address this problem and to provide information specific to gynecologic oncology, we developed a cancer information server called “OncoLink” at our institution that is available at no cost 24 hr per day, 7 days per week to all Internet users. OncoLink has two major goals: (1) To provide quality, original content for cancer patients and healthcare professionals and (2) to provide well-organized, consistent access to existing Internet cancer resources. This service may be used by anyone with a Microsoft Windows, Apple Macintosh, or UNIX computer. The service is rich in multimedia content containing text, pictures, illustrations, sound, and video. The information includes (1) original content written by authors at our institution, (2) original content submitted by authors from other institutions and, (3) publicly available information from other resources. Patient-oriented articles, physician-oriented review articles, and NIH, NCI, and FDA documents are available. All content is reviewed by an Editorial Board prior to posting. We have kept a detailed log file of each time the system has been accessed by an Internet user. OncoLink went online in March 1994. During the first 18 months (542 days) of operation, the service received 4,051,901 requests for information from 105,589 unique Internet addresses worldwide. There is tremendous public and professional demand for online cancer information via the Internet. We feel that the Internet is an outstanding vehicle for providing quality cancer information for gynecologic oncologists other healthcare professionals, and the public.

Heat shock response (HSR) that protects cells from proteotoxic stresses is downregulated in aging, as well as upon replicative senescence of cells in culture. Here we demonstrate that HSR is suppressed in fibroblasts from the patients with segmental progerioid Werner Syndrome, which undergo premature senescence. Similar suppression of HSR was seen in normal fibroblasts, which underwent senescence in response to DNA damaging treatments. The major DNA-damage-induced signaling (DDS) pathways p53–p21 and p38-NF-kB-SASP contributed to the HSR suppression. The HSR suppression was associated with inhibition of both activity and transcription of the heat shock transcription factor Hsf1. This inhibition in large part resulted from the downregulation of SIRT1, which in turn was because of decrease in the expression of the translation regulator HuR. Importantly, we uncovered a positive feedback regulation, where suppression of Hsf1 further activates the p38–NF-κB-SASP pathway, which in turn promotes senescence. Overexpression of Hsf1 inhibited the p38–NFκB-SASP pathway and partially relieved senescence. Therefore, downregulation of Hsf1 plays an important role in the development or in the maintenance of DNA damage signaling-induced cell senescence.

Because ovarian cancer is asymptomatic until the late stages of the disease and because accurate methods of early detection are lacking, only about 40% of these cancers present in stages I and II. As a result, ovarian carcinoma remains the leading cause of death from gynecologic malignancy in the United States. However, proper management of early cases may lead to a good prognosis for long-term survival and, in some cases, may even permit preservation of reproductive capacity. The appropriate management of these early cases includes meticulous and thorough staging at the time of the initial surgery. In women who do not desire further reproduction, total abdominal hysterectomy and bilateral salpingo-oophorectomy should be carried out. In those who eagerly wish to maintain reproductive potential, the uterus and contralateral ovary may be preserved, providing certain criteria have been met. Patients with stage Ia or Ib grade 1 disease can be followed-up without further therapy after definitive surgery; those with Ic or grade 3 tumors should receive adjuvant therapy. Patients with stage I epithelial ovarian cancer who are without evidence of disease after comprehensive staging surgery and primary adjuvant chemotherapy do not require second-look laparotomy. In the future, laparoscopy will play an increasingly important role in the diagnosis and management of early-stage epithelial ovarian cancer.

With the ready availability of powerful desktop computers, the ability to manage large clinical databases has become practical. A computer can enhance the capability of a gynecologic oncology service to catalog, recall, and analyze data about patients, tumors, and therapies. While commercially available database packages can be used for this purpose, we have developed a custom database for tracking the clinical activity of a busy gynecologic oncology service. The system catalogs data about patients, admissions, tumors, and therapeutic modalities and uses this information to generate several useful reports. The reports are used for daily patient care, fellow and resident case statistics, and clinical research. What is unique about the system is that it is optimized for ease of use. The development of this tumor registry, its user friendliness, and advantages over a manual recordkeeping system are described. Unlike other tumor registries, our system is utilized on a daily basis for patient care. Therefore, the data being entered have an immediate usefulness in addition to being simultaneously added to the tumor register for retrospective clinical research. One may hypothesize that it would be useful if all gynecologic oncology services used a common computerized tumor registry that could allow for the sharing of information on a national or global Scale.

