bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multispecialty approach to immuno-oncology education for community providers.
Authors: Perloff Tara , Dawkins Monique , Crews Jennie Robertson , Gregg Jeffrey P. , Abraham Ivo , Schwartzberg Lee S. 
Published: July 2019

80 Background: The Association of Community Cancer Centers (ACCC) Immuno-Oncology Institute was developed in 2015 to prepare all members of the multidisciplinary cancer care team for the complex implementation of immuno-oncology in the community setting. Today, with more than 50 cancer immunotherapy indications and over 2,500 clinical trials with cancer immunotherapies, the challenges and issues related to recognizing and managing immune-related adverse events (irAEs) have grown even more complex for community practitioners. Methods: The ACCC Immuno-Oncology Institute assembled 4 working groups focused on addressing the diverse issues around the delivery and management of patients on cancer immunotherapies. The working groups were divided by 4 topics: staff training and education; multispecialty care coordination and communication; telemedicine; and big data. A detailed systemic review of the literature was conducted for each topic in the context of immuno-oncology, to determine the current landscape of information and available resources. The findings were then shared with the working group members and collaborative discussions ensued over 12 virtual committee meetings. The 19 working group members are diverse by discipline, including specialties such as emergency medicine, dermatology, primary care, survivorship, pathology, and academic researchers. Results: The ACCC Working Group Summit convened in September 2018 to develop innovative educational opportunities for community practitioners related to managing irAEs across the 4 topic areas. Eight unique action plans were developed by working group members. Conclusions: For each of the 4 key areas, working group members identified a list of opportunities that would improve how clinicians are managing irAEs for patients being treated with immunotherapy. It is critical for future educational interventions to encompass the multispecialty team perspective related to the management of irAEs.
Immune-related adverse events in advanced NSCLC treated with immunotherapy alone or concurrent chemotherapy and immunotherapy.
Authors: Melson John , Reed Daniel , Horton Bethany J. , Moore Margaret , Brown Jacqueline Theresa , Gentzler Ryan D. , Hall Richard Delmar 
Published: July 2019

83 Background: Concurrent chemotherapy (CTX) with checkpoint inhibitors (CPI) has become a new standard of care for treatment naïve stage IV non-small cell lung cancer (NSCLC). Little is known about the timing and pattern of immune-related adverse events (irAEs) when CTX and CPI are combined. We sought to characterize irAEs and determine if combination CTX+CPI affects time to first irAE in comparison to patients (pts) receiving CPI alone. Methods: Advanced NSCLC patients who received at least one dose of a CPI at our institution between 2015 and 2018, either alone or with CTX, were identified. Retrospective review for occurrence of irAEs and clinical outcomes was performed. Proportional hazards models were used to assess time to first irAE for CPI vs CTX+CPI and overall survival (OS) for CPI alone. Results: 149 pts were identified. 112 pts received CPI alone and 37 received CTX+CPI. The proportion of pts with at least 1 irAE was higher in the combination therapy group than the monotherapy group (59% vs 34% of patients). Time to any grade first irAE was shorter with CTX+CPI vs CPI alone (6.0 m vs 36.7 m, HR 1.8, p = 0.0304). Among pts treated with CPI alone, OS was significantly longer with any irAE (38.0 m vs 11.4 m, HR 2.9, p = 0.0026). While there were more irAEs in the CTX+CPI cohort, the frequency of irAEs by organ system was similar to previous reports. Conclusions: For patients receiving CTX+CPI, there is an increased risk of irAEs and a significantly shorter time to first irAE occurrence compared to CPI alone. Among patients receiving CPI alone, the presence of irAE was associated with a 3-fold improvement in OS. Further analysis of OS for the CTX+CPI group is planned with additional follow-up. [Table: see text]
Identifying obstacles to optimal integration of cancer immunotherapies in the community setting.
Authors: Shivakumar Latha , Weldon Christine B. , Lucas Lorna , Perloff Tara 
Published: July 2019

