tbuckley/cabot-search huggingface dataset:
Molecular correlates of clinical benefit in previously treated patients (pts) with <i>BRAF</i> V600E-mutant metastatic colorectal cancer (mCRC) from the BEACON study.
Authors: Scott Kopetz, Danielle A. Murphy, Jie Pu, Fortunato Ciardiello, Jayesh Desai, Axel Grothey, Eric Van Cutsem, Harpreet Singh Wasan, Rona Yaeger, Takayuki Yoshino, Amber C Donahue, Adele Golden, Ashwin Gollerkeri, Zhou Zhu, Josep Tabernero
Journal: Journal of Clinical Oncology (2021)

3513 Background: Encorafenib + binimetinib + cetuximab (enco/bini/cetux; triplet) and enco + cetux (doublet) regimens improved overall survival and objective response rate vs standard of care in pts with previously treated BRAF V600E-mutant mCRC in the randomized phase 3 BEACON study. To identify molecular correlates of clinical outcome, we performed molecular profiling in tumors from pts in the study. Methods: Baseline tumor samples were retrospectively analyzed by whole-exome sequencing (WES) and whole transcriptome sequencing (WTS) using ImmunoID NeXT (Personalis, Menlo Park, CA, USA). BRAF-mutant (BM) and consensus molecular subtypes (CMS) were determined using published classifiers. Pathway activities were evaluated with gene set variation analysis. Objective tumor response was evaluated according to each subtype. Additional association and interaction analyses between molecular features and clinical outcomes by treatments are ongoing and will be presented. Results: Baseline tumor samples were analyzed by WES and/or WTS from 527 of 665 (79.2%) randomized pts. The biomarker analyses set is representative of the total pt population and had similar clinical outcomes. Of the 460 pts analyzed by WTS (165/224 [73.7%] in the triplet arm, 146/220 [66.4%] in the doublet arm, and 149/221 [67.4%] in the control arm), 84.6% were classified as either CMS1 (n = 225) or CMS4 (n = 164). The proportion of pts classified as BM1 was 32.2% (n = 148) and the majority (84.5%) of these were CMS4, whereas many of those classified as BM2 (67.8%, n = 312) were CMS1 (64.7%). In the BM1 and CMS4 tumors, expression of inflammatory response and epithelial mesenchymal transition genes were elevated, and expression of cell cycle genes was reduced. The response rate in pts with CMS4 and/or BM1 tumors was higher in the triplet arm (CMS4: 33.3% [95% CI: 21.7–46.7]; BM1: 33.3% [95% CI: 21.4–47.1]) compared with the doublet arm (CMS4: 19.2% [95% CI: 9.6–32.5]; BM1: 14.9% [95% CI: 6.2–28.3]). Conclusions: Molecular characteristics and biological properties observed in BRAF V600E-mutant mCRC suggest that a subset of pts with specific molecular features may derive greater clinical benefit from triplet than doublet therapy. Additionally, these findings support the utility of gaining further understanding of the biological landscape in BRAF-mutant mCRC to enable potential hypotheses for pt selection to improve clinical outcome in future studies. Clinical trial information: NCT02928224.
HGG-11. LEPTOMENINGEAL DISEASE AND TUMOR DISSEMINATION ALONG CSF PATHWAYS IN A MURINE DIPG MODEL: IMPLICATIONS FOR STUDY OF THE TUMOR-CSF-EPENDYMAL MICROENVIRONMENT
Authors: Shelei Pan, Dezhuang Ye, Yimei Yue, Lihua Yang, Christopher Pacia, Sonika Dahiya, David Limbrick, Joshua Rubin, Hong Chen, Jennifer Strahle
Journal: Neuro-Oncology (2021)

