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Patients with gynecologic malignancies may have varied responses to COVID-19 infection. We aimed to describe clinical courses, treatment changes, and short-term clinical outcomes for gynecologic oncology patients with concurrent COVID-19 in the United States.The Society of Gynecologic Oncology COVID-19 and Gynecologic Cancer Registry was created to capture clinical courses of gynecologic oncology patients with COVID-19. Logistic regression models were employed to evaluate factors for an association with hospitalization and death, respectively, within 30 days of COVID-19 diagnosis.Data were available for 348 patients across 7 institutions. At COVID-19 diagnosis, 125 patients (36%) had active malignancy. Delay (n = 88) or discontinuation (n = 10) of treatment due to COVID-19 infection occurred in 28% with those on chemotherapy (53/88) or recently receiving surgery (32/88) most frequently delayed. In addition to age, performance status, diabetes, and specific COVID symptoms, both non-White race (adjusted odds ratio (aOR) = 3.93, 95% CI 2.06-7.50) and active malignancy (aOR = 2.34, 95% CI 1.30-4.20) were associated with an increased odds of hospitalization. Eight percent of hospitalized patients (8/101) died of COVID-19 complications and 5% (17/348) of the entire cohort died within 30 days after diagnosis.Gynecologic oncology patients diagnosed with COVID-19 are at risk for hospitalization, delay of anti-cancer treatments, and death. One in 20 gynecologic oncology patients with COVID-19 died within 30 days after diagnosis. Racial disparities exist in patient hospitalizations for COVID-19, a surrogate of disease severity. Additional studies are needed to determine long-term outcomes and the impact of race.

Examining synchronous chats from an online suicide crisis intervention, we used contrapuntal analysis to identify competing discourses of meaning among online suicide chat users. Contrapuntal analysis revealed two emergent discourses in competition to make meaning of suicide among crisis chat users: Discourses of the Precious Life (DPL) and Discourses of Life as a Thing (DLT). The results provide a nuanced understanding of the cultural meaning of suicide presented in chat visitors’ discourse. Aside from the theoretical implications for RDT 2.0 focused research, this study extends a growing body of suicide research that foregrounds culture as a basis for understanding the meaning of suicide from the perspective of the lived experience.

Epithelial adenocarcinoma of the ovary and colon are associated with the highest rates of cancer-related deaths in women in the U.S. The literature supports the role of HDL-associated apolipoproteins in the treatment of cancer and other pro-inflammatory diseases. Previously, we developed a novel 20-amino acid mimetic peptide, HM-10/10, which potently inhibits tumor development and growth in colon and ovarian cancer. Here, we report the properties of HM-10/10 relative to its stability in vitro. The results demonstrated that HM-10/10 had the highest half-life in human plasma compared to plasma from other species tested. HM-10/10 demonstrated stability in human plasma and simulated gastric environment, increasing its promise as an oral pharmaceutical. However, under conditions modeling the small intestine, HM-10/10 demonstrated significant degradation, likely due to the peptidases encountered therein. Furthermore, HM-10/10 demonstrated no evidence of time-dependent drug–drug interactions, although it demonstrated CYP450 induction slightly above cutoff. As proteolytic degradation is a common limitation of peptide-based therapeutics, we are pursuing strategies to improve the stability properties of HM-10/10 by extending its bioavailability while retaining its low toxicity profile. HM-10/10 holds promise as a new agent to address the international women’s health crisis of epithelial carcinomas of the ovary and colon.

Preeclampsia is a multifactorial pathology with negative outcomes in affected patients in both the peripartum and postpartum period. Black patients in the United States, when compared to their White and Hispanic counterparts, have higher rates of preeclampsia. This article aims to review the current literature to investigate how race, social determinants of health, and genetic profiles influence the prevalence and outcomes of patients with preeclampsia. Published studies utilized in this review were identified through PubMed using authors' topic knowledge and a focused search through a Medline search strategy. These articles were thoroughly reviewed to explore the contributing biosocial factors, genes/biomarkers, as well as negative outcomes associated with disparate rates of preeclampsia. Increased rates of contributing comorbidities, including hypertension and obesity, which are largely associated with low access to care in Black patient populations lead to disparate rates of preeclampsia in this population. Limited research shows an association between increased rate of preeclampsia in Black patients and specific APOL1, HLA-G, and PP13 gene polymorphisms as well as factor V Leiden mutations. Further research is required to understand the use of certain biomarkers in predicting preeclampsia within racial populations. Understanding contributing biosocial factors and identifying genes that may predispose high-risk populations may help to address the disparate rates of preeclampsia in Black patients as described in this review. Further research is required to understand if serum, placental, or urine biomarkers may be used to predict individuals at risk of developing preeclampsia in pregnancy. Key Points

Background While the importance of commensal microbes in vaginal health is well appreciated, little is known about the effects of gynecological cancer (GynCa) and radiation therapy (RT) on the vaginal microbiome (VM) of postmenopausal women. Methods We studied women with GynCa, pre‐ (N = 65) and post‐RT (N = 25) and a group of healthy controls (N = 67) by sequencing the V4 region of the 16S rRNA gene from vaginal swabs and compared the diversity and composition of VMs between the three groups accounting for potential confounding factors in multivariate analysis of variance. Results Comparisons of cancer vs healthy groups revealed that Lactobacillus and Bifidobacterium have significantly higher relative abundance in the healthy group, while the cancer group was enriched in 16 phylogroups associated with bacterial vaginosis (BV) and inflammation, including Sneathia, Prevotella, Peptoniphilus, Fusobacterium, Anaerococcus, Dialister, Moryella, and Peptostreptococcus. In our sample, RT affected the α‐diversity and correlated with higher abundance of typically rare VM species, including several members of the Lacnospiraceae family, a taxon previously linked to vaginal dysbiosis. In addition to cancer and treatment modalities, age and vaginal pH were identified as significant parameters that structure the VM. Conclusions This is among the first reports identifying VM changes among postmenopausal women with cancer. RT alone seems to affect several phylogroups (12 bacterial genera), while gynecological cancer and its treatment modalities are associated with even greater significant shifts in the vaginal microbiota including the enrichment of opportunistic bacterial pathogens, which warrants further attention., Vaginal microbial communities in postmenopausal women undergoing gynecologic cancer treatments have small but detectable differences compared to healthy controls, including higher diversity and abundance of opportunistic bacterial pathogens. Radiation therapy alone seems to affect several phylogroups (12 bacterial genera), while gynecological cancer and its treatment modalities (surgery and chemotherapy) are associated with even greater significant shifts in the vaginal microbiota including the enrichment of opportunistic bacterial pathogens, which warrants further attention.