87 Background: The rapidly expanding indications for cancer immunotherapies pose a significant challenge to community clinicians to integrate this new class of agents into practice. Community cancer centers need guidance around the practical issues that must be addressed to implement immunotherapy safely and effectively to patients in their own communities. The Association of Community Cancer Centers (ACCC) initiated a quality improvement (QI) research study to assess the impact of comprehensive educational interventions targeting the multidisciplinary cancer care (MDCC) team on evidence-based integration of immunotherapies in the community setting. Methods: The QI study collected baseline data from two community cancer centers to identify barriers to optimal implementation of immunotherapies at each institution for the following metrics: co-morbidities in patients, immune-related adverse events (irAEs), laboratory tests, ER visits and hospitalizations, patient education materials, and immunotherapeutic adherence. Retrospective data was collected for 100 patients initiating immunotherapy between Dec 2017-April 2018. Results: Analysis of the data revealed that only 61% of the patients fully completed the immunotherapy treatment as planned. Eighty-one percent of patients were found to have 4 or more irAEs. On average patients were each diagnosed with more than 2 co-morbidities, including cardiac disease, diabetes, dyslipidemia, hypothyroidism, hypertension, and obesity. Using Fisher’s exact test to calculate two-tailed P values, we attempted to investigate a correlation between the number of co-morbidities to the lack of treatment adherence. We found a trend towards statistical significance between lack of treatment adherence and patients with two or more co-morbidities ( P value = 0.1256). Conclusions: Timely management of irAEs is crucial for the adherence to the immunotherapy regimen. The baseline data collected in our QI study revealed a trend towards the impact of the presence of two or more co-morbidities on treatment adherence. However, we did not find a statistically significant correlation between treatment adherence and the number of irAEs recorded in patients.
Publication statuses of clinical trials supporting immune checkpoint inhibitors recently approved by the United States Food and Drug Administration: A meta-epidemiological investigation.
Authors: Omae Kenji , Kataoka Yuki , Tsujimoto Yasushi , Tsutsumi Yusuke , Fukuhara Shunichi , Furukawa Toshi 
Published: July 2019

89 Background: The low trial publication rate for drugs approved by the U.S. Food and Drug Administration (FDA) and the discrepancies between data submitted to the FDA and data found in published trials remain concerning. We investigated the publication statuses of trials of recently approved anticancer drugs documented by the FDA, especially immune checkpoint inhibitors (ICPis), to determine the discrepancies between data submitted to the FDA and those published. Methods: We identified all ICPis approved between 2011 (the year the first ICPi was approved by the FDA) and 2014 (selected to assure a follow-up of at least 3 years post-approval). We assessed the clinical trials for each drug indication and matched each trial with publications in the literature. The primary outcome was the publication status 2 years post-approval. We examined the association between time to publication and drug type using a multilevel Cox regression model, adjusted for clustering within drug indications and individual covariates. Results: Between 2011 and 2014, 36 anticancer drugs including 3 ICPis were newly approved by the FDA. Of 19 trials investigating the 3 ICPis, 11 (58%) were published within 2 years post-approval. We randomly selected 10 of the 33 remaining anticancer drugs; 68 of 101 trials investigating these drugs (67%) were published. Overall, the publication rate was 66% at 2 years post-approval with a median time to publication of 2.3 years. There was no significant difference in time to trial publication between ICPis and other anticancer drugs (adjusted hazard ratio [HR], 1.1; 95% confidence interval [CI], 0.8–1.7; P = 0.55); however, non-ICPIs investigated specifically in randomized phase 2 or 3 trials were significantly more likely to be published earlier than ICPis (adjusted HR, 7.4; 95% CI, 1.8–29.5; P = 0.005). Conclusions: One in three trials of the newest anticancer drugs remained unpublished 2 years after FDA approval. The ICPi publication rate was similar to that of other anticancer drugs. (Protocol registration: UMIN000030475).
Emotional and cognitive disturbances in long-term melanoma survivors treated with ipilimumab.
Authors: Rogiers Anne , Awada Gil , Schwarze Julia , De Cremer Jennifer , Ben Salama Laila , Theuns Peter , Neyns Bart 
Published: July 2019

