tbuckley/cabot-search huggingface dataset:
The impact of skeletal muscle loss for hepatocellular carcinoma treated with lenvatinib.
Authors: Mao Okada, Hiroyuki Nakanishi, Masayuki Kurosaki, Kento Inada, Sakura Kirino, Koji Yamashita, Shuhei Sekiguchi, Yuka Hayakawa, Leona Osawa, Wan Wang, Mayu Higuchi, Kenta Takaura, Chiaki Maeyashiki, Shun Kaneko, Nobuharu Tamaki, Yutaka Yasui, Kaoru Tsuchiya, Jun Itakura, Yuka Takahashi, Namiki Izumi
Journal: Journal of Clinical Oncology (2020)

493 Background: Many previous reports have shown that skeletal muscle loss (SML) is one of the prognostic factors for hepatocellular carcinoma (HCC) patients treated with sorafenib. However, there are few reports about the impact of SML for the HCC patients treated with lenvatinib. Therefore, we evaluated the relation between SML and overall survival (OS) of HCC patients treated with lenvatinib (LEN). Methods: We retrospectively analyzed 50 HCC patients treated with LEN from April 2018 to February 2019. We included 36 patients who continued LEN more than 8 weeks and evaluated CT scans before treatment and after 8 weeks. Skeletal muscle area was measured on axial image at the level of the third lumber vertebra (L3) using sliceOmatic. Skeletal Mass Index (SMI) was calculated by dividing the muscle area (㎠) with square of height (㎡). The definition of myopenia is based on the guideline described by the Japan Society of Hepatology (42㎠/㎡ in men and 38 ㎠/㎡ in women). ΔSMI is a chronological change of SMI for 8 weeks. We calculated decreasing rate of ΔSMI. We evaluated the relation between chronological change of SMI and OS. Results: The patients with myopenia at baseline were 12 (33.3 %). The decreasing rate of ΔSMI at 8 weeks was -2.57 % [-5.9, 0.2]. SMI had decreased in 27 patients (75 %) for 8 weeks. There was no significant difference between OS and baseline myopenia (p = 0.2), ALBI grade (p = 0.2), BCLC stage (p = 0.5), up to 7 in or out (p = 0.35), previous TKI treatment (p = 0.15), metastasis (p = 0.91), or vascular invasion (p = 0.12). However, the patients who had decreased SMI had significantly poor prognosis (p = 0.028). In backgrounds, there was no significant difference between patients with or without decreasing of ΔSMI, such as baseline myopenia (p = 0.7), ALBI grade (p = 0.4), BCLC stage (p = 1.0), Child Pugh score (p = 0.8), age (p = 0.6), sex (p = 0.3), up to7 in or out (p = 1.0), previous TKI treatment (p = 0.3), and relative dose intensity at 4 weeks (p = 0.9). Conclusions: There was no significant correlation between baseline myopenia and OS. However, chronological decreasing of SMI for 8 weeks was a prognostic factor of HCC patients treated with LEN. Therefore, monitoring and preventing of decreasing of skeletal muscle mass may be important.
A unique <i>ex vivo</i> tumor model: 3D cocultured system with cancer and stromal cells including blood microvessels.
Authors: Yuki Takahashi, Kei Tsukamoto, Rii Morimura, Isana Nada, Yuki Shimizu, Ryohei Katayama, Eiji Shinozaki, Satoshi Nagayama, Michiya Matsusaki, Shiro Kitano, Kensei Yamaguchi, Naoya Fujita
Journal: Journal of Clinical Oncology (2020)

