tbuckley/cabot-search huggingface dataset:
Fibroageing: An ageing pathological feature driven by dysregulated extracellular matrix-cell mechanobiology
Authors: Moisés Selman, Annie Pardo
Journal: Ageing Research Reviews (2021)

Ageing is a multifactorial biological process leading to a progressive decline of physiological functions. The process of ageing includes numerous changes in the cells and the interactions between cell-cell and cell-microenvironment remaining as a critical risk factor for the development of chronic degenerative diseases. Systemic inflammation, known as inflammageing, increases as a consequence of ageing contributing to age-related morbidities. But also, persistent and uncontrolled activation of fibrotic pathways, with excessive accumulation of extracellular matrix (ECM) and organ dysfunction is markedly more frequent in the elderly. In this context, we introduce here the concept of Fibroageing, that is, the propensity to develop tissue fibrosis associated with ageing, and propose that ECM is a key player underlying this process. During ageing, molecules of the ECM become damaged through many modifications including glycation, crosslinking, and accumulation, leading to matrix stiffness which intensifies ageing-associated alterations. We provide a framework with some mechanistic hypotheses proposing that stiff ECM, in addition to the well-known activation of fibrotic positive feedback loops, affect several of the hallmarks of ageing, such as cell senescence and mitochondrial dysfunction, and in this context, is a key mechanism and a driver thread of Fibroageing.
Flow redesign to improve prostate cancer access and care at the public healthcare system in Sao Jose dos Campos, Brazil.
Authors: Carlos Frederico Pinto, Danilo Stanzani, Elitania Pontes, Stela Maris Coelho, Margarete Correa, Joana Benjamin, Messias Borges Silva
Journal: Journal of Clinical Oncology (2021)

e13595 Background: Prostate cancer is the second most common cancer diagnosis in São José dos Campos (SJC) and the sixth cause of cancer mortality. Access to early diagnosis and treatment is one big challenge in the local public healthcare system (Sistema Único de Saude) due limited resources. Between 2018 and 2020 the healthcare public system of SJC redesigned the access flow for diagnosis and prostate cancer care in SJC is a mid-sized city (720,000 hab.) in Sao Paulo state, Brazil. Methods: The local SUS was designed to provide access to all patients with elevated PSA (&gt;4.00µg) to a urologist for further evaluation and subsequent reevaluation if needed. This process created long queues and median time to access the few overburdened specialists available to over a year (410 days median), risking significant disease progression and stage upgrade. The flow redesign was done using lean and queue theory techniques and involved basically a new Fast Track to patients with PSA &gt; 10.0µg with age between 50 and 79, considering the probability of 67% chance of prostate cancer (Catalona, et al. NEJM 1991; 324: 1156-61). Patients were referred from the primary care doctor straight forward to a biopsy and then to a medical oncologist, that would recommend further treatment, including a urologist evaluation. Patients with PSA between 4 and 10 would keep regular access to urology. The aim was to guarantee access to specialist up to 60 days from the first PSA &gt; 4.0µg. Results: From April 2019 to September 2020, 277 patients (PSA &gt; 10.0µg) were submitted to a biopsy through the Fast Track; 150 were positive (54,2%) for prostate cancer; and 72% with Gleason score 7 or higher. The diagnosis of prostate cancer from 2017 to 2020 increased over 300% (from 93 to 283), and access to treatment in less than 60 days increased from 15 to 140 patients in 2020. Patient with PSA &gt; 4.0µg access to urology in less than 60 days also increased dramatically by eliminating several medical appointments and unneeded process steps (Table). Conclusions: The process redesign for patients with elevated PSA was able to provide access to care &lt; 60 days for more than 80% of patients with elevated PSA or positive for prostate cancer by splitting high risk and low risk patients and using alternative flows to reduce urology overloaded agenda. Access to Urology for patients with PSA &gt;4.00 &lt; 10.00µg (not in Fast Track).[Table: see text]
Cardiovascular toxicities associated with ibrutinib in elderly patients.
Authors: Jason Yudiono, Hormozan Sorooshian
Journal: Journal of Clinical Oncology (2021)

