tbuckley/cabot-search huggingface dataset:
HGG-12. HUMAN IPSC-DERIVED H3.3K27M NEUROSPHERES: A NOVEL MODEL FOR INVESTIGATING DIPG PATHOGENESIS AND DRUG RESPONSE
Authors: Kasey Skinner, Tomoyuki Koga, Shunichiro Miki, Robert F Gruener, R Stephanie Huang, Frank Furnari, C Ryan Miller
Journal: Neuro-Oncology (2021)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a subset of high-grade glioma that occurs predominantly in children and has no cure. Up to 80% of DIPG harbor a heterozygous point mutation that results in a lysine 27 to methionine substitution in histone variant H3.3 (H3.3K27M). Existing DIPG models have provided insight into the role of H3.3K27M but have limitations: genetically engineered murine models often rely on overexpression of the mutant histone to form tumors; patient-derived xenografts (PDX) are more genetically faithful but preclude examination of the effect of individual mutations on pathogenesis. To address these shortcomings and better recapitulate the genetics of human tumors, we designed a novel DIPG model based on human induced pluripotent stem cells (iPSC) edited via CRISPR to express heterozygous H3.3K27M. Edited iPSC were chemically differentiated into neural progenitor cells, which upon implantation into the brainstems of immunodeficient mice formed diffusely invasive tumors that were histologically consistent with high-grade glioma. Further, neurospheres cultured from primary tumors formed secondary tumors upon reimplantation with more diffuse invasion, suggesting in vivo evolution. To validate this model’s relevance to DIPG transcriptionally, we performed RNA-sequencing on a cohort of primary and secondary tumor neurospheres (termed primary and secondary iDIPG) and compared them to published RNA-seq data from pediatric PDX and patient tumor samples. Hierarchical clustering and principal component analysis on differentially expressed genes (P&amp;lt;0.05) showed that H3.3K27M iDIPG cluster with H3.3K27M PDX and patient tumors. Further, ssGSEA showed that H3.3K27M iDIPG are enriched for astrocytic and mesenchymal signature genes, a defining feature of H3.3K27M DIPG. Finally, we found that primary H3.3K27M iDIPG neurospheres are sensitive to panobinostat, an HDAC inhibitor shown to be effective against H3.3K27M DIPG cells in vitro. Overall, these data suggest that H3.3K27M iDIPG are a promising tool for investigating DIPG biology and new therapeutic strategies.
Metformin-Induced Pancreatitis
Authors: Filippo Luca Fimognari, Andrea Corsonello, Ruggero Pastorell, Raffaele Antonelli-Incalzi
Journal: Diabetes Care (2006)

About 2% of episodes of acute pancreatitis are caused by drugs (1). Phenformin was repeatedly associated with acute pancreatitis (1), but only two case reports highlighted a possible causative role for metformin (2,3). In one case, acute pancreatitis occurred for the coexistence of correct metformin treatment and acute renal failure (2); in the other, metformin overdose was deemed responsible (3).

A 61-year-old woman with diabetes and hypercholesterolemia presented after 5 days of vomiting, followed by oliguria and epigastric pain. At home, the therapy of 3 …
m6A modification regulates lung fibroblast-to-myofibroblast transition through modulating KCNH6 mRNA translation
Authors: Jia-xiang Zhang, Pei-jie Huang, Da-peng Wang, Wen-yu Yang, Jian Lu, Yong Zhu, Xiao-xiao Meng, Xin Wu, Qiu-hai Lin, Hui Lv, Hui Xie, Rui-lan Wang
Journal: Molecular Therapy (2021)

Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal lung disease characterized by progressive and non-reversible abnormal matrix deposition in lung parenchyma. Myofibroblasts originating mainly from resident fibroblasts via fibroblast-to-myofibroblast transition (FMT) are the dominant collagen-producing cells in pulmonary fibrosis. N6-methyladenosine (m6A) modification has been implicated in various biological processes. However, the role of m6A modification in pulmonary fibrosis remains elusive. In this study, we reveal that m6A modification is upregulated in a bleomycin (BLM)-induced pulmonary fibrosis mouse model, FMT-derived myofibroblasts, and IPF patient lung samples. Lowering m6A levels through silencing methyltransferase-like 3 (METTL3) inhibits the FMT process in vitro and in vivo. Mechanistically, KCNH6 is involved in the m6A-regulated FMT process. m6A modification regulates the expression of KCNH6 by modulating its translation in a YTH-domain family 1 (YTHDF1)-dependent manner. Together, our study highlights the critical role of m6A modification in pulmonary fibrosis. Manipulation of m6A modification through targeting METTL3 may become a promising strategy for the treatment of pulmonary fibrosis.
A phase II trial of bevacizumab and rucaparib in recurrent carcinoma of the cervix or endometrium.
Authors: Camille Catherine Jackson, Leigh Cantrell, Britt Kristina Erickson, Kathleen N. Moore, Linda R. Duska, Debra L. Richardson, Lisa Michelle Landrum, Laura L. Holman, Joan L. Walker, Robert S. Mannel, Katherine M. Moxley, Lurdes Queimado, Kai Ding, Andrew Cohoon, Sara Vesely, Lauren E. Dockery
Journal: Journal of Clinical Oncology (2021)

5527 Background: Treatment options for patients with recurrent cervical and endometrial cancer remain limited. Even with optimum care, median survival has stalled at 12-17 months. The PARP inhibitor rucaparib has demonstrated activity in both BRCA wild-type and mutant cancers. Furthermore, preclinical studies suggest a synergistic effect of PARP inhibitors and antiangiogenic agents. We hypothesized that the combination of rucaparib and the VEGF inhibitor bevacizumab would yield a clinically-significant anti-cancer effect in patients with persistent or recurrent cervical or endometrial carcinoma. Methods: NCT03476798 is a phase II trial of adults with histologically-documented carcinoma of the cervix or endometrium. Patients with evaluable lesions who had undergone at least one prior line of systemic therapy, had adequate performance status and organ function, with a life expectancy of at least three months were eligible. Biopsies were obtained prior to treatment initiation for assessment of baseline tumor biomarkers, including ARID1A mutation status. Each cycle comprised 21 days. Rucaparib was administered orally at 600 mg, twice daily. Bevacizumab was administered by IV at 15 mg/kg on day 1 of each cycle. The primary objective was to estimate the proportion of patients with persistent or recurrent cervical or endometrial cancer who survive progression-free for at least six months (PFS6). Kaplan-Meier analysis was used to estimate progression-free survival. Results: There were 28 evaluable patients; six had cervical and 22 had endometrial cancer. Median age was 60.5 years (range, 30-74). Self-reported patient races were White (82.1%), Black (10.7%), and Native American (7.1%). Self-identified Hispanic or Latina patients comprised 3.6% of the cohort. Twenty-two of 28 patients had progressive disease by six months [survival distribution function estimate = 0.214 (lower CI, 0.087; upper CI, 0.378)]. Of the six patients who achieved PFS6, one had cervical and five had endometrial cancer. Six patients had a mutation in the ARID1A gene and those patients achieved PFS6 at a rate of 66.7%. Conclusions: The study hypothesis was evaluated in a two-stage design, and the interim analysis occurred once 28 evaluable patients were enrolled. In order to move on to the second stage, at least seven patients needed to remain progression-free at six months, but only six did. Thus, the study was ended after the interim analysis. The combination of rucaparib and bevacizumab did not provide the expected clinical benefit in this cohort of patients, but may warrant further exploration in patients with ARID1A mutations. Clinical trial information: NCT03476798.
Associations Between Schizophrenia Polygenic Liability, Symptom Dimensions, and Cognitive Ability in Schizophrenia
Authors: Sophie E. Legge, Alastair G. Cardno, Judith Allardyce, Charlotte Dennison, Leon Hubbard, Antonio F. Pardiñas, Alexander Richards, Elliott Rees, Arianna Di Florio, Valentina Escott-Price, Stanley Zammit, Peter Holmans, Michael J. Owen, Michael C. O’Donovan, James T. R. Walters
Journal: JAMA Psychiatry (2021)