Abstract Background Leptomeningeal disease and hydrocephalus are present in up to 30% of patients with diffuse intrinsic pontine glioma (DIPG), however there are no animal models of cerebrospinal fluid (CSF) dissemination. As the tumor-CSF-ependymal microenvironment may play an important role in tumor pathogenesis, we identified characteristics of the Nestin-tumor virus A (Nestin-Tva) genetically engineered mouse model (GEMM) that make it ideal to study the interaction of tumor cells with the CSF and its associated pathways with implications for the development of treatment approaches to address CSF dissemination in DIPG. Methods A Nestin-TVa model of DIPG utilizing the three most common DIPG genetic alterations (H3.3K27M, PDGF-B, p53) was used for this study. All animals underwent MR imaging and a subset underwent histopathologic analysis with H&amp;E and beta-IV tubulin. Results Tumor dissemination within the CSF pathways (ventricles, leptomeninges) was present in 76% (25/33) of animals, with invasion of the choroid plexus, disruption of the ciliated ependyma and regional subependymal fluid accumulation. Ventricular enlargement consistent with hydrocephalus was present in 94% (31/33). Ventricle volume correlated with region specific transependymal CSF flow (periventricular T2 signal), localized anterior to the lateral ventricles. Subependymal tumor cells were also present subjacent to the 4th ventricle in a post-mortem human specimen. Conclusions This is the first study to report CSF pathway tumor dissemination an animal model of DIPG and is representative of CSF dissemination seen clinically. Understanding the CSF-tumor-ependymal microenvironment has significant implications for treatment of DIPG through targeting mechanisms of tumor spread within the CSF pathways.
KMT2C as a positive predictor for treatment of immune checkpoint inhibitor and correlation with immune infiltrates in colorectal cancer (CRC).
Authors: Ling Zhang, Jianping Song, Yiting Wang, Yaoxu Chen
Journal: Journal of Clinical Oncology (2021)

3538 Background: Lysine Methyltransferase 2C (KMT2C), a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family, possesses histone methylation activity and is involved in transcriptional co-activation. Present study has shown that KMT2C is positive correlated with better efficacy of Immune checkpoint inhibitor (ICI) in NSCLC. However, the role of KMT2C in treatment of ICI on colorectal cancer (CRC) is still unknown. Methods: NGS (Next Generation Sequencing) was performed on 1628 CRC patients. TMB of these patients were analyzed. A public accessible cohort (Samstein2018) with data from 130 CRC patients were used to investigate the correlation between KMT2C mutation and efficacy of ICI. WES and survival data of TCGA database (1099 CRC) was used to analyze prognostic effect of KMT2C mutation. Furthermore, CIBERSORT was used to analyze the tumor-infiltrating immune cells present in COAD（colon adenocarcinoma, 404 patients）from TCGA database. Results: Among 1628 CRC patient, 230(14.1%) had KMT2C mutation. TMB was positive correlated with KMT2C mutation (Mut vs. WT, 30.75 vs. 7.26 mut/Mb, p &lt; 0.0001). The Samstein2018 cohort showed that KMT2C mutations (15.4%, 20/130) were significantly associated with better OS (Mut vs. WT, 11.5 vs. 7.5 month, HR = 0.29; 95% CI, 0.1-0.81; P = 0.012), and a higher TMB was also observed in KMT2C-Mut group (p = 1.98e-08). In TCGA, no association between KMT2C mutation and OS was observed (P = 0.23), suggesting that was not prognostic factor. Moreover, we analyzed the relationship between KMT2C mutation and immune cell infiltration through CRC TCGA database. The results showed, in COAD, KMT2C mutation was positively correlated with the abundance of CD8+ T cells (P = 0.0014), B cells (P = 0.014), M1 macrophages (P = 0.015), neutrophil (P = 0.0019) and NK cells (P = 0.043), and negatively correlated with Treg cells (p = 0.0063). Conclusions: KMT2C has an impact on the immune microenvironment and may be used as a potential positive predictor for treatment of ICI on CRC patients. The role of KMT2C in immunotherapy warrant further studies.
Genomic profiling of biliary tract cancers to reveal clinically actionable genes and therapeutic biomarkers.
Authors: Yang Shao, Qiuxiang Ou, Zhenhao Fang, Rui Liu, Hua Bao, Xue Wu
Journal: Journal of Clinical Oncology (2021)

