Tumor-reactive antibodies evolve from non-binding and autoreactive precursors.

The tumor microenvironment hosts antibody-secreting cells (ASCs) associated with a favorable prognosis in several types of cancer. Patient-derived antibodies have diagnostic and therapeutic potential; yet, it remains unclear how antibodies gain autoreactivity and target tumors. Here, we found that somatic hypermutations (SHMs) promote antibody antitumor reactivity against surface autoantigens in high-grade serous ovarian carcinoma (HGSOC). Patient-derived tumor cells were frequently coated with IgGs. Intratumoral ASCs in HGSOC were both mutated and clonally expanded and produced tumor-reactive antibodies that targeted MMP14, which is abundantly expressed on the tumor cell surface. The reversion of monoclonal antibodies to their germline configuration revealed two types of classes: one dependent on SHMs for tumor binding and a second with germline-encoded autoreactivity. Thus, tumor-reactive autoantibodies are either naturally occurring or evolve through an antigen-driven selection process. These findings highlight the origin and potential applicability of autoantibodies directed at surface antigens for tumor targeting in cancer patients.

Proteomic signature for detection of high-grade ovarian cancer in germline BRCA mutation carriers.

No current screening methods for high-grade ovarian cancer (HGOC) guarantee effective early detection for high-risk women such as germline BRCA mutation carriers. Therefore, the standard-of-care remains risk-reducing salpingo-oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high-risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7-protein diagnostic signature, with AUC >0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was >0.94 and the NPV >99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high-risk for HGOC and the application of the BRCA-specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility and safety. Similar classifier for an average-risk population is warranted.

Microvesicle Proteomic Profiling of Uterine Liquid Biopsy for Ovarian Cancer Early Detection.

High-grade ovarian cancer (HGOC) is the leading cause of mortality from gynecological malignancies, because of diagnosis at a metastatic stage. Current screening options fail to improve mortality because of the absence of early-stage-specific biomarkers. We postulated that a liquid biopsy, such as utero-tubal lavage (UtL), may identify localized lesions better than systemic approaches of serum/plasma analysis. Further, while mutation-based assays are challenged by the rarity of tumor DNA within nonmutated DNA, analyzing the proteomic profile, is expected to enable earlier detection, as it reveals perturbations in both the tumor as well as in its microenvironment. To attain deep proteomic coverage and overcome the high dynamic range of this body fluid, we applied our method for microvesicle proteomics to the UtL samples. Liquid biopsies from HGOC patients (n = 49) and controls (n = 127) were divided into a discovery and validation sets. Data-dependent analysis of the samples on the Q-Exactive mass spectrometer provided depth of 8578 UtL proteins in total, and on average ∼3000 proteins per sample. We used support vector machine algorithms for sample classification, and crossed three feature-selection algorithms, to construct and validate a 9-protein classifier with 70% sensitivity and 76.2% specificity. The signature correctly identified all Stage I lesions. These results demonstrate the potential power of microvesicle-based proteomic biomarkers for early cancer diagnosis.

Neoadjuvant Chemotherapy for Elderly Patients with Advanced Stage Ovarian Carcinoma.

BACKGROUND: The treatment of elderly patients with advanced stage ovarian carcinoma is challenging due to a high morbidity. OBJECTIVES: To evaluate the clinical course and outcome of elderly patients with advanced stage ovarian carcinoma receiving neoadjuvant chemotherapy (NACT). METHODS: A retrospective study of all patients with stage IIIC and IV ovarian carcinoma receiving NACT in one medical center (between 2005 and 2017). The study group criteria age was above 70 years. The control group criteria was younger than 70 years old at diagnosis. Demographics and treatment outcomes were compared between groups. Primary outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: Overall, 105 patients met the inclusion criteria, 71 patients (67.6%) were younger than 70 years and 34 patients (32.4%) older. Rates of interval cytoreduction were significantly higher in younger patients (76.1% vs. 50.0%, P = 0.01). Of those who underwent interval cytoreduction, no difference was found in rates of optimal debulking between groups (83.35% vs. 100%, P = 0.10). Using a Kaplan-Meier survival analysis, no significant differences were observed between groups in PFS or OS, P > 0.05. Among the elderly group alone, patients who underwent interval cytoreduction had significantly longer PFS than those without surgical intervention (0.4 ± 1.7 vs. 19.3 ± 19.4 months, P = 0.001). CONCLUSIONS: Elderly patients with ovarian carcinoma who received NACT undergo less interval cytoreduction than younger patients, with no difference in PFS and OS. However, among the elderly, interval cytoreduction is associated with significantly higher PFS.

