The selenoenzyme type I iodothyronine deiodinase: a new tumor suppressor in ovarian cancer.

The selenoenzyme type I iodothyronine deiodinase (DIO1) catalyzes removal of iodine atoms from thyroid hormones. Although DIO1 action is reported to be disturbed in several malignancies, no work has been conducted in high-grade serous ovarian carcinoma (HGSOC), the most lethal gynecologic cancer. We studied DIO1 expression in HGSOC patients [The Cancer Genome Atlas (TCGA) data and tumor tissues], human cell lines (ES-2 and Kuramochi), normal Chinese hamster ovarian cells (CHO-K1), and normal human fallopian tube cells (FT282 and FT109). To study its functional role, DIO1 was overexpressed, inhibited [by propylthiouracil (PTU)], or knocked down (KD), and cell count, proliferation, apoptosis, cell viability, and proteomics analysis were performed. Lower DIO1 levels were observed in HGSOC compared to normal cells and tissues. TCGA analyses confirmed that low DIO1 mRNA expression correlated with worse survival and therapy resistance in patients. Silencing or inhibiting the enzyme led to enhanced ovarian cancer proliferation, while an opposite effect was shown following DIO1 ectopic expression. Proteomics analysis in DIO1-KD cells revealed global changes in proteins that facilitate tumor metabolism and progression. In conclusion, DIO1 expression and ovarian cancer progression are inversely correlated, highlighting a tumor suppressive role for this enzyme and its potential use as a biomarker in this disease.

Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer.

BACKGROUND: Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States. METHODS: We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes. RESULTS: A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%). CONCLUSIONS: Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).

Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial.

PURPOSE: To explore whether patients with BRCA1/2-mutated or homologous recombination deficient (HRD) ovarian cancers benefitted from atezolizumab in the phase III IMagyn050 (NCT03038100) trial. PATIENTS AND METHODS: Patients with newly diagnosed ovarian cancer were randomized to either atezolizumab or placebo with standard chemotherapy and bevacizumab. Programmed death-ligand 1 (PD-L1) status of tumor-infiltrating immune cells (IC) was determined centrally (VENTANA SP142 assay). Genomic alterations, including deleterious BRCA1/2 alterations, genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI), were evaluated using the FoundationOne assay. HRD was defined as gLOH ≥ 16%, regardless of BRCA1/2 mutation status. Potential associations between progression-free survival (PFS) and genomic biomarkers were evaluated using standard correlation analyses and log-rank of Kaplan-Meier estimates. RESULTS: Among biomarker-evaluable samples, 22% (234/1,050) harbored BRCA1/2 mutations and 46% (446/980) were HRD. Median TMB was low irrespective of BRCA1/2 or HRD. Only 3% (29/1,024) had TMB ≥10 mut/Mb, and 0.3% (3/1,022) were MSI-high. PFS was better in BRCA2-mutated versus BRCA2-non-mutated tumors and in HRD versus proficient tumors. PD-L1 positivity (≥1% expression on ICs) was associated with HRD but not BRCA1/2 mutations. PFS was not improved by adding atezolizumab in BRCA2-mutated or HRD tumors; there was a trend toward enhanced PFS with atezolizumab in BRCA1-mutated tumors. CONCLUSIONS: Most ovarian tumors have low TMB despite BRCA1/2 mutations or HRD. Neither BRCA1/2 mutation nor HRD predicted enhanced benefit from atezolizumab. This is the first randomized double-blind trial in ovarian cancer demonstrating that genomic instability triggered by BRCA1/2 mutation or HRD is not associated with improved sensitivity to immune checkpoint inhibitors. See related commentary by Al-Rawi et al., p. 1645.

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.

Upfront surgery in patients with epithelial ovarian cancer and enlarged supradiaphragmatic lymph nodes associated with comparable to neoadjuvant chemotherapy.