e16187 Background: Bile tract cancers are genetically and clinically heterogenous with a poor prognosis. Identifying novel biomarkers for targeted therapy is required to improve the clinical outcome of bile tract cancer patients. Methods: Tumor tissue samples of 482 Chinese biliary tract cancer (BTC) patients were genetically profiled using targeted next generation sequencing. Tumor mutation burden (TMB) was calculated by counting all nonsynonymous mutations per megabase of coding sequences. The R package ReactomePA was used in pathway enrichment analysis. Genomic instability was characterized by an in-house developed NGS-based Homologous Recombination Deficiency (HRD) panel and a HRD score was an unweighted sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST) scores. Results: The BTC cohort consisted of 135 gallbladder cancer (GBC), 73 intrahepatic cholangiocarcinoma (iCCA), 18 distal cholangiocarcinoma (dCCA), 14 perihilar cholangiocarcinoma (pCCA), while the remaining 242 BTC patients of no specific subtype information. Most frequently mutated genes included TP53 (56%), KRAS (25%), ARID1A (17%), SMAD4 (11%), and CDKN2A (10%) . A preliminary pathway analysis revealed that mutations of DNA damage repair (DDR) pathway genes were enriched in the cohort ( p&lt; 1e-10), accounting for over 70% of the patients, particularly in homologous recombination repair (HRR), Fanconi anemia (FA), mismatch repair (MMR), and base excision repair (BER) genes. More specifically, approximately 50% of the cohort carried at least one mutation of the HRR genes (43%) or MMR genes (14%). Patients with impaired MMR had increased microsatellite instability status (MSI) comparing to those with wildtype MMR (33% vs. 3.1%, p&lt; 0.0001), and patients harboring HRR mutations demonstrated elevated genomic instability than those without such mutations (median HRD: 18 vs.14, p &lt; 0.05), indicative of potential response to poly (ADP-ribose) polymerase (PARP) inhibitors and other DNA-damage agents. Furthermore, high TMB was found to be highly correlated with DDR gene alterations ( p =0.004). In addition, we observed higher mutation frequencies of BRCA1/2 genes (including somatic and germline) in GBCs in contrast to other BTC subtypes. Conclusions: We herein reported the genomic features of 482 Chinese BTC samples and highlighted the role of DDR pathways including HRR and MMR. These findings could be useful to establish treatment and diagnostic strategies for BTC patients based on genetic information.
Systemic Lupus Erythematosus
Authors: Mara Feingold-Link
Journal: Annals of Internal Medicine (2018)

Ad Libitum20 March 2018Systemic Lupus ErythematosusMara Feingold-LinkMara Feingold-LinkBoston, Massachusetts (M.F.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M17-2553 Audio Reading - “Systemic Lupus Erythematosus” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "Systemic Lupus Erythematosus," by M. Feingold-Link. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Her dusky feline form prowlsshadowed streets when sun recedes,placing noiseless paws alongthe plastered joints of pavement slabs.Twilight spreads his heavy blanketover urban roofs, and towering metallic beastsslice through its plum folds.These skyscraper tips, stretched endlessly towardmoonlight, appear pale in its chilled glow.She rubs both whiskered cheeksagainst graffitied alley wall, applyingdouble the pheromone strandsfor territory's signpost:her scent below a spray-paint signature,hastily scrawled.that throbbing sack of blood.... Author, Article, and Disclosure InformationAffiliations: Boston, Massachusetts (M.F.)Current Author Address: Mara Feingold-Link; e-mail, [email protected]com. PreviousarticleNextarticle Advertisement Audio Reading - “Systemic Lupus Erythematosus” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "Systemic Lupus Erythematosus," by M. Feingold-Link. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 20 March 2018Volume 168, Issue 6Page: 452KeywordsBloodKidneysLupus erythematosusPharynxRibsTongue ePublished: 20 March 2018 Issue Published: 20 March 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
“No problem” health-related quality of life (HRQoL) in patients treated with regorafenib (Reg) for relapsed metastatic colorectal cancer (mCRC).
Authors: Yun Su, Helene Ostojic, Savina Jaeger
Journal: Journal of Clinical Oncology (2021)

