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Objective: To investigate racial disparities in uterine carcinosarcoma (UCS) and ovarian carcinosarcoma (OCS) in Commission on Cancer®-accredited facilities., Methods: Non-Hispanic Black (NHB) and non-Hispanic White (NHW) women in the National Cancer Database diagnosed with stage I-IV UCS or OCS between 2004 and 2014 were eligible. Differences by disease site or race were compared using Chi-square test and multivariate Cox analysis., Results: There were 2830 NHBs and 7366 NHWs with UCS, and 280 NHBs and 2586 NHWs with OCS. Diagnosis of UCS was more common in NHBs (11.5%) vs. NHWs (3.7%) and increased with age (P < .0001). OCS diagnosis remained <5% in both races and all ages. NHBs with UCS or OCS were more common in the South and more likely to have a comorbidity score ≥ 1, low neighborhood income and Medicaid or no insurance (P < .0001). Diagnosis at stage II-IV was more common in NHBs than NHWs with UCS but not OCS. NHBs with both UCS and OCS were less likely to undergo surgery and to achieve no gross residual disease with surgery (P = .002). Risk of death in NHB vs. NHW patients with UCS was 1.38 after adjustment for demographic factors and dropped after sequential adjustment for comorbidity score, neighborhood income, insurance status, stage and treatment by 4%, 16%, 7%, 19% and 10%, respectively, leaving 43.5% of the racial disparity in survival unexplained. In contrast, risk of death in NHBs vs. NHWs with OCS was 1.19 after adjustment for demographic factors and became insignificant after adjustment for comorbidity. Race was an independent prognostic factor in UCS but not in OCS., Conclusions: Racial disparities exist in characteristics, treatment and survival in UCS and OCS with distinctions that merit additional research., Competing Interests: Declaration of competing interest Christine Rojas, Chunqiao Tian, Nicholas Bateman, Nathaniel Jones, Craig Shriver, G. Larry Maxwell and Kathleen Darcy have no conflicts of interest to disclose. Matthew Powell reports consulting, honoraria and reimbursement from Tesaro, AstraZeneca, Clovis Oncology, Merck, Abbvie, Jannsen and NRG Oncology/GOG outside the submitted work. John Chan reports consulting, honoraria, reimbursement and is on the Speakers' Bureau for AstraZeneca, Clovis, Tesaro/GSK and Genentech/Roche; honoraria, reimbursement and is on the Speakers' Bureau for Merck; and is consulting for AbbVie, Aceta, Aravive, Biodesix, Eisai, Janssen and Oxigene outside the submitted work. Thomas Conrads reports consulting and a grant from AbbVie outside the submitted work. Rodney Rocconi reports being on the Speakers' Bureau for Genentech and Clovis, and is an expert witness for Johnson & Johnson outside the submitted work. Chad Hamilton reports being on the Speakers' Bureau for Tesaro/GSK and AstraZeneca outside the submitted work. Yovanni Casablanca reports that her spouse is stockholder/shareholder in Celsion Corporation, an oncology company, but this relationship is not associated with this submission., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Determine the impact of adjuvant chemotherapy (ACT) and prognostic factors in surgically managed patients with stage I uterine leiomyosarcoma (ULMS)., Methods: Women who underwent hysterectomy and were diagnosed with stage I ULMS between 2010 and 2014 in the National Cancer Database were eligible for this observation study. Inverse probability of treatment weighting based on propensity score was used to balance clinical characteristics between ACT and no ACT patients. Hazard ratio (HR) and 95% confidence interval (CI) were estimated from Cox modeling., Results: There were 1059 eligible patients with stage I ULMS including 514 treated with ACT and 545 with no ACT. Patient characteristics and tumor features varied in patients treated with ACT vs. no ACT (P < .0001). Multivariate survival analysis demonstrated that patient age, comorbidity score, tumor size, lymphovascular space invasion (LVSI) and grade were independent prognostic factors. After propensity score weighting to control for imbalance of prognostic clinical factors, adjusted five-year survival was 61.7% vs. 61.3% and restricted mean survival time was 39.7 vs. 40.6 months for ACT vs. no ACT, respectively. Risk of death in a weighted Cox analysis of overall survival was similar (HR = 1.08, 95% CI = 0.85-1.37, P = .054) for ACT vs. no ACT patients. Subset analysis demonstrated that survival was similar in ACT vs. no ACT patients categorized by age, tumor size and LVSI or with high grade or ungraded tumors. In contrast, patients with low grade tumors had worse 5-year survival (82.3% vs. 91.5%) and an increased risk of death (HR = 3.79, 95% CI = 1.15-12.40, P = .028) following ACT vs. no ACT., Conclusions: ACT did not improve survival over no ACT in patients with stage I ULMS and was inferior in patients with low grade tumors., Competing Interests: Declaration of competing interest The authors report no conflict of interest with the exception of of the following. Dr. Casablanca reports that her spouse owns <5 k stock interest in Celsion not related to the submitted work., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Patients with multiple sclerosis (MS) experience progressive thinning in optical coherence tomography (OCT) measures of neuroaxonal structure regardless of optic neuritis history. Few prospective studies have investigated the effects of disease-modifying therapies on neuroaxonal degeneration in the retina. Alemtuzumab is a monoclonal antibody shown to be superior to interferon β-1a in treating relapsing-remitting MS (RRMS). The purpose of this study was to assess the effects of alemtuzumab and first-line injectable treatments on OCT measures of neuroaxonal structure including peripapillary retinal nerve fiber layer (RNFL) thickness and combined ganglion cell-inner plexiform (GCIP) layer volume in RRMS patients followed up over 5 years., Methods: In this retrospective pilot study with prospectively collected double cohort data, spectral domain OCT measures of RNFL thickness and GCIP volume were compared between alemtuzumab-treated RRMS patients (N = 24) and RRMS patients treated with either interferon-β or glatiramer acetate (N = 21)., Results: Over a median of 60 months (range 42-60 months), the alemtuzumab cohort demonstrated a change in the mean RNFL thickness (thinning from baseline) of -0.88 μm (95% confidence interval [CI] -2.63 to 0.86; P = 0.32) and mean GCIP volume of +0.013 mm (95% CI -0.006 to 0.032; P = 0.18). Over the same time period, the first-line therapy-treated cohort demonstrated greater degrees of RNFL thinning (mean change in RNFL thickness was -3.65 μm [95% CI -5.40 to -1.89; P = 0.0001]). There was also more prominent GCIP volume loss relative to baseline in the first-line therapy group (-0.052 mm [95% CI -0.070 to -0.034; P < 0.0001])., Conclusions: Alemtuzumab-treated patients with RRMS demonstrated relative stability of OCT-measured neuroaxonal structure compared with RRMS patients treated with either interferon-β or glatiramer acetate over a 5-year period. These findings, along with previous demonstration of improved brain atrophy rates, suggest that alemtuzumab may offer long-term preservation of neuroaxonal structure in patients with RRMS.

To determine the location patterns of distant metastases at initial staging and outcomes of ovarian, uterine, and cervical cancer patients. Data were obtained from the SEER database from 2010 to 2015. Analyses were performed using Kaplan-Meier and multivariate Cox proportional hazard methods. Of 3035 patients (median age: 63, range: 17-95) with stage IV gynecologic cancer, ovarian, uterine, and cervical cancers were present in 42%, 40%, and 18% of the cohort. The proportion of lung, liver, bone and brain metastases were identified in 38%, 57%, 4%, and 1% of ovarian cancer patients, 62%, 22%, 13%, and 3% of uterine cancer patients, and 59%, 16%, 23%, and 2% of cervical cancer patients, respectively. The 5-year disease-specific survival for all patients was 19%. Those with liver metastases had survival rates of 26% compared to 15% for lung, 13% for bone, and 6% for brain (p < 0.0001). Patients with ovarian, uterine, and cervical cancers had survival rates of 28%, 12%, and 12%, respectively (p < 0.0001). On multivariate analysis, brain metastasis (HR = 1.64, 95% CI 1.21-2.22, p < 0.01), uterine (HR = 1.77, 95 CI 1.56-2.02, p < 0.0001) and cervical (HR = 1.35, 95% CI 1.11-1.63, p < 0.01) cancers, and lack of insurance (HR = 1.41, 95% CI 1.16-1.73, p < 0.001) were independent predictors for poorer survival. Age, year, region, and race did not affect prognosis. Stage IV ovarian cancer most frequently metastasizes to the liver, whereas uterine and cervical cancers spread more to the lung. Overall, these patients have poor prognosis, particularly those with uterine or cervical primary disease or brain metastases.

