bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pembrolizumab plus chemotherapy for previously untreated, HER2-negative unresectable or metastatic advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: KEYNOTE-859.
Authors: Tabernero Josep , Bang Yung-Jue , Van Cutsem Eric , Fuchs Charles S. , Janjigian Yelena Y. , Bhagia Pooja , Li Kan , Adelberg David E. , Qin Shu Kui 
Published: January 2021

TPS263 Background: For patients with unresectable, locally advanced recurrent or metastatic G/GEJ cancer, the standard of care includes a fluoropyrimidine plus a platinum-based agent as first-line therapy. The PD-1 inhibitor pembrolizumab has demonstrated durable antitumor activity in this patient population across lines of therapy. Herein, we describe the randomized, double-blind, phase 3 KEYNOTE-859 trial (NCT03675737) of first-line pembrolizumab plus chemotherapy in patients with advanced G/GEJ adenocarcinoma. Methods: Patients with histologically or cytologically confirmed, locally advanced unresectable or metastatic G/GEJ adenocarcinoma with known PD-L1 expression status, HER2-negative disease, measurable disease per RECIST v1.1, and ECOG performance status of 0 or 1 will be randomly assigned 1:1 to receive pembrolizumab plus chemotherapy or placebo plus chemotherapy. Randomization will be stratified by geographic region (Europe/Israel/North America/Australia vs Asia vs rest of world), PD-L1 tumor expression status (combined positive score < 1 vs ≥1), and combination chemotherapy (FP vs CAPOX). Pembrolizumab or placebo will be administered at 200 mg IV every 3 weeks (Q3W). The chemotherapy regimen will be investigator’s choice of FP (continuous infusion of 5-fluorouracil [800 mg/m2/day on days 1-5 of each cycle] plus IV cisplatin [80 mg/m2] Q3W) or CAPOX (oral capecitabine [1000 mg/m2 twice daily on days 1-14 of each cycle] plus IV oxaliplatin [130 mg/m2 on day 1 of each cycle] Q3W). Duration of cisplatin or oxaliplatin may be capped at 6 cycles per local country guidelines; treatment with 5-fluorouracil or capecitabine may continue per protocol. Treatment with pembrolizumab or placebo will continue for ≤35 administrations (~2 years) or until disease progression, unacceptable toxicity, intercurrent illness that prevents further administration of treatment, investigator decision, or noncompliance. Imaging will be performed at screening and subsequently every 6 weeks until disease progression, start of new anticancer treatment, withdrawal of consent, or death. Adverse events will be monitored throughout the study from the time of randomization to 30 days after the last dose of study treatment (90 days for serious adverse events). The dual primary end points are OS and PFS per RECIST v1.1 as assessed by blinded independent central review (BICR). Secondary end points include ORR and DOR per RECIST v1.1 as assessed by BICR, safety, and tolerability. Enrollment is ongoing. Clinical trial information: NCT03675737.
Trial-in-progress: A pilot study of combined immune checkpoint inhibition in combination with ablative therapies in subjects with hepatocellular carcinoma (HCC).
Authors: Carroll Hailey Kathryn , Aleem Umair , Varghese Pooja , Galligan Marie , Bourke Michele , Hoey Katherine , Ryan Ronan , Doran Peter , Stewart Stephen , O'Farrelly Cliona , Greten Tim F. , Houlihan Diarmaid , McDermott Raymond S. , Duffy Austin G. 
Published: January 2021