Malignant Ascites: Validation of a Novel Ascites Symptom Mini-Scale for Use in Patients With Ovarian Cancer.

BACKGROUND: Ascites is a common finding in patients with ovarian cancer. Paracentesis is a relatively simple, safe, and effective procedure for draining fluid from the peritoneum, but valid quality-of-life tools are needed to determine its subjective value for alleviating symptoms and improving patient quality of life. The objective of this study was to prospectively evaluate the performance of a novel Ascites Symptom Mini-Scale (ASmS) and compare it with a previously available questionnaire. METHODS: Patients with ovarian cancer-related ascites presenting for paracentesis were asked to complete the newly devised ASmS before the procedure and 1 and 24 hours after. Patients also completed a pain assessment scale and a previously validated ascites questionnaire at the same time points. RESULTS: The cohort included 28 patients of median age 68 years (range, 51-86 years), 13 (46.4%) with primary ovarian cancer and 15 with recurrent disease. A median of 3300 mL of ascites was drained. The median score on the ASmS decreased significantly from 21.5 before paracentesis to 11.0 at 1 hour after paracentesis (P < 0.001) and remained low at 24 hours. No demographic factor predicted greater benefit from the procedure. Patients with both mild and severe symptoms reported significant relief. CONCLUSIONS: The ASmS is a robust quality-of-life tool for the specific assessment of symptoms of ovarian cancer-related malignant ascites. It can be used in the clinical trial setting assessing interventions aimed at treating ascites and in the clinic to identify those patients with mild symptoms, who may benefit from paracentesis.

Simple Hysterectomy for Residual Cervical Intraepithelial Neoplasm.

OBJECTIVE: Many patients undergo hysterectomy for the treatment of cervical dysplasia. Factors that correlate with residual high-grade squamous intraepithelial lesions (HGSIL) at hysterectomy are not clear. We set out to determine preoperative features that may predict residual disease for patients treated for cervical dysplasia. MATERIALS AND METHODS: A retrospective database was reviewed for women who underwent simple hysterectomy for HGSIL between 1990 and 2013. Clinical data included age, history of dysplasia, initial treatment, follow-up colposcopy, indications for surgery, time elapsed between initial treatments, and pathology findings after hysterectomy. Significant residual disease was defined as HGSIL or cervical carcinoma. Statistical analyses were performed with the SPSS, independent Student t test, and Pearson χ test. Significance was set at p < .05. RESULTS: Eighty-three women met the study criteria. The indication for hysterectomy was residual histological finding at conization pathology in 30 women and patients' request in 53 women. Residual disease was found in 42 hysterectomy specimens: in 16 of 30 with residual histological finding and in 26 of the 53 patients' request. Reason for the hysterectomy was not statistically significant for residual disease (p = .708). Median age of patients with residual disease was 46.5 years versus 44.1 years for those without residua (p = .02). Postmenopausal patients had a higher rate of residual disease, 12 (32.4%) of the 28 premenopausal patients and 25 (67.6%) of the 54 postmenopausal patients (p = .04). Conization margin status was not associated with residual disease (p = .878). CONCLUSIONS: Older women and those in menopause are at significantly higher risk of residual disease at hysterectomy.

Fertility preservation in women with borderline ovarian tumors - how does it impact disease outcome? A cohort study.