Background: Patients ≥75 years old with ovarian cancer experience high perioperative morbidity, but recruitment into prospective trials to assess the role of surgery continues to be challenging., Objective: To compare overall survival for patients ≥75 years old with ovarian cancer after chemotherapy alone vs neoadjuvant chemotherapy with interval cytoreductive surgery., Study Design: Data were extracted from the National Cancer Data Base from 2004 to 2014. Kaplan-Meier and Cox proportional hazards models were used for statistical analyses., Results: Of 1661 patients (median age: 79 years), most were white (88%) and had stage III-IV disease (95%), and 51% had serous histology. Of those who did not receive primary surgery, 58% had chemotherapy alone and the remainder had neoadjuvant chemotherapy with interval cytoreductive surgery. The use of neoadjuvant chemotherapy with interval cytoreductive surgery increased from 28% to 50% in years 2004-2007 to 2012-2014 (P<.001). Compared with neoadjuvant chemotherapy with interval cytoreductive surgery, chemotherapy-only patients were older (80 vs 78 years; P<.001) and had more advanced stage disease (98% vs 91%; P<.001). The 5-year overall survival of the entire study group was 14%; those who underwent neoadjuvant chemotherapy with interval cytoreductive surgery had overall survival of 25% compared with only 7% in chemotherapy alone group (P<.001). In multivariable analysis, neoadjuvant chemotherapy with interval cytoreductive surgery (hazard ratio, 0.44; 95% confidence interval, 0.36-0.54; P<.001) was an independent predictor for improved survival. Older (80-84 years) age (hazard ratio, 1.35; 95% confidence interval, 1.12-1.63; P=.002), advanced (stage III-IV) disease (hazard ratio; 2.06, 95% confidence interval, 1.37-3.09; P=.001), and clear cell histology (hazard ratio; 2.17, 95% confidence interval, 1.10-4.28; P=.03) portended for worse outcome., Conclusion: Patients ≥75 years with ovarian cancer old have an overall poor prognosis. Receiving neoadjuvant chemotherapy followed by interval cytoreductive surgery is associated with greater overall survival compared to chemotherapy alone., (Copyright © 2019. Published by Elsevier Inc.)

Mosquitoes are important vectors of disease and require sources of carbohydrates for reproduction and survival. Unlike host-related behaviors of mosquitoes, comparatively less is understood about the mechanisms involved in nectar-feeding decisions, or how this sensory information is processed in the mosquito brain. Here we show that Aedes spp. mosquitoes, including Aedes aegypti , are effective pollinators of the Platanthera obtusata orchid, and demonstrate this mutualism is mediated by the orchid's scent and the balance of excitation and inhibition in the mosquito's antennal lobe (AL). The P. obtusata orchid emits an attractive, nonanal-rich scent, whereas related Platanthera species-not visited by mosquitoes-emit scents dominated by lilac aldehyde. Calcium imaging experiments in the mosquito AL revealed that nonanal and lilac aldehyde each respectively activate the LC2 and AM2 glomerulus, and remarkably, the AM2 glomerulus is also sensitive to N,N-diethyl-meta-toluamide (DEET), a mosquito repellent. Lateral inhibition between these 2 glomeruli reflects the level of attraction to the orchid scents. Whereas the enriched nonanal scent of P. obtusata activates the LC2 and suppresses AM2, the high level of lilac aldehyde in the other orchid scents inverts this pattern of glomerular activity, and behavioral attraction is lost. These results demonstrate the ecological importance of mosquitoes beyond operating as disease vectors and open the door toward understanding the neural basis of mosquito nectar-seeking behaviors., Competing Interests: Competing interest statement: A provisional patent on the odor that mimics the orchid scent was recently filed (62/808,710)., (Copyright © 2020 the Author(s). Published by PNAS.)

Objective: Determine the utility of a clinical calculator to predict the benefit of chemotherapy in stage IA uterine papillary serous cancer (UPSC)., Patients and Methods: Data were collected from NCDB from years 2010-2014. Based on demographic and surgical characteristics, a clinical score was developed using the random survival forest machine learning algorithm., Results: Of 1,751 patients with stage IA UPSC, 1,012 (58%) received chemotherapy and 739 (42%) did not. Older age (HR 1.06), comorbidities (HR 1.31), larger tumor size (HR 1.27), lymphovascular invasion (HR 1.86), positive peritoneal cytology (HR 2.62), no pelvic lymph node dissection (HR 1.51), and no chemotherapy (HR 2.16) were associated with poorer prognosis. Compared to no chemotherapy, patients who underwent chemotherapy had a 5-year overall survival of 80% vs. 67%. To better delineate those who may derive more benefit from chemotherapy, we designed a clinical calculator capable of dividing patients into low, moderate, and high-risk groups with associated 5-year OS of 86%, 73%, and 53%, respectively. Using the calculator to assess the relative benefit of chemotherapy in each risk group, chemotherapy improved the 5-year OS in the high (42% to 64%; p < 0.001) and moderate risk group (66% to 79%; p < 0.001) but did not benefit the low risk group (84% to 87%; p = 0.29)., Conclusion: Our results suggest a clinical calculator is useful for counseling and personalizing chemotherapy for stage IA UPSC., (Published by Elsevier Inc.)

This study aimed to identify the trends in the incidence of thymic cancer, i.e., thymoma, thymic carcinoma, and thymic neuroendocrine tumor, in the United States. Data from the United States Cancer Statistics (USCS) database (2001-2015) and those from the Surveillance, Epidemiology, and End Results (SEER) database (SEER 9 [1973-2015], SEER 13 [1992-2015], and SEER 18 [2000-2015]) were used in this study. All incidences were per 100,000 population at risk. The trends in incidence were described as annual percent change (APC) using the Joinpoint regression program. Data from the USCS (2001-2015) database showed an increase in thymic cancer diagnosis with an APC of 4.89% from 2001 to 2006, which is mainly attributed to the significant increase in the incidence of thymoma and thymic carcinoma particularly in women. The incidence of thymic cancer did not increase from 2006 to 2015, which may be attributed to the increase in the diagnosis of thymic carcinoma from 2004 to 2015, with a concomitant decrease in thymoma from 2008 to 2015. Before declining, the age-specific incidence of thymic cancer peaked at ages 70-74 years, with a peak incidence at 1.06 per 100,000 population, and decreased in older age groups. The incidence of thymic cancer was higher in men than in women. Asian/Pacific Islanders had the highest incidence of thymoma, followed by black and then white people. The incidence of thymic carcinoma increased from 2004 to 2015, with a concomitant decrease in thymoma from 2008 to 2015. Asian/Pacific Islanders had the highest incidence of thymoma than other races., Competing Interests: The authors have declared that no competing interests exist.