e15061 Background: Ibrutinib is as a first line treatment option for chronic lymphocytic leukemia/small lymphocytic lymphoma and Waldenström’s macroglobulinemia. It is also FDA approved as a subsequent therapy for mantle cell lymphoma, marginal zone lymphoma, and chronic graft versus host disease. Cardiovascular (CV) toxicities, such as atrial fibrillation (afib), are some of the most common reasons for modifying ibrutinib therapy and tend to occur within the first few months of initiation. There is currently no FDA approved recommendation to reduce the dose of ibrutinib in the elderly, despite the greater incidence of afib in this patient population. It is unclear if this increased incidence leads to subsequent treatment modification in the elderly. Thus, further review of CV toxicities amongst Kaiser Permanente members may provide evidence to offer a reduced starting dose of ibrutinib in the elderly. Methods: This retrospective, multi-center study evaluated patients who started ibrutinib between January 1, 2014 and January 1, 2020 at an FDA approved dose per indication. Patient charts were reviewed from the time of treatment initiation up to one year of treatment or death, whichever came first. Data such as demographic information, diagnosis, adverse events, and ibrutinib treatment modifications were collected from chart review. The primary objective of this study was to determine if elderly (70 years or older) patients starting ibrutinib experienced a greater incidence of CV toxicities resulting in treatment modification and/or death. CV toxicities were only included if they occurred within the first year after starting ibrutinib. Results: Of the 50 patients included in this study, 23 (46%) patients initiated ibrutinib at an elderly age (70 years or older). Three (11.1%) non-elderly and two (8.7%) elderly patients underwent treatment modifications due to CV toxicities (p=0.78). Three additional patients experienced CV toxicities without further treatment modifications. Two (one per patient group) patients had already suspended ibrutinib for hepatic and/or hematological toxicities when they experienced afib. One non-elderly patient was hospitalized for afib but continued ibrutinib as originally prescribed. Conclusions: This study did not detect a significant difference in CV toxicities between elderly and non-elderly patients. Cardiac arrhythmia rates appeared slightly higher than those reported in clinical trials, but this may be due to the smaller sample size of this study. At this time, further evidence is needed to support a lower starting dose for elderly patients on ibrutinib.
Syndrome of inappropriate antidiuretic hormone secretion and hypothalamic hypocortisolism in neuromyelitis optica
Authors: Charidimos Tsagkas, Silke Schäfer, Annette Baumgartner, Jannis Müller, Tim Sinnecker, Matthias Mehling, Jan Gerrit van der Stouwe, Susan Felder, Anneza Panagiotou, Eliska Potlukova, Bettina Winzeler, Marleen Carina Scholz, Katharina Timper, Kristine Blackham, Christian H Nickel, Mirjam Christ-Crain, Roland Bingisser, Philippe Lyrer, Ludwig Kappos, Özgür Yaldizli
Journal: The Lancet (2021)
The effect of primary tumor location on second- or later-line treatment with anti-EGFR antibodies in patients with metastatic colorectal cancer: A single-center cohort study.
Authors: Anita Archwamety, Naravat Poungvarin, Charuwan Akewanlop, Krittiya Korphaisarn
Journal: Journal of Clinical Oncology (2021)

3541 Background: The guideline recommends anti-EGFR monoclonal antibodies (anti-EGFR Ab) as first-line treatment only for patients with left-sided RAS wild type (RASwt) metastatic colorectal cancer (mCRC). However, there are no recommendations on tumor sidedness in subsequent lines. This study aimed to evaluate the effect of primary tumor location on second- or later-line treatment outcomes in patients with KRASwt mCRC. Methods: Medical records of patients diagnosed with mCRC at Siriraj Hospital between 2008 and 2019 were retrospectively reviewed. Patients with KRASwt who received anti-EGFR Ab in second- or later-line treatment were included. The impact of tumor sidedness on progression-free survival (PFS) was determined using the Kaplan-Meier method and compared using the log-rank test. Results: Of 671 patients who had data on KRAS analysis, 396 patients (59%) had KRASwt. Of these, 210 patients received anti-EGFR Ab in second- or later-line treatment. Twenty-nine percent of patients (60 out of 210) had extended RAS analysis. Thirty patients (14%) had right-sided tumors, while 180 patients (86%) had left-sided tumors. Sixty-nine percent of patients (146 of 210) were treated in the third line, while 19% and 12% were treated in the second and the fourth line, respectively. Single-agent irinotecan was the most commonly used chemotherapy backbone (92%). Patients with right-sided tumors had non-significantly inferior PFS compared with patients with left-sided tumors (median PFS was 4.7 months, 95% CI 0.8–8.7 vs. 6 months, 95% CI 4.6–7.3; p = 0.55). Subgroup analysis on the impact of primary tumor location showed no difference in PFS when stratified by treatment lines. Conclusions: This study demonstrated that tumor sidedness has no impact on treatment outcomes in patients treated with anti-EGFR Ab in second- or later-line treatment. Therefore, there is not enough evidence to use tumor sidedness for treatment selection in these settings. A multi-center retrospective study is ongoing.
Influence of first-line chemotherapy regimen on survival outcomes of patients with advanced urothelial carcinoma who receive second-line immunotherapy.
Authors: Benjamin Miron, Elizabeth A. Handorf, Kevin Zarrabi, Matthew R. Zibelman, Pooja Ghatalia, Fern Anari, Elizabeth R. Plimack, Daniel M. Geynisman
Journal: Journal of Clinical Oncology (2021)

