bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trial in progress: A phase 2 study of sotorasib as first-line treatment in patients with stage IV non–small cell lung cancer (NSCLC) whose tumors harbor a KRAS p.G12C mutation (CodeBreaK 201).
Authors: Arbour Kathryn Cecilia , Khurana Monica , Dai Tian , Skoulidis Ferdinandos 
Published: June 2022

TPS9150 Background: Chemo-immunotherapy regimens represent a standard of care for the first-line treatment of metastatic NSCLC, yet clinical outcomes in patients bearing tumors that lack PD-L1 expression [PD-L1 Tumor Proportion Score (TPS) < 1%)] or harbor a serine/threonine kinase 11 ( STK11) mutation remain poor. Sotorasib is a selective, irreversible small molecule KRASG12C inhibitor that is approved for the treatment of patients with locally advanced or metastatic KRAS p.G12C-mutated NSCLC following failure of at least one prior line of systemic therapy and has previously demonstrated robust antitumor activity in subgroups of KRAS p.G12C mutant NSCLC with PD-L1 TPS <1% and/or STK11 co-mutations. We hypothesized that sotorasib may represent an effective first-line therapy for subgroups of NSCLC patients who may have suboptimal chemo-immunotherapy outcomes and a high unmet clinical need. Methods: This phase 2, open-label, global study is designed to evaluate the efficacy and safety of sotorasib (960 mg or 240 mg daily) as first-line treatment in approximately 170 patients with KRAS p.G12C-mutated, metastatic NSCLC with PD-L1 TPS <1% as determined by immunohistochemical assay and/or presence of STK11 mutation as determined by next-generation sequencing (NGS). Key eligibility criteria include patients with untreated metastatic NSCLC without active brain metastases. Patients will be stratified by known presence of STK11 mutation. The primary endpoint is objective response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary endpoints include disease control, duration of response, time to response, progression-free survival per RECIST 1.1, overall survival, safety and tolerability, and pharmacokinetic profile. Enrollment began in January 2022 and is ongoing. Contact Amgen Medical Information for more information. Clinical trial information: NCT04933695.
Additional chemotherapy for EGFRm patients with the continued presence of plasma ctDNA EGFRm at week 3 after start of osimertinib first-line treatment (PACE).
Authors: Stratmann Jan Alexander , Acker Fabian , Aspacher Lukas , Alt Juergen , Althoff Friederike C , Heinzen Sophie , Gökbuget Nicola , Müller Ina , Reiser Lena , Hehn Sina , Serve Hubert , Mänz Martin , Meyer Frauke , Sebastian Martin 
Published: June 2022

TPS9157 Background: Epidermal growth factor receptor (EGFR) – mutated non-small cell lung cancer (NSCLC) is susceptible to EGFR targeting tyrosine kinase inhibitors (TKI), such as the third generation TKI osimertinib. However, response rate and duration vary between patients. Among others, the specific subtype of EGFR-mutation, its co-occurrence with other genetic alterations, and the detection of phosphorylated EGFR (pEGFR) in the plasma, and its clearance upon treatment were previously identified as markers that predict therapy response. A high proportion of patients with early (3-6 weeks after start) pEGFR clearance from plasma show impressive survival upon single-agent TKI. However, failure to achieve early clearance upon Osimertinib is associated with unfavorable outcome. For these patients, treatment concepts are lacking. Here, we report about the initiation of a clinical trial that evaluates the combination of EGFR-directed TKI and platinum-based chemotherapy as an early treatment escalation strategy for this high-risk patient population. Methods: PACE is a prospective multicenter single-arm investigator-initiated phase II trial. Patients with NSCLC harboring L858R or del19 EGFR mutation, who are treated with first-line Osimertinib are subjected to liquid biopsy-based early response assessment three weeks after start of therapy. Failure to clear pEGFR from plasma at this time point triggers treatment escalation with the addition of platinum-based doublet chemotherapy to the Osimertinib treatment. The primary outcome measure of the trial is progression-free survival (PFS), with the objective to assess the efficacy of biomarker-driven escalation of osimertinib therapy with a combination platinum-based regimen. Secondary outcome measures are the overall response rate (ORR), overall survival (OS), and the Quality of life (QLQ-C30, CTCAE-PROs) of the treated patients. In exploratory analyses, we will assess whether specific patterns of co-mutations are associated with early treatment failure (upon TKI) and pEGFR persistence. Fig. 1 illustrates the trial concept. A sample of 46 subjects achieves 80% power at a 0.05 significance level to detect a PFS of 14.4 months in the experimental treatment group when the PFS of the historic control group is 9.1 months; a total of 400 patients need to be screened within the national Network Genomic Medicine. Enrollment started in 12/2021. The clinical trial is supported by AstraZeneca and Guardant. EudraCT registration number: 2019-004757-88 .
ARTISTRY-6: Nemvaleukin alfa monotherapy in patients with advanced mucosal and cutaneous melanoma.
Authors: Weber Jeffrey S. , Carvajal Richard D. , Hamid Omid , Kim Seung Tae , Kim Miso , Sullivan Ryan J. , Lee Dae Ho , Mehmi Inderjit , Grewal Jaspreet Singh , Lee Hyo Jin , Dudek Arkadiusz Z. , Du Yangchun , Desai, MD Monali , Wang Yan , Mayo Carlos Alberto , Middleton Mark R. 
Published: June 2022