Background: Secondary surgical cytoreduction in women with platinum-sensitive, recurrent epithelial ovarian, primary peritoneal, or fallopian-tube ("ovarian") cancer is widely practiced but has not been evaluated in phase 3 investigation., Methods: We randomly assigned patients with recurrent ovarian cancer who had received one previous therapy, had an interval during which no platinum-based chemotherapy was used (platinum-free interval) of 6 months or more, and had investigator-determined resectable disease (to no macroscopic residual disease) to undergo secondary surgical cytoreduction and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Adjuvant chemotherapy (paclitaxel-carboplatin or gemcitabine-carboplatin) and use of bevacizumab were at the discretion of the investigator. The primary end point was overall survival., Results: A total of 485 patients underwent randomization, 240 to secondary cytoreduction before chemotherapy and 245 to chemotherapy alone. The median follow-up was 48.1 months. Complete gross resection was achieved in 67% of the patients assigned to surgery who underwent the procedure. Platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance was administered to 84% of the patients overall and was equally distributed between the two groups. The hazard ratio for death (surgery vs. no surgery) was 1.29 (95% confidence interval [CI], 0.97 to 1.72; P = 0.08), which corresponded to a median overall survival of 50.6 months and 64.7 months, respectively. Adjustment for platinum-free interval and chemotherapy choice did not alter the effect. The hazard ratio for disease progression or death (surgery vs. no surgery) was 0.82 (95% CI, 0.66 to 1.01; median progression-free survival, 18.9 months and 16.2 months, respectively). Surgical morbidity at 30 days was 9%; 1 patient (0.4%) died from postoperative complications. Patient-reported quality of life decreased significantly after surgery but did not differ significantly between the two groups after recovery., Conclusions: In this trial involving patients with platinum-sensitive, recurrent ovarian cancer, secondary surgical cytoreduction followed by chemotherapy did not result in longer overall survival than chemotherapy alone. (Funded by the National Cancer Institute and others; GOG-0213 ClinicalTrials.gov number, NCT00565851.)., (Copyright © 2019 Massachusetts Medical Society.)

Objectives: Effects of Zika virus (ZIKV) infection on placental development during pregnancy are unclear., Methods: Full-term placentas from three women, each infected with ZIKV during specific pregnancy trimesters, were harvested for anatomic, immunologic and transcriptomic analysis., Results: In this study, each woman exhibited a unique immune response with raised IL-1RA, IP-10, EGF and RANTES expression and neutrophil numbers during the acute infection phase. Although ZIKV NS3 antigens co-localised to placental Hofbauer cells, the placentas showed no anatomic defects. Transcriptomic analysis of samples from the placentas revealed that infection during trimester 1 caused a disparate cellular response centred on differential eIF2 signalling, mitochondrial dysfunction and oxidative phosphorylation. Despite these, the babies were delivered without any congenital anomalies., Conclusion: These findings should translate to improve clinical prenatal screening procedures for virus-infected pregnant patients., Competing Interests: The authors declare no conflict of interest., (© 2019 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology Inc.)

Purpose : The first aim of this study was to compare inferior tear meniscus height (TMH) measured by keratography and swept-source optical coherence tomography (OCT). Effect of locations of fluorescein instillation and subjects' subjective sensation, and the TMH results were also investigated. Methods : Forty-one eyes from 41 healthy adults had TMH randomly measured by keratography (K5M, Oculus, Germany) and swept-source OCT (Casia SS-1000, Tomey Corp, Japan) at baseline, followed by touching either the inferior bulbar or inferior palpebral conjunctiva, randomly assigned, with a moistened fluorescein strip. Two-way analysis of variance (ANOVA) was used to compare TMH obtained from the two devices and three measurement conditions. Subjective sensation of conjunctival touch was obtained through a 4-point scale with zero representing no sensation, and one to three representing ocular sensation in an ascending order. Results : Two-way ANOVA revealed no significant difference in TMH between keratography and swept-source OCT (Factor (devices): F = 0.579, p = .451) while there was a significant difference among fluorescein instillations (Factor (conditions): F = 10.146, p < .001). Baseline TMH was around 0.25 mm, and increased to around 0.28 mm after instillation of fluorescein sodium. Ocular sensation was similar between the two conjunctival touch, and TMH was not significantly associated with ocular sensation. Conclusions : Keratography and swept-source OCT provided similar TMH results. Applying fluorescein sodium through moistened fluorescein strip could over-estimate TMH by around 0.03 mm. Applying moistened fluorescein strip at bulbar or palpebral conjunctival led to similar subjective sensations and did not affect TMH measurement.

Purpose: We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma., Methods: A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m 2 ) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry., Results: Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non- BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2 , HRR, and CD31 were not predictive of bevacizumab activity., Conclusion: No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.

Purpose: To compare patient/tumor characteristics and outcomes of Asians to Caucasian patients with epithelial ovarian cancer., Methods: Ancillary data were pooled and analyzed from ten prospective randomized front-line Gynecologic Oncology Group clinical trials from 1996 to 2011. Demographic, clinicopathologic features, disease-specific and all-cause survival were analyzed., Results: Of 7914 patients, 7641 were Caucasian and 273 Asian. When compared to Caucasians, Asians were younger at trial enrollment, had a better performance status, earlier-stage cancers (17.2% vs. 8.1% with stage I; p < 0.001), and were more likely to be of clear cell (15.8% vs. 6.2%, p < 0.001) and mucinous (3.3% vs. 1.9%, p < 0.001) histology. Asians had an improved 5-year disease-specific survival of 54.1% compared to 46.1% for Caucasians, p = 0.001. In multivariate analysis, the Asian race remained a significant prognostic factor for all-cause survival (HR: 0.84; 95% CI: 0.72-0.99; p = 0.04). Other factors predictive of improved survival included younger age, better performance status, optimal cytoreduction, earlier stage, non-clear cell histology, and lower grade tumors., Conclusion: Asians enrolled into phase III ovarian cancer clinical trials were younger, with better performance status, earlier-stage of disease, and have a greater number of clear cell and mucinous tumors. After adjusting for these prognostic factors, Asians have a better survival compared to Caucasians., (Copyright © 2019. Published by Elsevier Inc.)

Background: Late-line treatment options for patients with ovarian cancer are few, with the proportion of patients achieving an overall response typically less than 10%, and median overall survival after third-line therapy of 5-9 months. In this study (QUADRA), we investigated the activity of niraparib monotherapy as the fourth or later line of therapy., Methods: QUADRA was a multicentre, open-label, single-arm, phase 2 study that evaluated the safety and activity of niraparib in adult patients (≥18 years) with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with three or more previous chemotherapy regimens. The study was done in the USA and Canada, and 56 sites screened patients (50 sites treated at least one patient). Patients received oral niraparib 300 mg once daily continuously, beginning on day 1 and every cycle (28 days) thereafter until disease progression. The primary objective was the proportion of patients achieving an investigator-assessed confirmed overall response in patients with homologous recombination deficiency (HRD)-positive tumours (including patients with BRCA and without BRCA mutations) sensitive to their last platinum-based therapy who had received three or four previous anticancer therapy regimens (primary efficacy population). Efficacy analyses were additionally done in all dosed patients with measurable disease at baseline., Findings: Between April 1, 2015 and Nov 1, 2017, we screened 729 patients for eligibility and enrolled 463 patients, who were initiated on niraparib therapy. At the time of database lock (April 11, 2018), enrolment had closed and the study was ongoing, with 21 patients still on treatment. Patients had received a median of four (IQR 3-5) previous lines of therapy, and the median follow-up for overall survival was 12·2 months (IQR 3·7-22·1). 151 (33%) of 463 patients were resistant and 161 (35%) of 463 patients were refractory to the last administered platinum therapy. 13 (28%) of 47 patients in the primary efficacy population achieved an overall response according to RECIST (95% CI 15·6-42·6; one-sided p=0·00053). The most common drug-related grade 3 or worse treatment-emergent adverse events were anaemia (113 [24%] of 463 patients) and thrombocytopenia (95 [21%] of 463 patients). The most common treatment-emergent serious adverse events were small intestinal obstruction (34 [7%] of 463 patients), thrombocytopenia (34 [7%] of 463 patients), and vomiting (27 [6%] of 463 patients). One death due to gastric haemorrhage was considered treatment related., Interpretation: We observed clinically relevant activity of niraparib among women with heavily pretreated ovarian cancer, especially in patients with HRD-positive platinum-sensitive disease, which includes not only patients with a BRCA mutation but also a population with BRCA wild-type disease. We identified no new safety signals. Our data support expansion of the treatment indication for poly(ADP-ribose) polymerase inhibitors to include patients with HRD-positive ovarian cancer beyond those with BRCA mutations., Funding: Tesaro., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: Anticancer drugs may cause cardiovascular toxicities, including QT interval prolongation. Niraparib, a potent and selective once-daily oral poly (ADP-ribose) polymerase inhibitor, is approved as a maintenance therapy in platinum-sensitive recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC). Here, we present the effects of niraparib on cardiac repolarization, and the correlation between changes in baseline QT interval corrected by Fridericia's formula (ΔQTcF) and niraparib plasma concentrations., Methods: Patients with EOC from the NOVA study (subset of n = 15), the food effect NOVA substudy (n = 17), and a QTc substudy (n = 26) underwent intensive electrocardiographic (ECG) monitoring that included triplicate ECG testing on Day 1 at baseline (predose) and at 1, 1.5, 2, 3, 4, 6, and 8 h postdose concurrent with time-matched blood sampling for determination of niraparib plasma concentrations. All patients received once-daily 300-mg niraparib until disease progression or toxicity., Results: Across the 3 substudies, the upper limit of the two-sided 90% confidence interval (CI) of ΔQTcF was ≤ 10 ms at every postdose timepoint, with a maximum upper limit of 4.3 ms, which indicates no clinically meaningful effect on QTc prolongation. No statistically significant relationship between ΔQTcF and niraparib plasma concentration was observed (estimated slope: 0.0049; 95% CI: - 0.0020, 0.0117; P = 0.164). There were no clinically relevant changes in other ECG parameters that could be attributable to niraparib., Conclusion: Niraparib administration at the recommended daily dose of 300 mg for EOC is not associated with clinically relevant alteration of ECGs, including QTc prolongation.