4535 Background: Treatment of advanced urothelial carcinoma (mUC) has improved following approvals of PD-1/PD-L1 inhibitors. Platinum chemotherapy remains the standard-of-care in the first-line (1L). Cisplatin (Cis) regimens are accepted to be superior to carboplatin (Carbo) regimens for patients (pts) who are Cis-eligible. We sought to evaluate if differences in efficacy of 1L Cis vs. Carbo have meaningful impact on overall survival (OS) in the era of second-line (2L) immunotherapy (IO). Methods: We conducted a retrospective, observational cohort study to compare OS for pts treated with 1L Cis or Carbo combined with gemcitabine (Gem) followed by 2L IO using patient-level data from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Pts included were diagnosed with mUC between 9/1/2015 and 9/15/2020. 2L IO was defined as single-agent atezolizumab, avelumab, durvalumab, nivolumab, or pembrolizumab. OS was calculated from start of 1L and 2L therapy and compared using Kaplan-Meier curves. Time to 2L IO was calculated from start of 1L to start of IO. Adjusted OS was calculated using multivariable Cox regression models, adjusting for age, gender, race, ECOG performance status, primary site, prior cystectomy, smoking status, and year of diagnosis. Results: A total of 1882 pts were included, 924 (49.1%) received Gem/Cis and 958 (50.9%) received Gem/Carbo in 1L. A similar percentage of pts did not receive any 2L therapy following Gem/Cis (46.4%) or Gem/Carbo (46.0%). Our analysis focused on the 780 pts (41.4%) who received 2L IO—381 after Gem/Cis and 399 after Gem/Carbo. Median follow-up time for the group was 35 months (mo). Pts in the Gem/Cis cohort were younger, had better performance status and lower incidence of upper tract disease (Table). OS from start of 1L therapy was numerically longer in pts who received Gem/Cis compared to Gem/Carbo on unadjusted (median 18.0 v 16.2 mo, p = 0.06) and adjusted analyses (HR = 0.83, 95% CI 0.69-1.00, p = 0.055) but neither result was statistically significant. Time to 2L IO was longer for pts receiving Gem/Cis (6.5 mo) vs Gem/Carbo (5.5 mo, p = 0.008). Survival time on 2L IO did not differ significantly by 1L regimen (Gem/Cis 8.0 mo vs Gem/Carbo 8.2 mo p = 0.36). Conclusions: Real world data suggests that in pts with mUC who are able to receive second-line IO, the choice of first-line platinum chemotherapy may not provide a distinguishable OS benefit. Despite methodologic limitations of this data, a greater focus in discussions with patients on toxicity associated with cisplatin vs carboplatin may be warranted.[Table: see text]
Comprehensive genomic profiling analysis of HBV-infected hepatocellular carcinoma patients.
Authors: Xiaoliang Liu, Xiaohui Wang, Jianfei Yao, Shifu Chen, Yu Li
Journal: Journal of Clinical Oncology (2021)