INTRODUCTION: Borderline ovarian tumors are typically indolent neoplasms. Since many are diagnosed in younger women, fertility conservation is an important consideration and has been advocated based on retrospective data. The objective of this study was to identify features impacting on recurrence and survival in a series of borderline ovarian tumors, and to assess the safety of a fertility-sparing approach. MATERIAL AND METHODS: A historical cohort study of consecutive borderline ovarian tumors cases treated at a single institution over 30 years (1981-2011). Data on surgical approach (fertility-sparing or otherwise), disease stage, CA125 levels, histological features, adjuvant treatment and follow-up data were collected. Recurrence and survival were assessed using the Kaplan-Meier method and associations with the variables of interest were evaluated using a multivariate Cox proportional hazards model. RESULTS: 213 patients were included. Of 132 women age 40 years and below at diagnosis, 112 (85%) had a fertility-sparing procedure and 60 (46%) had conservation of an involved ovary. Fifty patients (24%) developed recurrences; fertility preservation (hazard ratio = 2.57; 95% confidence interval 1.1-6; p = 0.029) and advanced stage (hazard ratio = 4.15; 95% confidence interval 2.3-7.6; p < 0.001) were independently associated with recurrence on multivariate analysis. Eleven (5%) patients died of their disease. Fertility preservation was not associated with compromised survival. CONCLUSIONS: Borderline ovarian tumors carry a good prognosis overall. Fertility preservation is associated with a higher risk of disease relapse; however, as most relapses are localized and may be salvaged with surgical treatment, overall survival is not compromised.

Diagnosis of deep pelvic masses on a gynaecology service: Trans-vaginal ultrasound-guided needle aspiration of pelvic solid and cystic lesions.

OBJECTIVES: Women with undiagnosed pelvic lesions are often referred for evaluation and treatment. Transvaginal ultrasound-guided fine needle aspiration (TVUS-FNA) biopsy can assist in making management decisions. We describe our experience with this modality. METHODS: We performed a retrospective chart review of all women who had a TVUS-FNA biopsy between January 2004 and December 2014. Charts were reviewed for clinicopathologic information. The pathologic results of the TVUS-FNA were compared with the final diagnosis. RESULTS: Fifty-nine women underwent TVUS-FNA; the median age was 66 years (range 27-85). Thirty-three lesions were evaluated by fine-needle aspiration biopsy of the solid structure and 26 by aspiration of fluid for cytology. Pathologic feasibility rate was 88% (52/59). Of those with evaluable tissue, the sensitivity of the procedure was 100% and the specificity 92%. Considering the seven inconclusive results, the procedure had sensitivity of 88% (29/33) and specificity of 88% (23/26). Overall accuracy of TVUS-FNA for this patient cohort was 85%. No patient characteristics were found to distinguish between accurate and inaccurate or inconclusive TVUS-FNA result. No complications were noted. CONCLUSIONS: TVUS-FNA offers an excellent modality for the diagnosis and management of deep pelvic lesions otherwise not amenable for histologic evaluation.

Retrospective analysis of prenatal ultrasound of children with Hirschsprung disease.

OBJECTIVE: Hirschsprung disease (HD) is a rare gastrointestinal disorder. Our aim was to study the prenatal ultrasound findings of children who were diagnosed with HD after birth. METHODS: The study population included children who suffered from HD between 1990 and 2008. Data of anomaly scan findings in prenatal ultrasound, demographic and post-natal physical abnormalities and treatment were retrieved from medical files and interviews with the parents. RESULTS: Twenty-two patients confirmed histopathological diagnosis of HD at age of 1 day to 15 months. Nineteen fetuses had anomaly scan during pregnancy, which revealed minor sonographic abnormalities in three fetuses; two of them had hyperechogenic bowel. One fetus with hyperechogenic bowel had polyhydramnion, and another had a family history of three brothers with HD. A third fetus had dilated pelvic kidney. None of them had sonographic evidence of bowel dilatation. After birth, six patients (31%) were found to have other structural anomalies: ventriculoseptal defect, atriseptal defect, atrio-ventricular septal defect, and pyloric stenosis. CONCLUSIONS: Abnormal sonographic findings of fetal bowel are absent in the vast majority of fetuses who are diagnosed with HD after birth. In women with a family history of HD, a third trimester anomaly scan may be warranted.

Malignant Pericardial Effusion in Ovarian Malignancy: A Treatable Oncologic Emergency.