Background: Progressive solitary sclerosis is a unifocal demyelinating disease recently proposed as a possible multiple sclerosis variant., Objective: To compare myelin content and brain metabolite ratio qualitatively in the normal-appearing white matter of progressive solitary sclerosis cases compared to multiple sclerosis and healthy control participants., Methods: Case report., Results: Progressive solitary sclerosis cases showed abnormal myelin in normal-appearing white matter tracts and global normal-appearing white matter as well as lower N-acetyl-aspartate to total creatine ratio compared to multiple sclerosis and healthy control groups., Conclusion: Despite a single demyelinating lesion along the corticospinal tract in progressive solitary sclerosis, we showed evidence of more extensive abnormality within the normal-appearing white matter.

Introduction: This study investigated the differences in clinical pregnancy rate (CPR), live birth rate (LBR) and multiple pregnancy rate (MPR) between double cleavage-stage embryo transfers compared to single and double blastocysts stage embryo transfers in a single academic medical centre., Materials and Methods: This was a retrospective cohort study performed at the KK Women's and Children's Hospital In Vitro Fertilisation (KKIVF) Centre of all women who underwent fresh-cycle in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) cycles over a 5-year period. The outcome measures were CPR, LBR and MPR. The study included 5294 cycles, of which 539 patients underwent single embryo transfer (SET); 4533 patients underwent double embryo transfer (DET); 84 patients underwent double blastocyst embryo transfer (DBT); and 65 patients underwent single blastocyst embryo transfer (SBT)., Results: The mean age of patients undergoing single blastocysts stage embryo transfer was lower than the other 2 groups. The DET, single and double blastocysts stage embryo transfer groups achieved similar LBR (33.9%, 38.7%, 35.4%, P >0.05) and CPR (42.4%, 46.2%, 46.9%)., Conclusion: We found that single blastocysts stage embryo transfer is associated with similar LBR and CPR compared to double blastocysts stage embryo transfer and DET, with lower MPRs, and should be offered as standard practice, where possible.

Objective: To evaluate the hospital-acquired condition (HAC) following oophorectomy and/or hysterectomy for gynecologic cancer patients based on clinical outcomes and costs., Materials and Methods: Data were obtained from the Nationwide Inpatient Sample from 2005 to 2011. Chi-squared and Wilcoxon rank sum two-sample tests and multivariate logistic regression model were used for statistical analysis., Results: Of 82,304 women (median age: 60 years, range: 1-101), 49,386 (60.0%) had endometrial, 23,510 (28.6%) had ovarian, and 9408 (11.4%) had cervical cancers. Of 135 HAC events, these involved catheter-associated urinary tract infections (n = 47), vascular catheter-associated infection (n = 41), foreign object retained after surgery (n = 19), pressure ulcers (n = 16), manifestation of poor glycemic control (n = 10), and air embolism (n = 2). Older patients (≥60 years) experienced more HACs relative to younger (0.23% vs. 0.09%; OR = 2.13, 95% CI: 1.30-3.50; p = 0.003), and patients with Medicaid experienced more HACs compared to those with private insurance (0.35% vs. 0.10%; OR = 3.09, 95% CI: 1.70-5.62; p < 0.001). Laparoscopic surgeries were associated with less HACs compared to open surgeries (0.05% vs. 0.19%; OR = 0.41, 95% CI: 0.19-0.90; p = 0.03). Length of hospitalization and hospital charges were greater for those with HACs, (12 days vs. 3 days; p < 0.001; $89,324 vs. $31,107; p < 0.001), respectively., Conclusion: The odds of hospital-acquired conditions were higher in older patients, open surgery, Medicaid insured with higher associated hospital charges., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To determine the efficacy and tolerability of sunitinib in recurrent or persistent clear cell ovarian cancer patients., Methods: All patients had one or two prior regimens with measurable disease. Tumors were at least 50% clear cell histomorphology and negative for WT-1 antigen and estrogen receptor expression by immunohistochemistry. Sunitinib 50 mg per day for 4 weeks was administered in repeated 6-week cycles until disease progression or prohibitive toxicity. Primary end points were progression-free survival (PFS) at 6 months and clinical response. The study was designed to determine if the drug had a response rate of at least 20% or 6-month PFS of at least 25%., Results: Of 35 patients enrolled, 30 were treated and eligible (median age: 51, range: 27-73). Twenty-five (83%) were White, 4 (13%) Asian, and 1 (3%) unknown. The majority 28 (83%) patients, underwent ≤3 but 2 (7%) had 16 courses of study therapy. Five (16.7%) patients had PFS ≥6 months (90% CI: 6.8%-31.9%). Two (6.7%) patients had a partial or complete response (90% CI: 1.2%-19.5%). The median PFS was 2.7 months. The median overall survival was 12.8 months. The most common grade 3 adverse events were fatigue (4), hypertension (4), neutropenia (4), anemia (3), abdominal pain (3), and leukopenia (3). Grade 4-5 adverse events included: thrombocytopenia (5), anemia (2), acute kidney Injury (1), stroke (1), and allergic reaction (1)., Conclusion: Sunitinib demonstrated minimal activity in the second- and third-line treatment of persistent or recurrent clear cell ovarian carcinoma. ClinicalTrials.gov number, NCT00979992., (Copyright © 2018. Published by Elsevier Inc.)

Gynecologic cancers comprise of mostly uterine, ovarian, and cervical malignancies and are responsible for 95,000 new cases annually in the United States. Uterine cancer is the most common and the number of new cases and mortality has been increasing. Cervical cancer has decreased due to screening, early detection, and treatment of pre-invasive cancers. However, ovarian cancer remains the most lethal because of advanced stage at diagnosis and drug resistance. The metastatic spread pattern differs amongst these cancers, with uterine and cervical cancer found mostly in the primary organ and ovarian cancer disseminating throughout the peritoneum and upper abdomen at presentation. The primary treatment of ovarian cancer typically involves surgery followed by systemic therapy for more advanced disease. Previously, systemic chemotherapy with platinums, taxanes, doxorubicin, topotecan, and gemcitabine has been the standard in either upfront or recurrent setting. With molecular and genetic breakthroughs, we now have over eight new indications and five novel biologic therapies including antiangiogenics, poly ADP ribose polymerase inhibitors, and immunotherapies approved over the last 3 years. In this review, we will examine the biology of gynecologic cancer metastasis and focus on new treatment options for these cancers with a focus on ovarian cancer.