Highlights • Small cell carcinoma of the ovary is a very rare, highly undifferentiated, aggressive malignancy that affects young women and linked to a poor prognosis (especially women under 40 years of age). We present a 22 years old African woman with complete remission 30 months after diagnosis despite a conservative surgery and only 3 cycles of chemotherapy. • SCCOHT seems to be a monogenic disease with mutations in the tumour suppressor gene, a chromatin remodeler: SMARCA4 and can involve germline or somatic lines. Mutation can also be a de novo sequence. Research for new treatments includes target therapy. • Because of the rareness of SCCOHT (about 300 cases in the world) no standard treatment guidelines for SCCOHT are established, but combination of surgical debulking and chemotherapy based on cisplatin, are common practice. • Autologous stem cell transplant after high-dose adjuvant chemotherapy seems to lead to the best survival rates, because it allows perform doses 2- to 10-fold higher than standard chemotherapy doses., Introduction Small cell carcinoma of the ovary (SCC) is a very rare (less than 1 % of ovarien neoplasia), highly undifferentiated, aggressive malignancy affecting young women and linked to a poor prognosis. Overall survive rate is very low (about 16 %). SCCOHT has recently been shown to be associated with SMARCA4 gene mutations and shows some genetic similarities to malignant rhabdoid tumors (MRT). Presentation of case After a reminder of the clinical, histological description of the SCCOHT and concensus about the medical management, we describe the rare case of a 22 years old patient with complete remission after diagnosis of un undifferentiated SCCOHT stage IV treated by conservative surgery and high-doses chemotherapy, 30 months after diagnosis. Discussion Thus far, no standard therapy exists for SCCOHT. Treatment modalities are surgery, chemotherapy, radiotherapy and autologous stem cell transplant after high-dose chemotherapy. Research for new treatments includes target therapy. Conclusion Autologous stem cell transplant after high-dose adjuvant chemotherapy seems to lead to the best survival rates. Invasiveness of the treatment depends on the stage of the disease, age of the patient and her fertility-sparing desire. An international collaboration will be needed to standardise practices due of the small number of patients.

To identify the incidence, type, and grade of postoperative adverse events in minimally invasive radical hysterectomy vs abdominal radical hysterectomy (ARH) for patients with early-stage cervical cancer and determine risk factors associated with these adverse events.The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) was queried to identify patients with early-stage cervical cancer undergoing radical hysterectomy. Multivariable logistic regression was used to assess risk factors associated with adverse postoperative outcomes among patients undergoing radical hysterectomy.ACS NSQIP participating institutions within the United States.Patients were collected from the ACS NSQIP databases (2014-2017) undergoing radical hysterectomy for early-stage cervical cancer.N/A MEASUREMENTS AND MAIN RESULTS: ARH had a significantly increased incidence of any 30-day postoperative adverse event compared with minimally invasive radical hysterectomy (31.2% vs 19.9%, p.001). There was a higher incidence of surgical site infection, both deep and superficial, and blood transfusions in ARH. On multivariable logistic regression, the abdominal surgical approach was the only risk factor significantly associated with any postoperative adverse event (odds ratio, 1.4; confidence interval, 1.1-1.9; p = .018; 95% CIs).In this study, the abdominal surgical approach for radical hysterectomy in early-stage cervical cancer was associated with a higher incidence of postoperative adverse events than the minimally invasive approach.

Access to multi-detector computed tomography (MDCT) scanning for interventional procedures can prove to be logistically challenging as resources are often in different areas within the hospital. At some institutions, interventional radiology suites have moved to the operating room, separate from the diagnostic radiology department. At these institutions, complex interventional procedures requiring both fluoroscopy and MDCT may pose logistical challenges, especially as they pertain to timely patient transfers. Hybrid CT/fluoroscopy suite provides rapid, reliable MDCT assessment of trauma patients before and after emergent surgery, as well as access to the entire spectrum of emergent image-guided interventions in the same suite.

BackgroundHereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder characterized by recurrent epistaxis (nose bleeds), mucosal telangiectasias (spider veins), and arteriovenous malformations. Although HHT affects all racial groups, few studies have explored racial disparities among patients with HHT.MethodsWe performed a retrospective chart review of HHT patients who were seen at a single academic center between July 1, 2014 and January 1, 2022. The primary outcomes of this study were the Epistaxis Severity Score (ESS) and the presence of pulmonary, cerebral, gastrointestinal, spinal, and hepatic arteriovenous malformations (AVMs). We analyzed racial differences using t-tests and analysis of variance (ANOVA) for continuous variables, and chi-squared tests for categorical variables. We then performed multivariable linear and logistic regressions on outcomes.ResultsOur review identified 35 Asian, 6 Black or African American, 72 Hispanic or Latino, and 244 White or Caucasian patients who met the inclusion criteria. Through an analysis of variance model, race/ethnicity was not significantly associated with ESS. Two univariable logistic regression models between race and both pulmonary and brain AVMs showed that race was associated with the incidence of pulmonary AVMs (pConclusionPatients who identified as Asian may have higher rates of pulmonary AVMs while patients identifying as Hispanic or Latino may have more cerebral AVMs. The correlations may be important for identifying risk factors in certain patient populations.

