tbuckley/cabot-search huggingface dataset:
Advances in Revascularization for Peripheral Artery Disease: Revascularization in PAD
Authors: Joshua A. Beckman, Peter A. Schneider, Michael S. Conte
Journal: Circulation Research (2021)

Effective revascularization of the patient with peripheral artery disease is about more than the procedure. The approach to the patient with symptom-limiting intermittent claudication or limb-threatening ischemia begins with understanding the population at risk and variation in clinical presentation. The urgency of revascularization varies significantly by presentation; from patients with intermittent claudication who should undergo structured exercise rehabilitation before revascularization (if needed) to those with acute limb ischemia, a medical emergency, who require revascularization within hours. Recent years have seen the rapid development of new tools including wires, catheters, drug-eluting technology, specialized balloons, and biomimetic stents. Open surgical bypass remains an important option for those with advanced disease. The strategy and techniques employed vary by clinical presentation, lesion location, and lesion severity. There is limited level 1 evidence to guide practice, but factors that determine technical success and anatomic durability are largely understood and incorporated into decision-making. Following revascularization, medical therapy to reduce adverse limb outcomes and a surveillance plan should be put in place. There are many hurdles to overcome to improve the efficacy of lower extremity revascularization, such as restenosis, calcification, microvascular disease, silent embolization, and tools for perfusion assessment. This review highlights the current state of revascularization in peripheral artery disease with an eye toward technologies at the cusp, which may significantly impact current practice.
Improving patient and caregiver understanding of risks and benefits of immunotherapy for melanoma or lung cancer.
Authors: Laura A Petrillo, Ashley Zhou, Angelo E. Volandes, Ryan J. Sullivan, Areej El-Jawahri, Joseph A. Greer, Jennifer S. Temel
Journal: Journal of Clinical Oncology (2021)

TPS6596 Background: Immune checkpoint inhibitors (ICI) extend survival for patients with advanced cancer, particularly melanoma and lung cancer, though responses are heterogeneous and treatment may be complicated by immune-related adverse events that are important for patients and their caregivers to recognize. The aim of this trial is to evaluate the feasibility and preliminary efficacy of an educational video and question prompt list (QPL) in improving patients’ and caregivers’ understanding of what to expect from immunotherapy. Methods: In this randomized controlled trial of a novel educational intervention to improve immunotherapy knowledge, we will enroll 140 adult patients with advanced melanoma or lung cancer (small cell or non-small cell) who have a plan to initiate therapy with an ICI and their caregivers. Patients assigned to the intervention will receive a link to a video about the risks and benefits of ICI treatment developed by the study team as well as an ICI-focused QPL that includes questions about the goal and likelihood of benefit of ICIs. We will enroll the first ten patients in an open pilot and we will refine the intervention and study procedures based on pilot findings. We will randomize the remaining 130 patients to receive either the intervention or a usual care control. Randomization will be carried out using the permuted block approach with stratification by cancer type, and patient-caregiver dyads will be assigned to the same study arm. Participants on both arms will complete surveys at enrollment (baseline), 72 hours post-enrollment, and 6 weeks post-enrollment. The primary outcome of the study is feasibility of intervention delivery, defined as 70% of approached patients enrolling in the trial and 80% of enrolled patients watching the video, reviewing the QPL and completing the first assessment. We will also evaluate the preliminary efficacy of the intervention in 1) improving patient and caregiver knowledge, measured by a survey of knowledge questions that we developed and previously pilot tested with a sample of 105 patients; 2) enhancing patient-clinician communication, assessed by evaluating the number of questions patients asked in audio-recorded visits with their oncology clinicians after reviewing the QPL; and 3) reducing anxiety, measured by the State and Trait Anxiety Index. We will assess change in knowledge scores and anxiety from baseline to 72 hours post-enrollment and 6-weeks post-enrollment using the analysis of covariance model, adjusting for baseline scores and relevant covariates. The number of questions asked by patients and caregivers will be assessed by coding transcripts of oncology visits and comparing between arms using the negative binomial model. Study accrual to the open pilot phase began in February 2021. Current enrollment: n = 5. Clinical trial information: 04670445.
Spatial analysis of the T-cell repertoire in non-small cell lung cancer reveals a clonality gradient from the tumor to the distal lung.