Schizophrenia is a clinically heterogeneous disorder. It is currently unclear how variability in symptom dimensions and cognitive ability is associated with genetic liability for schizophrenia.To determine whether phenotypic dimensions within schizophrenia are associated with genetic liability to schizophrenia, other neuropsychiatric disorders, and intelligence.In a genetic association study, 3 cross-sectional samples of 1220 individuals with a diagnosis of schizophrenia were recruited from community, inpatient, and voluntary sector mental health services across the UK. Confirmatory factor analysis was used to create phenotypic dimensions from lifetime ratings of the Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, and the MATRICS Consensus Cognitive Battery. Analyses of polygenic risk scores (PRSs) were used to assess whether genetic liability to schizophrenia, other neuropsychiatric disorders, and intelligence were associated with these phenotypic dimensions. Data collection for the cross-sectional studies occurred between 1993 and 2016. Data analysis for this study occurred between January 2019 and March 2021.Outcome measures included phenotypic dimensions defined from confirmatory factor analysis relating to positive symptoms, negative symptoms of diminished expressivity, negative symptoms of motivation and pleasure, disorganized symptoms, and current cognitive ability. Exposure measures included PRSs for schizophrenia, bipolar disorder, major depression, attention-deficit/hyperactivity disorder, autism spectrum disorder, and intelligence.Of the 1220 study participants, 817 were men (67.0%). Participants' mean (SD) age at interview was 43.10 (12.74) years. Schizophrenia PRS was associated with increased disorganized symptom dimension scores in both a 5-factor model (β = 0.14; 95% CI, 0.07-0.22; P = 2.80 × 10-4) and a 3-factor model across all samples (β = 0.10; 95% CI, 0.05-0.15; P = 2.80 × 10-4). Current cognitive ability was associated with genetic liability to schizophrenia (β = -0.11; 95% CI, -0.19 to -0.04; P = 1.63 × 10-3) and intelligence (β = 0.23; 95% CI, 0.16-0.30; P = 1.52 × 10-10). After controlling for estimated premorbid IQ, current cognitive performance was associated with schizophrenia PRS (β = -0.08; 95% CI, -0.14 to -0.02; P = 8.50 × 10-3) but not intelligence PRS.The findings of this study suggest that genetic liability for schizophrenia is associated with higher disorganized dimension scores but not other symptom dimensions. Cognitive performance in schizophrenia appears to reflect distinct contributions from genetic liabilities to both intelligence and schizophrenia.
A pooled analysis of response to selective RET inhibitors among patients with medullary thyroid cancer with M918T versus non-M918T RET mutations.
Authors: Janice Kim, Diana Bradford, Somak Chatterjee, Pallavi Shruti Mishra-Kalyani, Yuan-Li Shen, Julia A. Beaver, Harpreet Singh
Journal: Journal of Clinical Oncology (2021)

6078 Background: Medullary thyroid cancer (MTC) accounts for 1 to 2% of thyroid cancers in the United States; RET alterations occur in &gt;95% of hereditary and 50% of sporadic forms. Up to 80% of patients with sporadic MTC have somatic M918T RET mutations, which is associated with poor prognosis (1). The tyrosine kinase inhibitors (TKIs) cabozantinib and vandetanib are approved to treat patients with MTC regardless of RET status; however, retrospective analyses have suggested that there may be greater benefit in patients with M918T mutations (1,2). Newly approved therapies selpercatinib and pralsetinib, developed for patients with RET mutations, have demonstrated higher response rates than previous first line therapies. In this analysis, we examine the differences in overall response rate (ORR) between patients with MTC with RET M918T non- RET M918T mutations. Methods: An analysis of ORR in patients with MTC with RET M918T mutations with non-M918T mutations was conducted using the efficacy populations used to support the approvals of pralsetinib and selpercatinib using the following groups: Patients who received prior cabozantinib or vandetanib (referred to as “previously treated”). Patients with no prior cabozantinib or vandetanib (“TKI naïve”). All patients regardless of prior therapy. Results: Exploratory analysis of ORR of pooled population of Selpercatinib and Pralsetinib in patients with MTC with RET M918T mutations and non-M918T mutations. 1 Prior vandetanib or cabozantinib. 2 No prior vandetanib or cabozantinib. Two groups of patients were analyzed ( RET M918T mutation and RET non-M918T mutation), with subgroups with respect to prior treatment. Among all patients regardless of prior therapy, the ORR was similar between M918T non-M918T groups. Among previously treated patients, the ORR was lower in the M918T group vs. the non-M918T group, while in the TKI naïve group the ORR was higher in the M918T groups vs the non-M918T group although the 95% CIs overlap in both comparisons. Conclusions: There were no major differences in ORR among mutational subtypes in patients with MTC treated with RET inhibitors, regardless of prior therapy. ORR was similar between patients with M918T and non-M918T mutations. Additional experience in ongoing clinical studies may provide additional data regarding responses across specific mutation types. References: 1.Sherman SI et al “Correlative analyses of RET and RAS mutations in a phase 3 trial of cabozantinib...” Cancer. 2016;122(24):3856-3864. 2.Wells SA Jr et al “Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer...” J Clin Oncol. 2012;30(2):134-41.[Table: see text]
Engineering aluminum hydroxyphosphate nanoparticles with well-controlled surface property to enhance humoral immune responses as vaccine adjuvants
Authors: Zhihui Liang, Yun Yang, Ge Yu, Haoru Zhu, Xinyu Xia, Chen Chen, Duo Fu, Min Li, Gang Cheng, Changying Xue, Li Shi, Hao Zeng, Bingbing Sun
Journal: Biomaterials (2021)
Bone metastatic burden as a predictor of survival benefit from prostate radiotherapy in newly-diagnosed metastatic prostate cancer
Authors: A Ali, AP Hoyle, CC Parker, CD Brawley, A Cook, C Amos, J Calvert, D Hassan, Mason, G Attard, Mkb Parmar, M Sydes, ND James, NW Clarke, Stampede investigators
Journal: JAMA Oncology (2021)