Objective: To identify the trends in incidence of serous fallopian tube, ovarian, and peritoneal epithelial cancers in the United States., Methods: Data was obtained from United States Cancer Statistics (USCS) from 2001 to 2014. All incidences are per 100,000 women. Analyses were performed using SEER*Stat and Joinpoint regression programs., Results: Of the 146,470 patients with serous cancers, 9381 (6.4%) were fallopian tube, 121,418 (82.9%) were ovarian, and 15,671 (10.7%) were primary peritoneal. The study period was divided from 2001 to 2005, 2006-2010, and 2011-2014, and there was an increase in fallopian tube incidence from 0.19 to 0.35 to 0.63, with a corresponding decrease in ovarian incidence from 5.31 to 5.08 to 4.86. There was no significant change in peritoneal cancers from 0.64 to 0.69 to 0.62. The age-specific peak incidence of fallopian tube cancer was younger at age 70-74, compared to ovarian and peritoneal cancer at age 75-79. Further, the incidence of serous fallopian tube cancer was highest in Whites at 0.42, compared to Blacks at 0.24, Hispanics at 0.27, and Asians at 0.28., Conclusion: From 2001 to 2014, the diagnosis of serous fallopian tube cancer increased fourfold with a corresponding decrease in ovarian cancer. The peak incidence of tubal cancer was 70-74years with an increased incidence in Whites., (Published by Elsevier Inc.)

Objective: To determine the factors associated with inpatient palliative care (PC) use in patients with metastatic gynecologic cancer., Methods: Data were obtained from the Nationwide Inpatient Sample (NIS) for patients with metastatic cervical, uterine, and ovarian cancers. Chi-square and multivariate models were used for statistical analyses., Results: Of 67 947 inpatients with metastatic gynecologic cancer, 3337 (5%) utilized PC (median age: 63 years, range: 18-102 years). For the entire cohort, the majority was white (59%) and the remainder was black (10%), Hispanic (8%), and Asian (3%). Sixty-one percent had ovarian, 25% uterine, and 14% cervical cancers. Forty-four percent had Medicare, 37% private insurance, 12% Medicaid, and 3% were uninsured. Fifty-three percent of patients were treated at teaching hospitals, while 33% were treated at nonteaching hospitals. In multivariate analysis, the use of PC was associated with older age (≥63, median; odds ratio [OR] = 1.52, 95% confidence interval [CI]: 1.36-1.70; P < .0001) and black race (OR = 1.22, CI: 1.08-1.39; P < .01). Compared to patients with ovarian cancer, patients with uterine (OR = 1.63, CI: 1.46-1.83; P < .0001) and cervical (OR = 1.14, CI: 1.104-1.25; P < .01) cancer had higher rates of PC utilization. The proportion of patients receiving PC increased from 2% in 2005 to 10% in 2011. In a subset analysis of the 4517 patients who died during hospitalization, only 1056 (23%) patients received PC., Conclusion: Patients who were older, black, or had uterine and cervical cancers were more likely to use PC. Although the overall use of PC has increased, less than one-quarter of patients who died in the hospital used PC services during their final hospital admission.

Introduction: Although black patients with endometrial cancer (EC) have worse survival compared with white patients, the interaction between age/race has not been examined. The primary objective was to evaluate the impact of age at diagnosis on racial disparities in disease presentation and outcome in EC., Methods: We evaluated women diagnosed with EC between 1991 and 2010 from the Surveillance, Epidemiology, and End Results. Mutation status for TP53 or PTEN, or with the aggressive integrative, transcript-based, or somatic copy number alteration-based molecular subtype were acquired from the Cancer Genome Atlas. Logistic regression model was used to estimate the interaction between age and race on histology. Cox regression model was used to estimate the interaction between age and race on survival., Results: 78,184 white and 8518 black patients with EC were analyzed. Median age at diagnosis was 3-years younger for black vs. white patients with serous cancer and carcinosarcoma (P<0.0001). The increased presentation of non-endometrioid histology with age was larger in black vs. white patients (P<0.0001). The racial disparity in survival and cancer-related mortality was more prevalent in black vs. white patients, and in younger vs. older patients (P<0.0001). Mutations in TP53, PTEN and the three aggressive molecular subtypes each varied by race, age and histology., Conclusions: Aggressive histology and molecular features were more common in black patients and older age, with greater impact of age on poor tumor characteristics in black vs. white patients. Racial disparities in outcome were larger in younger patients. Intervention at early ages may mitigate racial disparities in EC., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Mycobacterium tuberculosis ( M. tb ), a rod-shaped acid-fast bacterium, is the causative agent of tuberculosis (TB). TB remains one of the leading causes of morbidity and mortality worldwide. Additionally, approximately one-third of the world's population has latent tuberculosis infection (LTBI) as a result of the body's primary mechanism of defense against M. tb infection, the formation of a granuloma. A granuloma is the aggregation of immune cells that encapsulate the bacteria to keep them localized to prevent further infection and thus the bacteria become quiescent. However, if an individual becomes immunocompromised, they become more susceptible to M. tb , which may lead to bacterial reactivation and an active infection, because the host is no longer able to generate adequate immune responses. In this study, we examined liposomal glutathione's (L-GSH) effectiveness in promoting the formation of solid, stable granulomas. We assessed this ability by generating in vitro human granulomas constructed from peripheral blood mononuclear cells (PBMCs) that were derived from healthy subjects and testing their granulomatous effector responses against both M. bovis bacille Calmette-Guérin (BCG) and the highly virulent Erdman strain of M. tb . Additionally, we measured the survival and immune characteristics of the Erdman strain of M. tb in THP-1 originated macrophages as well as in vitro granulomas generated from individuals from type 2 diabetes (T2DM). Our results demonstrate that L-GSH treatment can decrease the intracellular survival of both BCG and virulent M. tb , as well as downregulate the levels of overexpressed proinflammatory cytokines delegated from the granulomas derived from not only healthy subjects but also individuals with T2DM., Competing Interests: The authors declare no conflict of interest.

Objective: Gestational choriocarcinoma is a malignant form of gestational trophoblastic disease that usually arises after a molar pregnancy, but may follow any antecedent pregnancy. Investigations in this rare cancer are limited. We evaluated the prognostic effects of age, race, and stage in choriocarcinomas diagnosed for 4 decades., Methods: Patients diagnosed as having gestational choriocarcinoma between 1973 and 2014 from the Surveillance, Epidemiology, and End Results program were eligible. Relationships with overall survival and cancer-specific survival were evaluated using log-rank testing and Cox modeling. Multivariate analyses included adjustments for age, race, and stage., Results: There were 947 patients with choriocarcinoma including 403 non-Hispanic white (NHW) patients, 473 with distant stage, and 142 who died. Median age at diagnosis was 25 years for non-Hispanic black (NHB) patients and 35 years for Asian/Pacific Islanders (API) compared with 29 years for NHW patients (P = 0.0001). Five-year overall survival varied between 82% and 92% when diagnosed at the age of at least 40 years compared with less than 20 years (P < 0.0001), and from 85% to 95% in patients with distant vs local disease (P < 0.0001), respectively. Multivariate analysis demonstrated that age, race, and stage were independent predictors of mortality. Risk of death increased incrementally in patients diagnosed at 20 to 39 years of age (adjusted hazard ratio [aHR], 3.87; 95% confidence interval [CI], 1.69-8.86; P = 0.001) and at least 40 years of age (aHR, 7.18; 95% CI, 2.95-17.49; P < 0.0001) compared with 20 years or younger. Non-Hispanic black patients were the only racial group at higher risk of death compared with NHW patients (aHR, 1.86; 95% CI, 1.22-2.82; P < 0.004). Distant vs local disease added an additional risk of death (aHR, 2.43; 95% CI, 1.57-3.75; P < 0.0001) over that attributable to age at diagnosis and NHB race. Similar relationships to cancer-specific survival were also observed (P < 0.05)., Conclusions: Most patients with choriocarcinoma have excellent prognosis. However, NHB patients and patients who are diagnosed at the age of at least 20 years or have distant stage have significantly worse mortality.