Authors: Meredith Frank, Fenglei Yu, Alexandre Reuben, Muyun Peng, Gao Yang, Xiaofeng Chen, Liyan Ji, Pansong Li, Xuefeng Xia, Yan-Fang Guan, Jianjun Zhang
Journal: Journal of Clinical Oncology (2021)

e20544 Background: The immunomodulatory effects of the tumor microenvironment (TME) significantly impact the T cell repertoire resulting in different anti-tumor immune responses. Previous work by our group and others has highlighted intratumor heterogeneity in T cell clonality, spatial distribution, and diversity, as well as infiltration of bystander T cells in early-stage non-small cell lung cancer (NSCLC). However, little is known about how the TME impacts the T cell repertoire in distant or surrounding adjacent uninvolved lung tissue. Methods: We investigated the interplay between tumor and surrounding lung tissues by investigating the T cell repertoire at the tumor site, tumor margin, and 1cm, 2cm, 5cm, and 10cm away from the tumor as well as in peripheral blood in 21 NSCLC patients with a total of 123 samples undergoing T cell receptor (TCR) CDR3b sequencing using the Geneplus technology. Differences in regional T cell repertoires were analyzed based on clonality, diversity, and Morisita Overlap Index (MOI). GLIPH was utilized to identify motifs associated with pathogen specificity in each region. Results: Clonality was lowest within the tumor and progressively increases from tumor margin to tumor adjacent lung toward distant lung with “hot spot” regions of T cell expansion located in adjacent lung tissue proximal to the tumor, namely 2cm away (p = 0.0025). Dominant T cell populations were better conserved between the tumor margins and “hot regions” of high clonality compared to the tumors (p = 0.0009) highlighting the differences between these environments and possible T cell exclusion in immunosuppressive TME. GLIPH analysis revealed an inverse correlation between clonality and the proportion of pathogen-associated TCR motifs (r = -0.83, p = 0.0195). Interestingly, tumor tissue contained the highest proportion of predicted pathogen TCRs whereas regions of high clonality contained the lowest (p &lt; 0.0001), suggesting the antigen-independent nature of T cell trafficking. Conclusions: Combined, these results highlight isolated pockets of T cell expansion in the lungs outside the tumor and potential immune evasion mechanisms in NSCLC.
Multicenter, randomized phase II study of neoadjuvant pembrolizumab plus chemotherapy and chemoradiotherapy in esophageal adenocarcinoma (EAC).
Authors: Manish A. Shah, Khaldoun Almhanna, Syma Iqbal, Prashant Thakkar, Bryan J. Schneider, Rhonda Yantiss, Yiru Wu, Emma Futamura, Jeffrey L. Port, Cathy Spinelli, Sandipto Sarkar, Paul J. Christos, Gagandeep Brar, Doron Betel, Nicholas J. Sanfilippo, Nasser K. Altorki
Journal: Journal of Clinical Oncology (2021)

4005 Background: Recent transformative studies in the treatment of EAC support adjuvant nivolumab for patients with residual disease following neoadjuvant chemoradiotherapy (CRT) (Checkmate 577) and pembrolizumab (P) with chemotherapy in untreated metastatic disease (Keynote 590). We hypothesized that pre-operative P combined with CRT can further improve outcomes in patients with locally advanced EAC. Methods: Patients with cT3-4Nx or T2N1 M0 EAC or gastroesophageal junction (GEJ) adenocarcinoma eligible for curative surgery were randomized (1:1) to receive either full-dose paclitaxel (T)/ carboplatin (C) or T/C + P induction therapy. All patients then received CRT with weekly T/C, RT 41.4Gy in 23 fractions, and P every 3 weeks. Following resection, patients received P for one year. The primary endpoint is rate of major pathologic response (MPR), defined as pathologic complete response or near complete response ( &lt; 10% residual cancer), with 80% power and 0.1 one-sided significance level to detect the difference between a MPR proportion of 30% (historical control) and an alternative hypothesis of 47% (with preoperative P). Tissue was collected for tumor immune microenvironment (TIME) analysis including bulk and single cell RNA(scRNA) expression analysis, DNA sequencing, and flow cytometry. Results: From 8/4/17 to 10/26/20, 40 patients were enrolled: median age 68 [38-81], male 32, esophagus/GEJ type I (n = 16), GEJ II/III (n = 24). CRT was well tolerated, with no grade 3-4 adverse events attributed to P. Notable toxicity included grade 3-4 pneumonitis (13%), anastomotic leak (13%), infection (35%). In 31 evaluable patients to date, the MPR rate was 50.0% (95% CI, 32.7%-67.3%). 1-yr disease free survival was 100% for patients with MPR vs. 31.8% without MPR, p = 0.002. Esophageal/GEJ type I cancers had a significantly higher MPR rate when compared with GEJ type II/III (76.9% vs 37.5%, p = 0.03). scRNA seq on &gt; 100,000 tumor cells revealed EAC/GEJ type I had higher infiltration of activated dendritic cells (p = 0.12), whereas GEJ tumors have significantly higher infiltration of activated B cells (p = 0.02). Conclusions: The addition of P to preoperative CRT for EAC is safe and associated with a significantly higher MPR rate compared to historical data. We found MPR to be significantly enriched in EAC/GEJ type I tumors compared with GEJ II/III, associated with important differences in the baseline tumor immune microenvironment. Clinical trial information: NCT02998268.