Importance:  Prostate radiotherapy (RT) improves survival in men with low-burden metastatic prostate cancer. However, owing to the dichotomized nature of metastatic burden criteria, it is not clear how this benefit varies with bone metastasis counts and metastatic site.

Objective:  To evaluate the association of bone metastasis count and location with survival benefit from prostate RT.

Design, Setting, and Participants:  This exploratory analysis of treatment outcomes based on metastatic site and extent as determined by conventional imaging (computed tomography/magnetic resonance imaging and bone scan) evaluated patients with newly diagnosed metastatic prostate cancer randomized within the STAMPEDE trial’s metastasis M1 RT comparison. The association of baseline bone metastasis counts with overall survival (OS) and failure-free survival (FFS) was assessed using a multivariable fractional polynomial interaction procedure. Further analysis was conducted in subgroups.

Interventions:  Patients were randomized to receive either standard of care (androgen deprivation therapy with or without docetaxel) or standard of care and prostate RT.

Main Outcomes and Measures : The primary outcomes were OS and FFS.

Results : A total of 1939 of 2061 men were included (median [interquartile range] age, 68 [63-73] years); 1732 (89%) had bone metastases. Bone metastasis counts were associated with OS and FFS benefit from prostate RT. Survival benefit decreased continuously as the number of bone metastases increased, with benefit most pronounced up to 3 bone metastases. A plot of estimated treatment effect indicated that the upper 95% CI crossed the line of equivalence (hazard ratio [HR], 1) above 3 bone metastases without a detectable change point. Further analysis based on subgroups showed that the magnitude of benefit from the addition of prostate RT was greater in patients with low metastatic burden with only nonregional lymph nodes (M1a) or 3 or fewer bone metastases without visceral metastasis (HR for OS, 0.62; 95% CI, 0.46-0.83; HR for FFS, 0.57; 95% CI, 0.47-0.70) than among patients with 4 or more bone metastases or any visceral/other metastasis (HR for OS, 1.08; 95% CI, 0.91-1.28; interaction P = .003; HR for FFS, 0.87; 95% CI, 0.76-0.99; interaction P = .002).