Off-label bisphosphonate use in juvenile horses is widespread despite little scientific understanding of biological and welfare impacts on skeletally immature, exercising horses. Therefore, the objective was to determine the effects of clodronate disodium on growth parameters of young horses. Thirty-two yearling Quarter horses (335 ± 4 kg, 500 ± 13 d of age) were stratified by age, BW, sex, and initial bone density by aluminum equivalence into four treatment groups for a 168-d trial. The experimental period was divided into two phases mimicking common management practices in horses undergoing sales preparation (Phase I: d 0 to 83) and early performance training (Phase II: d 84 to 168). Horses were housed in individual stalls (3.6 m × 7.2 m). Diets were formulated to meet nutrient requirements including concentrate offered every 12 h and ad libitum access to coastal bermudagrass (Cynodon dactylon) hay and water. Treatments consisted of control (CON; n = 8), single-dose (1X; n = 8), two-dose (2X; n = 8), and four-dose groups (4X; n = 8). All horses received iso-volumetric intramuscular injections of either 1.8 mg/kg BW clodronate disodium (OSPHOSÒ) or saline (placebo) on d 0, 42, 84, and 126. Physical measurements including BW, wither height (WH), hip height (HH), body length (BL), and heart girth (HG) circumference were recorded every 42 d, beginning on d 0. Data were analyzed using PROC MIXED procedure of SAS. There were no treatment differences (P ≥ 0.62) or treatment ′ time interactions (P ≥ 0.25) for BW, WH, HH, BL, and HG, but all measurements increased over time (P ≤ 0.01). These results indicate that clodronate does not impact physical growth parameters in juvenile horses undergoing forced exercise. Further work is ongoing to determine tissue-specific effects of clodronate on bone growth and development in yearling Quarter horses.

The eddy covariance technique (EC) is used at hundreds of field sites worldwide to measure trace gas exchange between the surface and the atmosphere. Data quality and correction methods for EC have been studied empirically and theoretically for many years. The recent development of new gas analyzers has led to an increase in technological options for users. Open-path (no inlet tube) and closed-path (long inlet tube) sensors have been used for a long time, whereas enclosed-path (short inlet tube) sensors are relatively new. We tested the comparability of fluxes calculated from five different gas analyzers including two open-path (LI-7500 A from LI-COR, IRGASON from Campbell), two enclosed-path (CPEC200 from Campbell, LI-7200 from LI-COR), and one closed-path (2311-f from Picarro) analyzers, which were all located on a single tower at an irrigated alfalfa field in Davis, CA. To effectively compare sensors with different tube characteristics we used three different spectral correction methods. We found that all sensors, regardless of type, can be used to measure fluxes if appropriate corrections are applied and quality control measures are taken. However, the comparability strongly depended on the gas (CO2 or H2O) and the correction method. Average differences were below 4% for CO2 fluxes using any spectral correction method, but for H2O average differences were between 4% and 13% for the different methods. The magnitude of corrections also varied strongly, especially for water vapor fluxes. This study does not identify the best sensor, but rather weighs the benefits and difficulties of each sensor and sensor type. Our findings show that enclosed and closed-path gas analyzers that measure water vapor with inlet tubes experience large high frequency attenuation and should be corrected with empirical correction methods. This information presented here about different the diverse sensors be considered by investigators when choosing a sensor for a site or when analyzing EC measurements from multiple sites.

A collaboration between DESY, PSI and CERN has developed and built an advanced modular $X$-band transverse deflection structure (TDS) system with the new feature of providing variable polarization of the deflecting force. The prototype of the novel $X$-band TDS, the polarizable $X$-band (PolariX) TDS, was fabricated at PSI following the high-precision tuning-free production process developed for the C-band Linac of the SwissFEL project. Bead-pull rf measurements were also performed at PSI to verify, inparticular, that the polarization of the dipole fields does not have any rotation along the structure. The high-power test was performed at CERN and now the TDS is at DESY and has been installed in theFLASHForward beamline, where the first streaking experience with beam has been accomplished. We summarize in this paper the rf design of the TDS and its key components, such as the $X$-band pulse compressor, E-rotator, and phase shifter, the results of the bead-pull measurements and the high power test and finally the rf setup at DESY.

Summary Multielectrode array (MEA) technology has been extensively used for field potential recordings from excitable cells. However, its application for action potential (AP) measurements has not been harnessed. Here, we report a novel platform for high-resolution intracellular AP recordings from induced pluripotent stem cell-cardiomyocyte constructs derived from human cardiac fibroblasts. To gain intracellular access, micro-gold MEAs were used to electroporate multiple constructs simultaneously. High-throughput AP measurements were obtained from 41 multicellular constructs. Repeated electroporations of the same cells did not affect the signal stability. Our model has the capability to distinguish subtle differences in AP morphology to characterize the network profile. Furthermore, we confirm the reliability of the system by recapitulating known drug-induced physiological and arrhythmogenic responses. Overall, the model provides a unique cardio-electronic interface for non-invasive measurements of AP dynamics for drug screening and disease modeling. This technology opens the door for identifying novel cardio-factors to enhance electrophysiological maturation., Highlights • Electroporation-mediated action potential (AP) recordings using MEA technology • Simultaneous high-throughput AP measurement from multiple cell networks • Multiple electroporations of the same cells over days with stable signal • Model validation for developmental, disease, and drug screening studies, Joshi-Mukherjee and colleagues introduce an alternative approach for non-invasive, long-term action potential (AP) measurements in cell networks for drug screening and disease modeling. The authors describe a novel platform for high-throughput AP recordings from the same cells over days on iPSC-cardiomyocytes constructs derived from human cardiac fibroblasts. This technology opens the door for identifying novel cardio-factors to enhance electrophysiological maturation.

Heartland virus (HRTV) is an emerging tick-borne virus (Bunyaviridae, Phlebovirus) that has caused sporadic cases of human disease in several central and mid-eastern states of America. Animal models of HRTV disease are needed to gain insights into viral pathogenesis and advancing antiviral drug development. Presence of clinical disease following HRTV challenge in hamsters deficient in STAT2 function underscores the important role played by type I interferon-induced antiviral responses. However, the recovery of most of the infected animals suggests that other mechanisms to control infection and limit disease offer substantial protection. The most prominent disease sign with HRTV infection in STAT2 knockout hamsters was dramatic weight loss with clinical laboratory and histopathology demonstrating acute inflammation in the spleen, lymph node, liver and lung. Finally, we show that HRTV disease in hamsters can be prevented by the use of favipiravir, a promising broad-spectrum antiviral in clinical development for the treatment of influenza.