TPS9609 Background: Despite improved outcomes for melanoma patients with the introduction of checkpoint inhibitors (CPIs), ̃50% of patients do not respond. A subset of responders ultimately progress and have limited treatment options, underscoring a high unmet need for novel treatments with durable benefit. Patients with mucosal melanoma exhibit response rates and progression-free survival times ̃2 times lower than those with cutaneous melanoma. Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel, engineered cytokine that selectively binds the intermediate-affinity interleukin-2 receptor complex to preferentially activate CD8+ T and NK cells with minimal expansion of regulatory T cells. Nemvaleukin has been granted Orphan Drug designation for the treatment of mucosal melanoma by the FDA. In ARTISTRY-1, the intravenous (IV) recommended phase 2 dose (RP2D) of 6 µg/kg nemvaleukin monotherapy demonstrated durable antitumor activity in patients with advanced melanoma, including mucosal melanoma, previously treated with a CPI. In ARTISTRY-2, the subcutaneous (SC) RP2D of 3 mg q7d was identified demonstrating pharmacodynamic effects consistent with IV delivery. Data support further evaluation of nemvaleukin monotherapy among patients with advanced mucosal and cutaneous melanoma. Methods: ARTISTRY-6 is a phase 2, global, multicenter, open-label study. Eligible patients have had prior treatment with an anti–PD-(L)1 therapy with or without anti–CTLA-4 therapy and have an ECOG performance status of 0 or 1 and adequate hematologic reserve and hepatic and renal function. Patients with advanced cutaneous (Cohort 1) and mucosal (Cohort 2) melanoma will receive nemvaleukin at the SC and IV RP2D, respectively. Patients will receive nemvaleukin until progression or intolerable toxicity. The primary objective is to evaluate the antitumor activity of nemvaleukin monotherapy defined by overall response rate. Additional objectives include the evaluation of safety, health-related quality of life, predictive biomarkers, pharmacokinetics, immunogenicity, and pharmacodynamic effects. Clinical trial information: NCT04830124.
Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO
Authors: Rossini Daniele , Antoniotti Carlotta , Lonardi Sara , Pietrantonio Filippo , Moretto Roberto , Antonuzzo Lorenzo , Boccaccino Alessandra , Morano Federica , Brugia Marco , Pozzo Carmelo , Marmorino Federica , Bergamo Francesca , Tamburini Emiliano , Passardi Alessandro , Randon Giovanni , Murgioni Sabina , Borelli Beatrice , Buonadonna Angela , Giordano Mirella , Fontanini Gabriella , Conca Veronica , Formica Vincenzo , Aglietta Massimo , Bordonaro Roberto , Aprile Giuseppe , Masi Gianluca , Boni Luca , Cremolini Chiara 
Published: June 2022