Erythropoiesis is marked by progressive changes in morphological, biochemical and mechanical properties of erythroid precursors to generate red blood cells (RBC). The earliest enucleated forms derived in this process, known as reticulocytes, are multi-lobular and spherical. As reticulocytes mature, they undergo a series of dynamic cytoskeletal re-arrangements and the expulsion of residual organelles, resulting in highly deformable biconcave RBCs (normocytes). To understand the significant, yet neglected proteome-wide changes associated with reticulocyte maturation, we undertook a quantitative proteomics approach. Immature reticulocytes (marked by the presence of surface transferrin receptor, CD71) and mature RBCs (devoid of CD71) were isolated from human cord blood using a magnetic separation procedure. After sub-fractionation into triton-extracted membrane proteins and luminal samples (isobaric tags for relative and absolute quantitation), quantitative mass spectrometry was conducted to identify more than 1800 proteins with good confidence and coverage. While most structural proteins (such as Spectrins, Ankyrin and Band 3) as well as surface glycoproteins were conserved, proteins associated with microtubule structures, such as Talin-1/2 and ß-Tubulin, were detected only in immature reticulocytes. Atomic force microscopy (AFM)-based imaging revealed an extended network of spectrin filaments in reticulocytes (with an average length of 48 nm), which shortened during reticulocyte maturation (average spectrin length of 41 nm in normocytes). The extended nature of cytoskeletal network may partly account for increased deformability and shape changes, as reticulocytes transform to normocytes., (© 2017 John Wiley & Sons Ltd.)

Liver progenitor cells have the potential to repair and regenerate a diseased liver. The success of any translational efforts, however, hinges on thorough understanding of the fate of these cells after transplant, especially in terms of long-term safety and efficacy. Here, we report transplantation of a liver progenitor population isolated from human fetal livers into immune-permissive mice with follow-up up to 36 weeks after transplant. We found that human progenitor cells engraft and differentiate into functional human hepatocytes in the mouse, producing albumin, alpha-1-antitrypsin, and glycogen. They create tight junctions with mouse hepatocytes, with no evidence of cell fusion. Interestingly, they also differentiate into functional endothelial cell and bile duct cells. Transplantation of progenitor cells abrogated carbon tetrachloride-induced fibrosis in recipient mice, with downregulation of procollagen and anti-smooth muscle actin. Paradoxically, the degree of engraftment of human hepatocytes correlated negatively with the anti-fibrotic effect. Progenitor cell expansion was most prominent in cirrhotic animals, and correlated with transcript levels of pro-fibrotic genes. Animals that had resolution of fibrosis had quiescent native progenitor cells in their livers. No evidence of neoplasia was observed, even up to 9 months after transplantation. Human fetal liver progenitor cells successfully attenuate liver fibrosis in mice. They are activated in the setting of liver injury, but become quiescent when injury resolves, mimicking the behavior of de novo progenitor cells. Our data suggest that liver progenitor cells transplanted into injured livers maintain a functional role in the repair and regeneration of the liver. Stem Cells 2018;36:103-113., (© 2017 AlphaMed Press.)

The role of intraperitoneal (i.p.) chemotherapy in treating newly diagnosed advanced epithelial ovarian cancer (EOC) has been the subject of controversy for almost three decades. Three large intergroup phase III trials (GOG 104, 114, 172) have demonstrated a survival benefit associated with i.p. over intravenous (i.v.) therapy in advanced, low-volume EOC. Despite the positive clinical trial results and a subsequent National Cancer Institute alert in 2006, i.p. treatment has not been widely accepted as the standard of care in the United States and is infrequently used in Europe. The hesitancy of clinicians to use i.p. therapy is likely attributed to higher toxicity, inconvenience, catheter complications, and clinical trial design issues. On the other hand, In a long-term follow-up report from these trials, we showed that the effect of i.p. chemotherapy extends beyond 10 years and that the more cycles of i.p. therapy portends for improved survival over similar cycles of i.v. therapy with younger patients having a higher likelihood of completing 6 cycles of i.p., Treatment: More recently, a fourth randomized phase III trial, GOG 252, failed to show a survival advantage associated with i.p. cisplatin and i.p. carboplatin over dose-dense i.v. paclitaxel and carboplatin. Since the use of bevacizumab was incorporated in all arms of the study, this anti-vascular agent may have equalized or negated the clinical advantage of i.p. chemotherapy and dose-dense weekly as suggested in GOG 262. We are awaiting the results of the Asian iPocc trial comparing dose-dense paclitaxel to i.p. chemotherapy without bevacizumab, though the differences in the tumor histology and pharmacokinetics in Asian versus non-Asian patients may influence the interpretation of the results worldwide. In this review, we review the polarizing opinions on the relevance of i.p. therapy in today's clinical armamentarium. Never before, have oncologists examined the same datasets with divergent conclusions. This topic is confusing to patients and clinicians alike and has led to inconsistent guidelines and reimbursement. However, it might be time to move on. Now more than ever, we have novel combinations to personalize upfront treatments for advanced ovarian cancer. In addition to i.p. therapy we also need to focus on targeted therapy, biomarkers, survivorship, and the sequencing of therapy., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

•A case report of a 14 year remission of recurrent ovarian cancer with intraperitoneal aldesleukin (IL-2) is presented.•Intraperitoneal IL-2 was given with little toxicity.•Immunotherapy may have the potential for durable remissions in ovarian cancer.

Background: Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients., Methods: Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800mg was administered orally every day (1cycle=28days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) >6months and objective tumor response., Results: Of 28 eligible and evaluable women enrolled, 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had 2 prior regimens. Twelve (43%) had >2cycles of brivanib with 4 (14%) receiving >10cycles (range: 1-20). Seven (25%) patients had PFS >6months (90% CI: 7.3%-33.9%). Two (7%) (90% CI: 1.3%-20.8%) patients had partial tumor response with duration of 8 and 22months and 12 (43%) had stable disease. The median PFS was 3.2months (90% CI: 2.1-4.4). The median overall survival was 7.9months (90% CI: 6.1-11.7). More common grade 3 adverse events were hypertension, anemia, hyponatremia, hyperglycemia, elevated liver enzymes, nausea, headache, and colon hemorrhage. Grade 4 adverse events included sepsis and hypertension., Conclusions: Based on early results of this phase II trial, brivanib was well tolerated and demonstrated sufficient activity after first stage but trial was stopped due to lack of drug availability., (Copyright © 2017. Published by Elsevier Inc.)