BACKGROUND: There is little data regarding the optimal approach to advanced epithelial ovarian cancer (EOC) with isolated extra-peritoneal disease in the cardiophrenic lymph nodes. This study assessed whether the prognosis and surgical outcomes are affected by the treatment approach among these patients. MATERIAL AND METHODS: This retrospective cohort study included patients with advanced EOC, who were treated 2012-2020. Computed tomography scans were reviewed for disease extent and the presence of enlarged supradiaphragmatic nodes (SDLN). Demographic, clinical and oncologic data were recorded. Characteristics and outcomes of patients with and without enlarged SDLN were evaluated, and outcomes of patients with enlarged SDLN who underwent upfront surgery and neoadjuvant chemotherapy were compared. RESULTS: Among 71 women, 47 (66%) had enlarged supradiaphragmatic lymph nodes. Groups had similar baseline characteristics. Among 47 women who had enlarged SDLN. There was no significant difference in progression free survival among patients who had upfront cytoreduction compared to those who received neoadjuvant chemotherapy. Only one asymptomatic chest recurrence was observed. CONCLUSION: Patients with enlarged SDLN have comparable outcomes with either upfront surgery or neoadjuvant chemotherapy. Moreover, the frequency of chest recurrences in patients presenting with enlarged SDLN is exceedingly low.

Predictors of uncommon location of sentinel nodes in endometrial and cervical cancers.

OBJECTIVE: Sentinel node mapping is widely used in the treatment of gynecologic cancers. The current study aimed to identify predictors of uncommon sentinel lymph node (SLN) locations. METHODS: The current study included women who were operated for endometrial or cervical cancer with attempted sentinel lymph node mapping during surgical staging. Data were collected from electronic charts. The pelvis and the external ilia and obturator basins were common node locations. Para-aortic, pre-sacral, common iliac, internal iliac, and parametrial nodes were considered uncommon locations. We conducted analyses stratified according to common, uncommon, and very uncommon (para-aortic, pre-sacral, parametrial) node location sites. RESULTS: A total of 304 women were enrolled in the current study; 15.8% had SLN in uncommon locations and 4.3% had very uncommon node locations. Body mass index (BMI) was a negative predictor for uncommon SLN locations (OR 0.88, p = 0.03). The use of either indocyanine green (ICG) or Tc99 & blue dye was an independent predictor for uncommon SLN locations (OR 8.24, p = 0.006). More recent surgeries and the presence of positive nodes were independent predictors for very uncommon node locations (OR 2.13, p = 0.011, and OR 9.3, p = 0.002, respectively). CONCLUSIONS: BMI, tracer type, surgical year, and positive nodes were independent predictors for uncommon SLN locations. These findings suggest that surgical effort, technique and experience may result in better identification of uncommon SLN locations.

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001.

BACKGROUND: Pembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer (KEYNOTE-146/Study 111) after ≤2 previous lines of therapy. In a randomized phase 3 trial of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer (KEYNOTE-775/Study 309), after 1‒2 previous lines of therapy (including neoadjuvant/adjuvant), this combination improved objective response rates, progression-free survival, and overall survival compared with chemotherapy. PRIMARY OBJECTIVE: To compare the efficacy and safety of first-line pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease. STUDY HYPOTHESIS: Pembrolizumab plus lenvatinib is superior to chemotherapy with respect to progression-free survival and overall survival in patients with mismatch repair-proficient tumors and all patients (all-comers). TRIAL DESIGN: Phase 3, randomized (1:1), open-label, active-controlled trial. Patients will receive pembrolizumab intravenously every 3 weeks plus lenvatinib orally daily or paclitaxel plus carboplatin intravenously every 3 weeks, stratified by mismatch repair status (proficient vs deficient). Patients with mismatch repair-proficient tumors will be further stratified by Eastern Cooperative Oncology Group performance status (0/1), measurable disease (yes/no), and prior chemotherapy and/or chemoradiation (yes/no). MAJOR INCLUSION/EXCLUSION CRITERIA: Adults with stage III/IV/recurrent histologically confirmed endometrial cancer that is measurable or radiographically apparent per blinded independent central review. Patients may have received previous chemotherapy only as neoadjuvant/adjuvant therapy and/or concurrently with radiation. Patients with carcinosarcoma (malignant mixed Müllerian tumor), endometrial leiomyosarcoma, or other high grade sarcomas, or endometrial stromal sarcomas were excluded. PRIMARY ENDPOINTS: Progression-free and overall survival (dual primary endpoints). SAMPLE SIZE: About 875 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Enrollment is expected to take approximately 24 months, with presentation of results in 2022. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03884101.

