tbuckley/cabot-search huggingface dataset:
Correlation of circulating PD-L2 levels with outcomes of therapy with the anti-PD-1 antibody pembrolizumab (P) in patients (pts) with advanced soft tissue sarcomas (STS): Biomarker analysis of SARC028.
Authors: Melissa Amber Burgess, Jason Roszik, Brian Andrew Van Tine, James Hu, Scott Schuetze, Sandra P. D'Angelo, Steven Attia, Dennis A. Priebat, Scott H. Okuno, Richard F. Riedel, Lara Emily Davis, Sujana Movva, Damon R. Reed, Laurence H. Baker, Denise K. Reinke, Robert G. Maki, Shreyaskumar Patel, Hussein Abdul-Hassan Tawbi, Lisa Helene Butterfield
Journal: Journal of Clinical Oncology (2017)

60 Background: The activity of the anti-PD-1 antibody P in pts with advanced STS was evaluated in a prospective multicenter Phase II study conducted by the Sarcoma Alliance for Research through Collaboration (SARC). SARC028 enrolled 40 patients with advanced soft tissue sarcoma. Pembro had an ORR of 19% and PFS rate at 12 weeks of 55%, suggesting clinical activity. We investigated biomarkers of response to P. Methods: The primary endpoint was Objective Response Rate (ORR) by RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival, and biomarkers of response in blood and tumor. Pre- and on-treatment biopsies were required and obtained from over 90% and 72% of pts respectively. Serum was obtained from all pts at baseline and at multiple time points on therapy (pre-, week 8, and every 12 weeks). Sera were examined for candidate circulating biomarkers by Affymetrix Luminex platform array, including PD-L2. To determine whether there is a statistically significant difference between different conditions, we used Mann-Whitney and two-tailed t tests. Log-rank p-values in Kaplan-Meier survival analyses were calculated using the "survival" R package. Results: Forty pts with STS were enrolled into 4 cohorts (10 each) based on histological subtype including undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (LPS), synovial sarcoma (SS), and leiomyosarcoma (LMS). 4 pts with UPS, 2 pts with LPS, and one pt with SS achieved a response. Six of seven responses were durable at the time of this analysis. Circulating levels at baseline or after therapy of PD-1, PD-L1, 4-1BB, IDO, BTLA, CTLA-4, LAG-3, and TIM-3 did not correlate with outcome. However, pre-treatment and week 8 PD-L2 levels correlated best with clinical outcome: high PD-L2 levels were associated with better PFS (p=0.019) in STS. Conclusions: P has clinical activity in specific histologic subtypes of STS, namely UPS and LPS. Pre-treatment circulating PD-L2 levels correlated with progression-free survival and is a novel and promising predictor of improved clinical outcome of PD-1 therapy in STS.
CD38 as a novel immune checkpoint and a mechanism of resistance to the blockade of the PD-1/PD-L1 axis.
Authors: Limo Chen, Lauren Averett Byers, Stephen Ullrich, Ignacio Ivan Wistuba, Xiao-Feng Qin, Don Lynn Gibbons
Journal: Journal of Clinical Oncology (2017)

