bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II multi-cohort single-arm study of tiragolumab with atezolizumab plus bevacizumab in previously treated advanced non-squamous non–small-cell lung cancer.
Authors: Reuss Joshua E. , Wonser Dann , Smith Kellie Nicole , Ahn Jaeil , Byers Stephen , Creswell Karen , Kim Chul , Thompson Jillian , Crawford Jenny , Cohen Emil , Zeck Jay , Gutierrez Martin , Liu Stephen V. 
Published: June 2023

TPS9152 Background: Checkpoint inhibitor immunotherapy (CPI) offers durable, immune-mediated, anti-tumor responses to a subset of patients (pts) with advanced non-small cell lung cancer (NSCLC), but not all derive meaningful benefit. Two clinical unmet needs where CPI has fallen short include EGFR-mutated NSCLC, where CPI is minimally effective, and NSCLC with intrinsic or acquired resistance to currently available CPI. Novel combination strategies have shown promise. Two agents that have demonstrated synergy with the anti-PD-L1 CPI atezolizumab in NSCLC are bevacizumab, a vascular endothelial growth factor (VEGF)-blocking antibody, and tiragolumab, a T-cell immunoglobulin and ITIM domain (TIGIT) immune checkpoint-blocking antibody. This multi-cohort phase II trial seeks to evaluate the efficacy of tiragolumab with atezolizumab plus bevacizumab in 2 CPI-resistant cohorts - EGFR-wild type, CPI-refractory advanced NSCLC (cohort A) and EGFR-mutated, CPI-naïve advanced NSCLC (cohort B) - incorporating novel genomic and immunologic analyses to deliver mechanistic insight into the biology of CPI-resistance in NSCLC. Methods: This open-label, phase II study has two cohorts. Cohort A includes pts with advanced PD-L1+ (TPS ≥ 1%), EGFR/ALK/ROS1 wild type NSCLC with progression on prior anti-PD(L)1-based CPI therapy. Cohort B includes pts with targeted therapy-refractory EGFR-mutated NSCLC who are CPI-naïve. Pts must have measurable disease and those with symptomatic and/or untreated brain metastases are excluded. Pts in both arms will receive tiragolumab 600mg IV with atezolizumab 1200mg IV and bevacizumab 15mg/kg IV every 3 weeks until progressive disease or unacceptable toxicity. The primary efficacy endpoint will be assessed separately in each cohort by investigator-assessed objective response rate (ORR) according to RECIST v1.1. Each cohort utilizes a Simon 2-stage design in which a null ORR of 4% is tested against a one-sided alternative of 20%. A sample size of 21 pts/cohort provides 80% power with a one-sided type 1 error rate of 5% to determine a true ORR of 20%. Secondary efficacy endpoints include: duration of response, progression-free survival (PFS), 6-month PFS, overall survival. Blood and tumor specimens will be acquired pre- and on-treatment. Correlative analyses to illuminate the biology of CPI resistance will include multiplex imaging mass cytometry of tumor tissue. In addition, whole exome sequencing, T-cell receptor sequencing, and MANAFEST neoantigen prediction will be used to identify neoantigen-specific T-cells and track these temporally (during/post treatment) and spatially (across biologic compartments). The study is activated and both cohorts are accruing simultaneously with enrollment ongoing. Clinical trial information: NCT04958811 .
OMNIA-1: A phase I/II study, an IL-2R-βγ targeted antibody-IL-2 fusion protein, as monotherapy or in combination with anti-PD-1 or anti-CTLA-4 antibodies, in patients with advanced melanoma.
Authors: Ascierto Paolo Antonio , de Velasco Guillermo , Eigentler Thomas , Isambert Nicolas , Mouton Julie , Robert Caroline , Schusterbauer Claudia Michaela , Vijayakumar Jayanthi 
Published: June 2023