211 Background: Importance of interaction between cancer and stromal cells has been widely recognized in tumor progression and tolerance against treatment. Although 2D culture and spheroid consisting only cancer cells still remains the preferred platform for most laboratory preclinical studies while these provide only limited information about tumor microenvironment. In order to mimic the patient tumor tissue, ex vivo model which recaptures the tumor microenvironment is required. Methods: Layered 3D stromal tissues comprising microvascular network were produced by culturing fibroblasts and endothelial cells coated with the extra-cellular matrix (ECM) and natural polysaccharide, namely collagen and heparin. The layered 3D stromal tissues and co-cultured tumor were morphologically evaluated by HE stain, immunohistochemistry and immunofluorescence (IF). Their gene expression and secretome profile were characterized by RNA-sequencing and bio-plex suspension array technologies. Furthermore, drug sensitivity assay were conducted using popular colorectal cancer cell lines, and patient-derived cell lines (PDCs) established in the laboratory of JFCR. Remaining cancer cells post drug treatment were quantified by IF and imaging analysis. Results: The 3D stromal tissues including CD31 positive luminal structure were multi-layered (approximately 20 layers), and the tendency that dense microvascular network was formed nearby cancer cells was observed. In comparison with 2D culture or 3D mono-cultured spheroid model, decreased drug sensitivities were represented in the layered 3D co-cultured model. Omics profiles difference among models suggest that our 3D model has some similarity to in vivo tumor. Conclusions: We developed the layered 3D stromal tissue culture system including blood micro-vessels. Drug sensitivity in the co-cultured tumors may reflect the response of cancer cells in in vivo. Our unique 3D ex vivo model appear to be a valuable tool for drug evaluation, and thus testing approved and/or developing compounds with patient-derived cells would enable better prediction their efficacy.
The clinical prognostic significance of lymphovascular invasion in gastric cancer.
Authors: Hirohito Fujikawa, Takanobu Yamada, Keisuke Koumori, Hayato Watanabe, Kazuki Kano, Yota Shimoda, Yasushi Rino, Munetaka Masuda, Takashi Ogata, Takashi Oshima
Journal: Journal of Clinical Oncology (2020)

428 Background: Lymphovascular invasion (LVI) of malignant tumor is regarded as an initial state of metastasis, including the lymph nodes, and therefore may be a prognostic factor in many malignancies. However, in gastric cancer, according to the current Japanese guidelines, LVI is not clinically useful information, except for in predicting the curability of endoscopic resection, and its clinicopathological characteristics and biological behavior remain unclear. The present study explored the histopathological significance of LVI in gastric cancer and clarified its correlation with the prognosis. Methods: From January 2000 to December 2013, a total of 2090 cases of gastric cancer undergoing radical gastrectomy were enrolled in this study. The correlation of LVI and other histopathological factors with the prognosis was evaluated. Lymphatic vessel invasion (ly) and venous invasion (v) were diagnosed followed the current Japanese classification. LVI positivity (LVIP) and LVI negativity (LVIN) were defined as the presence of lymphatic vessel and/or venous invasion and the absence of LVI, respectively. Results: LVIP was noted in 894 cases (42.8%). The age (p &lt; 0.001), depth of tumor invasion (pT) (p &lt; 0.001), lymph node metastasis (pN) (p &lt; 0.001), and maximum tumor size (p &lt; 0.001) were significantly correlated with the presence of LVI. A multivariate analysis showed that pT (p &lt; 0.001), pN (p &lt; 0.001), and LVI (p = 0.03) were independent risk factors for the prognosis of all patients. On analyzing the significance of every T factor and N factor for the overall survival of LVIP and LVIN cases, no significant difference was recognized in the prognosis among all pT1 patients and pT2-4 patients without nodal metastasis. However, in pT2-4 patients with nodal metastasis, a significant difference was revealed, and the 5-year overall survival rates in LVIP cases were lower than those in LVIN (60.9% [95% confidence interval: 56.3-65.3] vs. 76.7% [95% confidence interval 65.2-84.8], p = 0.005). Conclusions: LVI in gastric cancer is an independent prognostic factor, and its effect tends to be particularly strong in advanced cancer with lymph node metastasis. These patients may therefore require more effective adjuvant therapy.
Economic impacts of care by high-volume providers for noncurative esophagogastric cancer: A population-based analysis.
Authors: Julie Hallet, Nicole Look Hong, Victoria Zuk, Laura Davis, Vaibhav Gupta, Craig Earle, Nicole Mittmann, Natalie Coburn
Journal: Journal of Clinical Oncology (2020)