79 Background: Although immune checkpoint inhibitors including PD-L1 blockade provide significant clinical benefit for patients with lung cancer, barriers to immunotherapy clinical successes have been due to a high rate of resistance. The therapeutic improvement requires a thorough understanding of the biological process of resistance. Until recently, there have been only a few studies reporting the mechanisms of resistance to PD-L1 blockade. The mechanistic basis remains poorly defined. Methods: In multiple immunocompetent syngeneic and K-rasLA1/+p53R172H?g/+ spontaneous animal models of lung cancer, we have explored the resistance mechanisms using pharmacological and genetic approaches (monoclonal antibody treatment and CRISPR/Cas9-mediated editing). The molecular and immune profiles of the tumor microenvironment were evaluated. More importantly, to determine the applicability to patients with lung cancer, we analyzed 259 patients specimens with IHC staining and mined many immune markers in TCGA adeno and squamous datasets. Results: We identified the up-regulation of CD38 on tumor cells as well as enrichment of CD38highTregs and CD38highMDSCs in tumor as the markers of treatment resistance. We observed the same resistance mechanism caused by CD38 in PD-L1 KO mice bearing PD-L1 KO Lewis lung tumors edited with the CRISPR/Cas9 system. Furthermore, by manipulating CD38 on a panel of lung cancer cell lines, in vitro and in vivo data demonstrates that CD38 inhibits CD8+ T cell proliferation, antitumor cytokine secretion, and tumor cell killing capability. To test whether CD38 blockade might be therapeutically efficacious to anti-PD-L1 resistance, we applied the combination therapy of anti-CD38 and anti-PD-L1 and demonstrated dramatic therapeutic benefit on primary tumor growth and metastasis. Additionally, in 259 lung patients, 18.5% of cases exhibited positive staining for CD38 on tumor cells, showing a great potential benefit for treating lung patients. Conclusions: CD38 is defined as a novel immune checkpoint and acts as a mechanism of resistance in the context of PD-L1 therapy. Targeting this novel immune checkpoint may broaden the benefit of PD-L1/PD-1 axis blockade for lung cancer treatment.
Study Limitations in HLA-Mismatched Microtransplant in Older Patients Newly Diagnosed With Acute Myeloid Leukemia
Authors: Robert Peter Gale
Journal: JAMA Oncology (2018)

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 Oncology 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 Oncology journal
Closure of a mucosal defect with clips and rubber band: a technical trick to improve edge apposition in large mucosal defects
Authors: Alexandru Lupu, Jérémie Jacques, Jérôme Rivory, Florian Rostain, Romain Legros, Thierry Ponchon, Mathieu Pioche
Journal: Endoscopy (2018)

Endoscopic mucosal resection (EMR) of duodenal adenomas is recommended by European Society for Gastrointestinal Endoscopy (ESGE) guidelines as offering complete resection with relatively low morbidity compared with surgery or endoscopic submucosal dissection (ESD) [1] [2]. Nevertheless, resection of duodenal adenomas carries a high risk of perforation (5 % – 10 %) and delayed bleeding (15 %) [3]. Systematic closure of mucosal defects could reduce the risk of delayed bleeding by protecting the resected area from bile and pancreatic secretions. Nevertheless, apposition of the two mucosal edges is not always feasible and can carry a risk of muscular damage from the clip itself.
149P Real-world outcomes with first-line afatinib in EGFR mutant NSCLC adenocarcinoma: A single centre experience exploring effects of dose-reduction
Authors: N. Tokaca, M. O'Brien, J. Bhosle, N. Yousaf, R. Kumar, S. Popat, D. Walder
Journal: Journal of Thoracic Oncology (2018)
Immunization with AgTRIO, a Protein in Anopheles Saliva, Contributes to Protection against Plasmodium Infection in Mice
Authors: Srdjan M. Dragovic, Tolulope A. Agunbiade, Marianna Freudzon, Jing Yang, Andrew K. Hastings, Tyler R. Schleicher, Xia Zhou, Sam Craft, Yu-Min Chuang, Floricel Gonzalez, Youquan Li, Gabriela Hrebikova, Abhai Tripathi, Godfree Mlambo, Lionel Almeras, Alexander Ploss, George Dimopoulos, Erol Fikrig
Journal: Cell Host & Microbe (2018)
High prevalence of pathogenic variants in individuals with colorectal cancer ≤ age 35.
Authors: Megan L. Marshall, Maegan Roberts, Lisa R. Susswein, Anna K. McGill, Zhixiong Xu, Rachel T. Klein, Kathleen S. Hruska
Journal: Journal of Clinical Oncology (2018)