Since the establishment of diplomatic relations in 1951, Pakistan's desire for strategic parity with India and China's efforts to propel Pakistan as a strategic balancer to India have been the overarching factors for the emergence of a security centric Sino–Pak relationship. Over the years, it has diversified into an economic-centric relationship. Although military and technological transactions continue to dominate the economic relationship, China began gradually pledging increased investment in Pakistan's economy and infrastructure. China became the primary investor for building the Gwadar deep-sea port in 2002. Both sides signed a free trade agreement and agreed to link China's rail network to Gwadar Port through the Karakoram Highway in 2008. The commitment to develop Gwadar Port is a good indicator of the steady expansion of Chinese maritime interests and strategic influence in India's neighbourhood.This paper attempts to analyse the significance and implications of the development of Gwadar ...

Inhibitors of nuclear PARP enzymes (e.g., PARP-1) have improved clinical outcomes in ovarian cancer, especially in patients with BRCA1/2 gene mutations or additional homologous recombination (HR) DNA repair pathway deficiencies. These defects serve as biomarkers for response to PARP inhibitors (PARPi). We sought to identify an additional biomarker that could predict responses to both conventional chemotherapy and PARPi in ovarian cancers. We focused on cellular ADP-ribosylation (ADPRylation), which is catalyzed by PARP enzymes and detected by detection reagents we developed previously. We determined molecular phenotypes of 34 high-grade serous ovarian cancers and associated them with clinical outcomes. We used the levels and patterns of ADPRylation and PARP-1 to distribute ovarian cancers into distinct molecular phenotypes, which exhibit dramatically different gene expression profiles. In addition, the levels and patterns of ADPRylation, PARP-1 protein, and gene expression correlated with clinical outcomes in response to platinum-based chemotherapy, with cancers exhibiting the highest levels of ADPRylation having the best outcomes independent of BRCA1/2 status. Finally, in cell culture-based assays using patient-derived ovarian cancer cell lines, ADPRylation levels correlated with sensitivity to the PARPi, Olaparib, with cell lines exhibiting high levels of ADPRylation having greater sensitivity to Olaparib. Collectively, our study demonstrates that ovarian cancers exhibit a wide range of ADPRylation levels, which correlate with therapeutic responses and clinical outcomes. These results suggest ADPRylation may be a useful biomarker for PARPi sensitivity in ovarian cancers, independent of BRCA1/2 or homologous recombination deficiency status.

Background: We previously reported that nab-paclitaxel (nP) increases the pathological complete response (pCR, ypT0 ypN0) rate when it replaces solvent-based paclitaxel (P) as part of a sequential taxane followed by epirubicin/cyclophosphamide (EC) neoadjuvant chemotherapy for patients with early breast cancer (Untch et al. SABCS 2014). Here, we report efficacy and safety of patients being treated either with 150 mg/m2 nab-paclitaxel (nP150) before an amendment or with 125 mg/m2 nab-paclitaxel (nP125) thereafter in comparison to solvent-formulated paclitaxel at 80 mg/m2 (P80). Methods: In the GeparSepto study (NCT01583426), 1207 patients were randomized to either nP150 or P80 q1w for 12 weeks followed by 4 cycles of conventionally dosed EC (E: 90mg/m2; C: 600 mg/m2) q3w. The primary objective of the study was to compare the pCR rate (pCR, ypT0 ypN0). Patients with untreated, histologically confirmed uni- or bilateral, cT2- cT4d carcinoma, and no clinically relevant cardiovascular and other co-morbidities were included. Patients with HER2+ tumors received trastuzumab (loading dose 8mg/kg; 6 mg/kg) plus pertuzumab (loading dose 840 mg; 420 mg) q3w concomitantly to all chemotherapy cycles. After a safety analysis showed a higher rate of dose reductions and treatment discontinuations with nP150 compared to P80, weekly dose of nP was reduced to 125 mg/m2. Results: nP was given for the majority of cycles at a dose of 150 mg/m2 to 179 patients and at a dose of 125 mg/m2 to 426 patients. Treatment characteristics were fairly balanced between these two sequential cohorts as well as compared to 601 patients receiving P80 except for HER2 status (HER2-positive: nP150 22%, nP125 37% and P80 33%) and Ki67 ( Conclusions: Risk-benefit ratio of nP125 was improved over nP150 with better drug adherence and RTDI, lower frequency of PNP but a higher pCR rate. It should therefore be considered as the preferred schedule when nP is used as neoadjuvant treatment for primary breast cancer. The trial was financially supported by Celgene and Roche. Citation Format: von Minckwitz G, Untch M, Jakisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Weibringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer J-U, Clemens M, Costa SD, Gerber B, Nekljudova V, Loibl S. nab-paclitaxel at a dose of 125 mg/m2 weekly is more efficacious but less toxic than at 150 mg/m2. Results from the neoadjuvant randomized GeparSepto study (GBG 69). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-11.