e16180 Background: Hepatocellular carcinoma (HCC) is one of the leading causes of tumor-related death worldwide which is dominantly caused by chronic infection of hepatitis B virus (HBV) and hepatitis C virus (HCV). Recent studies have shown that immune checkpoint inhibitors may enter the first-line treatment of HCC. Comprehensive investigation of the genetic alterations and their correlation with microsatellite instability (MSI) and PD-L1 expression in HBV-infected HCC is helpful to determine the therapy strategy for patients. Methods: The genomic information of HCC patients was obtained from HapLab database. HaploX 605- gene panel was performed to analyze the genomic data of patients. PD-L1 expression was detected by immunochemistry. Results: A total of 349 mutations were found by analyzing the genomic profiles of 115 HBV-infected HCC patients. The frequently mutated genes included TP53 (63%), TERT (27%), CTNNB1 (16%), CSMD3 (15%), LRP1B (14%), AXIN1 (13%), CDKN2A (13%), KIT (13%), MDM4 (12%) and CCND1 (12%). Besides, 279 mutations were identified by analyzing the genomic profiles of 82 HCC patients without HBV-infection. Mutation frequencies for several genes were relatively higher in the HBV-positive patients than that in HBV-negative HCC patients, including TP53 (63% versus 39%), CCND1 (12% versus 5%), RB1(12% versus 4%) and BRCA2 (11% versus 4%). The proportion of MSI-H/L in HBV-infection patients were higher than that in HBV-negative ones (7.83% versus 4.88%). Notably, the proportion of high PD-L1 expression in patients with HBV-infection was 40.57% (43/106), while it was 28.95% (22/76) in patients without HBV-infection. Conclusions: These results highlighted a potential impact of viral infection on the mutational signatures in hepatocarcinogenesis. The PD-L1 expression status and MSI were closely related to HBV-infected HCC. These results may contribute to understanding the mechanism of HBV-infected HCC and the selection of therapy for relative patients.
KEYNOTE-B15/EV-304: Randomized phase 3 study of perioperative enfortumab vedotin plus pembrolizumab versus chemotherapy in cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC).
Authors: Christopher J. Hoimes, Jens Bedke, Yohann Loriot, Hiroyuki Nishiyama, Xiao Fang, Ritesh S. Kataria, Blanca Homet Moreno, Matt D. Galsky
Journal: Journal of Clinical Oncology (2021)

TPS4587 Background: Standard of care for MIBC is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection (RC+PLND); however, in time, patients experience disease recurrence or progression. Enfortumab vedotin (EV) is a Nectin-4–directed antibody–drug conjugate comprising a fully human, monoclonal antibody and the microtubule-disrupting agent monomethyl auristatin E. The KEYNOTE-869/EV-103 phase 1/2 study (NCT03288545) showed that the PD-1 inhibitor pembrolizumab + EV had encouraging antitumor activity and acceptable safety as first-line treatment for cisplatin-ineligible patients with metastatic urothelial cancer (Rosenberg JE et al. J Clin Oncol. 2020;38[15 suppl]:5044). Based on these data, investigating EV + pembrolizumab in an earlier setting such as MIBC and in a perioperative fashion is appropriate. KEYNOTE-B15/EV-304 (NCT04700124) is a randomized, open-label, phase 3 study to evaluate the efficacy and safety of perioperative EV + pembrolizumab versus neoadjuvant chemotherapy using gemcitabine/cisplatin in cisplatin-eligible patients with MIBC. Methods: Patients must have histologically confirmed urothelial cancer/MIBC (clinical stage T2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology, have nonmetastatic disease (≥N2 disease and/or M1 excluded) confirmed by blinded independent central review (BICR), have ECOG PS 0 or 1, and not have previously received systemic therapy for MIBC. Approximately 784 patients will be randomly assigned 1:1 to receive either 4 cycles of neoadjuvant EV + pembrolizumab followed by 5 cycles of adjuvant EV + 13 cycles of adjuvant pembrolizumab after RC+PLND or 4 cycles of neoadjuvant cisplatin-based chemotherapy followed by observation after RC+PLND. Neoadjuvant and adjuvant pembrolizumab 200 mg + EV 1.25 mg/kg will be administered intravenously every 3 weeks (Q3W), and neoadjuvant chemotherapy will consist of gemcitabine 1000 mg/m 2 + cisplatin 70 mg/m 2 Q3W. Randomization will be stratified by centrally determined (pathology or imaging) initial T and N stage (T2N0 or T3/T4aN0 or T1-T4aN1), PD-L1 combined positive score (CPS ≥10 or CPS &lt; 10), and geographic region (United States or Europe or most of world). Imaging (CT or MRI) will be performed ≤6 weeks before cystectomy and 6 weeks after cystectomy. After postcystectomy imaging, additional imaging will be performed Q12W up to the end of year 2 (week 96) and at discontinuation. In year 3 and beyond, imaging will be performed Q24W. Primary end points are pathological complete response and event-free survival by BICR. Secondary end points are overall survival, disease-free survival, pathological downstaging, and safety and tolerability. Clinical trial information: NCT04700124.
Mutational Burden before and after Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients with Acute Myeloid Leukemia (AML)
Authors: Aziz Nazha, Betty K. Hamilton, Mikkael A. Sekeres, Sudipto Mukherjee, Aaron T. Gerds, Rabi Hanna, Cassandra M. Hirsch, Teodora Kuzmanovic, Karam Al-Issa, Bartlomiej P. Przychodzen, Ronald Sobecks, Matt Kalaycio, Navneet S. Majhail, Jaroslaw P. Maciejewski
Journal: Blood (2017)
Abstract 11013: Predictive Role of Late Gadolinium Enhancement on Cardiac Magnetic Resonance in Hypertrophic Cardiomyopathy: An Updated Meta-Analysis
Authors: Jialu Yao, Yafeng Zhou, Xiangjun Yang, Xiaodong Qian
Journal: Circulation (2015)