High grade, advanced, serous ovarian cancer with low serum CA125 levels.

This study compares characteristics of advanced stage, high grade serous ovarian cancer, presenting with high or low serum CA125 level. This was a retrospective cohort of 118 patients with high grade serous ovarian, fallopian tube or primary peritoneal cancer, stages IIIC-IV diagnosed from January 1 1997 through January 9 2017. Patient demographics, tumour characteristics, surgical findings, chemotherapy protocols and clinical outcomes were collected. Three groups were evaluated: group A: 21 patients with CA125 serum level ≤152 U/ml, group B: 97 patients with CA125 serum level >152 U/ml, group C: 43 patients from group B with CA125 serum level >500 U/ml and <1000 U/ml. No significant difference was found between groups regarding age, stage at diagnosis, extent of residual disease or disease volume. More group A patients had surgery as primary treatment compared to groups B and C (p=.003, p=.022, respectively). CA125 level at recurrence was lower in group A as compared to the other groups (162.2 vs. 851.7 and 603.4, p=.003, p=.006). Overall survival and progression-free survival did not differ based on CA125 levels. We conclude that patients with advanced stage, high grade, serous ovarian cancer with low CA125 serum levels had the same clinical outcome as patients with higher levels.Impact StatementWhat is already known on this subject? It is known that CA125 level is a prognostic and predictive factor for epithelial ovarian cancer (EOC) outcome. It is elevated in 80% of the patients and within normal range in only 10% of women with advanced stage EOC. Various studies had addressed the patients with advanced stage serous EOC who had high serum CA125 levels at time of diagnosis. But, no study has addressed the 10% of patients with advanced stage who had low serum CA125 levels at time of diagnosis.What the results of this study add? To the best of our knowledge, this is the first study addressing patients with advanced stage EOC who had low serum CA125 levels at time of diagnosis. According to the results of this study, patients with advanced stage, high grade serous EOC presenting with low serum CA125 levels have similar clinical outcomes as do patients with high serum CA125 levels.What the implications are of these findings for clinical practice and/or further research? Further translational research is encouraged for this group of tumours to identify specific molecular markers that might lead to better understanding and treatment for the disease.

Time interval from biopsy to surgery and risk for adjuvant therapy in patients with low-risk endometrial cancer.

OBJECTIVE: Among patients with endometrial cancer, longer wait times to surgery were associated with decreased survival. Although endometrial cancer survival rate is high, about 45% of patients receive adjuvant therapy. The aim of this study was to examine whether a longer interval from diagnosis to surgery is associated with increased need for adjuvant treatment among patients with low-risk endometrial cancer. METHODS: A retrospective cohort study of endometrioid endometrial cancer patients treated with surgery between the years 1999 and 2013 was conducted. Patients with pre-operative histology of hyperplasia, grade 1/2 cancers were included. Patients with stage IV disease were excluded. Demographic, clinicopathologic and surgical parameters were collected and correlation with wait time was evaluated. The risk for adjuvant therapy was in two-week intervals from biopsy to hysterectomy. RESULTS: 468 patients were included in the final cohort. 84.3% had stage I disease and 43.8% patients received adjuvant treatment. Mean time from diagnosis to surgery was 63.88 days (SD 10.3, 31-94). The risk for adjuvant therapy was not increased at any of the time intervals that were examined. CONCLUSION: In low risk endometrial cancer, longer time interval between diagnosis and surgery did not increase the need for adjuvant therapy.