Targeting E3 Ubiquitin Ligase WWP1 Prevents Cardiac Hypertrophy Through Destabilizing DVL2 via Inhibition of K27-Linked Ubiquitination
Authors: Dingsheng Zhao, Guohui Zhong, Jianwei Li, Junjie Pan, Yinlong Zhao, Hailin Song, Weijia Sun, Xiaoyan Jin, Yuheng Li, Ruikai Du, Jielin Nie, Tong Liu, Junmeng Zheng, Yixin Jia, Zifan Liu, Wei Liu, Xinxin Yuan, Zizhong Liu, Jinping Song, Guanghan Kan, Youyou Li, Caizhi Liu, Xingcheng Gao, Wenjuan Xing, Yan-Zhong Chang, Yingxian Li, Shukuan Ling
Journal: Circulation (2021)

Background: Without adequate treatment, pathological cardiac hypertrophy induced by sustained pressure overload eventually leads to heart failure. WWP1 (WW domain–containing E3 ubiquitin protein ligase 1) is an important regulator of aging-related pathologies, including cancer and cardiovascular diseases. However, the role of WWP1 in pressure overload–induced cardiac remodeling and heart failure is yet to be determined. Methods: To examine the correlation of WWP1 with hypertrophy, we analyzed WWP1 expression in patients with heart failure and mice subjected to transverse aortic constriction (TAC) by Western blotting and immunohistochemical staining. TAC surgery was performed on WWP1 knockout mice to assess the role of WWP1 in cardiac hypertrophy, heart function was examined by echocardiography, and related cellular and molecular markers were examined. Mass spectrometry and coimmunoprecipitation assays were conducted to identify the proteins that interacted with WWP1. Pulse-chase assay, ubiquitination assay, reporter gene assay, and an in vivo mouse model via AAV9 (adeno-associated virus serotype 9) were used to explore the mechanisms by which WWP1 regulates cardiac remodeling. AAV9 carrying cardiac troponin T (cTnT) promoter–driven small hairpin RNA targeting WWP1 (AAV9-cTnT-shWWP1) was administered to investigate its rescue role in TAC-induced cardiac dysfunction. Results: The WWP1 level was significantly increased in the hypertrophic hearts from patients with heart failure and mice subjected to TAC. The results of echocardiography and histology demonstrated that WWP1 knockout protected the heart from TAC-induced hypertrophy. There was a direct interaction between WWP1 and DVL2 (disheveled segment polarity protein 2). DVL2 was stabilized by WWP1-mediated K27-linked polyubiquitination. The role of WWP1 in pressure overload–induced cardiac hypertrophy was mediated by the DVL2/CaMKII/HDAC4/MEF2C signaling pathway. Therapeutic targeting WWP1 almost abolished TAC induced heart dysfunction, suggesting WWP1 as a potential target for treating cardiac hypertrophy and failure. Conclusions: We identified WWP1 as a key therapeutic target for pressure overload induced cardiac remodeling. We also found a novel mechanism regulated by WWP1. WWP1 promotes atypical K27-linked ubiquitin multichain assembly on DVL2 and exacerbates cardiac hypertrophy by the DVL2/CaMKII/HDAC4/MEF2C pathway.
Pruritic Lichenified Plaques on the Legs of a Man
Authors: Eva M. Sánchez-Martínez, Nohelia Rojas-Ferrer, Almudena Mateu-Puchades
Journal: JAMA Dermatology (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Assessing somatic and germline variants in cancer patients.