BACKGROUND: Pericardial tamponade is a life-threatening condition that can occur, albeit rarely, in patients with ovarian cancer. Whether or not prolonged survival is possible after such an event is debatable. Our aim was to describe our experience with seven ovarian cancer patients who experienced malignant cardiac tamponade at tumor diagnosis or at recurrence. CASE REPORT: Six patients were treated with pericardiocentesis and one with pericardial fenestration. Survival after tamponade ranged from 3 to 72 weeks. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: We suggest that when pericardial effusion occurs in patients with recurrent ovarian cancer, timely diagnosis and proper management might allow palliation and prolongation of life.

Effect of treatment delay on survival in patients with cervical cancer: a historical cohort study.

OBJECTIVE: The objective of this study was to evaluate the effect of treatment delay on prognosis in patients with cervical cancer. METHODS: The study group of this historic cohort study comprised 321 patients newly diagnosed with cervical cancer between 1999 and 2010. Time from diagnosis to treatment was analyzed both as a continuous variable and as a categorical variable in 3 groups that differed in waiting time between diagnosis and treatment initiation: 30 days or less (group 1, n = 134), 30 to 45 days (group 2, n = 86), and more than 45 days (group 3, n = 101). Associations between waiting time group, patients' characteristics, and disease outcome were investigated using t tests, analyses of variance and Cox regression analyses, Kaplan-Meier survival analysis, and log-rank (Mantel-Cox) tests. RESULTS: Time from diagnosis to treatment initiation, when analyzed as a continuous variable, was not a significant factor in survival. There were no between-group differences in age, smoking rate, marital status, gravidity, parity, tumor histology, or lymph node involvement. Early-stage disease and small tumor diameter were diagnosed most frequently in group 3. However, there was no significant between-group difference in 3-year survival rates (74.6%, 82.2%, and 80.8% in groups 1, 2, and 3, respectively; P = 0.38). On multivariate analysis, only stage, histology, and lymph node involvement were significant prognostic factors for survival. Before starting treatment, 28 patients underwent ovarian preservation procedures. CONCLUSIONS: Longer waiting time from diagnosis to treatment was not associated with worse survival. Our findings imply that if patients desire fertility or ovarian preservation procedures before starting treatment, it is acceptable to allow time for them.

Use of titanium spiral tacks for long-term oophoropexy before pelvic irradiation.

BACKGROUND: Ovarian transposition before planned pelvic irradiation can preserve ovarian function in young patients with pelvic malignancies. The transposed ovaries are fixed to the posterolateral abdominal wall. We described the use of a titanium spiral tack as a fixation device and compared it with other methods of oophoropexy. METHODS: Medical and surgical records of all consecutive patients who underwent oophoropexy in our institution between 2007 and 2013 were reviewed. Demographic and clinical data were summarized; follicle-stimulating hormone values, recorded; and imaging scans, reviewed. RESULTS: Oophoropexy was performed in 30 patients: 28 with cervical carcinomas and 2 with pelvic sarcomas. The procedure was done through laparoscopy in 13 patients and through laparotomy in 17. Titanium spiral tack was used for ovarian fixation in 14 patients, Vicryl suturing in 14, and in 2 cases the ovaries were pulled up through a retroperitoneal tunnel and fixed to the peritoneum with sutures. Titanium spiral tack fixation took a few seconds to perform. There were no immediate intraoperative or postoperative complications. Ovarian function was preserved in 15 patients (7/14 with spiral tack, 6/14 with sutures, and in both patients with retroperitoneal tunneling). Postoperative imaging results showed that all ovaries retained their extrapelvic location for a median period of 11.6 months (range, 2.3-63 months). CONCLUSIONS: Spiral tack is a simple, reliable method for oophoropexy before pelvic irradiation. Its efficacy is comparable with that of suture fixation, with the added advantage of ultrashort operative time. It is therefore worth considering as an alternative to suturing.

Unleashing Natural IL18 Activity Using an Anti-IL18BP Blocker Induces Potent Immune Stimulation and Antitumor Effects.