Chemotherapy Toxicity in BRCA Mutation Carriers Undergoing First-Line Platinum-Based Chemotherapy.

OBJECTIVE: BRCA mutations are the most frequent mutations causing homologous recombination defects in epithelial ovarian cancers (EOC). Germline mutation carriers are heterozygous for the mutation and harbor one defective allele in all cells. This has been hypothesized to cause increased susceptibility to DNA damage in healthy cells as well as neoplastic ones. Our objective was to assess chemotherapy-associated toxicities in patients with epithelial ovarian cancer with and without a germline BRCA mutation. MATEIALS AND METHODS: A retrospective cohort study of patients with EOC receiving first-line platinum-based chemotherapy at a single center between 2006 and 2016. Indices of chemotoxicity, including blood counts, transfusion requirements, granulocyte colony-stimulating factor (gCSF) prescriptions, episodes of febrile neutropenia, and treatment delays were compared for BRCA mutation carriers and noncarriers. RESULTS: A total of 90 women met the inclusion criteria, including 31 BRCA mutation carriers (34%) and 59 noncarriers (66%). Mean hemoglobin, neutrophil count, and platelet counts during treatment were comparable for the two patient groups. There was a trend toward a higher frequency of hematological events in BRCA mutation carriers (neutropenia <1500 per mL: 6% vs. 0%, p = .12; thrombocytopenia <100,000 per mL: 23% vs. 9%, p = .07), but these differences were not statistically significant. Similarly, no significant differences were found in surrogates of bone marrow toxicity such as blood transfusions, use of gCSF, episodes of febrile neutropenia, or treatment delays. CONCLUSION: BRCA mutation carriers and noncarriers receiving first-line platinum-based chemotherapy for EOC have similar hematologic toxicity profiles. Clinicians treating these patients can be reassured that chemotherapy dosing or schedule do not require adjustment in patients carrying BRCA mutations. IMPLICATIONS FOR PRACTICE: Patients with ovarian cancer carrying BRCA mutations are more likely to have serous tumors and present with higher CA125 levels. Germline BRCA mutation status is not associated with increased frequency of adverse hematologic events among patients with ovarian cancer being treated with first-line platinum-based chemotherapy. Germline BRCA mutations are also not associated with more treatment delays or a lower number of courses completed in this patient population. These findings should reassure practitioners engaged in care for patients with ovarian cancer that BRCA mutation status most likely will not affect chemotherapy dosing or schedule.

Conservative management for postmenopausal women with tubo-ovarian abscess.

OBJECTIVES: The aim of the study was to describe the experience of one institution in management and outcome of tubo-ovarian abscess (TOA) in pre- and postmenopausal women and to reassess the optimal approach for TOA in postmenopausal women. METHODS: A retrospective cohort study included women diagnosed with TOA between 2003 and 2017 in a tertiary referral center. TOA was diagnosed by sonography or computerized tomography and at least one of the following criteria: temperature more than 38°C, leukocytosis more than 15,000 mm, or surgically proven disease. Women were followed up for a mean of 7.6 years (range 6 mo to 14 y). The rates of conservative management and pelvic malignancy were evaluated. RESULTS: The study cohort included 144 (69.23%) women who met the inclusion criteria, of which 105 (72.92%) were premenopausal and 39 (27.08%) were postmenopausal. Univariate analysis found no differences in risk factors and disease characteristics between the two groups. Among the study sample, 22 (56.4%) postmenopausal women and 48 (45.7%) premenopausal women were treated surgically (P = 0.5). None of the premenopausal women and 1 (2.6%) postmenopausal woman were diagnosed with pelvic malignancy. CONCLUSION: In postmenopausal women with TOA, the prevalence of concurrent pelvic malignancy was 2.6%, which is higher than in the general population, but lower than that reported in the literature; 44% were conservatively managed without any apparent cases of misdiagnoses of cancer.