339 Background: Esophagogastric cancer (EGC) is one of the deadliest and costliest malignancies to treat. Care by high-volume providers can provide better outcomes for patients with EGC. Cost implications of volume-based cancer care are unclear. We examined the cost-effectiveness of care by high-volume medical oncology providers for non-curative management of EGC. Methods: We conducted a population-based cohort study of non-curative EGC over 2005-2017 by linking administrative healthcare datasets. High-volume was defined as &gt;11 patients/provider/year. Healthcare costs ($USD/patient/month-survived) were computed from diagnosis to death or end of follow-up from the perspective of the healthcare system using validated costing algorithms. Multivariable quantile regression examined the association between care by high-volume providers and costs. Sensitivity analyses were conducted by varying costing horizons and high-volume definitions. Results: Among 7,011 non-curative EGC patients, median overall survival was superior with care by high-volume providers with 7.0 (IQR: 3.3-13.3) compared to 5.9 (IQR: 2.6-12.1) months (p &lt; 0.001) for low-volume providers. Median costs/patient/month-lived were lower for high-volume providers ($5,518 vs. $5,911; p &lt; 0.001), owing to lower inpatient acute care costs, despite higher medication-associated and radiotherapy costs. Care by high-volume providers was independently associated with a reduction of $599 per patient/month-lived (95% confidence interval: -966 to -331) compared to low-volume providers. The incremental cost-effectiveness ratio was -393. Care by high-volume providers remained the dominant strategy when varying the high-volume definition and the costing time horizon. Conclusions: Care by high-volume providers for non-curative EGC is associated with superior survival and lower healthcare costs, indicating a dominant strategy that may provide an opportunity to improve cost-effectiveness of care delivery.
Validating enhancer signature classifications (ESCs) in pancreatic neuroendocrine tumors (PNETs).
Authors: Vincent Quoc-Huy Trinh, Chanjuan Shi, Jordan Berlin, Satya Das
Journal: Journal of Clinical Oncology (2020)

627 Background: Predicting recurrence risk (RR) for resected (res) PNET patients (pts) is challenging using existing pathologic criteria. Better predictive models to tailor surveillance for individual pts are needed. A recent study suggests expression patterns of the transcriptomic/epigenomic enhancers ARX and PDX1 may predict RR. In this study, distant metastases occurred almost exclusively in ARX+/PDX1- tumors. Our primary objective was to validate ESCs within our institutional cohort. Methods: We used a tissue microarray generated from res localized PNETs at Vanderbilt University Medical Center (VUMC) between 2002-2012. Clinical, pathological, and outcomes data were extracted from records. Immunohistochemistry was performed with PDX1 by Novus and ARX by Sigma. Patients were grouped as double-positives (DP), ARX+/PDX1-, ARX-/PDX1+ and double-negatives (DN). Time-dependent ROC analysis was performed in R (v3.6.1; survivalROC v1.0.3) to determine ARX and PDX1 positivity. Comparative analyses were performed in SPSS v23.0 (Kruskal-Wallis, Freeman-Halton exact test, Log-rank). Primary outcomes were progression-free survival (PFS) and cancer-specific survival (CSS). Results: 61 PNET specimens had adequate tissue for analysis. Table shows PFS plus CSS data by ESC distribution. Pts with ARX+ (DP &amp; ARX+/PDX1-) tumors were younger (P=0.015) and possessed larger tumors (P=0.065). Pts with ARX+ tumors demonstrated shorter PFS (log-rank P=0.006) and a trend toward lower CSS (log-rank P=0.09). Notably, pts with ARX-/PDX1+ and DN tumors had no deaths and only 1 progression event over a median follow-up period of 91 months (m). Conclusions: Building upon earlier data that ARX+ res PNETs are more likely to relapse, we demonstrate that pts with such tumors have diminished PFS and a trend toward diminished CSS. ESCs need prospective validation but carry the potential to guide surveillance for res PNET patients. [Table: see text]
Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility
Authors: C. Has, J.W. Bauer, C. Bodemer, M.C. Bolling, L. Bruckner‐Tuderman, A. Diem, J.‐D. Fine, A. Heagerty, A. Hovnanian, M.P. Marinkovich, A.E. Martinez, J.A. McGrath, C. Moss, D.F. Murrell, F. Palisson, A. Schwieger‐Briel, E. Sprecher, K. Tamai, J. Uitto, D.T. Woodley, G. Zambruno, J.E. Mellerio
Journal: British Journal of Dermatology (2020)