TPS9599 Background: ANV419 is a potent and selective IL-2Rβγ targeted antibody IL-2 fusion protein, designed to enable the delivery of high dose interleukin-2 (IL-2) to patients in order to stimulate anti-tumour response and minimise toxicities. Recombinant IL-2 (proleukin) induces durable responses in approximately 10% of patients with melanoma. Signalling through IL-2Rα expressing cells is believed to limit its therapeutic potential in cancer. By eliminating binding to IL-2Rα, ANV419 could lead to increased anti-tumor effect while increasing tolerability. The ANV419-001 first-in-human study (NCT 04855929) demonstrated that ANV419 preferentially stimulates cytotoxic CD8+ T and natural killer (NK) cells over immunosuppressive regulatory T cells, with a significantly longer half-life than that of conventional IL-2. The safety and tolerability data from this study confirmed that ANV419 delivers high molar equivalents of IL-2 in a tolerable and convenient way. Methods: ANV419 is being evaluated in a global multicentre, open-label, randomized Phase I/II study in patients with unresectable or metastatic cutaneous melanoma to assess the safety and efficacy of intravenous ANV419 as monotherapy and in combination with anti-PD1 or anti-CTLA-4 antibodies. The OMNIA-1 study leads in with a monotherapy dose expansion part, followed by a combination dose-finding with either anti-PD-1 or anti-CTLA-4 and a combination dose expansion part. ANV419 is administered intravenously every 2 weeks as monotherapy and every 3 weeks when given in combination. Patients with advanced cutaneous melanoma, no active brain metastases and whose disease has progressed on or following at least 1 line of standard of care immunotherapy are eligible. In Part 1, a total of 30 patients will be randomised and evaluated for response to Q2W ANV419 monotherapy (108 µg/kg or 243 µg/kg). In Part 2, escalating doses of Q3W ANV419 are evaluated to define the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) in combination with pembrolizumab (200 mg) or ipilimumab (3 mg/kg). In Part 3, the efficacy and safety of ANV419 in combination with the approved doses pembrolizumab or ipilimumab will be evaluated using a Simon’s 2-stage design. Up to 130 patients are planned to be enrolled. Patients will be stratified according to BRAF mutation status. AEs are assessed according to CTCAE V5.0. Tumour response is determined using RECIST 1.1 criteria. The study is conducted at sites in the US, France, Spain, Germany, Italy, and UK. The first patient was dosed in December 2022. Preliminary monotherapy efficacy data are expected by Q1/2024. Clinical trial information: NCT05578872 .
A randomized phase 2 trial of encorafenib + binimetinib + nivolumab vs ipilimumab + nivolumab in BRAFV600-mutant melanoma brain metastases: SWOG S2000.
Authors: Eroglu Zeynep , Moon James , Najjar Yana G. , Kotecha Rupesh , Spektor Vadim , Wu Michael , Sharon Elad , Grossmann Kenneth F. , Wolchok Jedd D. , Patel Sapna Pradyuman , Tawbi Hussein A. 
Published: June 2023

TPS9603 Background: While anti-PD-1 and anti-CTLA4 immunotherapies are widely used in the treatment of metastatic melanoma, including melanoma brain metastases (MBM), their efficacy in patients with symptomatic MBM is very limited. In the Checkmate-204 trial of ipilimumab with nivolumab in MBM, the 6-month progression free survival (PFS) rate was 19% with a median PFS of only 1.2 months in symptomatic participants (those with neurological symptoms including steroids up to 4 mg/day of dexamethasone, n=18). (Tawbi, Lancet et al., 2021) In the COMBI-MB study of BRAF/MEK-inhibitors in BRAF-V600 mutant MBM, median PFS was 5.5 months in those with symptomatic metastases (n=17). (Davies et al., Lancet Oncol, 2017) The combination of anti-PD-1/PD-L1 therapy with BRAF/MEK inhibitors has been tested in various trials. The single-arm phase 2 TRICOTEL study explored the triplet regimen of vemurafenib + cobimetinib + atezolizumab in MBM; in the symptomatic brain met cohort, 6-month PFS was 57% (n=24). (Dummer et al., Lancet Oncol 2022). Methods: SWOG S2000 is a randomized phase 2 trial exploring the efficacy of a triplet regimen of BRAF/MEK inhibitors with PD-1 therapy (encorafenib 450 mg qday + binimetinib 30 mg BID + nivolumab 480 mg IV q4 weeks) versus ipilimumab 3 mg/kg + nivolumab 1 mg/kg q3 weeks in patients with symptomatic BRAF-mutant MBM. (The study was amended to exclude patients with asymptomatic MBM.) Eligible patients are ≥18 years old, ECOG 0-2, and prior neoadjuvant or adjuvant anti-PD-1, CTLA-4, or BRAF/MEK-inhibitors is permitted. Steroids up to 8 mg of dexamethasone/day (or equivalent), leptomeningeal spread, and prior local therapy (radiation or surgery) for brain mets are permitted, if a patient has at least one measurable, progressing brain met ≥0.5 cm in size. Primary objective is to compare PFS per (RECIST 1.1) between the two study arms. Secondary objectives include overall survival, toxicity profile, objective tumor response, intracranial response and duration per modified RECIST 1.1, modified RANO-BM, and iRANO criteria, and evaluation of radiographic response criteria by centralized review of banked images. This study is powered to detect an increase in estimated 6-month PFS from 20% to 52% with 80% power and type I error rate of 10%, with 24 eligible patients required. Total sample size is 28 to account for ineligible patients. Available blood, tissue, CSF and stool samples are banked for future correlative studies. The study is currently enrolling patients through SWOG, ECOG and NRG centers. Funding: NIH/NCI grants U10CA180888, U10CA180819, U10CA180820 U10CA180868; and in part by Pfizer, Inc. Clinical trial information: NCT04511013 .
PLUME: A single-arm phase II trial evaluating the combination of pembrolizumab and lenvatinib in metastatic uveal melanoma (mUM) patients (pts) previously treated or not with tebentafusp.
Authors: Rodrigues Manuel , Saint-Ghislain Mathilde , Ramtohul Toulsie , de Koning Leanne , Bouchez Clémentine , Lafite Elsa , Castel Ajgal Zahra , Marret Gregoire , Sanchez Raphaël , Mariani Pascale , Nespoulous Sandra , Gillon Véronique , Servois Vincent , Piperno-Neumann Sophie 
Published: June 2023