97 Background: Immunotherapy with the CTLA-4 blocking mAb ipilimumab (IPI) has improved the long-term (>3 y) survival of a subpopulation (15-20%) of patients (pts) with metastatic melanoma. Little is known about the psychosocial outcome and the long-term effects of immune-related adverse events in these survivors. Methods: Pts with advanced melanoma (AJCC stages IIIC or IV) who were in complete remission for at least 2 y after treatment initiation, were eligible for this ongoing study. Data on health related quality of life (HRQOL), psychosocial outcome and neurocognitive function (NCF) were collected using 5 validated questionnaires, a semi-structured psychiatric examination (SSPE), and computer-based NCF testing. Results: Test results from 17 pts (5 F/12 M), median age 57 y (range 33-86) were analyzed. Median time since start of IPI was 5.5 y (range 2-7). Seven pts (41%) had elevated scores on the Cognitive Failure Questionnaire (CFQ). Nine pts (53%) had elevated scores on the Hospitalization Depression Scale (HADS) indicating moderate anxiety (4 pts), severe anxiety (2 pts), and moderate depression (3 pts). The SSPE revealed that all 10 pts who were professionally active at the time of diagnosis, had to change or stop work due to their illness. Nine pts (53%) reported persisting emotional distress: anxiety, existential problems, survivor guilt, post-traumatic stress symptoms or daily worrying about the disease. Three pts were referred for suicidal ideation in relation with their disease. Four pts (24%) developed hypophysitis and suffered from comorbid depression (1 pt), adjustment disorder (2 pt), or post-traumatic stress disorder related to the symptoms of hypopituitarism (1 pt). Five years after the incidence of hypophysitis, all pts had elevated scores on the Fatigue Severity Scale, the HADS; and 3 pts on the CFQ. All cases of skin toxicity (8 pts), hepatitis (2 pts), colitis (2 pts), sarcoidosis (2 pts), and Guillain-Barre syndrome (1 pt) resolved without long-term impact on HRQOL. Conclusions: A majority of melanoma survivors treated with IPI continues to suffer from emotional distress and cognitive problems impacting their HRQOL. Timely detection and providing adaptive care is imperative.
Stool donor qualification and collection from metastatic melanoma (MM) patients (pts) who have responded to checkpoint inhibitors (CPI) for manufacturing of fecal microbiota transplantation (FMT).
Authors: Burton Elizabeth M. , Glitza Isabella Claudia , Mahoney Jennifer , Wortman Jennifer , Aunis John , Litcofsky Kevin , Cook David , Jayaraman Lata , Ibrahim Ramy A. , LaVallee Theresa , Tawbi Hussein Abdul-Hassan , Wargo Jennifer A. 
Published: July 2019

TPS146 Background: There have been remarkable improvements in responses rates (RR) and outcomes for pts with MM with the use of single agent CPIs. However, only 35% of pts respond to therapy and less than 10% achieve a complete response (CR). Although CPIs are approved for advanced MM treatment, there is a critical need to identify predictors of response and improve outcomes for these pts, the majority of whom will die from their disease. In an analysis of stool from MM pts prior to receiving CPI (anti-PD1), MD Anderson reported the association of higher alpha diversity and a favorable “Type I” signature with improved RR and prolonged PFS. Subsequently, FMT in mice via oral gavage using stool from CR MM pts responding to anti-PD1 with a favorable microbiome signature and treated with CPI demonstrated improved RR compared to FMT with stool from non-responders. Although FMT has been studied and has shown efficacy in other diseases, clinical safety and utility in pts with MM requires investigation. We hypothesize that FMT from MM pts with CR to CPIs and a Type I signature will be tolerable and demonstrate favorable outcomes. Methods: To initiate the testing of this hypothesis, we designed a study to identify and screen pts with MM who have responded to anti-PD1 for FMT stool donation. Pts must be in CR from MM for 6 months on 2 consecutive scans. Screening procedures per standard practice of approved INDs for FMT include health history questionnaires, physical exam, confirmation of current disease status, infectious disease screening, and an evaluation of the stool sample to ensure Type I signature requirements. Notably, there have been specific modifications made to this protocol in donor eligibility criteria, as accepted by the FDA, to accommodate this unique patient population. Participants will donate stool for up to 4 weeks and may be considered for subsequent donation cycles after undergoing re-screening. Stool will be manufactured into capsule form and used in the clinical trial. This study is open and active at three sites, MD Anderson, MGH, and DFCI.
Hafnium oxide nanoparticles activated by SABR in combination with PD-1 inhibitors for the treatment of patients with advanced HNSCC or NSCLC: A phase I/II trial.
Authors: Seiwert Tanguy Y. , Foster Corey Christian , Le Tourneau Christophe , Calugaru Valentin , Bonvalot Sylvie 
Published: July 2019