Concerns have recently been raised regarding the presence of arsenic in California wine. Total arsenic concentrations in 101 wines produced or bottled in California were characterized using inductively coupled plasma mass spectrometry. Of these wines, 28 were wines identified in media reports as containing arsenic concentrations greater than the U.S. Environmental Protection Agency Maximum Contaminant Level for drinking water of 10 μg/L. The remaining 73 wines were randomly purchased at local retailers. Blush wines were found to contain the greatest total arsenic concentration (mean = 27.2 μg/L; SD = 16.9 μg/L) regardless of sampling group, followed by white wines (mean = 10.9 μg/L; SD = 11.0 μg/L) and red wines (mean = 6.75 μg/L; SD = 7.33 μg/L). Moreover, the publicized group of wines was found to have significantly (p

Background Diabetic kidney disease is a major cause of premature mortality in type 2 diabetes mellitus (T2DM). Worsening insulin sensitivity independent of glycemic control may contribute to the development of diabetic kidney disease. We investigated the longitudinal association of insulin sensitivity with hyperfiltration and increased albumin excretion in adolescents with T2DM. Study Design Observational prospective cohort study. Setting & Participants 532 TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) participants aged 12 to 17 years with T2DM duration less than 2 years at baseline. The TODAY Study was a multicenter randomized clinical trial that examined the efficacy of 3 treatment regimens (metformin monotherapy, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention program) to achieve durable glycemic control. Predictors Natural log–transformed estimated insulin sensitivity (reciprocal of fasting insulin), hemoglobin A1c concentration, age, race-ethnicity, treatment group, body mass index, loss of glycemic control, and hypertension. Outcomes Hyperfiltration was defined as 99th percentile or higher of estimated glomerular filtration rate (≥140mL/min/1.73m2) when referenced to healthy adolescents (NHANES 1999-2002) and albumin-creatinine ratio ≥ 30μg/mg at 3 consecutive annual visits. Results Hyperfiltration was observed in 7.0% of participants at baseline and in 13.3% by 5 years, with a cumulative incidence of 5.0% over 5 years. The prevalence of increased albumin excretion was 6% at baseline and 18% by 5 years, with a cumulative incidence of 13.4%. There was an 8% increase in risk for hyperfiltration per 10% lower estimated insulin sensitivity in unadjusted and adjusted models (P=0.01). Increased albumin excretion was associated with hemoglobin A1c concentration, but not estimated insulin sensitivity. Limitations Longer follow-up is needed to capture the transition from hyperfiltration to rapid glomerular filtration rate decline in youth-onset T2DM. Conclusions Lower estimated insulin sensitivity was associated with risk for hyperfiltration over time, whereas increased albumin excretion was associated with hyperglycemia in youth-onset T2DM.

ObjectivesTo evaluate the role of minimally invasive surgery (MIS) in gynecologic oncology fellowship training and fellows’ predictions of their use of MIS in their future practice.MethodsAll fellows-in-training in American Board of Obstetrics and Gynecology–approved training programs were surveyed in 2012 through an online or mailed-paper survey. Data were analyzed and compared to results of a similar 2007 survey.ResultsOf 172 fellows, 69 (40%) responded. Ninety-nine percent of respondents (n = 68) indicated that MIS was either very important or important in gynecologic oncology, a proportion essentially unchanged from 2007 (100%). Compared to 2007, greater proportions of fellows considered laparoscopic radical hysterectomy and node dissection for cervical cancer (87% vs 54%; P < 0.0001) and trachelectomy and staging for cervical cancer (83% vs 32%; P < 0.0001) appropriate for MIS. Of the respondents, 92% believed that maximum or some emphasis should be placed on robotic-assisted surgery and 89% on traditional laparoscopy during fellowship training. Ten percent rated their fellowship training in laparoendoscopic single-site surgery as very poor; 44% said that the question was not applicable. Most respondents (60%) in 2012 performed at least 11 procedures per month, whereas most respondents (45%) in 2007 performed 6 to 10 procedures per month (P = 0.005). All respondents at institutions where robotic surgery was used were allowed to operate at the robotic console, and 63% of respondents reported that in robotic-assisted surgery cases when a fellow sat at the robot, the fellow performed more than 50% of the case at the console.ConclusionsThese findings indicate that MIS in gynecologic oncology is here to stay. Fellowship programs should develop a systematic approach to training in MIS and in individual MIS platforms as they become more prevalent. Fellowship programs should also develop and apply an objective assessment of minimum proficiency in MIS to ensure that programs are adequately preparing trainees.

BACKGROUND Although greater than 40% of breast cancers occur in patients aged ≥65 years, these individuals are frequently undertreated. Taxane-based adjuvant chemotherapy is considered the treatment of choice but to the authors' knowledge has only limited evidence in elderly patients. METHODS Patients aged ≥65 years with a Charlson comorbidity index ≤2 and pT1/2 pN0/1 disease and either human epidermal growth factor receptor 2 (HER2)-positive, hormone receptor-negative, grade 3 (according to Common Terminology Criteria for Adverse Events [version 3.0]), high uPA/PAI-1 or any stage pT3/4 pN2/3 breast cancer were randomized to receive 4 cycles of adjuvant epirubicin and cyclophosphamide (EC) (epirubicin at a dose of 90 mg/m2 and cyclophosphamide at a dose of 600 mg/m2 intravenously [iv] on day 1 every 3 22 days) or 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (cyclophosphamide at a dose of 500 mg/m2, methotrexate at a dose of 40 mg/m2, and 5-fluorouracil at a dose of 600 mg/m2 iv on days 1 plus 8 every 29 days) versus 6 cycles of nab-paclitaxel and capecitabine (nPX) (nab-paclitaxel at a dose of 100 mg/m2 iv on days 1, 8, and 15 every 21 days with 1 week of rest every 6 weeks plus capecitabine at a dose of 2000 mg/m2 orally on days 1-14 every 21 days). Primary endpoints were treatment discontinuations and overall frequency of adverse events. RESULTS Thirteen of 198 patients (6.6%) discontinued EC/CMF and 69 of 193 patients (35.8%) discontinued nPX (P