Authors: Charité Ricker, Erika Amundson, Sandra Algaze, Marcia Ciccone, Stephen Dong, Anishka D'souza, Kimberly Felicetti, Daisy Hernandez, Priya Jayachandran, Irene Kang, Kavitha Narayanan, Jacob Stephen Thomas, Varsha Tulpule, Rebecca Umayam, Bing Xia, Gino Kim In
Journal: Journal of Clinical Oncology (2021)

10601 Background: The increasing integration of somatic and germline testing into oncology practice allows physicians to target oncologic therapy and identify those with cancer predisposition. We explored the impact of a somatic assay (liquid biopsy, LB) on the identification of patients appropriate for germline genetic testing. Methods: We identified a cohort of diverse cancer patients with LB to assess for targetable somatic gene variants at LAC+USC Medical Center between 2016 and 2020 (n= 467). To enrich the cohort for variants that may reflect germline findings, we focused on the 46 patients (9.9%) who had at least one variant identified with a cell-free DNA (cfDNA) fraction of 25.00% or greater. Retrospective chart review extracted demographics and medical history with variables related to cancer history and treatment. LB variants were classified based on whether germline confirmation was indicated and the results of germline tests, when done, were reviewed. Results: Table summarizes the characteristics of the 46 patients identified to have at least one variant on LB in ≤ 25% of the cfDNA. The most frequently mutated genes on LB were TP53 (n=18, 39%), KRAS (n=11, 24%), APC (n=8, 17%), BRCA2 (n=7, 15%), PIK3CA (n=6, 13.0%), and BRCA1 (n=4, 9%). Seventeen patients (40%) were referred for genetic counseling and 13 (30%) underwent germline testing of whom 10 (77%) carried pathogenic variants (PV). All germline PV were concordant with LB variants identified. Four patients with PV BRCA2 on LB and confirmed to be germline, had lung or biliary tract diagnoses, which are not part of the typical BRCA-tumor spectrum. Thirty-three patients were not referred for genetic counseling, though 24 (72%) had LB-identified variants in cancer predisposition genes and 18 (54%) merited a genetics referral. Among patients with germline mutations, three (23%) had targeted therapy and two (15%) had preventive surgery to address second primary cancer risk. Among the 467 patients with LB results, there were an additional 13 patients (not included in the enriched group) known to have a cancer predisposition gene PV. Only two (15%) had findings on LB reports that suggested germline testing would be indicated. Conclusions: While the purpose of somatic testing is to identify targeted therapy, it can provide germline insight, especially for patients not typically referred for genetic assessment. Further education and guidance is needed to assure that this aspect of somatic testing is appreciated by oncology providers and acted upon.[Table: see text]
Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study
Authors: Zhenggang Ren, Jianming Xu, Yuxian Bai, Aibing Xu, Shundong Cang, Chengyou Du, Qiu Li, Yinying Lu, Yajin Chen, Yabing Guo, Zhendong Chen, Baorui Liu, Weidong Jia, Jian Wu, Junye Wang, Guoliang Shao, Bixiang Zhang, Yunfeng Shan, Zhiqiang Meng, Jianbing Wu, Shanzhi Gu, Wei Yang, Chao Liu, Xuetao Shi, Zhenyuan Gao, Tao Yin, Jiuwei Cui, Ming Huang, Baocai Xing, Yilei Mao, Gaojun Teng, Yanru Qin, Jinhai Wang, Feng Xia, Guowen Yin, Yong Yang, Mingxia Chen, Yan Wang, Hui Zhou, Jia Fan
Journal: The Lancet Oncology (2021)
PD-1/PD-L1 inhibitors plus chemotherapy versus bevacizumab plus chemotherapy as first-line treatment for advanced nonsquamous non-small cell lung cancer: A Bayesian network meta-analysis of randomized controlled trials.