Several new genes and clinical subtypes have been identified since the publication in 2014 of the report of the last International Consensus Meeting on Epidermolysis Bullosa (EB). We sought to reclassify disorders with skin fragility, with a focus on EB, based on new clinical and molecular data. This was a consensus expert review. In this latest consensus report, we introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Other disorders with skin fragility, where blisters are a minor part of the clinical picture or are not seen because skin cleavage is very superficial, are classified as separate categories. These include peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility. Because of the common manifestation of skin fragility, these 'EB‐related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and genetic features of EB. What is already known about this topic? Epidermolysis bullosa (EB) is a group of genetic disorders with skin blistering. The last updated recommendations on diagnosis and classification were published in 2014. What does this study add? We introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Clinical and genetic aspects, genotype–phenotype correlations, disease‐modifying factors and natural history of EB are reviewed. Other disorders with skin fragility, e.g. peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility are classified as separate categories; these 'EB‐related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Linked Comment:Pope. Br J Dermatol 2020; 183:603.
Correction to: Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer
Authors: Martin P. Barr, Steven G. Gray, Kathy Gately, Emily Hams, Padraic G. Fallon, Anthony Mitchell Davies, Derek J. Richard, Graham P. Pidgeon, Kenneth J. O’Byrne
Journal: Molecular Cancer (2020)

Since the publication of this work [1] and in response to a recent query that was brought to our attention in relation to the Western Blot in Figure 1(C) for NP2, protein lysates prepared around the same time as those presented in the manuscript in question, were run by SDS-PAGE under similar experimental conditions and probed using the same primary antibodies to NP1 and NP2 that were used originally.
A phase II study of futibatinib (TAS-120) in patients (pts) with advanced (adv) solid tumors harboring fibroblast growth factor receptor (<i>FGFR)</i> genomic aberrations.
Authors: Antoine Hollebecque, Toshihiko Doi, Omar Saavedra, Osamu Takahashi, Helen He, Karim A. Benhadji, Kohei Shitara
Journal: Journal of Clinical Oncology (2020)