TPS9613 Background: Up to 50% of pts with uveal melanoma (UM) develop metastases, mainly hepatic, with poor overall survival and limited treatment options as response rate to first-line immune checkpoint inhibitors (ICI) is low in mUM pts. Tebentafusp, a bispecific T-cell engager, was recently approved in this setting but only in HLA A*02-01+ mUM patients. Lenvatinib is a tyrosine kinase inhibitor targeting multiple growth factor receptors including vascular endothelial growth factor receptors (VEGFRs), fibroblast growth factor receptors (FGFRs) and colony-stimulating factor receptor (CSF1-R), which are key pathways in UM. Lenvatinib showed an immune-modulating effect in preclinical models. The combination demonstrated synergic clinical anti-tumor activity in various tumor types including microsatellite-stable endometrial cancers, kidney cancers and ICI-resistant skin melanomas. We hypothesize that combining pembrolizumab with lenvatinib in mUM may lead to an improved immune response in mUM patients. Methods: Fifty-four, ICI-naïve, metastatic UM pts will be enrolled in this monocentric, single-arm phase II trial at Institut Curie, Paris, France. Because previous exposure to tebentafusp might increase the activity of subsequent ICI, the combination will be assessed in two independent cohorts: cohort 1 with HLA A*02-01neg, tebentafusp-naive patients (22 assessable patients), and cohort 2 with HLA A*02-01pos pts previously treated with tebentafusp (28 assessable patients). Up to 54 patients may be included according to an 8% drop-out rate. Each participant will receive pembrolizumab (200 mg Q3W, maximum of 35 cycles) plus lenvatinib (starting at 20mg QD) until reaching a discontinuation criterion. Liver MRI and chest-abdomen-pelvis CT will be performed every 9 weeks until progressive disease. Primary objective is to evaluate the progression-free survival (PFS) after nine cycles of treatment (27 weeks) as assessed by the investigator using the RECIST v1.1. Secondary objectives include PFS according to immune RECIST (iRECIST), overall survival, overall response rate, safety and tolerability, quality of life. Inclusion period started mid-July 2022 for two years. To date, twenty-four (21 in cohort 1, 3 in cohort 2) of planned 54 pts have been enrolled in six months. Biospecimens (longitudinal blood samples and tumor tissue at inclusion) will be collected during the study to allow biomarker research. Clinical trial information: NCT05282901 .
A 3D adipogenesis platform to study the fate of fibro/adipogenic progenitors in muscular dystrophies
Authors: Reggio Alessio , De Paolis Francesca , Bousselmi Salma , Cicciarelli Felice , Bernardini Sergio , Rainer Alberto , Seliktar Dror , Testa Stefano , Cirillo Carmine , Grumati Paolo , Cannata Stefano , Fuoco Claudia , Gargioli Cesare 
Published: June 2023