Recombinant strains of herpes simplex virus-1 (HSV-1) harboring mutations in the infected cell product (ICP)34.5 region lose their neurovirulence and replicate more efficiently in dividing tumor cells than stationary cells, becoming replication-selective oncolytic agents. Additional mutation of the ICP6 gene, which encodes ribonucleotide reductase, further impairs the ability of HSV-1 mutants to replicate in normal cells, enhancing tumor selectivity. The present study investigated the effect of HSV-G207, a recombinant HSV-1 lacking ICP34.5 and ICP6, against epithelial ovarian cancer (EOC) in vitro and in vivo in a mouse xenograft model. To assess the selectivity of multimutated HSV-G207 against malignant cells, HSV-G207 and wild-type HSV-F were comparatively tested against normal human peritoneal mesothelial cells and EOC cells in vitro. HSV-G207 infected both EOC cells and mesothelial cells; however, unlike EOC cells, mesothelial cells provided a poor substrate for replication of HSV-G207. In contrast to wild-type HSV-F, HSV-G207 exerted a potent oncolytic effect on EOC cells but spared normal mesothelial cells in vitro. Primary EOC cells were more sensitive to the virus than established EOC cell lines. A single intraperitoneal injection of HSV-G207 resulted in a significant reduction in tumor volume and tumor spread in vivo. HSV-G207 was shown to penetrate deeply within tumor nodules and caused no apparent intraperitoneal toxicity. Oncolytic therapy with multimutated replication-restricted HSV may offer a novel approach in the treatment of EOC.

Objective. The aim of this study is to evaluate the clinical characteristics of clear cell carcinoma of the ovary. Methods. Between 1986 and 1996, 45 patients with clear cell carcinoma of the ovary were identified by scanning the medical records department and the tumor registry at our institution. Results. Median age was 55 years (range 31–80 years). Tumors were 60% (27/45) stage I, 11% (5/45) stage II, 20% (9/45) stage III, and 9% (4/45) stage IV. All patients presented with a pelvic mass ranging in size from 2 × 3 to 20 × 30 cm and all except 1 had optimal cytoreduction. All patients received postoperative platinum-based chemotherapy, 47% (21/45) in combination with paclitaxel. One stage Ia patient refused therapy. Of the 6 stage III/IV patients with measurable residual tumor, 67% (4/6) partially responded to first line chemotherapy by CT scan or second look laparotomy. Recurrences occurred in 37% (10/27) stage I patients, including 18% (2/11) stage Ia, 33% (1/3) stage Ib, and 54% (7/13) stage Ic. Time to recurrence was 16 and 38 months for the two stage Ia patients and 35 months (median, range 18–56 months) for the stage Ic patients. Survival after recurrence was significantly related to disease-free interval after primary chemotherapy. With a median follow-up of 40 months (range 4–145 months), 93% (25/27) of stage I patients are alive, 20% (5/25) with disease, while 46% (6/13) of stage III/IV patients are alive. Median survival for the stage III/IV patients was 22 months (range 4–70 months). Conclusions. Clear cell tumors of ovary frequently present at early stages. However, these tumors have a propensity for recurrence even after primary chemotherapy in early stage tumors.

Treatment options for epithelial ovarian cancers are under constant evolution. Recent advances have occurred in both first-line and second-line chemotherapeutic regimens. A newly published approach to first-line therapy incorporating intraperitoneal chemotherapy has demonstrated a benefit in selected patients. There are several new drugs showing activity in platinum-resistant epithelial ovarian cancer.

Cytoreductive surgery plays a central role in the management of advanced ovarian cancer and selected patients with other gynecologic malignancies. It is one of the most challenging procedures preformed by the gynecologic oncologist. Since the entire peritoneal cavity is often involved with tumor in advanced gynecologic malignancies, surgical skill and sound judgment are needed to determine the extent of a cytoreductive effort in each individual case. The goal of cytoreductive surgery is simple: to remove as much tumor bulk as possible without compromising vital organs or producing untoward morbidity. As such, each operation is unique and must be tailored to the individual patient based upon intraoperative findings. For example, it may be appropriate to resect bowel, excise a portion of diaphragm, and perform a splenectomy if these procedures will afford optimal debulking. However, these procedures would add needless morbidity if they were performed in a patient in whom the pelvic tumor was unable to be resected. The technical details for performing surgical cytoreduction of intraabdominal tumor have been described elsewhere [1] and are not reiterated in this chapter. Instead this review focuses on new and controversial developments related to cytoreductive surgery for gynecologic malignancies.