e15593 Background: REG has been shown to improve survival and delay time to quality of life deterioration over placebo (PBO) in two large randomized, double-blind, placebo-controlled multi-center phase III trials CORRECT and CONCUR for the treatment of relapsed mCRC. We report on findings of the five-dimensions of HRQoL in the two trials. Methods: The five key dimensions of HRQoL were captured in the CORRECT and CONCUR trials using EuroQol 5-Dimension questionnaire 3-level version (EQ-5D-3L). The 5 dimensions are mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels: no problems, some problems, severe problems. We calculated the proportion of intent-to-treat (ITT) patients reporting “no problems” (NP) in each of the 5 dimensions by cycle and arm of treatment in the two trials. Results: Detailed descriptions of the trials have been reported previously. Due to space, data below focuses on CORRECT. ITT patients included 760 total in the CORRECT trial, 2:1 randomized to receive REG (N=505) and PBO (N=255). At baseline (BL), 95% of the ITT patients completed the questionnaire (Table), and patients reported the highest percentage of NP in self-care (87%) and lowest in pain/discomfort (35%). EQ-5D completion rates decline with each cycle of treatment, as are the percentages reporting NP in each dimension. The declines however appeared much more rapid for PBO than for REG. Both completion rate and percentages of NP were somewhat higher for PBO than for REG at BL, this continued until only cycle 2 and reversed completely from cycle 3 onward showing increasingly diminished proportion of those on PBO able to complete the questionnaire and reporting NP in each dimension. The differences between arms became larger with each cycle beginning cycle 3. Findings were similar for CONCUR (not shown). Conclusions: REG appeared to enable patients to maintain their mobility, self-care, usual activity, being pain-free and anxiety-free as well as their ability to complete the EQ-5D questionnaire, at much higher rates than PBO. Those whose EQ-5D were no longer available were likely poor performers that discontinued due to progression, death, toxicity or other unfavorable factors associated with their treatments. For PBO, toxicity was unlikely the reason. These findings suggest REG has a positive impact on quality of survival, as well as on length of survival. Further confirmatory analyses are needed.[Table: see text]
Efficacy and safety of the oral Janus kinase inhibitor baricitinib in the treatment of adults with alopecia areata: Phase 2 results from a randomized controlled study
Authors: Brett King, Justin Ko, Seth Forman, Manabu Ohyama, Natasha Mesinkovska, Guanglei Yu, Jill McCollam, Margaret Gamalo, Jonathan Janes, Emily Edson-Heredia, Katrin Holzwarth, Yves Dutronc
Journal: Journal of the American Academy of Dermatology (2021)

BackgroundThere are no treatments approved by the Food and Drug Administration for alopecia areata.ObjectiveTo evaluate the efficacy and safety of baricitinib in patients with ≥50% scalp hair loss in a phase 2 study of adults with alopecia areata (BRAVE-AA1).MethodsPatients were randomized 1:1:1:1 to receive placebo or baricitinib 1 mg, 2 mg, or 4 mg once daily. Two consecutive interim analyses were performed after all patients completed weeks 12 and 36 or had discontinued treatment prior to these time points. The primary endpoint was the proportion of patients achieving a Severity of Alopecia Tool (SALT) score ≤20 at week 36. Logistic regression was used with nonresponder imputation for missing data.ResultsA total of 110 patients were randomized (placebo, 28; baricitinib 1-mg, 28; 2-mg, 27; 4-mg, 27). The baricitinib 1-mg dose was dropped after the first interim analysis based on lower SALT30 response rate. At week 36, the proportion of patients achieving a SALT score of ≤20 was significantly greater in baricitinib 2-mg (33.3%, P = .016) and 4-mg (51.9%, P = .001) groups versus placebo (3.6%). Baricitinib was well tolerated with no new safety findings.LimitationsSmall sample size limits generalizability of results.ConclusionThese results support the efficacy and safety of baricitinib in patients with ≥50% scalp hair loss. There are no treatments approved by the Food and Drug Administration for alopecia areata. To evaluate the efficacy and safety of baricitinib in patients with ≥50% scalp hair loss in a phase 2 study of adults with alopecia areata (BRAVE-AA1). Patients were randomized 1:1:1:1 to receive placebo or baricitinib 1 mg, 2 mg, or 4 mg once daily. Two consecutive interim analyses were performed after all patients completed weeks 12 and 36 or had discontinued treatment prior to these time points. The primary endpoint was the proportion of patients achieving a Severity of Alopecia Tool (SALT) score ≤20 at week 36. Logistic regression was used with nonresponder imputation for missing data. A total of 110 patients were randomized (placebo, 28; baricitinib 1-mg, 28; 2-mg, 27; 4-mg, 27). The baricitinib 1-mg dose was dropped after the first interim analysis based on lower SALT30 response rate. At week 36, the proportion of patients achieving a SALT score of ≤20 was significantly greater in baricitinib 2-mg (33.3%, P = .016) and 4-mg (51.9%, P = .001) groups versus placebo (3.6%). Baricitinib was well tolerated with no new safety findings. Small sample size limits generalizability of results. These results support the efficacy and safety of baricitinib in patients with ≥50% scalp hair loss.
Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies
Authors: Qibin Qi, Jun Li, Bing Yu, Jee-Young Moon, Jin C Chai, Jordi Merino, Jie Hu, Miguel Ruiz-Canela, Casey Rebholz, Zheng Wang, Mykhaylo Usyk, Guo-Chong Chen, Bianca C Porneala, Wenshuang Wang, Ngoc Quynh Nguyen, Elena V Feofanova, Megan L Grove, Thomas J Wang, Robert E Gerszten, Josée Dupuis, Jordi Salas-Salvadó, Wei Bao, David L Perkins, Martha L Daviglus, Bharat Thyagarajan, Jianwen Cai, Tao Wang, JoAnn E Manson, Miguel A Martínez-González, Elizabeth Selvin, Kathryn M Rexrode, Clary B Clish, Frank B Hu, James B Meigs, Rob Knight, Robert D Burk, Eric Boerwinkle, Robert C Kaplan
Journal: Gut (2021)

Tryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota.
静脈血栓塞栓症患者の臨床的特徴と転帰における性差-COMMAND VTE登録から-
Authors: Yoshikawa Yusuke, Yamashita Yugo, Morimoto Takeshi, Amano Hidewo, Takase Toru, Hiramori Seiichi, Kim Kitae, Oi Maki, Akao Masaharu, Kobayashi Yohei, Toyofuku Mamoru, Izumi Toshiaki, Tada Tomohisa, Chen Po-Min, Murata Koichiro, Tsuyuki Yoshiaki, Saga Syunsuke, Sasa Tomoki, Sakamoto Jiro, Kinoshita Minako, Togi Kiyonori, Mabuchi Hiroshi, Takabayashi Kensuke, Shiomi Hiroki, Kato Takao, Makiyama Takeru, Ono Koh, Kimura Takeshi
Journal: Circulation (2019)
PI3Kγδ inhibitor combined radiation enhances the antitumor immune effect of PD-1 blockade in syngenic triple negative breast cancer models.
Authors: In Ah Kim, Min Guk Han, Bum Sup Jang, Mi Hyun Kang
Journal: Journal of Clinical Oncology (2021)

e13041 Background: Breast cancer is generally viewed as immunologically cold, imposing an immune-suppressive tumor microenvironment (TME) and responding poorly to lone immune checkpoint blockade (ICB). As an adjunct to ICB, radiation therapy (RT) holds promise in terms of in situ tumor vaccination effect, although it is known to promote immune suppression, increasing regulatory T cells (T reg ), myeloid-derived suppressor cells (MDSCs), and M2 tumor-associated macrophages (TAMs). It was our contention that combined use of RT and a PI3Kγδ inhibitor to combat immune suppression might enhance the efficacy of ICB. Methods: Murine breast cancer cells (4T1) were grown in both immune-competent BALB/c mice, humanized patient-derived xenograft (PDX) were established, and both were irradiated by 3 fractions of 24 Gy. A PD-1 blockade (10 mg/kg) and a PI3Kγδ inhibitor (IPI145; 15 mg/kg) were then administered every other day for 2 weeks. Tumors from humanized PDX was sequenced to identify immune-related pathways and to profile infiltrated immune cells. Transcriptomic and clinical data were acquired from The Cancer Genome Atlas (TCGA) pan-cancer cohort, and the deconvolution algorithm was used to profile immune cellular distributions at certain levels (high vs. low) of PIK3Cand PIK3CD expression. Results: In the immune-competent syngenic 4T1 murine tumor model, PD-1 blockade alone led to tumor hyperprogression, whereas a three-pronged strategy of PI3Kγδ inhibitor, RT, and PD-1 blockade significantly delayed primary tumor growth, boosted abscopal effect, and improved animal survival. According to FACS analysis, RT significantly increased not only CD8+cytotoxic T-cell fractions but also immune-suppressive T reg cells, MDSCs, and M2 TAMs. However, PI3Kγδ inhibitor significantly lowered proportions of T reg , MDSCs, and M2 TAMs, achieving dramatic gains in splenic, nodal, and tumor CD8+ T-cell populations after triple combination therapy. There were significantly decreased tumor expressions of p-AKT, PD-L1, and HIF1α by PI3Kγδ inhibition. Triple combination therapy significantly delayed primary tumor growth in humanized PDX model as well and analyses of RNA sequencing data of humanized PDX samples showed decreased immune suppressive pathways with decreased and M2 macrophage and increased CD8+ T-cell by triple combination therapy. In the TCGA pan-cancer cohort, high T reg /CD8+T-cell and M2/M1 TAM ratios and poor overall patient survival was associated with high PIK3CG (PI3Kγ) or PIK3CD (PI3Kδ) gene expression. Conclusions: These findings collectively indicate that PI3Kγ and PI3Kδ are clinically relevant targets in an immunosuppressive TME. Combining PI3Kγδ inhibitor, RT, and PD-1 blockade may thus be a viable approach, helping to overcome the therapeutic resistance of immunologically cold tumors such as breast cancer.