TPS355 Background: Locoregional therapies for hepatocellular carcinoma, such as transcatheter arterial chemoembolization (TACE) or ablation, can induce a peripheral anti-tumor immune response. This may be amplified by immune checkpoint inhibitors (ICI). Early and higher anti-CTLA4 dosing could potentially lead to better priming and a stronger immune response. Recent data has suggested that early (day 1 only), increased doses of anti-CTLA4 therapy, was associated with encouraging clinical activity and a tolerable safety profile. This study will evaluate dual immune checkpoint, CTLA4 (tremelimumab, day 1-only dosing) and PD-L1 (durvalumab) blockade in combination with TACE in patients with advanced HCC. Intensive peripheral immune-monitoring and longitudinal on-treatment tumor biopsies will focus on the role of the innate immune system, particularly Natural Killer cells, in anti-tumor responses. Methods: Patients with HCC (Childs Pugh A/B7; Barcelona Clinic Liver Cancer Stage B/C; ECOG 0/1; sorafenib-naïve or experienced) are being enrolled in a pilot study (Study Number UCDCRC/19/01) of tremelimumab at 2 dose levels (DL1 and DL2) in combination with durvalumab and TACE until disease progression (per irRECIST). DL1: tremelimumab (75mg q28 days for 4 doses) and durvalumab (1500mg q28 days). DL2: tremelimumab (300mg in a single dose on day 1) and durvalumab (1500mg q28 days). Subtotal TACE will be performed during study week 6 with the dose-limiting toxicity (DLT) evaluation period encompassing the first 8 weeks of the study. Primary endpoint is 6-month progression-free survival with secondary efficacy endpoints being safety, tolerability and overall survival. Exploratory objectives will evaluate changes in immune parameters in the tumor and peripheral blood of patients undergoing anti-CTLA4 therapy pre- and post-RFA or TACE. A major focus will be on the role of the innate immune system, particularly Natural Killer cells, in anti-tumor responses. Patients will be enrolled and treated at St Vincent’s University Hospital in Dublin, Ireland. This study is currently open and actively recruiting. Clinical trial information: EudraCT Number 2019-002767-98.
Randomized phase II trial of olaparib + pembrolizumab versus olaparib alone as maintenance therapy in metastatic pancreatic cancer patients with germline BRCA1 or BRCA2 (gBRCA1/2+) mutations: SWOG S2001.
Authors: Chung Vincent , Guthrie Katherine A , Pishvaian Michael J. , Lowy Andrew M. , Chiorean Elena Gabriela , Duong Mai T. , O'Reilly Eileen Mary , Philip Philip Agop 
Published: January 2021

TPS447 Background: Olaparib was approved in 2019 as maintenance therapy for g BRCA1/2+ metastatic pancreatic cancer (mPDA) patients (pts). The POLO trial showed an improvement in median progression free survival (mPFS) with olaparib compared to placebo (7.4 versus 3.8 months) for g BRCA1/2+ mPDA pts following either stable disease/response on first-line platinum chemotherapy. Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. Several clinical studies in solid tumors have shown preliminary efficacy with the combination of PARP plus immune checkpoint inhibitors. Based upon these data, SWOG S2001 aims to further improve the PFS of g BRCA1/2+ mPDA pts. Methods: S2001 was developed in collaboration with the Alliance and was activated in SWOG in October 2020. mPDA pts with gBRCA1/2 mutations identified with standard of care germline genetic testing will be eligibleif no progression after receiving 4 to 6 months of platinum chemotherapy (FOLFIRINOX, FOLFOX or gemcitabine/cisplatin). Zubrod performance status (PS) 0 or 1 pts are eligible. Pts will be stratified according to first line chemotherapy, PS 0 versus 1, and disease status after first-line treatment. The primary objective of this study is to evaluate the PFS of mPDA pts treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. Based upon the POLO trial, we expect a mPFS of 7 months in the control arm. Targeting a mPFS of 11.7 months in the experimental arm (hazard ratio 0.6) and assuming 15 months follow-up, 80% power and a 1-sided alpha=0.10, this design requires 78 evaluable pts to be accrued over 3 years. Prospective serial blood samples will be collected to bank DNA and RNA for future correlative studies. Support:NIH/NCI grants U10CA180888 and U10CA180819. Clinical trial information: TBD.
MEKiAUTO: A phase I/II open-label study of combination therapy with the MEK inhibitor cobimetinib, Immune-checkpoint blockade with atezolizumab, and the AUTOphagy inhibitor hydroxychloroquine in KRAS-mutated advanced malignancies.
Authors: Raufi Alexander , Wong Winston , Lee Shing Mirn , Manji Gulam Abbas 
Published: January 2021