Background: Anthracycline/taxane based regimen are standard of care for neoadjuvant therapy in breast cancer. A reverse sequence of taxanes followed by anthracyclines was suggested to achieve higher pCR rates (H.Earl, Lancet Oncol 2014). Dual HER2 blockade was shown to be superior to trastuzumab alone increasing the pCR rate by 20%. Nab-paclitaxel (nP) is a solvent-free formulation of paclitaxel (P) encapsulated in albumin which might further improve the pCR rate in breast cancer patients receiving neoadjuvant treatment and cause lower toxicity. Methods: In the GeparSepto study (NCT01583426) patients were randomized to either nP (125 mg/m2) q1w or P (80mg/m2) q1w for 12 weeks followed by 4 cycles of conventionally dosed EC (E, epirubicin 90mg/m2; C, cyclophosphamide 600 mg/m2) q3w. The primary objective is to compare the pathological complete response rate (pCR, ypT0 ypN0). Further objectives are to compare the pCR rate in predefined subgroups, pCR by other definitions, clinical response rate, rate of breast conserving surgery and toxicity and compliance. Patients with untreated, histologically confirmed uni- or bilateral, cT2- cT4d carcinoma, and no clinically relevant cardiovascular and other co-morbidities were included. HER2+ patients received trastuzumab (loading dose 8mg/kg; 6 mg/kg) plus pertuzumab (loading dose 840 mg; 420 mg) q3w concomitantly. HER2, estrogen receptor, progesterone receptor, Ki67 and SPARC status were centrally assessed prior to randomization for stratification. To increase the pCR rate from 33% with P to 41% with nP, corresponding to an odds ratio of 1.41 with an alpha of 0.05 and a power of 80%, 1200 patients would be needed. A window-of opportunity study was integrated to investigate response to anti-HER2 treatment without chemotherapy, HER2+ patients were randomized to receive 6 weeks of either trastuzumab, pertuzumab or the combination with biomaterial collection at the start and the end of the window. Results: A total of 1204/1229 (window study n=71) recruited patients (7/2012 - 12/2013) from 69 German centers were evaluable, 606 receiving nP. Baseline characteristics are well balanced; median age was 49/50 years (P/nP), 33/33% of the patients presented with HER2+ tumors, 23/23% triple negative breast cancer TNBC (ER and PR 20% 69/69%; SPARC positive 15.7/16%. 265 patients reported SAEs (119 P/146 nP) and 4 died on study (1 P: cardiac decompensation; 3 nP: accident at home, multiorgan failure, sepsis during EC). The pCR rate (ypT0 ypN0) is 29% with P and 38% with nP, OR 1.5; p Conclusions: GeparSepto showed that the pCR rate is significantly higher with nab-paclitaxel compared to solvent-based paclitaxel given weekly before anthracycline based chemotherapy. Subgroupanalyses and 2ndary endpoints will be presented at the meeting. The trial was financially supported by Roche and Celgene. The window-substudy was funded within the EU-FP7 project RESPONSIFY No 278659. Citation Format: Michael Untch, Christian Jackisch, Andreas Schneeweiß, Bettina Conrad, Bahriye Aktas, Carsten Denkert, Holger Eidtmann, Hermann Wiebringhaus, Sherko Kümmel, Jörn Hilfrich, Mathias Warm, Stefan Paepke, Marianne Just, Claus Hanusch, John Hackmann, Jens-Uwe Blohmer, Michael Clemens, Serban Dan Costa, Bernd Gerber, Valentina Nekljudova, Sibylle Loibl, Gunter von Minckwitz. A randomized phase III trial comparing neoadjuvant chemotherapy with weekly nanoparticle-based paclitaxel with solvent-based paclitaxel followed by anthracyline/cyclophosphamide for patients with early breast cancer (GeparSepto); GBG 69 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S2-07.

ADP-ribosylation is an enzyme-catalyzed post-translational modification of proteins in which the ADP-ribose (ADPR) moiety of NAD(+) is transferred to a specific amino acid in a substrate protein. The biological functions of ADP-ribosylation are numerous and diverse, ranging from normal physiology to pathological conditions. Biochemical and cellular studies of the diverse forms and functions of ADPR require immunological reagents that can be used for detection and enrichment. The lack of a complete set of tools that recognize all forms of ADPR [i.e., mono-, oligo-, and poly(ADP-ribose)] has hampered progress. Herein, we describe the generation and characterization of a set of recombinant antibody-like ADP-ribose binding proteins, in which naturally-occurring ADPR binding domains, including macrodomains and WWE domains, have been functionalized by fusion to the Fc region of rabbit immunoglobulin. These reagents, which collectively recognize all forms of ADPR with different specificities, are useful in a broad array of antibody-based assays, such as immunoblotting, immunofluorescent staining of cells, and immunoprecipitation. Observations from these assays suggest that the biology of ADPR is more diverse, rich, and complex than previously thought. The ARBD-Fc fusion proteins described herein will be useful tools for future exploration of the chemistry, biochemistry, and biology of ADP-ribose.

Background and objectives Age and frailty have been correlated with poor clinical outcomes in cancer. Core muscle index (CMI) and nutritional status are integral in assessing frailty. We explored the effect of pre-operative serum albumin and body composition on clinical outcomes in patients with epithelial ovarian cancer (EOC). Methods We identified stage III-IV EOC patients undergoing primary cytoreductive surgery from 2007 to 2015. Data were abstracted from medical records. Body composition measurements were obtained from pre-operative imaging. Psoas muscle cross-sectional area was normalized to height2 to determine CMI. Sarcopenia was defined as CMI below the population mean. The influence of sarcopenia on short-term morbidity was evaluated. Relationships among body composition measurements and albumin were assessed with Spearman correlations. Patient characteristics and body composition measurements between patients with and without sarcopenia were compared with parametric and non-parametric statistical methods. Kaplan-Meier survival curves were compared using log-rank. Results 102 women met inclusion criteria. Sarcopenia correlated with albumin (P = 0.0002). Sarcopenia was not associated with short-term morbidity or time to recurrence. Sarcopenia was associated with nearly a fourfold increased risk of death when hypoalbuminemia was present (P = 0.02). Conclusions Pre-operative sarcopenia in combination with hypoalbuminemia was associated with significantly worse survival.