PURPOSE To verify whether the intensification of the upfront chemotherapy backbone with a modified schedule of modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) increases the activity of fluorouracil, leucovorin, and oxaliplatin when both regimens are combined with panitumumab as initial treatment for RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC). METHODS TRIPLETE was a prospective, open-label, phase III trial in which previously untreated patients with unresectable RAS and BRAF wt mCRC were randomly assigned 1:1 to modified FOLFOX/panitumumab (control group) or mFOLFOXIRI/panitumumab (experimental group) up to 12 cycles, followed by fluorouracil/-leucovorin/panitumumab until disease progression. The primary end point was objective response rate (ORR) according to RECIST 1.1. Hypothesizing an ORR of 60% in the control group, 432 cases provided 90% power to a two-sided chi-square test for heterogeneity with a two-sided alpha error of .05 to detect ≥ 15% differences between arms (ClinicalTrials.gov identifier: NCT03231722 ). RESULTS From September 2017 to September 2021, 435 patients were enrolled (control group/experimental group: 217/218) in 57 Italian sites. One hundred sixty (73%) patients treated with mFOLFOXIRI plus panitumumab and 165 (76%) patients treated with modified FOLFOX plus panitumumab achieved RECIST response (odds ratio 0.87, 95% CI, 0.56 to 1.34, P = .526). No differences in early tumor shrinkage rate (57%/58%, P = .878) and deepness of response (median: 48%/47%, P = .845) were reported, nor in R0 resection rate (25%/29%, P = .317). No significant difference between arms was reported in terms of progression-free survival (median progression-free survival: 12.7 in the experimental group v 12.3 months in the control group, hazard ratio: 0.88, 95% CI, 0.70 to 1.11, P = .277). CONCLUSION The intensification of the upfront chemotherapy backbone in combination with panitumumab does not provide additional benefit in terms of treatment activity at the price of increased gastrointestinal toxicity in patients with RAS and BRAF wt mCRC.
Biomarkers for Cyclin-Dependent Kinase 4/6 Inhibitors in the Treatment of Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced/Metastatic Breast Cancer: Translation to Clinical Practice
Authors: Bui Tam Binh V. , Burgering Boudewijn M.T. , Goga Andrei , Rugo Hope S. , van ‘t Veer Laura J. 
Published: June 2022

PURPOSECyclin-dependent kinase 4/6 (CDK4/6) inhibitors have emerged as effective treatments for patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2–) advanced/metastatic breast cancer (mBC). Dedicated research efforts have been undertaken to find predictive biomarkers of response or resistance to these therapies although no molecular biomarkers for mBC have reached the clinic so far. This review aims to summarize and evaluate the performance of biomarkers in predicting progression-free survival in phase II and III clinical trials of CDK4/6 inhibitors in HR+/HER2– mBC.METHODSFor this narrative review, a structured literature search of PubMed, Embase, and the Cochrane library (CENTRAL) was performed. Phase II or III clinical trials of a CDK4/6 inhibitor in patients with HR+/HER2– mBC reporting on at least one molecular biomarker analysis of progression-free survival were included. Publications and selected conference abstracts were included up until November 2021.RESULTSTwenty-two articles reporting biomarker results of 12 clinical trials were included. Retinoblastoma protein status and cyclin E1 mRNA expression were promising baseline biomarkers, whereas PIK3CA circulating tumor DNA ratio on treatment relative to baseline, change in plasma thymidine kinase activity, and circulating tumor cell count were potential dynamic biomarkers of response. A number of biomarkers were unsuccessful, despite a strong mechanistic rationale, and others are still being explored.CONCLUSIONOur review of clinical trials showed that there are a number of promising biomarkers at baseline and several dynamic biomarkers that might predict response to CDK4/6 inhibitors. Validation of these findings and assessment of clinical utility are crucial to make the final translation to clinical practice. Better understanding of disease heterogeneity and further elucidation of resistance mechanisms could inform future studies of rationally selected biomarkers.
Prolactin and Maternal Metabolism in Women With a Recent GDM Pregnancy and Links to Future T2D: The SWIFT Study
Authors: Zhang Ziyi , Piro Anthony L , Allalou Amina , Alexeeff Stacey E , Dai Feihan F , Gunderson Erica P , Wheeler Michael B 
Published: June 2022

Abstract

Context
Prolactin is a multifaceted hormone known to regulate lactation. In women with gestational diabetes mellitus (GDM) history, intensive lactation has been associated with lower relative risk of future type 2 diabetes (T2D). However, the role of prolactin in T2D development and maternal metabolism in women with a recent GDM pregnancy has not been ascertained.