TPS450 Background: Pancreatic ductal adenocarcinoma (PDAC) and colorectal carcinoma (CRC) are aggressive diseases which account for the third and second leading causes of cancer-related death, respectively. Limited progress has been made towards effective treatments or cure. K RAS is mutated or amplified in nearly 30% of all cancers, including up to 95% of PDAC and 45% of CRC. Although no successful KRAS directed therapy has been approved to date, data has emerged demonstrating that inhibition of downstream targets of KRAS, namely MEK/ERK, increases autophagic flux in KRAS-mutated tumors. This catabolic process is used by many tumors to maintain viability and recent preclinical studies have shown that combining MEK/ERK and autophagy inhibitors in KRAS-mutated tumors can synergistically suppress cancer cell proliferation. Inhibition of autophagy has demonstrated an increase in antigen presentation which sensitize tumors to immune checkpoint inhibitors. Presented here is a trial-in-progress that will evaluate combination of cobimetinib (MEK inhibitor), atezolizumab (anti-PDL1), and hydroxychloroquine (autophagy inhibitor) in KRAS-mutated advanced malignancies. Methods: This is a phase 1/2 multicenter, open-label study of combination cobimetinib (40-60mg) orally once daily on days 1-21, hydroxychloroquine (600mg) orally twice daily on days 1-28, and atezolizumab 840 mg IV on days 1 and 15 of each 28 day cycle. Patients with histologically confirmed metastatic or unresectable KRAS-mutant adenocarcinoma for which standard curative or meaningful life-prolonging treatment options do not exist or are no longer effective will be enrolled. The primary objective of the phase I portion of this trial, which seeks to enroll 18 patients, is to estimate the maximum tolerated dose (MTD) of these agents using a two-stage time-to-event continual reassessment method (TITE-CRM). The primary objective of the phase II portion of this trial, which seeks to enroll approximately 66-157 patients, is to evaluate the preliminary efficacy of this combination, based on the objective response by 16 weeks. Secondary endpoints include PFS, OS, and safety. Correlative aims include analyses of pre- and on-treatment biopsies with quantitative multiplex immunofluorescence, RNA-sequencing, reverse phase protein array for association with clinical benefit and to determine mechanisms of action/resistance. An interim analysis will be performed at the conclusion of the phase I portion of the study. This study is open with 4 patients enrolled at the time of submission. Clinical trial information: NCT04214418 . This trial is being conducted as part of the imCORE collaboration. Clinical trial information: NCT04214418.
Chemo4MetPanc: A phase II study with combination chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) motif receptor 4 inhibitor (motixafortide), and immune checkpoint blockade (cemiplimab) in metastatic treatment naïve pancreas adenocarcinoma (PDAC).
Authors: Pellicciotta Ilenia , Alouani Emily Linda , Raufi Alexander , Pan Samuel M , Hu Jianhua , Manji Gulam Abbas 
Published: January 2021

TPS454 Background: Pancreas adenocarcinoma (PDAC) is an aggressive cancer projected to be the second leading cause of cancer-related death in the United States by 2030 for which improved treatment options are desperately needed. Immune checkpoint blockade (ICB) for PDAC has failed as monotherapy in early phase clinical trials likely due to a highly immunosuppressive tumor microenvironment. The CXCR4/CXCL12 axis is a key immune evasion mechanism thought to deter CD8+ T-cells (CTLs) from infiltrating the tumor. We performed a large seven arm survival and biopsy/necropsy study in KPC mice (KrasLSL.G12D/+;p53R172H/+;Pdx1Cretg/+) where we demonstrate that addition of gemcitabine to CXCR4 inhibition in combination with ICB, enhanced tumor stabilization and neoplastic cell death, and improved survival by 50 percent. Multiplex immunofluorescence indicated an increased CTL to regulatory T-cell ratio and clustering of CTLs around neoplastic cells. Presented here is a trial-in progress that will evaluate combination of a CXCR4 inhibitor, ICB, and chemotherapy in treatment naïve patients with PDAC. Methods: This is a multicenter, single arm, open-label phase 2 study of combination motixafortide 1.25mg/kg SC monotherapy for 5 days during priming followed by twice weekly, cemiplimab 350mg IV once every 21 days, gemcitabine 1000mg/m2 IV with nab-paclitaxel 125mg/m2 IV on days 1, 8, and 15 every 28 days. Patients with histologically confirmed metastatic PDAC who have not received prior therapy will be enrolled. The primary endpoint is overall response rate by 16 weeks. A response rate greater than 45% by 16 weeks is considered promising, whereas a response rate of less than 23% is considered not promising. We will use a Simon optimal 2-stage design, where we will enroll 10 patients in the first stage. If 3 or more patients meet the endpoint in the first stage, the study will be expanded to a total of 40 patients. If a total of 14 or more patients achieve CR or PR by 16 weeks, the agent will be considered promising and worthy of further study. Secondary endpoints include safety, mPFS, disease control rate (DCR), and mOS. Correlative aims include analyses of pre- and on-treatment biopsies with quantitative multiplex immunofluorescence, RNA-sequencing, and generation of patient derived organoids for association with clinical benefit and to determine mechanisms of action/resistance. An interim analysis will be performed at the conclusion of the stage I portion of the study. Clinical trial information: NCT04543071.
Haematopoietic ageing through the lens of single-cell technologies
Authors: Strzelecka Paulina M. , Damm Frederik 
Published: January 2021