In order to determine whether optimal surgical debulking in Stage IV epithelial ovarian cancer impacts survival, a retrospective review of patients treated at the University of Pennsylvania Cancer Center (UPCC) from 1984 to 1995 diagnosed with Stage IV epithelial ovarian cancer was performed. Data were collected regarding grade, histology, reason for allocation to Stage IV, extent of surgery performed and residual disease at initial staging procedure, major perioperative complications, first-line chemotherapy regimen, length of inpatient hospital stay, outcome at second-look laparotomy, follow-up, and survival. For the purposes of this study, optimal cytoreduction was defined as a residual disease of 2 cm or less. Forty-seven patients with Stage IV epithelial ovarian cancer identified in the Society of Gynecologic Oncologists (SGO) Database at UPCC are included. Fourteen of 47 (30%) were optimally cytoreduced at the time of their staging procedure. Twenty-six of 47 (55%) were deemed Stage IV by virtue of positive pleural effusion cytology only. Twenty-one of 47 (45%) had intraparenchymal liver involvement or metastatic disease outside of the abdomen. The median survival of the suboptimally debulked group was 17 months, while median survival in the optimal group was 37 months (P = 0.0295). These data suggest that Stage IV epithelial ovarian cancer patients with less than 2 cm residual disease have a survival advantage over patients with greater than 2 cm residual.

To determine whether survival from gynecologic cancer is different between African-American and white patients at an inner-city hospital with both a large clinic and a private service.We studied 538 patients (89 African American, 449 white) diagnosed with cervical, uterine, or ovarian cancer at a single institution from January 1, 1989 through December 31, 1993. Information was obtained on age, stage, site of disease, histology, and type of health insurance (public or commercial). Insurance coverage was used as a proxy for socioeconomic status. Overall survival was estimated by the method of Kaplan and Meier and compared by the log-rank test. Cox proportional hazard modeling was used to evaluate the effects of multiple factors on survival.African-American patients were significantly older and were more likely to have cervical cancer and public insurance than white patients. Overall survival was worse for African-American patients than for white patients (P.05). However, stage for stage, there was no significant difference in survival between the groups. There was also no difference when patients were grouped by insurance status. African Americans had a significantly worse survival for cervical cancer than whites, and African-American patients older than 65 years had a worse survival than whites of similar age. On multivariate analysis, only stage and insurance coverage were significant predictors of survival.African-American patients with gynecologic cancer at our institution have worse overall survival than white patients. The survival difference seems to be due predominantly to differences in socioeconomic status and stage at diagnosis.

To evaluate the effect of platinum-based chemotherapy on tumor response in patients with advanced-stage serous ovarian carcinoma of low malignant potential.We conducted a retrospective review of hospital records, pathology slides, and office charts of patients identified as having Stage III or IV serous ovarian cancer of low malignant potential.Between November 1979 and April 1993, 21 patients with advanced-stage serous ovarian carcinoma of low malignant potential received platinum-based chemotherapy following initial cytoreductive surgery. The amount of residual disease was recorded in 20 patients; 8 (40%) had macroscopic residual tumor2 cm in largest diameter, and 12 (60%) had only microscopic disease. Sixteen patients underwent a second-look laparotomy following chemotherapy; 10 (62.5%) had no evidence of disease, 1 (6%) had a partial response, 2 (12.5%) had stable disease, and 3 (19%) had progressive disease. During a mean follow-up of 64 months, only 1 patient had died of disease. She had progressive disease noted at second-look laparotomy. Five of 6 patients who did not have a complete response to initial chemotherapy underwent further therapy with oral etoposide (1), intraperitoneal platinum (2), intraperitoneal mitoxantrone (1), or both (1). The sixth patient received no further therapy. Three of the patients subsequently receiving salvage intraperitoneal therapy underwent a third-look laparotomy. Two had partial responses noted, while the third patient had stable disease.Platinum-based chemotherapy is effective in achieving surgically documented responses in patients with advanced-stage serous ovarian tumors of low malignant potential. The benefit of this therapy in improving survival is unproven.

Surgery has a significant role in the management of most gynecologic cancers. Recent developments in the diagnosis and management of ovarian, cervical, endometrial, and vulvar cancer are worthy of addressing in this review. Significant advances have occurred in the understanding of molecular genetic lesions, leading to a predisposition for ovarian cancer that may have a profound influence on prophylactic oophorectomy. Interval debulking surgery may provide a survival advantage for patients with advanced ovarian cancer. The loop electrosurgical excision procedure has become an integral part of the management of preinvasive disease of the cervix. Advances in the application of surgical stapling devices may lead to reduced operative time and blood loss for radical hysterectomy. Recent studies have addressed the adequacy of endometrial biopsy for the evaluation of postmenopausal bleeding. Advances in lymphatic mapping techniques have led to a novel application to the intraoperative identification of the sentinel node in vulvar cancer.