Objectives To examine cardiac biomarkers over time in youth-onset type 2 diabetes, and relate serum concentrations to cardiovascular disease risk factors, and left ventricular structure and function. Study design TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) was a multicenter randomized trial of 3 treatments including 521 participants with type 2 diabetes, aged 10-17 years, and with 2-6 years of follow-up. Participants were 36% male, obese, and ethnically diverse. Annual serum concentrations of brain natriuretic peptide, troponin, tumor necrosis factor (TNF)-α, receptors 1 and 2 were related to blood pressure, body mass index, hemoglobin A1c, and left ventricular ejection fraction, diastolic function, relative wall thickness, and mass. Results Elevated concentrations of brain natriuretic peptide (≥100 pg/mL), TNF-α (≥5.6 pg/mL) and troponin (≥0.01 ng/mL), were present in 17.8%, 18.3%, and 34.2% of the cohort, respectively, at baseline, and in 15.4%, 17.1%, and 31.1% at the end of the study, with wide variability over time, without persistence in individuals or clear relationship to glycemia or cardiovascular structure/function. TNF receptors concentrations were increased at baseline and not significantly different from end-of-study concentrations. Adverse echocardiographic measures were more likely in the highest TNF receptor tertile (all P Conclusions Elevated serum concentrations of cardiac biomarkers were common in youth with type 2 diabetes, but their clinical significance is unclear and will require further long-term study. Trial registration ClinicalTrials.gov NCT00081328 .

Dose-dense (dd) regimens are one of the preferred options for the adjuvant treatment of breast cancer patients with intermediate to high risk. The German Adjuvant Intergroup Node-positive trial aimed at optimizing intense dd (idd) strategies by evaluating drug combinations and the addition of capecitabine.Women (aged 18 years and biologically 65 years) with histologically involved axillary lymph nodes were randomly assigned to receive three courses each of epirubicin (E) 150 mg/m2, paclitaxel (P) 225 mg/m2 and cyclophosphamide (C) 2500 mg/m2 (reduced to 2000 mg/m2 after recruitment of 1200 patients) q2w intravenously (i.v.) (iddEPC-regimen) or ddEC (E 112.5 mg/m2 + C 600 mg/m2, i.v. q2w for 4 cycles) followed by paclitaxel weekly (Pw 67.5 mg/m2 i.v. q8d for 10 weeks) plus capecitabine (X 2000 mg/m2 p.o. days 1-14, q22 for 4 cycles) (ddEC-PwX-regimen). Further randomization assigned patients to ibandronate for 2 years versus observation and to pegfilgrastim day 2 versus 4.From June 2004 to August 2008, 2994 patients were randomized to either iddEPC (N = 1498), or ddEC-PwX (N = 1496) and started treatment. Median age was 50 years; pN1 (37.8%), pN2 (35.3%); pN3 (26.9%); 46.4% were G3 tumors; 76.9% hormone receptor-positive and 22% HER2-positive. After a median follow-up of 74 months, 645 events and 383 deaths were recorded. Hematological adverse events grades 3-4 were more common with iddEPC (P 0.001), nonhematological with ddEC-PwX (P = 0.04), even if the toxicity profile of the two regimens was different. At 5 years, estimated disease-free survival rates for ddEC-PwX and iddEPC were 81.7% [95% confidence interval (CI) 79.5-83.6] versus 80.2% (95% CI 78.0-82.2). Hazard ratio (HR)=0.95 (95% CI 0.81-1.11, log-rank P = 0.49). Five-year overall survival rates were 89.4% for ddEC-PwX (95% CI 87.7-91.0) and 89.0% for iddEPC (95% CI 87.2-90.6), HR = 0.85 (95% CI 0.69-1.04, log-rank P = 0.10).Adding capecitabine to ddEC-Pw did not improve outcome in comparison to iddEPC but increased toxicity and should not be recommended for further use.

Background: Sorafenib was tested for neoadjuvant treatment with an anthracycline/taxane-based chemotherapy in the open-label, multicentre, single-arm phase II study, ‘SOFIA'. Patients and Methods: Inclusion criteria were: HER2 negative, cT3, cT4 or cT2 cN+, M0 primary breast cancer. Patients received 4 × epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 (EC) intravenously (i.v.) in 3-weekly cycles followed or preceded by 12 weeks of paclitaxel (Pw) 80 mg/m2. In cohort 1, sorafenib started at 800 mg daily with chemotherapy. An initial daily sorafenib dose of 200 mg was escalated, based on individual toxicities, every 3 weeks in cohort 2 (starting with EC) and every 2 weeks in cohort 3 (starting with Pw). The primary objective was to identify the most feasible regimen; secondary objectives were safety, pathological complete response (pCR) at surgery and pharmacokinetics. Results: Of the 36 recruited patients, 7/12 patients completed the study in cohort 1 and 24/24 patients in cohorts 2 and 3. The median cumulative sorafenib dose per patient was 37%, 65% and 46% in cohorts 1, 2 and 3, respectively. The main grade 3-4 toxicities were neutropenia and hand-foot syndrome. The pCR (ypT0/is) rate was 27.7%. No pharmacokinetic interaction was observed between sorafenib and epirubicin. Conclusion: Sorafenib EC-Pw is feasible if the starting dose is 200 mg, escalated every 3 weeks based on the patients' individual toxicities.

Purpose Bisphosphonates prevent skeletal-related events in patients with metastatic breast cancer. Their effect in early breast cancer is controversial. Ibandronate is an orally and intravenously available amino-bisphosphonate with a favorable toxicity profile. It therefore qualifies as potential agent for adjuvant use. Patients and Methods The GAIN (German Adjuvant Intergroup Node-Positive) study was an open-label, randomized, controlled phase III trial with a 2 × 2 factorial design. Patients with node-positive early breast cancer were randomly assigned 1:1 to two different dose-dense chemotherapy regimens and 2:1 to ibandronate 50 mg per day orally for 2 years or observation. In all, 2,640 patients and 728 events were estimated to be required to demonstrate an increase in disease-free survival (DFS) by ibandronate from 75% to 79.5% by using a two-sided α = .05 and 1-β of 80%. We report here the efficacy analysis for ibandronate, which was released by the independent data monitoring committee because the futility boundary was not crossed after 50% of the required DFS events were observed. Results Between June 2004 and August 2008, 2,015 patients were randomly assigned to ibandronate and 1,008 to observation. Patients randomly assigned to ibandronate showed no superior DFS or overall survival (OS) compared with patients randomly assigned to observation (DFS: hazard ratio, 0.945; 95% CI, 0.768 to 1.161; P = .589; OS: HR, 1.040; 95% CI, 0.763 to 1.419; P = .803). DFS was numerically longer if ibandronate was used in patients younger than 40 years or older than 60 years compared with patients age 40 to 59 years (test for interaction P = .093). Conclusion Adjuvant treatment with oral ibandronate did not improve outcome of patients with high-risk early breast cancer who received dose-dense chemotherapy.