TPS23 Background: Despite proven efficacy, a limited number of patients (pts) with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or metastatic non-small cell lung cancer (NSCLC) benefit from anti-PD-1 treatment. Indeed, most pts do not respond to initial therapy due to intrinsic resistance to checkpoint inhibition. There is thus an important unmet medical need for a curative treatment in these pts and converting the local immune microenvironment to a “hot” phenotype may help to overcome therapeutic resistance. Hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy (RT) increase radiation dose deposit within cancer cells compared to RT alone. Recently, a phase II/III randomized trial of NBTXR3 in locally advanced soft tissue sarcoma (STS) met primary and main secondary endpoints with significant superiority compared to RT alone. Furthermore NBTXR3+RT demonstrated an immunogenic cell death-mediated abscopal effect in a pre-clinical setting, and immune cell infiltration was observed in some tumors from STS pts treated with NBTXR3+RT but not in tumors from pts treated with RT alone. NBTXR3 is currently being evaluated in 7 clinical trials, including a phase I/II study in elderly frail patients with locally advanced HNSCC. To date, no early dose limiting toxicities (DLTs) have been observed. Methods: Overall, these results have led us to evaluate NBTXR3 activated by stereotactic ablative radiotherapy (SABR) in combination with an approved anti-PD-1 antibody in an open label phase I/II, non-randomized clinical trial in pts with more advanced diseases: locoregionally recurrent or metastatic HNSCC, metastatic NSCLC, and liver metastasis pts. The phase I primary objectives are to determine NBTXR3 maximum tolerated dose(s), incidence of early DLTs and recommended dose(s). The phase II primary objectives are Complete Response Rate of target lesions and Objective Response Rate for the locoregional recurrent and the metastatic group respectively by RECIST 1.1, and safety/tolerability of treatment at the recommended dose(s). [NCT02379845] [NCT01946867]. Clinical trial information: NCT03589339.
Human Trophoblast Differentiation Is Associated With Profound Gene Regulatory and Epigenetic Changes
Authors: Kwak Youn-Tae , Muralimanoharan Sribalasubashini , Gogate Aishwarya A , Mendelson Carole R 
Published: July 2019

Abstract
Defective placental implantation and vascularization with accompanying hypoxia contribute to preeclampsia (PE), a leading cause of maternal and neonatal morbidity and mortality. Genetic and epigenetic mechanisms underlying differentiation of proliferative cytotrophoblasts (CytTs) to multinucleated syncytiotrophoblast (SynT) are incompletely defined. The SynT performs key functions in nutrient and gas exchange, hormone production, and protection of the fetus from rejection by the maternal immune system. In this study, we used chromatin immunoprecipitation sequencing of midgestation human trophoblasts before CytT and after SynT differentiation in primary culture to analyze changes in binding of RNA polymerase II (Pol II) and of active and repressive histone marks during SynT differentiation. Our findings reveal that increased Pol II binding to promoters of a subset of genes during trophoblast differentiation was closely correlated with active histone marks. This gene set was enriched in those controlling immune response and immune modulation, including interferon-induced tetratricopeptide repeat and placenta-specific glycoprotein gene family members. By contrast, genes downregulated during SynT differentiation included proinflammatory transcription factors ERG1, cFOS, and cJUN, as well as members of the NR4A orphan nuclear receptor subfamily, NUR77, NURR1, and NOR1. Downregulation of proinflammatory transcription factors upon SynT differentiation was associated with decreased promoter enrichment of endogenous H3K27Ac and H3K9Ac and enhanced binding of H3K9me3 and histone deacetylase 1. However, promoter enrichment of H3K27me3 was low in both CytT and SynT and was not altered with changes in gene expression. These findings provide important insight into mechanisms underlying human trophoblast differentiation and may identify therapeutic targets for placental disorders, such as PE.
Dancing Queens
Authors: Shomali Mejdulene B. 
Published: July 2019