Background: Myocardial fibrosis detected by late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) is currently used to predict adverse cardiovascular events in patients with hypertrophic cardiomyopathy (HCM). However, controversies remain about its prediction value of sudden cardiac death (SCD). Objective: The aim of this study was to perform an updated meta-analysis of the prediction value of late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) for future events and death in hypertrophic cardiomyopathy (HCM). Methods: We searched PubMed and Web of Science for clinical trials that investigated the prognosis indexes of LGE in HCM patients. The outcomes of interest comprised all-cause mortality, cardiac death, SCD, aborted SCD and heart failure death. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the role of LGE CMR in the risk stratification of HCM. Results: Seven studies were retrieved from 393 citations for the analysis, and in total, 3423 patients (mean age: 52.3 years; median follow up: 37.7 months) were included in the analysis. After synthesizing data, the meta-analysis showed that LGE by CMR was associated with SCD/Aborted SCD (OR=2.921, 95%CI=1.760-4.848; P&lt;0.001) and all cause mortality (OR=1.715, 95%CI=1.013-2.901; P=0.044), and showed a trend toward significance of predicting cardiac death (OR=2.174, 95%CI=1.000-4.727; P=0.05). However, we did not observe a correlation between LGE and heart failure death (OR=2.066, 95%CI=0.788-5.416; P=0.14). Conclusions: LGE by CMR exhibited a substantial prognostic value in SCD events prediction. Significant associations were found between LGE and SCD, and all cause mortality. Moreover, LGE displayed a trend toward significance on cardiac death but not on heart failure death. Myocardial fibrosis assessed by LGE is effective in SCD risk stratification in patients with HCM.
Aligned fibrin/functionalized self-assembling peptide interpenetrating nanofiber hydrogel presenting multi-cues promotes peripheral nerve functional recovery
Authors: Shuhui Yang, Jinjin Zhu, Changfeng Lu, Yi Chai, Zheng Cao, Jiaju Lu, Zhe Zhang, He Zhao, Yin-Yuan Huang, Shenglian Yao, Xiangdong Kong, Peixun Zhang, Xiumei Wang
Journal: Bioactive Materials (2021)

Nerve guidance conduits with hollow lumen fail to regenerate critical-sized peripheral nerve defects (15 mm in rats and 25 mm in humans), which can be improved by a beneficial intraluminal microenvironment. However, individual cues provided by intraluminal filling materials are inadequate to eliminate the functional gap between regenerated nerves and normal nerves. Herein, an aligned fibrin/functionalized self-assembling peptide (AFG/fSAP) interpenetrating nanofiber hydrogel that exerting synergistic topographical and biochemical cues for peripheral nerve regeneration is constructed via electrospinning and molecular self-assembly. The hydrogel possesses an aligned structure, high water content, appropriate mechanical properties and suitable biodegradation capabilities for nerve repair, which enhances the alignment and neurotrophin secretion of primary Schwann cells (SCs) in vitro, and successfully bridges a 15-mm sciatic nerve gap in rats in vivo. The rats transplanted with the AFG/fSAP hydrogel exhibit satisfactory morphological and functional recovery in myelinated nerve fibers and innervated muscles. The motor function recovery facilitated by the AFG/fSAP hydrogel is comparable with that of autografts. Moreover, the AFG/fSAP hydrogel upregulates the regeneration-associated gene expression and activates the PI3K/Akt and MAPK signaling pathways in the regenerated nerve. Altogether, the AFG/fSAP hydrogel represents a promising approach for peripheral nerve repair through an integration of structural guidance and biochemical stimulation.