576 Background: Young age at onset is a hallmark feature of an inherited predisposition to cancer. Recent evidence suggests that the incidence of pathogenic/likely pathogenic variants (PV) in cancer predisposition genes among individuals diagnosed with colorectal cancer (CRC) ≤ age 35 is high, but few studies have examined the frequency identified by multi-gene hereditary cancer panel testing. We report on PV yield and clinical presentation of individuals diagnosed with CRC ≤ 35 years (y). Methods: We retrospectively reviewed test requisition forms and provided pathology reports for 4,727 individuals with CRC who underwent panel testing of, at a minimum, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, and MUTYH. Two-tailed Fisher’s exact tests were used to determine statistically significant differences between groups. Results: Of the 691 individuals diagnosed with CRC ≤35y, 137 PV were identified in 126 individuals (126/691, 18.2%), including 72 with Lynch syndrome, 16 with familial adenomatous polyposis (FAP), five with MUTYH-associated polyposis, four with constitutional mismatch repair deficiency, one with juvenile polyposis syndrome, and one with Peutz-Jeghers syndrome. Thirty-eight additional PVs were identified in other non-CRC genes. Microsatellite instability (MSI) and immunohistochemistry (IHC) results were reported for 277 individuals and were reportedly abnormal in 63. The yield of PV in individuals with abnormal tumor studies was 52.4% (33/63); PV in genes other than the Lynch syndrome-associated genes were identified, commonly in the MSI-H group. While statistical significance was not observed, the positive rate was higher for individuals with non-rectal cancers (colon cancer: 104/534, 19.5%; rectal cancer: 22/157, 14.0%, p = 0.13). Conclusions: In our cohort, 18.2% of individuals diagnosed with CRC ≤35y were found to harbor a PV. Yield increased in those with abnormal MSI/IHC as well as non-rectal tumor location. Hereditary predispositions in patients diagnosed with very early-onset CRC are not limited to Lynch syndrome and FAP. Therefore, individuals with very early-onset CRC may benefit from multi-gene panel testing rather than syndromic-based testing.
Sixty seconds on . . . dandruff
Authors: Zosia Kmietowicz
Journal: BMJ (2018)

Absolutely not. NHS England is on the warpath against unnecessary prescribing of over-the-counter (OTC) products and it has dandruff firmly in its sights, along with 34 other minor ailments and self limiting conditions.

I couldn’t possibly say. But the upshot is that prescriptions for OTC products cost the NHS in England £569m (€651m; $798m) last year. …
Exploring Variation in Glycemic Control Across and Within Eight High-Income Countries: A Cross-sectional Analysis of 64,666 Children and Adolescents With Type 1 Diabetes
Authors: Dimitrios Charalampopoulos, Julia M. Hermann, Jannet Svensson, Torild Skrivarhaug, David M. Maahs, Karin Akesson, Justin T. Warner, Reinhard W. Holl, Niels H. Birkebæk, Ann K. Drivvoll, Kellee M. Miller, Ann-Marie Svensson, Terence Stephenson, Sabine E. Hofer, Siri Fredheim, Siv J. Kummernes, Nicole Foster, Lena Hanberger, Rakesh Amin, Birgit Rami-Merhar, Anders Johansen, Knut Dahl-Jørgensen, Mark Clements, Ragnar Hanas
Journal: Diabetes Care (2018)

International studies on childhood type 1 diabetes (T1D) have focused on whole-country mean HbA1c levels, thereby concealing potential variations within countries. We aimed to explore the variations in HbA1c across and within eight high-income countries to best inform international benchmarking and policy recommendations.Data were collected between 2013 and 2014 from 64,666 children with T1D who were <18 years of age across 528 centers in Germany, Austria, England, Wales, U.S., Sweden, Denmark, and Norway. We used fixed- and random-effects models adjusted for age, sex, diabetes duration, and minority status to describe differences between center means and to calculate the proportion of total variation in HbA1c levels that is attributable to between-center differences (intraclass correlation [ICC]). We also explored the association between within-center variation and children's glycemic control.Sweden had the lowest mean HbA1c (59 mmol/mol [7.6%]) and together with Norway and Denmark showed the lowest between-center variations (ICC ≤4%). Germany and Austria had the next lowest mean HbA1c (61-62 mmol/mol [7.7-7.8%]) but showed the largest center variations (ICC ∼15%). Centers in England, Wales, and the U.S. showed low-to-moderate variation around high mean values. In pooled analysis, differences between counties remained significant after adjustment for children characteristics and center effects (P value <0.001). Across all countries, children attending centers with more variable glycemic results had higher HbA1c levels (5.6 mmol/mol [0.5%] per 5 mmol/mol [0.5%] increase in center SD of HbA1c values of all children attending a specific center).At similar average levels of HbA1c, countries display different levels of center variation. The distribution of glycemic achievement within countries should be considered in developing informed policies that drive quality improvement.
Cardiac c-Kit Biology Revealed by Inducible Transgenesis
Authors: Natalie A. Gude, Fareheh Firouzi, Kathleen M. Broughton, Kelli Ilves, Kristine P. Nguyen, Christina R. Payne, Veronica Sacchi, Megan M. Monsanto, Alexandria R. Casillas, Farid G. Khalafalla, Bingyan J. Wang, David E. Ebeid, Roberto Alvarez, Walter P. Dembitsky, Barbara A. Bailey, Jop van Berlo, Mark A. Sussman
Journal: Circulation Research (2018)