Tamarisk ( Tamarix spp.) has in recent decades come to dominate riparian corridors throughout much of the western U.S. The implementation of biological control, utilizing the tamarisk leaf beetle ( Diorhabda spp., particularly Diorhabda carinulata ), has focused attention and research on this method for Tamarix suppression. Researchers are just beginning to understand how herbivory by Diorhabda affects Tamarix physiology and nutritional dynamics. The purpose of this study was to investigate whether herbivory by D. carinulata altered leaf litter nitrogen and stem starch content, and if so, how such alteration varied across a gradient of herbivory chronosequence. Leaf litter and stem analysis showed significantly higher levels of both nitrogen and stem starch content in trees that had experienced herbivory by the leaf beetle. However, there were no significant differences in nitrogen or stem starch content based on years of beetle herbivory. Higher levels of nitrogen in leaf litter from beetle-affected trees may be a result of herbivory-induced desiccation and foliar mortality prior to the translocation of nitrogen back into plant reserves. Additionally, higher stem starch may be a result of either phloem damage reducing the translocation of photoassimilates, or an increase in the shunting of carbohydrates to the site of new leaf growth. Finally, the lack of correlation between years of herbivory and both leaf litter nitrogen and stem starch may indicate that as of yet there have not been sufficient defoliation events to yield anticipated host plant impact.

Funding sources: The study was supported by a grant from The Fetal Medicine Foundation (UK Charity No: 1037116), by the Swiss Federal Government through the Federal Office of Education and Science, and by Genesupport. The computations were performed at the Vital-IT Center (http://www.vital-it.ch) for high-performance computing of the SIB Swiss Institute of Bioinformatics. Conflicts of interest: Genesupport offers this test for commercial use.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease endemic in parts of Asia. The etiologic agent, SFTS virus (SFTSV; family Bunyaviridae , genus Phlebovirus ) has caused significant morbidity and mortality in China, South Korea, and Japan, with key features of disease being intense fever, thrombocytopenia, and leukopenia. Case fatality rates are estimated to be in the 30% range, and no antivirals or vaccines are approved for use for treatment and prevention of SFTS. There is evidence that in human cells, SFTSV sequesters STAT proteins in replication complexes, thereby inhibiting type I interferon signaling. Here, we demonstrate that hamsters devoid of functional STAT2 are highly susceptible to as few as 10 PFU of SFTSV, with animals generally succumbing within 5 to 6 days after subcutaneous challenge. The disease included marked thrombocytopenia and inflammatory disease characteristic of the condition in humans. Infectious virus titers were present in the blood and most tissues 3 days after virus challenge, and severe inflammatory lesions were found in the spleen and liver samples of SFTSV-infected hamsters. We also show that SFTSV infection in STAT2 knockout (KO) hamsters is responsive to favipiravir treatment, which protected all animals from lethal disease and reduced serum and tissue viral loads by 3 to 6 orders of magnitude. Taken together, our results provide additional insights into the pathogenesis of SFTSV infection and support the use of the newly described STAT2 KO hamster model for evaluation of promising antiviral therapies. IMPORTANCE Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral disease for which there are currently no therapeutic options or available vaccines. The causative agent, SFTS virus (SFTSV), is present in China, South Korea, and Japan, and infections requiring medical attention result in death in as many as 30% of the cases. Here, we describe a novel model of SFTS in hamsters genetically engineered to be deficient in a protein that helps protect humans and animals against viral infections. These hamsters were found to be susceptible to SFTSV and share disease features associated with the disease in humans. Importantly, we also show that SFTSV infection in hamsters can be effectively treated with a broad-spectrum antiviral drug approved for use in Japan. Our findings suggest that the new SFTS model will be an excellent resource to better understand SFTSV infection and disease as well as a valuable tool for evaluating promising antiviral drugs.

Purpose Observational studies suggested that luteinizing hormone–releasing hormone agonists (LHRHa) might prevent premature ovarian failure resulting from adjuvant chemotherapy in premenopausal patients. We aimed to test the efficacy of ovarian function preservation with the LHRHa goserelin in patients with breast cancer. Patients and Methods In a prospective, randomized, open-label, controlled multicenter study, 60 patients younger than age 46 years with hormone-insensitive breast cancer were allocated to receive anthracycline/cyclophosphamide (with or without taxane) –based neoadjuvant chemotherapy with or without goserelin. The first goserelin injection was administered at least 2 weeks before the first chemotherapy cycle, continuing at 3.6 mg subcutaneously every 4 weeks until the end of the last cycle. The primary objective was the reappearance of normal ovarian function, defined as two consecutive menstrual periods within 21 to 35 days at 6 months after end of chemotherapy. Results Fifty-three patients (88.3%) experienced temporary amenorrhea (93.3% with v 83.3% without goserelin). No significant difference was observed regarding the reappearance of menstruation at 6 months after chemotherapy (70.0% with v 56.7% without goserelin; difference of 13.3%; 95% CI, −10.85 to 37.45; P = .284). All but one evaluable patient reported regular menses at 2 years after chemotherapy. Time to restoration of menstruation was 6.8 months (95% CI, 5.2 to 8.4) with goserelin and 6.1 months (95% CI, 5.3 to 6.8) without goserelin (P = .304). Chemotherapy resulted in a decreased ovarian reserve measured by inhibin B and anti-Müllerian hormone during follow-up, supporting the other findings. Conclusion Premenopausal patients with breast cancer receiving goserelin simultaneously with modern neoadjuvant chemotherapy did not experience statistically significantly less amenorrhea 6 months after end of chemotherapy compared with those receiving chemotherapy alone.