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.

Impact of adjuvant treatment on outcome in high-risk early-stage endometrial cancer: a retrospective three-center study.

OBJECTIVE: High grade and non-endometrioid endometrial cancers carry a poor prognosis, and the lack of randomized prospective data has led to a wide range of practice regarding adjuvant therapy. The objective of this study was to evaluate the outcomes of different treatment strategies in patients with high-risk, early-stage endometrial cancer. METHODS: Patients with high-grade endometrioid, serous endometrial cancer and carcinosarcoma diagnosed between 2000 and 2012 were identified from databases in three gynecologic oncology divisions, in Toronto and in Israel. Adjuvant treatment practices differed across the centers, creating a heterogeneous cohort. A comparison of stage I patients stratified by adjuvant treatment was undertaken. Log-rank tests and Cox proportional hazards models were employed to compare recurrence and survival across treatment groups. RESULTS: 490patients with high risk endometrial cancer were identified, among them 213 patients with stage I disease. Israeli patients received more chemotherapy (41% vs 10% in stage I disease; P<0.001) than patients in Toronto. Chemotherapy was not associated with improved disease-free, disease-specific or overall survival, nor was it associated with fewer distant recurrences (50% vs 54%). Radiation was also not associated with improved recurrence or survival, nor did it affect the pattern of recurrence. On Cox multivariable analysis, neither radiation treatment nor chemotherapy were significantly associated with outcome (HR for recurrence, 0.72 for pelvic radiation (P=0.46) and 1.99 for chemotherapy (P=0.09); HR for death, 0.67 for pelvic radiation (P=0.29) and 1.03 for chemotherapy (P=0.94)). CONCLUSIONS: In this retrospective analysis, neither adjuvant radiation nor chemotherapy were associated with improved outcome in stage I, high risk endometrial cancer.

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.

About different packing states of alkyl groups in comb-like polymers with rigid backbones.

We report a comparative X-ray diffraction study on three series of comb-like polymers with rigid backbones and layered morphologies [regio-regular poly(3-alkyl thiophenes), alkoxylated polyesters, alkoxylated polyphenylenevinylenes] highlighting the importance of the volume per methylene unit VCH2 in alkyl nanodomains for the overall packing state. We demonstrate that there is a large (≈30%) variation in the VCH2 values for different polymer series and packing states but no significant change in VCH2 depending on the length of the alkyl side groups. This calls into question commonly used structural models which are based only on tilting and interdigitation of ideally stretched alkyl side groups. We argue that a linear dependence of the layer spacings with side chain length can also be explained by a constant VCH2 value and unchanged main chain packing. The potential importance of side chain packing for the occurrence of different (liquid-) crystalline modifications in various polymer series and possible interrelations between main and side chain packings are discussed.

Activation-Induced Cytidine Deaminase Links Ovulation-Induced Inflammation and Serous Carcinogenesis.

In recent years, the notion that ovarian carcinoma results from ovulation-induced inflammation of the fallopian tube epithelial cells (FTECs) has gained evidence. However, the mechanistic pathway for this process has not been revealed yet. In the current study, we propose the mutator protein activation-induced cytidine deaminase (AID) as a link between ovulation-induced inflammation in FTECs and genotoxic damage leading to ovarian carcinogenesis. We show that AID, previously shown to be functional only in B lymphocytes, is expressed in FTECs under physiological conditions, and is induced in vitro upon ovulatory-like stimulation and in vivo in carcinoma-associated FTECs. We also report that AID activity results in epigenetic, genetic and genomic damage in FTECs. Overall, our data provides new insights into the etiology of ovarian carcinogenesis and may set the ground for innovative approaches aimed at prevention and early detection.

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.

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.

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.

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.