Conclusions and Relevance:  In this exploratory analysis of a randomized clinical trial, bone metastasis count and metastasis location based on conventional imaging were associated with OS and FFS benefit from prostate RT in M1 disease.
Cisplatin versus carboplatin for the treatment of limited-stage small cell lung cancer (LS-SCLC).
Authors: Ibrahim Azar, Adam Austin, Seongho Kim, Hyejeong Jang, Malini Surapaneni, Daniel Kurtz, Omid Yazdanpanah, Amit Chopra, Syed Mehdi, Hirva Mamdani
Journal: Journal of Clinical Oncology (2021)

8565 Background: Standard of care therapy for LS- SCLC is concurrent chemo-radiation (CRT) with a platinum-etoposide backbone. Cisplatin is traditionally the preferred platinum agent in the curative intent setting. Data comparing the efficacy of the less toxic carboplatin to cisplatin in LS-SCLC are lacking. Methods: Data from the National VA Cancer Cube were collected. Pathologically confirmed cases of LS-SCLC that received concurrent CRT with platinum-based multiagent chemotherapy were included. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median overall survival (OS) and hazard ratio (HR), respectively. Survival curves were compared by a Wald test. Results: 801 LS-SCLC patients who received carboplatin-based therapy (Carbo-SCLC) and 1018 who cisplatin-based therapy (Cis-SCLC) were included in the analysis. Median OS with Carbo-SCLC and Cis-SCLC were 2.13 years (95% CI 1.97-2.31) and 2.24 years (95% CI 2.09-2.4), respectively (HR=1.04;95% CI, 0.94-1.16; p=0.46). Subset analysis showed similar median OS for Carbo-SCLC and Cis-SCLC in patients with ECOG-PS of 0, 1 and 2, as well as patients in their 50s, 60s and &gt;70. Multivariable regression analysis accounting for age and ECOG-PS shows a HR of 0.99 (95% CI 0.86-1.14; p=0.91). Conclusions: Concurrent CRT with carboplatin-etoposide was associated with similar OS compared to cisplatin-etoposide in LS-SCLC, irrespective of PS and age. Carboplatin’s advantageous toxicity profile and comparable OS indicate that it is an acceptable choice of platinum for LS- SCLC.[Table: see text]
A phase 2 study using ipilimumab, nivolumab, and trabectedin for previously untreated metastatic soft tissue sarcoma.
Authors: Erlinda Maria Gordon, Victoria S. Chua, Ted T. Kim, Neal Shiv Chawla, Don Arlen Brigham, Ishrat Bhuiyan, Mark Agulnik, Warren Allen Chow, Sant P. Chawla
Journal: Journal of Clinical Oncology (2021)

11562 Background: Sarcoma cells are most immunogenic earlier in the disease course and before treatment when the immune system can recognize and destroy them. Hypothesis: Immune checkpoint inhibitors would be most effective when given to previously untreated patients with metastatic soft tissue sarcoma. Methods: Eligible patients for this Phase 2 study are previously untreated patients ≥ 18 years of age with unresectable or metastatic soft tissue sarcoma, with measurable disease by RECIST v1.1. Immune checkpoint inhibitors Ipilimumab (I) and Nivolumab (N) were given with Trabectedin (T), a marine derived alkaloid with defined doses of I (1 mg/kg i.v. q 12 weeks), N (3 mg/kg i.v. q 2 weeks), and T (1.2 mg/m2 i.v. q 3 weeks). Primary endpoints: (1) Objective response rate by RECIST v1.1 via CT scan or MRI, (2) Progression-free survival (PFS): from first day of treatment to disease progression or death due to any cause; otherwise, it is censored at the time of last follow-up, and (3) Overall survival: from first day of treatment to death due to any cause; otherwise, it is censored at the time of last follow-up. Results: There were eighty-two evaluable subjects, having completed the first cycle of I, N, and T and have had a CT or MRI scan at the 6-week follow-up period. Best Overall Response by RECIST v1.1 = 7 CR (2 surgical CR), 9 PR, 54 SD, and 12 PD. Disease control rate was 85.4%. The median PFS was &gt;6.4 (range: 0-32) months; 6-month PFS rate: 57.3%. The median OS was &gt;12.0 (0-38) months; 6-month OS rate: 78.8%. Safety analysis: The most common Grade 3 TRAEs include increased ALT (26), anemia (11), increased AST (9), and fatigue (8). Common Grade 4 TRAEs include thrombocytopenia (2), increased AST (2), increased ALT (2), and increased CPK (2). There was one Grade 5 TRAE of rhabdomyolysis (1). Conclusions: Taken together, these results suggest that first-line combinatorial therapy with I, N, and T are (1) synergistic, and (2) may be equal or superior to, and safer than, standard first line therapy for advanced/metastatic soft tissue sarcoma. Clinical trial information: NCT03138161.