TPS470 Background: FGFR genomic aberrations are known to drive oncogenesis in multiple tumor types via FGFR signaling pathway dysregulation. Futibatinib is an oral, highly selective, irreversible FGFR1–4 inhibitor that has shown potent antiproliferative activity against FGFR-deregulated tumors of diverse tissue origins in preclinical studies. In a phase 1 dose-escalation/expansion study, futibatinib showed promising antitumor activity and tolerability in previously treated pts with tumors harboring FGFR aberrations. This phase 2 study was designed to evaluate the efficacy and safety of futibatinib in pts with tumors harboring FGFR aberrations. The study will enroll pts in multiple cohorts based on diagnosis and FGFR aberration status; cohorts enrolling pts with adv solid tumors are reported here. Methods: In this global, open-label, phase 2 study, pts (≥18 years; Eastern Cooperative Oncology Group performance status of 0 or 1) will be enrolled in cohort A (~60 pts with metastatic/locally adv solid tumors, except primary brain tumors or intrahepatic cholangiocarcinoma, harboring FGFR1–4 rearrangements and with disease progression after standard treatment) or cohort B (~35 pts with metastatic/locally adv gastric tumors harboring FGFR2 amplifications and with ≥2 prior therapies). Key exclusion criteria are clinically significant alterations in calcium–phosphorus homeostasis, ectopic mineralization/calcification, and prior FGFR inhibitor treatment. Pts will receive 20 mg futibatinib once daily in a continuous 28-day cycle until disease progression, unacceptable toxicity, or other discontinuation criteria are met. The primary endpoint is objective response rate (ORR) per independent central review. Secondary endpoints include ORR per investigator, disease control rate, duration of response, progression-free survival, overall survival, and safety. The anticipated start date is in April 2020.
The treatment strategy of the second-line chemotherapy for metastatic colorectal cancer (mCRC) patients (pts) with early progression in the first-line chemotherapy with bevacizumab (BEV), BEV beyond progression (BBP), or non-BBP.
Authors: Takeshi Kawakami, Shun Yamamoto, Seiichiro Mitani, Taito Esaki, Yasushi Tsuji, Naoki Izawa, Kentaro Kawakami, Yoshiyuki Yamamoto, Akitaka Makiyama, Kentaro Yamazaki, Toshiki Masuishi, Takako Eguchi Nakajima, Hiroyuki Okuda, Toshikazu Moriwaki, Narikazu Boku
Journal: Journal of Clinical Oncology (2020)

113 Background: BBP has been recognized as one of the standard 2nd-line treatment strategy for pts with mCRC based on the ML18147 trial. However, this trial excluded pts with disease progression &lt; 3 months in the 1st-line BEV-containing chemotherapy. Methods: The subjects were mCRC pts who received the 2nd-line chemotherapy after experiencing disease progression &lt; 100 days in the 1st-line BEV-containing chemotherapy between Apr 2010 and Dec 2016. This multi-institutional retrospective study compared the efficacy and safety between the 2nd-line chemotherapy with BEV (BBP) and without BEV (non-BBP), adjusting ECOG PS, WBC, ALP, number of metastatic sites, RAS status, and sidedness using Cox proportional hazard model. Results: 61 pts were evaluated. Patients' backgrounds were numerically different between BBP (n = 36) and non-BBP (n = 25), such as PS (0-1/2≤/unknown: 89/8/3 and 56/40/4%) and RASstatus (wild/mutant/unknown: 28/56/16 and 76/16/8%). There were no significant differences in age (median: 59 and 57), sex (male/female: 53/47 and 32/68%), tumor location (right/left: 44/56 and 40/60%), disease status (stage IV/recurrence: 67/33 and 84/16%), number of metastatic sites (1/2≤: 33/67 and 20/80%), the 1st-line regimens (oxaliplatin-based/irinotecan-based: 83/17 and 96/4%) between two arms. The 2nd-line chemotherapy regimens with EGFR antibody-containing/cytotoxic alone were 64/36% in non-BBP, respectively. The response rates were 5.9 and 8.7% in BBP and non-BBP. Median PFS were 3.7 and 2.8 months (HR 0.83, 95%CI 0.49-1.41, p = 0.486; adjusted HR 0.97, 95%CI 0.48-1.96, p = 0.932), respectively. The proportions of pts who received subsequent chemotherapy were 58 and 32% (p = 0.068). Median OS were 7.6 and 5.4 months (HR 0.70, 95%CI 0.41-1.19, p = 0.193; adjusted HR 0.65, 95%CI 0.34-1.25, p = 0.195). Common grade 3-4 adverse events (AEs) were neutropenia (11/24%) and anemia (3/16%), and other AEs were similar between two arms. Conclusions: The 2nd-line chemotherapy for pts with early progression in the 1st-line BEV-containing chemotherapy showed poor outcomes regardless of strategy.
Chikungunya infection: de-linking replication from symptomatology reveals the central role of muscle
Authors: Anne Moscona
Journal: Journal of Clinical Investigation (2020)