Recombinant cytokines have limited anticancer efficacy mostly due to a narrow therapeutic window and systemic adverse effects. IL18 is an inflammasome-induced proinflammatory cytokine, which enhances T- and NK-cell activity and stimulates IFNγ production. The activity of IL18 is naturally blocked by a high-affinity endogenous binding protein (IL18BP). IL18BP is induced in the tumor microenvironment (TME) in response to IFNγ upregulation in a negative feedback mechanism. In this study, we found that IL18 is upregulated in the TME compared with the periphery across multiple human tumors and most of it is bound to IL18BP. Bound IL18 levels were largely above the amount required for T-cell activation in vitro, implying that releasing IL18 in the TME could lead to potent T-cell activation. To restore the activity of endogenous IL18, we generated COM503, a high-affinity anti-IL18BP that blocks the IL18BP:IL18 interaction and displaces precomplexed IL18, thereby enhancing T- and NK-cell activation. In vivo, administration of a surrogate anti-IL18BP, either alone or in combination with anti-PD-L1, resulted in significant tumor growth inhibition and increased survival across multiple mouse tumor models. Moreover, the anti-IL18BP induced pronounced TME-localized immune modulation including an increase in polyfunctional nonexhausted T- and NK-cell numbers and activation. In contrast, no increase in inflammatory cytokines and lymphocyte numbers or activation state was observed in serum and spleen. Taken together, blocking IL18BP using an Ab is a promising approach to harness cytokine biology for the treatment of cancer.

Appendectomy and cancer risk in Jewish BRCA1 and BRCA2 mutation carriers.

Previous studies suggested that appendectomy may affect cancer risk in the general population. No data on the effect of appendectomy on cancer risk in BRCA1 and BRCA2 carriers is available. Data on appendectomy, cancer type, and age at diagnosis were collected from BRCA1 (n = 677) and BRCA2 (n = 270) female Jewish Israeli mutation carriers counseled in a single medical center. Data were also collected on 225 consecutive ovarian cancer cases treated at the same medical center. Overall, 367/947 (38.7%) of mutation carriers had breast cancer (age at diagnosis 44.1 ± 10.4 years), 142 (15.0%) ovarian cancer (53.6 ± 10.1 years), and 438 (46.25%) were asymptomatic carriers (age at counseling 41.4 ± 11.2 years). Mean age at diagnosis of consecutive ovarian cancer cases was 53.6 ± 10.1 years. Of mutation carriers, 28/367 breast cancer cases (7.6%), 15/142 ovarian cancer cases (10.6%), and 11/438 asymptomatic carriers (2.5%) underwent prior appendectomy (P = 0.001 for breast/ovarian cancer when compared with asymptomatic carriers). In all but two cases, appendectomy was performed more than 10 years before cancer diagnosis or age at counseling. Of ovarian cancer patients, 12/225 (5.3%) underwent appendectomy, and in 10 appendectomy was performed 10 years or more before ovarian cancer diagnosis (P = 0.068 when compared with inherited ovarian cancer cases). This study suggests that prior appendectomy is more frequently noted in BRCA1 and BRCA2 carriers with breast and ovarian cancer than in unaffected mutation carriers. The mechanism for this association is elusive, and future analyses of ethnically diverse mutation carriers are needed to validate these results.

Neutrophil-to-lymphocyte ratio as a prognostic factor in advanced stage ovarian carcinoma treated with neoadjuvant chemotherapy.

OBJECTIVES: To evaluate the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) upon diagnosis, and its impact on surgical outcome, among patients with advanced stage ovarian carcinoma treated with neoadjuvant chemotherapy (NACT). METHODS: A retrospective cohort study included all women with stage IIIC and IV ovarian carcinoma receiving NACT in Rabin Medical Center, Petah-Tikva, Israel; January 1, 2005, to June 30, 2017. Demographics and treatment outcome were compared between patients with NLR at diagnosis ≥6.0 and those with NLR <6.0. Primary outcome was optimal debulking (<1 cm largest residual disease). Overall survival was compared between groups using Kaplan-Meier survival analysis. RESULTS: Of 111 patients, 33 (29.7%) had NLR ≥6.0 at diagnosis, and 78 (70.3%) had NLR <6.0. No difference was found in rates of optimal debulking between the group with NLR ≥6.0 and that with NLR <6.0 (78.9% vs 84.7%, respectively, P=0.555). Using Kaplan-Meier survival analysis, NLR ≥6.0 was associated with significantly worse overall survival (P<0.05). In a multivariate Cox proportional hazard model, elevated NLR was not statistically associated with poor overall survival (P=0.080). CONCLUSIONS: In advanced stage ovarian carcinoma, NLR ≥6.0 at diagnosis did not predict surgical outcome, however it was a predictive factor for poor overall survival.