Authors: Zhibo Zhang, Jinzhao Zhai, Xiang Yan, Fan Zhang, Xiaoyan Li, Sujie Zhang, Fang Yuan, Shuai Mu, Xiaoyu Zhi, Xiangwei Ge, Di Lu, Yi Hu, Jinliang Wang
Journal: Journal of Clinical Oncology (2021)

e21152 Background: Chemotherapy in combination with PD-1/PD-L1 inhibitor or bevacizumab have demonstrated superior efficacy to chemotherapy in the first-line treatment for non-squamous non-small-cell lung cancer (NS-NSCLC). However, there has been no randomized study comparing PD-1/PD-L1 inhibitors plus chemotherapy (immune-chemo) with bevacizumab plus chemotherapy (bev-chemo). Thus, we performed this network meta-analysis (NMA) to evaluate the comparative efficacy and safety of immune-chemo and bev-chemo as first-line treatment for NS-NSCLC. Methods: The randomized controlled trials (RCTs) were identified by searching PubMed, Embase, the Cochrane library, and conference abstracts until Oct 2020. Bayesian NMA with fixed effect consistency model was applied to estimate hazard ratio (HR) and Odds ratio (OR) with their 95% confidence intervals (CIs). The outcomes included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and grade ≥3 treatment-related adverse events (TRAEs). Results: 15 RCTs involving 6541 advanced NS-NSCLC patients were eligible for analysis. For OS, immune-chemo (HR 0.70, 95% CI 0.64-0.79) and bev-chemo (0.87, 0.79-0.95) significantly prolonged survival compared with chemotherapy. For PFS, immune-chemo (0.58, 0.53-0.62) and bev-chemo (0.66, 0.61-0.71) were significantly superior to chemotherapy. For ORR, immune-chemo (2.42, 1.93-3.08) and bev-chemo (2.27, 1.75-2.92) were associated with better benefits than chemotherapy. However, immune-chemo (1.61, 1.08-2.35) and bev-chemo (1.83, 1.08-2.90) increased grade ≥3 TRATEs compared with chemotherapy. The results of Bayesian NMAs shown that immune-chemo (PFS: 0.88[0.80-0.97]; OS: 0.81[0.72-0.92]) was associated with better outcomes than bev-chemo, while there were no significant differences in ORR and the risk of grade ≥3 TRATEs (Table). Conclusions: Immune-chemo and bev-chemo are superior to chemotherapy in first-line treatment of NS-NSCLC. Immune-chemo could significantly improve clinical outcomes compared with bev-chemo without higher severe TRAEs. [Table: see text]
The clinicopathological and survival analysis of urological mucosal melanoma: A single-center retrospective observational study.
Authors: Bixia Tang, Xieqiao Yan, Zhihong Chi, Siming Li, Chuanliang Cui, Bin Lian, Lu Si, Lili Mao, Xuan Wang, Xue Bai, Li Zhou, Rong Duan, Huayan Xu, Caili Li, Jun Guo, Xinan Sheng
Journal: Journal of Clinical Oncology (2021)

e21588 Background: Primary mucosal melanoma arising in the urinary tract is rare and poorly characterized. Methods: The records of patients with urological mucosal melanoma who presented to the department of Renal Cancer and Melanoma of Peking University Cancer Hospital between September, 2004 and April, 2019 were reviewed. Available clinicopathological and molecular characteristics were summarized, including pathological parameters, gene mutation, primary surgical intervention, systemic treatment and clinical course. The rates of local recurrence rate, loco-regional lymph node metastasis and distant metastasis were assessed. American Joint Committee on Cancer (AJCC) TNM Staging System for bladder cancer/renal pelvis and ureter cancer/urethral carcinoma (8th ed., 2017) were adopted for staging. Results: Fifty-eight patients were involved in the study with a median age of 62.5 years (range: 32-82). The anatomic sites of the primary urological mucosal melanomas were from the urethra (89.7%), bladder (6.9%), ureter (0%) and kidney (0%), and the left (4.4%) were from multiple loci. At initial diagnosis, 75.9% (n=44) were stage I/II disease, 1.7% (n=1) stage III, and 22.4% (n=13) stage IV. There was 3.4% incidence of CKIT mutation and 1.7% of BRAF mutation. After median follow-up of 22.6 mo, 31.4% (16/51) relapsed locally after organ-preserved surgery. 21.6% (11/51) and 39.2% (20/51) developed metastases to reginal lymph nodes and distance, respectively. The median relapse free survival and median overall survival were 12.2 (95%CI: 7.9-16.4) mo and 33.9 (95%CI: 19.2-48.6) mo, respectively. Univariate Cox analysis showed that TNM stage and systemic adjuvant therapy were the prognostic factors of OS, while no association was found with Breslow thickness, miotic rate, ulceration and gender. Conclusions: Urological mucosal melanoma predominantly arises from lower urinary tract with rare BRAF and CKIT mutation. AJCC TNM Staging System for urothelial carcinoma is proved practical for urothelial melanoma, which should be validated in larger population. Future research is required to identify adjuvant treatment approaches to improve disease outcomes.