ABSTRACT
Human lifespan is now longer than ever and, as a result, modern society is getting older. Despite that, the detailed mechanisms behind the ageing process and its impact on various tissues and organs remain obscure. In general, changes in DNA, RNA and protein structure throughout life impair their function. Haematopoietic ageing refers to the age-related changes affecting a haematopoietic system. Aged blood cells display different functional aberrations depending on their cell type, which might lead to the development of haematologic disorders, including leukaemias, anaemia or declining immunity. In contrast to traditional bulk assays, which are not suitable to dissect cell-to-cell variation, single-cell-level analysis provides unprecedented insight into the dynamics of age-associated changes in blood. In this Review, we summarise recent studies that dissect haematopoietic ageing at the single-cell level. We discuss what cellular changes occur during haematopoietic ageing at the genomic, transcriptomic, epigenomic and metabolomic level, and provide an overview of the benefits of investigating those changes with single-cell precision. We conclude by considering the potential clinical applications of single-cell techniques in geriatric haematology, focusing on the impact on haematopoietic stem cell transplantation in the elderly and infection studies, including recent COVID-19 research.
Plasma Conversion of Toluene, Naphthalene, and Phenol as Model Tar Compounds in Simulated Synthetic Gas
Authors: Xu Ruiyang , Zhang Hao , Zhu Fengsen , Ruya Petric Marc , Yan Jianhua , Li Xiaodong 
Published: January 2021

Abstract
A rotating gliding arc (RGA) reactor was investigated for conversion of multiple model tar compounds including toluene, naphthalene, and phenol in simulated synthetic gas, with special focus on the effects of steam concentration (0–20%) and preheating temperature (300–700 °C). The maximum conversions of toluene, naphthalene, and phenol were 89.3%, 84.6% and 95.5%, respectively, at a steam concentration of 12% and a preheating temperature of 500 °C. The tar conversion reaction facilitated the formation of fuel gas H2 and CO and reduced the CH4 and CO2 content, thus increasing the heating value of the simulated synthetic gas, by a maximum of 5.1% at a steam concentration of 20%. The results indicated that the RGA plasma is promising for achieving efficient conversion of tar of complex composition in high temperature simulated synthetic gas and upgrading gaseous products.
An Evidence-based Protocol for the Management of Orthodontic Patients Undergoing MRI Scans
Authors: Shivam Rachael , Rogers Sheelagh , Drage Nicholas 
Published: January 2021

Magnetic resonance imaging (MRI) uses strong magnetic fields, magnetic gradients and radio waves to produce images of the body. The demand for MRI is steadily increasing as it does not use ionizing radiation and has excellent soft tissue contrast. Certain materials used in components of fixed orthodontic appliances can cause unwanted effects and affect the diagnostic quality of MR images by producing artefacts. This article proposes an evidence-based protocol that aims to standardize the management of orthodontic patients undergoing MRI scans. CPD/Clinical Relevance: As the use of MRI continues to increase, it is becoming more likely that orthodontists will encounter patients requiring MRI scans of the head and neck region during the course of their orthodontic treatment.
Deep neural network for fringe pattern filtering and normalization
Authors: Reyes-Figueroa Alan , Flores Victor H. , Rivera Mariano 
Published: January 2021

We propose a new framework for processing fringe patterns (FPs). Our novel, to the best of our knowledge, approach builds upon the hypothesis that the denoising and normalization of FPs can be learned by a deep neural network if enough pairs of corrupted and ideal FPs are provided. The main contributions of this paper are the following: (1) we propose the use of the U-net neural network architecture for FP normalization tasks; (2) we propose a modification for the distribution of weights in the U-net, called here the V-net model, which is more convenient for reconstruction tasks, and we conduct extensive experimental evidence in which the V-net produces high-quality results for FP filtering and normalization; (3) we also propose two modifications of the V-net scheme, namely, a residual version called ResV-net and a fast operating version of the V-net, to evaluate potential improvements when modifying our proposal. We evaluate the performance of our methods in various scenarios: FPs corrupted with different degrees of noise, and corrupted with different noise distributions. We compare our methodology versus other state-of-the-art methods. The experimental results (on both synthetic and real data) demonstrate the capabilities and potential of this new paradigm for processing interferograms.
Burden of depression and anxiety among leprosy affected and associated factors—A cross sectional study from India
Authors: Govindasamy Karthikeyan , Jacob Immanuel , Solomon Raju Moturu , Darlong Joydeepa 
Published: January 2021

Background
Leprosy is a Neglected Tropical Diseases (NTDs) known to cause stigma and discrimination in low-and middle-income countries. It often results in visible impairments, thus pre-disposing to poor mental health. Aim of the study was to estimate the prevalence of depression and anxiety among people affected by Leprosy and to determine the associated factors.