Purpose: ACRIN 6695 was a feasibility study investigating whether CT perfusion (CTP) biomarkers are associated with progression-free survival (PFS) at 6 months (PFS-6) in patients with advanced ovarian cancer who were treated with carboplatin and either dose-dense (weekly) or conventional (3-weekly) paclitaxel, with optional bevacizumab in the prospective phase III GOG-0262 trial. Experimental Design: ACRIN 6695 recruited participants with residual disease after primary cytoreductive surgery or planned interval cytoreduction following neoadjuvant therapy, to undergo CTP studies before (T0), 3 weeks (T1), and 4 weeks (T2) after chemotherapy initiation. Tumor blood flow (BF) and blood volume (BV) were derived with commercial software. Fisher exact tests assessed the associations of CTP biomarkers changes from T0 to T2 dichotomized at zero with PFS-6 and overall radiographic response rate, while Cox regression assessed the associations between CTP biomarker changes and PFS and overall survival (OS). Bonferroni correction was used to account for multiple comparisons. Results: Seventy-six of 120 enrolled patients from 19 centers were evaluable with a median age of 61 years. BV increase was significantly associated with lower chance of PFS-6 ( P = 0.028), while BF achieves borderline significance ( P = 0.053). In addition, BF increase was associated with shorter PFS (HR 2.9, 95% CI, 1.3-6.4, P = 0.008) and remained significant after adjusting for age, change in tumor volume, and surgery status ( P = 0.007). Neither BF nor BV changes were significantly associated with treatment response rate or OS. Conclusions: Early CTP biomarkers measurement may provide early prognostic information for PFS in newly diagnosed ovarian cancer. Clin Cancer Res; 23(14); 3684-91. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Platinum-based chemotherapy doublets are a standard of care for women with ovarian cancer recurring 6 months after completion of initial therapy. In this study, we aimed to explore the roles of secondary surgical cytoreduction and bevacizumab in this population, and report the results of the bevacizumab component here., Methods: The multicentre, open-label, randomised phase 3 GOG-0213 trial was done in 67 predominantly academic centres in the USA (65 centres), Japan (one centre), and South Korea (one centre). Eligible patients were adult women (aged ≥18 years) with recurrent measurable or evaluable epithelial ovarian, primary peritoneal, or fallopian tube cancer, and a clinical complete response to primary platinum-based chemotherapy, who had been disease-free for at least 6 months following last infused cycle of platinum. Patients were randomly assigned (1:1) to standard chemotherapy (six 3-weekly cycles of paclitaxel [175 mg/m 2 of body surface area] and carboplatin [area under the curve 5]) or the same chemotherapy regimen plus bevacizumab (15 mg/kg of bodyweight) every 3 weeks and continued as maintenance every 3 weeks until disease progression or unacceptable toxicity. Individuals who participated in both the bevacizumab objective and surgical objective (which is ongoing) were randomly assigned (1:1:1:1) to receive either of these two chemotherapy regimens with or without prior secondary cytoreductive surgery. Randomisation for the bevacizumab objective was stratified by treatment-free interval and participation in the surgical objective. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00565851., Findings: Between Dec 10, 2007, and Aug 26, 2011, 674 women were enrolled and randomly assigned to standard chemotherapy (n=337) or chemotherapy plus bevacizumab (n=377). Median follow-up at the end of the trial on Nov 5, 2014, was 49·6 months in each treatment group (IQR 41·5-62·2 for chemotherapy plus bevacizumab; IQR 40·8-59·3 for chemotherapy), at which point 415 patients had died (214 in the chemotherapy group and 201 in the chemotherapy plus bevacizumab group). Based on pretreatment stratification data, median overall survival in the chemotherapy plus bevacizumab group was 42·2 months (95% CI 37·7-46·2) versus 37·3 months (32·6-39·7) in the chemotherapy group (hazard ratio [HR] 0·829; 95% CI 0·683-1·005; p=0·056). We identified incorrect treatment-free interval stratification data for 45 (7%) patients (equally balanced between treatment groups); a sensitivity analysis of overall survival based on the audited treatment-free interval stratification data gave an adjusted HR of 0·823 (95% CI 0·680-0·996; p=0·0447). In the safety population (all patients who initiated treatment), 317 (96%) of 325 patients in the chemotherapy plus bevacizumab group had at least one grade 3 or worse adverse event compared with 282 (86%) of 332 in the chemotherapy group; the most frequently reported of these in the chemotherapy plus bevacizumab group compared with the chemotherapy group were hypertension (39 [12%] vs two [1%]), fatigue (27 [8%] vs eight [2%]), and proteinuria (27 [8%] vs none). Two (1%) treatment-related deaths occurred in the chemotherapy group (infection [n=1] and myelodysplastic syndrome [n=1]) compared with nine (3%) in the chemotherapy plus bevacizumab group (infection [n=1], febrile neutropenia [n=1], myelodysplastic syndrome [n=1], secondary malignancy [n=1]; deaths not classified with CTCAE terms: disease progression [n=3], sudden death [n=1], and not specified [n=1])., Interpretation: The addition of bevacizumab to standard chemotherapy, followed by maintenance therapy until progression, improved the median overall survival in patients with platinum-sensitive recurrent ovarian cancer. Although the intention-to-treat analysis for overall survival was not significant, our sensitivity analysis based on corrected treatment-free interval stratification indicates that this strategy might be an important addition to the therapeutic armamentarium in these patients., Funding: National Cancer Institute and Genentech., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: We report the results of a rapid assessment of Zika virus awareness among key clinical specialties in Singapore., Methods: Between June 6 and June 19, 2016 we conducted an online survey of doctors working in obstetrics and gynaecology, neonatology and paediatrics in Singapore. The survey included 15 multiple choice questions to measure respondents' knowledge of Zika virus in four domains covering clinical and public health., Results: A total of 110 survey responses (15% response rate) were obtained, 82% of respondents worked in the public sector. Overall, the median respondent score was 9.4 (Max score=15), with substantial variation (range: 3.5 - 14.7). Microcephaly and Guillain-Barré syndrome were recognised as causal complications of Zika virus infection by 99% and 50% of respondents respectively.  Clinical features which could help differentiate Zika from Dengue were less well understood with 50% and 68% correctly identifying conjunctivitis and low grade fever respectively. Worryingly, 14% favoured non-steroidal anti-inflammatory drugs as part of treatment, without first excluding dengue as a diagnosis. Also, only 36% of respondents were aware of the current recommendation for preventing sexual transmission of Zika virus. Fewer than 50% were aware of the need for ophthalmological evaluation as part of congenital Zika virus infection., Discussion: Our assessment demonstrates that there is good awareness of the clinical manifestation of Zika virus disease among key specialty doctors, but confusion with Dengue disease remains. It also highlights knowledge gaps in the prevention of sexually-transmitted Zika virus infection and the clinical management of congenital Zika virus infection in newborns. Our study identified strategic areas to improve communication to front-line doctors during public health response to the Zika epidemic.

Background: The unprecedented reemergence of Zika virus (ZIKV) has startled the world with reports of increased microcephaly in Brazil. ZIKV can infect human neural progenitors and impair brain growth. However, direct evidence of ZIKV infection in human fetal brain tissues remains elusive., Methods: Investigations were performed with brain cell preparations obtained from 9 donors. Virus infectivity was assessed by detection of virus antigen by flow cytometry together with various hematopoietic cell surface markers. Virus replication was determined by viral RNA quantification. Cytokine levels in supernatant obtained from virus-infected fetal brain cells were measured simultaneously in microbead-based immunoassays., Results: We also show that ZIKV infection was particularly evident in hematopoietic cells with microglia, the brain-resident macrophage population being one of the main targets. Infection induces high levels of proinflammatory immune mediators such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), and monocyte chemotactic protein 1 (MCP-1)., Conclusions: Our results highlight an important role for microglia and neuroinflammation during congenital ZIKV pathogenesis., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Aims: The vast majority of type A thymomas are diagnosed in tumour stages 1 or 2, and metastatic cases are exceedingly rare. The histological and genetic features of such metastatic type A thymomas have not been described in detail., Methods and Results: Five metastatic type A thymomas in tumour stage Masaoka IVb that had been reviewed by a panel of expert pathologists were analysed using comparative genomic hybridization (CGH). Cases 1, 2 and 3 showed the prototypical morphology of type A thymomas with mainly solid growth patterns. These cases displayed only very subtle nuclear irregularities and slight nuclear crowding, but no other atypical features. Mitoses were absent. Cases 3 and 4, in contrast, had a distinctly atypical morphology. CGH revealed partially recurrent alterations in four cases (with and without atypical morphology), including gains on chromosome 1q (one case), 17q (two cases), chromosome 19 (three cases) and 22q (one case) and losses on chromosome 17p (two cases) and 22q (one case)., Conclusion: Rare metastatic type A thymomas, both with typical and 'atypical' histological features, show partially recurrent genomic alterations that differ from the much more frequent localized and indolent tumours. The fact that these alterations were recurring points to a link between clinical behaviour and molecular features. Our findings may have implications for the management and treatment of such tumours., (© 2016 John Wiley & Sons Ltd.)