Objective
We examined the relationships among prolactin, future T2D risk, and key clinical and metabolic parameters.

Methods
We utilized a prospective GDM research cohort (the SWIFT study) and followed T2D onset by performing 2-hour 75-g research oral glucose tolerance test (OGTT) at study baseline (6-9 weeks postpartum) and again annually for 2 years, and also by retrieving clinical diagnoses of T2D from 2 years through 10 years of follow up from electronic medical records. Targeted metabolomics and lipidomics were applied on fasting plasma samples collected at study baseline from 2-hour 75-g research OGTTs in a nested case-control study (100 future incident T2D cases vs 100 no T2D controls).

Results
Decreasing prolactin quartiles were associated with increased future T2D risk (adjusted odds ratio 2.48; 95% CI, 0.81-7.58; P = 0.05). In women who maintained normoglycemia during the 10-year follow-up period, higher prolactin at baseline was associated with higher insulin sensitivity (P = 0.038) and HDL-cholesterol (P = 0.01), but lower BMI (P = 0.001) and leptin (P = 0.002). Remarkably, among women who developed future T2D, prolactin was not correlated with a favorable metabolic status (all P &gt; 0.05). Metabolomics and lipidomics showed that lower circulating prolactin strongly correlated with a T2D–high risk lipid profile, with elevated circulating neutral lipids and lower concentrations of specific phospholipids/sphingolipids.

Conclusion
In women with recent GDM pregnancy, low circulating prolactin is associated with specific clinical and metabolic parameters and lipid metabolites linked to a high risk of developing T2D.
Characterization of gene cluster heterogeneity in single-cell transcriptomic data within and across cancer types
Authors: Tiong Khong-Loon , Lin Yu-Wei , Yeang Chen-Hsiang 
Published: June 2022

ABSTRACTDespite the remarkable progress in probing tumor transcriptomic heterogeneity by single-cell RNA sequencing (sc-RNAseq) data, several gaps exist in prior studies. Tumor heterogeneity is frequently mentioned but not quantified. Clustering analyses typically target cells rather than genes, and differential levels of transcriptomic heterogeneity of gene clusters are not characterized. Relations between gene clusters inferred from multiple datasets remain less explored. We provided a series of quantitative methods to analyze cancer sc-RNAseq data. First, we proposed two quantitative measures to assess intra-tumoral heterogeneity/homogeneity. Second, we established a hierarchy of gene clusters from sc-RNAseq data, devised an algorithm to reduce the gene cluster hierarchy to a compact structure, and characterized the gene clusters with functional enrichment and heterogeneity. Third, we developed an algorithm to align the gene cluster hierarchies from multiple datasets to a small number of meta gene clusters. By applying these methods to nine cancer sc-RNAseq datasets, we discovered that cancer cell transcriptomes were more homogeneous within tumors than the accompanying normal cells. Furthermore, many gene clusters from the nine datasets were aligned to two large meta gene clusters, which had high and low heterogeneity and were enriched with distinct functions. Finally, we found the homogeneous meta gene cluster retained stronger expression coherence and associations with survival times in bulk level RNAseq data than the heterogeneous meta gene cluster, yet the combinatorial expression patterns of breast cancer subtypes in bulk level data were not preserved in single-cell data. The inference outcomes derived from nine cancer sc-RNAseq datasets provide insights about the contributing factors for transcriptomic heterogeneity of cancer cells and complex relations between bulk level and single-cell RNAseq data. They demonstrate the utility of our methods to enable a comprehensive characterization of co-expressed gene clusters in a wide range of sc-RNAseq data in cancers and beyond.
Distinct spatiotemporal contribution of morphogenetic events and mechanical tissue coupling during Xenopus neural tube closure
Authors: Christodoulou Neophytos , Skourides Paris A. 
Published: June 2022