AbstractThis article analyzes two popular Golden Era belly-dance films, Sigara wa Kass (A Cigarette and a Glass, 1955) and Habibi al Asmar (My Dark Darling, 1958), through concepts of queer spectatorship, queer time and space, homoerotic triangulation, and queer containment. The analysis centers women, attends to women’s homoeroticism and nonnormative desires, and reads popular film as constituted by and constituting of mainstream conventions of gender and sexuality. It argues that mainstream belly-dance films made considerable space for homoerotic exchanges amid women. Golden Era belly-dance films reveal a rich gender and sexual diversity in Egyptian cultural production, rather than the Orientalist representation of an explicitly homophobic “traditional” Arab culture. In this sense, the article recovers women’s nonnormative and queer legacies within popular Egyptian texts. It does not insinuate homosexuality as inherent but instead locates possible Arab cultural engagements with women’s queerness that have been overlooked.
Parcas is the predominant Rab11-GEF for rhodopsin transport in Drosophila photoreceptors
Authors: Otsuka Yuna , Satoh Takunori , Nakayama Nozomi , Inaba Ryota , Yamashita Hitomi , Satoh Akiko K. 
Published: July 2019

ABSTRACT
Rab11 is essential for polarized post-Golgi vesicle trafficking to photosensitive membrane rhabdomeres in Drosophila photoreceptors. Here, we found that Parcas (Pcs), recently shown to have guanine nucleotide exchange (GEF) activity toward Rab11, co-localizes with Rab11 on the trans-side of Golgi units and post-Golgi vesicles at the base of the rhabdomeres in pupal photoreceptors. Pcs fused with the electron micrography tag APEX2 localizes on 150–300 nm vesicles at the trans-side of Golgi units, which are presumably fly recycling endosomes. Loss of Pcs impairs Rab11 localization on the trans-side of Golgi units and induces the cytoplasmic accumulation of post-Golgi vesicles bearing rhabdomere proteins, as observed in Rab11 deficiency. In contrast, loss of Rab11-specific subunits of the TRAPPII complex, another known Rab11-GEF, does not cause any defects in eye development nor the transport of rhabdomere proteins; however, simultaneous loss of TRAPPII and Pcs results in severe defects in eye development. These results indicate that both TRAPPII and Pcs are required for eye development, but Pcs functions as the predominant Rab11-GEF for post-Golgi transport to photosensitive membrane rhabdomeres.
Feasibility of Two High-Intensity Interval Training Protocols in Cancer Survivors
Authors: SCHLÜTER KATHRIN , SCHNEIDER JUSTINE , SPRAVE TANJA , WISKEMANN JOACHIM , ROSENBERGER FRIEDERIKE 
Published: July 2019

ABSTRACT

Purpose
High-intensity interval training (HIIT) is a time-efficient and promising tool for enhancing physical fitness. However, there is lack of research concerning safety and feasibility of HIIT in cancer survivors. Therefore, two different HIIT protocols were investigated in terms of safety, feasibility, and acute exercise responses.

Methods
Forty cancer survivors (20 breast and 20 prostate cancer survivors, 62.9 ± 9.2 yr, BMI 27.4 ± 3.9 kg·m−2, 6 to 52 wk after the end of primary therapy) completed a maximal cardiopulmonary exercise test and two HIIT protocols on a cycle ergometer: 10 × 1 min at peak power output (10 × 1) and 4 × 4 min at 85%–95% peak HR (4 × 4). Safety (adverse events), acute physiological responses (HR, blood lactate concentration) and acute psychological responses (RPE, enjoyment) were recorded.

Results
No major but three minor adverse events occurred. Ninety-five percent of participants were able to complete each HIIT protocol. Estimated energy expenditure (159 ± 15 vs 223 ± 45 kcal, P < 0.001), HR (128 ± 20 vs 139 ± 18 bpm; P < 0.001), blood lactate concentration (5.4 ± 1.0 vs 5.9 ± 1.9 mmol·L−1; P = 0.035), and RPE legs/breathing (13.8 ± 2.0/13.1 ± 2.0 vs 14.6 ± 2.1/14.3 ± 2.0; P = 0.038/0.003) were significantly higher in the 4 × 4. Enjoyment did not differ between protocols (P = 0.301).

Conclusions
The two HIIT protocols as single sessions appear safe and in the vast majority of breast and prostate cancer survivors after the end of primary therapy also feasible and enjoyable. The 4 × 4 elicited higher energy expenditure and higher cardio-circulatory and metabolic strain and might therefore be preferred if a high training stimulus is intended.