Plasma 25-hydroxyvitamin D (25OHD) deficiency, poor sleep quality, and night-time eating, have been independently associated with adverse pregnancy outcomes, but their inter-relationships are yet to be evaluated. We aimed to investigate the associations between maternal plasma 25OHD status and sleep quality and circadian eating patterns during pregnancy. Data on pregnant women ( n = 890) from a prospective cohort (Growing Up in Singapore Towards healthy Outcomes) were analyzed. Plasma 25OHD concentration was measured, while the Pittsburgh sleep quality index (PSQI) and 24-h dietary recall were administered to women at 26-28 weeks' gestation. Plasma 25OHD status was defined as sufficient (>75 nmol/L), insufficient (50-75 nmol/L), or deficient (<50 nmol/L). Poor sleep quality was defined by a total global PSQI score >5. Predominantly day-time (pDT) and predominantly night-time (pNT) were defined according to consumption of greater proportion of calories (i.e., >50%) from 07:00-18:59 and from 19:00-06:59, respectively. After adjustment for confounders, women with plasma 25OHD deficiency had higher odds of poor sleep quality (odds ratio (OR) 3.49; 95% confidence interval (CI) 1.84-6.63) and pNT eating (OR: 1.85; 95% CI 1.00-3.41) than those who were 25OHD sufficient. Our findings show the association of maternal plasma 25OHD deficiency with poor sleep quality and pNT eating at mid-pregnancy.

The 48-basepair (48-bp) variable number tandem repeat (VNTR) polymorphism in exon 3 of the dopamine receptor D4 gene (DRD4) is implicated in the etiology of attention-deficit/ hyperactivity disorder (ADHD). In particular, ADHD in European-ancestry population is associated with an increased prevalence of the 7-repeat (7R) allele of the exon 3 VNTR. However, it is intriguing to note that the 7R allele has been found to be of very low prevalence in the Chinese general population. In a previous case-control study, our research team had found that the 7R allele was similarly absent in Chinese ADHD children in Hong Kong. Instead, there was an increased prevalence of the 2R allele in Chinese ADHD children. Interestingly, in Asian samples, the 2R allele had been found to be an evolutionary derivative of the 7R allele with equivalent biochemical functionality. So, the finding of an association between ADHD and 2R allele in Chinese population does not exactly contradict the original 7R allele finding in European-ancestry population. However, given the potential pitfall of population stratification in the previous case-control design, this current study tested the 2R allele and ADHD association using a methodologically more rigorous family-based approach on 33 Chinese ADHD probands who had favorable clinical responses to stimulant medication (methylphenidate). Haplotype Relative Risk (HRR) analysis and Transmission Disequilibrium Test (TDT) both showed a significant preferential transmission of the 2R allele from the biological parents to ADHD probands (pone-tailed = 0.038, OR = 2.04; pone-tailed = 0.048, OR = 2.29, respectively). A second hypothesis speculates that it is the deviation, including 7R and 2R alleles, from the conserved ancestral 4R allele which confers risk to ADHD. Thus, a preferential transmission of non-4R alleles, against the 4R allele, from biological parents to their ADHD probands is predicted. Both HRR analysis and TDT confirmed such prediction (pone-tailed = 0.029, OR = 2.07; pone-tailed = 0.032, OR = 2.43, respectively). This study re-confirmed the original finding of a previous study that in Chinese population, the 2R allele of the DRD4 exon 3 VNTR was related to ADHD. This endorses the general thesis that DRD4 exon 3 VNTR polymorphism is related to ADHD, despite that the exact length or number of repeats of the associated alleles varies across ethnicity. This in turn supports the dopamine dysregulation theory of ADHD.

Large numbers of human mesenchymal stromal cells (MSCs) used for a variety of applications in tissue engineering and cell therapy can be generated by scalable expansion in a bioreactor using microcarriers (MCs) systems. However, the enzymatic digestion process needed to detach cells from the growth surface can affect cell viability and potentially the potency and differentiation efficiency. Thus, the main aim of our study was to develop biocompatible and biodegradable MCs that can support high MSC yields while maintaining their differentiation capability and potency. After cell expansion, the cells that covered MCs can be directly implanted in vivo without the need for cell harvesting or use of scaffold. Poly-ε-caprolactone (PCL) is known as a biocompatible and biodegradable material. However, it cannot be used for generation of MCs because its high density (1.14 g/cm 3 ) would exclude its applicability for suspension MCs in stirred reactors. In this article, we describe expansion and potency of MSCs propagated on low-density (1.06 g/cm 3 ) porous PCL MCs coated with extracellular matrices (LPCLs) in suspended stirred reactors. Using these LPCLs, cell yields of about 4 × 10 4 cells/cm 2 and 7- to 10-fold increases were obtained using four different MSC lines (bone marrow, cord blood, fetal and Wharton's jelly). These yields were comparable with those obtained using non-degradable MCs (Cytodex 3) and higher than two-dimensional monolayer (MNL) cultures. A fed-batch process, which demonstrated faster cell expansion (4.5 × 10 4 cells/cm 2 in 5 days as compared with 7 days in batch culture) and about 70% reduction in growth media usage, was developed and scaled up from 100-mL spinner flask to 1-L controlled bioreactor. Surface marker expression, trilineage differentiation and clonogenic potential of the MSCs expanded on LPCL were not affected. Cytokine secretion kinetics, which occurred mostly during late logarithmic phase, was usually comparable with that obtained in Cytodex 3 cultures and higher than MNL cultures. In conclusion, biodegradable LPCL can be used to efficiently expand a variety of MSC lines in stirred scalable reactors in a cost-effective manner while maintaining surface markers expression, differentiation capability and high levels of cytokine secretion. This study is the first step in testing these cell-biodegradable porous MC aggregates for tissue engineering and cell therapy, such as bone and cartilage regeneration, or wound healing., (Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objectives: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review B-cell proliferations of varied malignant potential associated with immunodeficiency., Methods: The Workshop Panel reviewed all cases of B-cell hyperplasias, polymorphic B-lymphoproliferative disorders, Epstein-Barr virus (EBV)-positive mucocutaneous ulcer, and large B-cell proliferations associated with chronic inflammation and rendered consensus diagnoses. Disease definitions, boundaries with more aggressive B-cell proliferations, and association with EBV were explored., Results: B-cell proliferations of varied malignant potential occurred in all immunodeficiency backgrounds. Presentation early in the course of immunodeficiency and in younger age groups and regression with reduction of immunosuppression were characteristic features. EBV positivity was essential for diagnosis in some hyperplasias where other specific defining features were absent., Conclusions: This spectrum of B-cell proliferations show similarities across immunodeficiency backgrounds. Localized forms of immunodeficiency disorders arise in immunocompetent patients most likely due to chronic immune stimulation and, despite aggressive histologic features, often show indolent clinical behavior., (© American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Objectives: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review immunodeficiency-related T- and natural killer (NK)-cell lymphoproliferations., Methods: The Workshop Panel reviewed 88 T- or NK-cell lymphoproliferations and rendered consensus diagnoses., Results: Hyperplasias of T-cell subsets may be clonal; retained architecture and the clinical setting support a benign diagnosis. Specific associations include hepatosplenic T-cell lymphoma with iatrogenic immunosuppression and breast implants with an indolent variant of anaplastic large cell lymphoma. Epstein-Barr virus (EBV)-positive T-cell lymphomas rarely occur in the acquired immunodeficiency setting. Systemic T- and NK-cell lymphoma of childhood overlaps with chronic active EBV and reversible hemophagocytic lymphohistiocytosis-related T-cell lymphoproliferations., Conclusions: Immunodeficiencies predispose to T-cell hyperplasias, which must not be overdiagnosed as lymphoma. Many T-cell lymphomas in the immunodeficiency setting are likely coincidental, with specific exceptions. Systemic T- or NK-cell lymphomas are part of a spectrum of EBV+ T or NK lymphoproliferations and can present in the acquired immunodeficiency setting., (© American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)