ABSTRACT
Neural tube closure (NTC) is a fundamental process during vertebrate development and is indispensable for the formation of the central nervous system. Here, using Xenopus laevis embryos, live imaging, single-cell tracking, optogenetics and loss-of-function experiments, we examine the roles of convergent extension and apical constriction, and define the role of the surface ectoderm during NTC. We show that NTC is a two-stage process with distinct spatiotemporal contributions of convergent extension and apical constriction at each stage. Convergent extension takes place during the first stage and is spatially restricted at the posterior tissue, whereas apical constriction occurs during the second stage throughout the neural plate. We also show that the surface ectoderm is mechanically coupled with the neural plate and its movement during NTC is driven by neural plate morphogenesis. Finally, we show that an increase in surface ectoderm resistive forces is detrimental for neural plate morphogenesis.
Deep phenotyping for precision medicine in Parkinson's disease
Authors: Schalkamp Ann-Kathrin , Rahman Nabila , Monzón-Sandoval Jimena , Sandor Cynthia 
Published: June 2022

ABSTRACT
A major challenge in medical genomics is to understand why individuals with the same disorder have different clinical symptoms and why those who carry the same mutation may be affected by different disorders. In every complex disorder, identifying the contribution of different genetic and non-genetic risk factors is a key obstacle to understanding disease mechanisms. Genetic studies rely on precise phenotypes and are unable to uncover the genetic contributions to a disorder when phenotypes are imprecise. To address this challenge, deeply phenotyped cohorts have been developed for which detailed, fine-grained data have been collected. These cohorts help us to investigate the underlying biological pathways and risk factors to identify treatment targets, and thus to advance precision medicine. The neurodegenerative disorder Parkinson's disease has a diverse phenotypical presentation and modest heritability, and its underlying disease mechanisms are still being debated. As such, considerable efforts have been made to develop deeply phenotyped cohorts for this disorder. Here, we focus on Parkinson's disease and explore how deep phenotyping can help address the challenges raised by genetic and phenotypic heterogeneity. We also discuss recent methods for data collection and computation, as well as methodological challenges that have to be overcome.
Cerebellar neuronal dysfunction accompanies early motor symptoms in spinocerebellar ataxia type 3
Authors: Mayoral-Palarz Kristin , Neves-Carvalho Andreia , Duarte-Silva Sara , Monteiro-Fernandes Daniela , Maciel Patrícia , Khodakhah Kamran 
Published: June 2022

ABSTRACT
Spinocerebellar ataxia type 3 (SCA3) is an adult-onset, progressive ataxia. SCA3 presents with ataxia before any gross neuropathology. A feature of many cerebellar ataxias is aberrant cerebellar output that contributes to motor dysfunction. We examined whether abnormal cerebellar output was present in the CMVMJD135 SCA3 mouse model and, if so, whether it correlated with the disease onset and progression. In vivo recordings showed that the activity of deep cerebellar nuclei neurons, the main output of the cerebellum, was altered. The aberrant activity correlated with the onset of ataxia. However, although the severity of ataxia increased with age, the severity of the aberrant cerebellar output was not progressive. The abnormal cerebellar output, however, was accompanied by non-progressive abnormal activity of their upstream synaptic inputs, the Purkinje cells. In vitro recordings indicated that alterations in intrinsic Purkinje cell pacemaking and in their synaptic inputs contributed to abnormal Purkinje cell activity. These findings implicate abnormal cerebellar physiology as an early, consistent contributor to pathophysiology in SCA3, and suggest that the aberrant cerebellar output could be an appropriate therapeutic target in SCA3.
Late Evolution of Deep Neck Space Abscess: Was Intubation the Cause?
Authors: Ali Ruhma , Owolabi Modupeoluwa , Patel Aditya , Hussain Muhammad , Slim Jihad 
Published: June 2022

Introduction: Deep neck abscess in adults may occur as a result of local trauma, foreign body inoculation or immunosuppression. Method: We describe a case of deep neck abscess that developed after recent hospitalization and intubation for chronic obstructive pulmonary disease (COPD) exacerbation. Discussion: The incidence of deep neck abscesses has dramatically reduced due to the use of antibiotics. However, if present, they need prompt surgical drainage due to their proximity to the nearby vasculature of the neck. Conclusion: This case highlights the need for physician awareness of the clinical presentation of the unique complications of deep neck abscess developing after hospitalization.