ABSTRACT
In human dystrophies, progressive muscle wasting is exacerbated by ectopic deposition of fat and fibrous tissue originating from fibro/adipogenic progenitors (FAPs). In degenerating muscles, the ability of these cells to promote successful healing is attenuated, and FAPs aberrantly expand and differentiate into adipocytes and fibroblasts. Thus, arresting the fibro/adipogenic fate of FAPs, without affecting their physiological role, represents a valuable therapeutic strategy for patients affected by muscle diseases. Here, using a panel of adipose progenitor cells, including human-derived FAPs, coupled with pharmacological perturbations and proteome profiling, we report that LY2090314 interferes with a genuine adipogenic program acting as WNT surrogate for the stabilization of a competent β-catenin transcriptional complex. To predict the beneficial impact of LY2090314 in limiting ectopic deposition of fat in human muscles, we combined a poly-ethylene-glycol-fibrinogen biomimetic matrix with these progenitor cells to create a miniaturized 3D model of adipogenesis. Using this scalable system, we demonstrated that a two-digit nanomolar dose of this compound effectively represses adipogenesis at higher 3D scale, thus indicating the potential for LY2090314 to limit FAP-derived fat infiltrates in dystrophic muscles.
Case Report: A prenatal diagnosis of osteogenesis imperfecta in a patient with a novel pathogenic variant in COL1A2
Authors: Peláez Chomba Melissa Sindy , Vásquez Gómez Guillermo Raúl , Sullcahuaman Allende Yasser Ciro , Mendoza Fernández Julio Cesar , Purizaca Rosillo Nelson David , Zevallos Alejandra , Cruzate Cabrejos Vicente Leandro 
Published: June 2023

Osteogenesis imperfecta is considered a rare genetic condition which is characterized by bone fragility. In 85% of cases, it is caused by mutations in COL1A1 and COL1A2 genes which are essential to produce type I collagen. We report the case of a female neonate delivered to a 27-year-old women at San Bartolomé Teaching Hospital with a family history of clavicle fracture. A prenatal control with ultrasound was performed to the mother at 29 weeks. A fetus with altered morphology and multiple fractures was found. Therefore, a prenatal diagnosis of osteogenesis imperfecta was performed. The neonate was born with a respiratory distress syndrome and an acyanotic congenital heart disease. Therefore, she remained in NICU until her death. We highlight the importance of prenatal diagnosis, genetic counseling and a multidisciplinary evaluation in this type of pathologies and report a new probably pathogenic variant in the COL1A2 gene detected by exomic sequencing in amniotic fluid.
An empirical investigation on the impact of attitudes towards organ donation in India
Authors: Nayak Vinod C. , Nayak Smitha 
Published: June 2023

Background: Organ shortage is a global issue and it is imperative to take steps to bridge this gap. In the Indian context, despite its demographic dividend, the rate of organ donation has been abysmally low. This emphasizes a need to demystify the antecedents of organ donation intention among the Indian population. Methods: Using a cross-sectional research design and adopting a post-positivism research philosophy, this study identified 259 respondents by adopting a purposive sampling approach and data on knowledge of organ donation was collected using a structured, pretested questionnaire. Results: Awareness of organ donation law in India is low on specific issues and respondents from the health science & medicine discipline scored better on knowledge about organ donation. The findings show that most participants had heard about organ donation and had a favourable attitude toward it. The primary sources of information on organ donation were television and newspapers, and healthcare service providers. A complementary partial median is established (β = .217, t = 5.889, p < .001) which implies that willingness to discuss with family significantly mediates the association between attitude towards organ & tissue donation and willingness to sign the donor card. Conclusion: This study revealed that there is a general awareness of organ and tissue donation among the Indian population, but they lack clarity on certain specific issues. Mass media has to be effectively used to build awareness campaigns revolving around enhancing knowledge on a specific issue and building acceptance of the concept of organ and tissue donation.
COVID-19 vaccinations and their side effects: a scoping systematic review
Authors: Monadhel Hind , Abbas Ayad , Mohammed Athraa 
Published: June 2023