Neoadjuvant Chemotherapy Treatment Modifications in Ovarian Carcinoma: The Impact on Surgical Outcome and Progression-free Survival.

OBJECTIVE: Little is known on the impact of neoadjuvant chemotherapy (NACT) treatment modifications on surgical outcome and progression-free survival (PFS) in patients with ovarian carcinoma. We aimed to report the changes we made during NACT and to evaluate its impact on patient outcome. METHODS: A retrospective cohort study of all women with advanced stage ovarian carcinoma treated with NACT followed by interval cytoreduction in one university-affiliated medical center (January 2005 to June 2017). We excluded those who were treated with NACT without any surgical intervention. NACT modifications included delay in treatment, change in chemotherapy, and dose reduction. Demographics, tumor characteristics, surgical outcome, and PFS were compared between patients exposed to NACT treatment modifications and those who received standard treatment. RESULTS: Seventy-nine patients met inclusion criteria of whom, 59 patients received standard, nonmodified treatment and 20 patients modified NACT. There were no intergroup differences with respect to age at diagnosis (59.5±11.6 vs. 64.70±8.09, P=0.09) and stage of disease (P=0.13). Radiologic complete response rates (25.0% vs. 32.2%, P=0.545) and optimal cytoreduction rates (75.0% vs. 86.4%, P=0.23) were similar in both treatment groups. Mean PFS (in months) was comparable between patients receiving standard treatment and those who required NACT modifications (18.5 vs. 12.2, P=0.125). CONCLUSIONS: NACT treatment modifications did not affect surgical outcome and PFS. We conclude that when clinically indicated, dose alteration and scheduling can be implemented without apparent detriment to outcome.

Hysteroscopically guided transvaginal ultrasound tubal catheterization-a novel office procedure.

OBJECTIVE: Investigate a novel office hysteroscopic tubal catheterization therapeutic method for proximal tubal occlusion. STUDY DESIGN: Prospective cohort study in a tertiary referral center. We evaluated the procedure on a group of 27 patients that were referred to our unit for proximal tubal occlusion demonstrated by hysterosalpingography, 9 (33.3%) of them with primary infertility and 18 of them (66.6%) with secondary infertility. The intervention included the usage of the modified Novy cornual cannulation set which was inserted through a 5F working cannel during an office operative hysteroscopy, followed by fallopian tube irrigation with saline-air mixture under ultrasonographic imaging. RESULTS: Our series revealed no complication during or after the procedure; anesthesia was not required. One patient lost from follow-up. Of the remaining 26, 10 patients (38.4%) conceived either spontaneously or with treatment by clomiphene or gonadotropine associated with intrauterine insemination. The median time to conception was 5 months (range 4-17). CONCLUSION: We therefore concluded that office hysteroscopic tubal catheterization is a simple (without anesthesia required) option for the treatment of patients suffering from proximal tubal occlusion. Fertility outcomes in our series are comparable to other treatments options for tubal catheterization. Therefore, tubal catheterization should not delay the assisted reproducted techniques if indicated but we propose to include it in a global integrated approach.

Risk Factors for Cervical Cancer and CIN3 in Jewish Women in Israel - Two Case Control Studies.

PURPOSE: The aim of the study was to identify risk and protective factors/markers for cervical cancer and cervical intraepithelial neoplasia 3 (CIN3) in Israeli Jewish women in order to settle the discrepancy of low incidence rate of cervical cancer and relatively high incidence rate of CIN3. MATERIALS AND METHODS: We conducted two case control studies, which examined the association between potential risk and protective factors/markers for cervical cancer or CIN3 using self administered detailed questionnaires. RESULTS: For studying cervical cancer, 40 cases and 40 matched controls were interviewed. In the univariable and multivariable analyses older age, depression or anxiety and ever smoking seemed to act as independent risk factors/markers, while older age at first intercourse was protective. For studying CIN3, 99 cases and 79 controls were interviewed. Multivariable analysis has demonstrated that being born in Israel, depression or anxiety and ever smoking were independent risk factors/markers for CIN3. CONCLUSIONS: The risk factors/markers studied, that were associated with cervical cancer or CIN3 among Jewish women in Israel, are similar to those reported in other parts of the world, and do not explain the observed discrepancy of high in-situ cervical cancer rates and low invasive cervical cancer incidence in Israel.