Chikungunya virus (CHIKV) is an emerging arbovirus, endemic in many parts of the world, that is spread by travelers and adapts to new mosquito vectors that live in temperate climates. CHIKV replicates in many host tissues and initially causes a self-limiting febrile illness similar to dengue. However, in 30%–40% of cases, CHIKV also causes long-term painful and debilitating muscle and joint pain, the pathogenesis of which remains unknown. In this issue of the JCI, Lentscher et al. engineered a skeletal muscle–restricted CHIKV to show that while musculoskeletal disease requires viral replication in affected muscle, muscular pathology is mediated by host immunological factors. These findings de-link viral replication and disease symptoms, illuminate the virus-host interplay in CHIKV symptomatology, and raise the possibility that immune modulation is a therapeutic option. The results also highlight possible solutions to existing vaccine barriers and provide insights that may apply to other viral diseases.
Cuprizone-induced oligodendrocyte loss and demyelination impairs recording performance of chronically implanted neural interfaces
Authors: Steven M. Wellman, Kelly Guzman, Kevin C. Stieger, Lauren E. Brink, Sadhana Sridhar, Mitchell T. Dubaniewicz, Lehong Li, Franca Cambi, Takashi D.Y. Kozai
Journal: Biomaterials (2020)
Interleukin-17A Serves a Priming Role in Autoimmunity by Recruiting IL-1β-Producing Myeloid Cells that Promote Pathogenic T Cells
Authors: Aoife M. McGinley, Caroline E. Sutton, Sarah C. Edwards, Charlotte M. Leane, Joseph DeCourcey, Ana Teijeiro, John A. Hamilton, Louis Boon, Nabil Djouder, Kingston H.G. Mills
Journal: Immunity (2020)
Circulating tumor DNA-based decision for adjuvant treatment in colon cancer stage II evaluation: (CIRCULATE-trial) AIO-KRK-0217.
Authors: Gunnar Folprecht, Anke Reinacher-Schick, Andrea Tannapfel, Juergen Weitz, Thibaud Kossler, Lukas Weiss, Daniela Ellen Aust, Nikolas von Bubnoff, Michael Kramer, Christian Thiede
Journal: Journal of Clinical Oncology (2020)

TPS273 Background: The benefit of adjuvant chemotherapy in stage II colon cancer is unclear, and clear clinical or molecular marker are not available for decision making. Recently, postoperative circulating tumour (ct)DNA has been demonstrated to be prognostic in colorectal cancer and other tumours. Methods: For the CIRCULATE trial we enrol patients (pts) with colon cancer stage II in Germany (AIO), Austria (ABCSG) and Switzerland (SAKK). Microsatellite stable pts are screened after resection of the primary by analysing the tumour block with panel sequencing and measuring patient specific mutations in the postoperative plasma sample. MSI-H pts are excluded from the trial. ctDNA positive (ctDNApos) pts are randomised (2:1) to receive adjuvant capecitabine based chemotherapy or no chemotherapy. Oxaliplatin can be added according to investigator’s choice. ctDNA negative (ctDNAneg) pts are randomised (1:4) to be followed-up within the study or to receive standard follow-up outside the trial. Pts in the follow-up group and their investigators are blinded for the ctDNA result. The primary aim is to compare the disease free survival (DFS) in ctDNApos pts randomised to chemotherapy or to follow-up. Secondary aims are to compare the overall survival (OS) in ctDNApos pts with or without chemo, to compare the DFS and OS in ctDNApos vs. ctDNAneg follow-up pts, to describe the DFS and OS in ctDNAneg pts, to describe the location of recurrences/metastases according ctDNA status, the ctDNA clearance rate and time to ctDNA negativity during adjuvant chemotherapy, further translational endpoints, and safety. To demonstrate a treatment effect in the ctDNA group with a hazard ratio of 0.617 (3 year DFS rate of 42.5 % vs. 25 %), 231 ctDNApos will be randomised (approx. 2310 pts in total) from 2019 – 2022. Clinical trial information: NCT04089631.