Methodology/Principal findings
A multi-centric, cross-sectional study was carried out in four leprosy endemic states of India—Chhattisgarh, Maharashtra, West Bengal and Tamil Nadu in randomly selected blocks (a sub-unit of district), from one district in each state. From selected blocks those registered for leprosy treatment at public health or referral centres, people above the age of 18 years were interviewed with PHQ-9 and GAD-7 questionnaires for Depression and Anxiety, respectively. Disease profile like leprosy classification, deformity grade, number and site of the patches and socio-economic status were collected along with individual data.
Of the total 220 respondents, prevalence of depression and anxiety symptoms was, 33% (73) and 19% (42), respectively. Presence of disability (47%) and Female gender (46%) were significantly associated with depression. Presence of disability (32%), Lower income group (27%) and low education (22%) were significantly associated with symptoms of anxiety. As the severity of disability increased, risk of developing depression and anxiety increased.

Conclusion
The study indicates that more than 30% of people affected by leprosy have mental health problems, which emphasizes the importance of mental health care services in leprosy. Women, those who had lower level of education, those belonging to lower socio-economic status and those with any level of disability due to leprosy are at risk of developing depression and/or anxiety. The study concludes more attention to be paid to the categories identified to be at risk.
Determining factors for the prevalence of depressive symptoms among postpartum mothers in lowland region in southern Nepal
Authors: Singh Devendra Raj , Sunuwar Dev Ram , Adhikari Shraddha , Singh Sunita , Karki Kshitij 
Published: January 2021

BackgroundPostpartum depression is the most common mental health problem among women of childbearing age in resource-poor countries. Poor maternal mental health is linked with both acute and chronic negative effects on the growth and development of the child. This study aimed to assess the prevalence and factors associated with depressive symptoms among postpartum mothers in the lowland region in southern Nepal.MethodsA hospital-based analytical cross-sectional study was conducted from 1stJuly to 25thAugust 2019 among 415 randomly selected postpartum mothers attending the child immunization clinic at Narayani hospital. The postpartum depressive symptoms were measured using the validated Nepalese version of the Edinburg Postnatal Depression Scale (EPDS). The data were entered into EpiData software 3.1v and transferred into Stata version 14.1 (StataCorp LP, College Station, Texas) for statistical analyses. To identify the correlates, backward stepwise binary logistic regression models were performed separately for the dichotomized outcomes: the presence of postpartum depressive symptoms. The statistical significance was considered at p-value <0.05 with 95% confidence intervals (CIs).ResultsAmong the total 415 study participants, 33.7% (95% CI: 29.2–38.5%) of postpartum mothers had depressive symptoms. Study participant’s whose family monthly income <150 USD compared to ≥150 USD (aOR = 13.76, 95% CI: 6.54–28.95), the husband had migrated for employment compared to not migrated (aOR = 8.19, 95% CI:4.11–15.87), nearest health facility located at more than 60 minutes of walking distance (aOR = 4.52, 95% CI: 2.26–9.03), delivered their last child by cesarean section compared to normal (vaginal) delivery (aOR = 2.02, 95% CI: 1.12–3.59) and received less than four recommended antenatal care (ANC) visits (aOR = 2.28, 95% CI:1.25–4.15) had higher odds of depressive symptoms. Participants who had planned pregnancy (aOR = 0.44, 95% CI: 0.25–0.77) were associated with 56% lower odds of depressive symptoms.ConclusionsOne-third of the mothers suffered from postpartum depressive symptoms. The participant’s husband migrated for employment, family income, distance to reach a health facility, delivery by cesarean section, not receiving recommended ANC visits, and plan of pregnancy were independent predictors for postpartum depressive symptoms. The study results warranted the urgency for clinical diagnosis of PPD and implementation of preventive package in study settings. Mental health education to pregnant women during ANC visits and proper counseling during the antepartum and postpartum period can also play a positive role in preventing postpartum depression.