Treating gynecologic malignancies in elderly patients.

AIM: To determine the relative benefits of full and partial treatment for gynecologic malignancies in elderly patients. METHODS: A retrospective cohort study of all consecutive patients (n=169) aged 79 and older (median age 82 y; range, 79 to 94 y), diagnosed between 1971 and 2007 with various types of gynecologic malignancies (endometrial, 52%; ovarian, 26%; vulvar, 11%; cervical, 5%; other, 6%) was conducted. Stages were I to II (47%), III to IV (35.5%), and unknown (17.5%). Major comorbidities were hypertension (51%), diabetes (17%), cardiac diseases (34%), and other malignancy (12%). Regardless of age or chronic illnesses, patients were grouped on the basis of having been treated optimally (100 patients; 59.2%), defined as the accepted standard for each diagnosis and stage including surgery and adjuvant radiation or chemotherapy as indicated; or suboptimally (69 patients; 40.8%), that is, no or only partial treatment. Kaplan-Meier survival analysis and Cox proportional hazard models, univariate and multivariable were conducted. RESULTS: For all patients with suboptimal treatment, the age-and-stage-adjusted hazard ratio for death was 1.76 (95% CI, 1.203-2.570; P=0.004) compared with optimal treatment. Age-adjusted hazard ratio was 2.15 (95% CI, 1.127-4.114; P=0.02) and 2.3 (95% CI, 1.415-3.779; P=0.001) for ovarian and endometrial cancer patients, respectively. Age-adjusted and stage-adjusted hazard ratio was 2.8 (95% CI, 1.099-5.157; P=0.028) and 1.53 (95% CI, 0.867-2.702; P=0.1420) for ovarian and endometrial cancer patients, respectively. CONCLUSIONS: Optimal treatment in patients with gynecologic malignancies evidently improves survival in elderly patients at any age, and in patients with ovarian cancer at any stage. Regardless of chronological age, the aim should be to deliver optimal treatment.

Safety of ovarian conservation and fertility preservation in advanced borderline ovarian tumors.

OBJECTIVE: To assess the impact of a fertility-sparing approach on disease recurrence in women with advanced borderline ovarian tumors. DESIGN: Historic cohort study. SETTING: A tertiary referral center for gynecological oncology patients and a university teaching hospital. PATIENT(S): Consecutive patients with advanced borderline ovarian tumors defined as stage IC and above, treated at a single institution during a span of 30 years. INTERVENTION(S): Data on surgical approach (e.g., fertility sparing, ovarian conserving) as well as histopathology, disease stage, CA-125 level, and use of chemotherapy were collected from the medical records, and their impact on disease recurrence was assessed. MAIN OUTCOME MEASURE(S): Recurrence-free interval. Its association with the type of surgery and with other clinical and pathological features was assessed using the Kaplan Meier and Cox proportional hazards methods. RESULT(S): Fifty-nine patients with advanced disease were identified. Median follow-up was 55.3 months. Mean age at diagnosis was 35 years. Most of the tumors (51, 84.4%) had serous histology. Twenty-seven patients (45.8%) developed recurrences and 6 (10%) died of their disease. Mean time to recurrence was 30.6 months. Of 44 women ≤40 years, 33 (75%) had a fertility-sparing procedure. Fertility preservation was not associated with disease recurrence. A total of 34 pregnancies and 26 live births were documented among 21 patients attempting conception. CONCLUSION(S): Borderline ovarian tumors carry a favorable prognosis, even at an advanced stage. Fertility preservation was not found to be associated with an increased risk of relapse in young patients with advanced disease, and may be reasonably considered.