Introduction: The COVID-19 virus has impacted people worldwide, causing significant changes in their lifestyles. Since the emergence of the epidemic, attempts have begun to prepare a vaccine that can eliminate the virus and restore balance to life in the entire world. Over the past two years, countries and specialized companies have competed to obtain a license from the World Health Organization for the vaccines that were discovered. After the appearance of vaccines in the health community, comparisons and fears of their side effects began, but people don’t get an answer to the question of which is the best vaccine. Methods: IEEE Xplore, ScienceDirect, the New England Journal of Medicine, Google Scholar, and PubMed databases were searched for literature on the COVID-19 vaccine and its side effects. we surveyed the literature on the COVID-19 vaccine’s side effects and the sorts of side effects observed after vaccination. Depending on data from the literature, we compared these vaccines in terms of side effects, then we analyzed the gaps and obstacles of previous studies and made proposals to process these gaps in future studies. Results: Overall, 17 studies were included in this scoping systematic review as they fulfilled the criteria specified, the majority of which were cross-sectional and retrospective cross-sectional studies. Most of the side effects were mild, self-limiting, and common. Thus, they usually resolve within 1–3 days after vaccination. Factors associated with higher side effects included advanced age, allergic conditions, those taking other medications (particularly immunosuppressive ones), those with a history of type II diabetes, heart disease, hypertension, COVID-19 infection, and female sex. Our meta‐analyses also found that mRNA vaccines looked to be more effective, while inactivated vaccinations had fewer side effects. Conclusion: This review shows that the COVID-19 vaccine is safe to administer and induces protection.
General public awareness, knowledge and attitude toward COVID-19 infection and prevention: a cross-sectional study from Pakistan
Authors: Alam Beenish Fatima , Almojaibel Abdullah A. , Aziz Ansari Khalid , Haroon Mohammad , Noreen Sara , Tauqir Saman , Almas Khalid , Farooqi Faraz A. , Ali Saqib 
Published: June 2023

Background: The aim of this study is to evaluate the knowledge, perceptions, and attitude of the public in Pakistan (using social media) towards COVID-19. Methods: A cross-sectional study was conducted amongst 1120 individuals nationwide. A self-developed, pre-tested questionnaire was used that comprised of sections covering demographic characteristics, medical history, hygiene awareness, COVID-19-related knowledge, and learning attitude. Descriptive statistics were used for frequencies, percentages, averages and standard deviations. Inferential statistics were done using the Student’s t-test and ANOVA. Results: The average age of participants was 31 years (range 18-60 years). In total 56 individuals (5%) had completed primary or secondary school education; 448 (40%) were employed (working from home) and 60% were jobless due to the COVID-19 crisis. Almost all the study subjects (1030 (92%)) were washing their hands multiple times a day. A total of 83% had awareness regarding quarantine time, 82% used face masks whenever they left their homes, 98% were aware of the origin of the disease, and 70% had knowledge regarding the most common symptoms of COVID-19. Conclusion: It can be concluded from the current study that female participants had higher level of education, and more awareness regarding the coronavirus. The majority of the participants followed proper hand washing regimes and washed their faces. Further knowledge and awareness should be promoted.
Prevalence of primary malignant tumours, rates of pathological fracture, and mortality in the setting of metastatic bone disease
Authors: Christ Alexander B. , Piple Amit S. , Gettleman Brandon S. , Duong Andrew , Chen Matthew , Wang Jennifer C. , Heckmann Nathanael D. , Menendez Lawrence 
Published: June 2023

AimsThe modern prevalence of primary tumours causing metastatic bone disease is ill-defined in the oncological literature. Therefore, the purpose of this study is to identify the prevalence of primary tumours in the setting of metastatic bone disease, as well as reported rates of pathological fracture, postoperative complications, 90-day mortality, and 360-day mortality for each primary tumour subtype.MethodsThe Premier Healthcare Database was queried to identify all patients who were diagnosed with metastatic bone disease from January 2015 to December 2020. The prevalence of all primary tumour subtypes was tabulated. Rates of long bone pathological fracture, 90-day mortality, and 360-day mortality following surgical treatment of pathological fracture were assessed for each primary tumour subtype. Patient characteristics and postoperative outcomes were analyzed based upon whether patients had impending fractures treated prophylactically versus treated completed fractures.ResultsIn total, 407,893 unique patients with metastatic bone disease were identified. Of the 14 primary tumours assessed, metastatic bone disease most frequently originated from lung (24.8%), prostatic (19.4%), breast (19.3%), gastrointestinal (9.4%), and urological (6.5%) malignancies. The top five malignant tumours resulting in long bone pathological fracture were renal (5.8%), myeloma (3.4%), female reproductive (3.2%), lung (2.8%), and breast (2.7%). Following treatment of pathological fractures of long bones, 90-day mortality rates were greatest for lung (12.1%), central nervous system (10.5%), lymphoma (10.4%), gastrointestinal (10.1%), and non-renal urinary (10.0%) malignancies. Finally, our study demonstrates improved 90-day and 360-day survival in patients treated for impending pathological fracture compared to completed fracture, as well as significantly lower rates of deep vein thrombosis, pulmonary embolism, urinary tract infection, and blood transfusion.ConclusionThis study defines the contemporary characteristics of primary malignancies resulting in metastatic bone disease. These data should be considered by surgeons when prognosticating patient outcomes during treatment of their metastatic bone disease.Cite this article: Bone Jt Open 2023;4(6):424–431.