Biological significance of c-Kit as a cardiac stem cell marker and role(s) of c-Kit+ cells in myocardial development or response to pathological injury remain unresolved because of varied and discrepant findings. Alternative experimental models are required to contextualize and reconcile discordant published observations of cardiac c-Kit myocardial biology and provide meaningful insights regarding clinical relevance of c-Kit signaling for translational cell therapy.The main objectives of this study are as follows: demonstrating c-Kit myocardial biology through combined studies of both human and murine cardiac cells; advancing understanding of c-Kit myocardial biology through creation and characterization of a novel, inducible transgenic c-Kit reporter mouse model that overcomes limitations inherent to knock-in reporter models; and providing perspective to reconcile disparate viewpoints on c-Kit biology in the myocardium.In vitro studies confirm a critical role for c-Kit signaling in both cardiomyocytes and cardiac stem cells. Activation of c-Kit receptor promotes cell survival and proliferation in stem cells and cardiomyocytes of either human or murine origin. For creation of the mouse model, the cloned mouse c-Kit promoter drives Histone2B-EGFP (enhanced green fluorescent protein; H2BEGFP) expression in a doxycycline-inducible transgenic reporter line. The combination of c-Kit transgenesis coupled to H2BEGFP readout provides sensitive, specific, inducible, and persistent tracking of c-Kit promoter activation. Tagging efficiency for EGFP+/c-Kit+ cells is similar between our transgenic versus a c-Kit knock-in mouse line, but frequency of c-Kit+ cells in cardiac tissue from the knock-in model is 55% lower than that from our transgenic line. The c-Kit transgenic reporter model reveals intimate association of c-Kit expression with adult myocardial biology. Both cardiac stem cells and a subpopulation of cardiomyocytes express c-Kit in uninjured adult heart, upregulating c-Kit expression in response to pathological stress.c-Kit myocardial biology is more complex and varied than previously appreciated or documented, demonstrating validity in multiple points of coexisting yet heretofore seemingly irreconcilable published findings.
Maturing Methods for Cardiovascular Disease and Stroke Surveillance in the United States
Authors: Mark D. Huffman
Journal: JAMA Cardiology (2018)

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 Cardiology 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 Cardiology journal
Zuma-6: Phase 1-2 multicenter study evaluating safety and efficacy of axicabtagene ciloleucel (axi-cel; KTE-C19) in combination with atezolizumab in patients with refractory diffuse large b-cell lymphoma (DLBCL).
Authors: Frederick Lundry Locke, Jason R. Westin, David Bernard Miklos, Alex Francisco Herrera, Caron Alyce Jacobson, Lillian Lee, John Rossi, Adrian Bot, Allen Xue, Lynn Navale, Jeff Aycock, Jeffrey S. Wiezorek, Zachary Roberts
Journal: Journal of Clinical Oncology (2017)

TPS7572 Background: Approximately 1/3 of patients with DLBCL, the most common type of B-cell lymphoma, will become refractory to standard combination chemotherapy and have uniformly poor clinical outcomes (Crump, ASCO 2016). Axi-cel (autologous anti-CD19 chimeric antigen receptor [CAR] T cell therapy) has shown promising response rates in patients with refractory DLBCL compared with standard approaches, although some patients do not respond or progress after an initial response (Locke, Mol Ther 2016). Expression of PD-L1 on DLBCL cells and activation-dependent expression of PD-1 on CAR T cells after infusion led to the hypothesis that PD-1 pathway blockade may augment the activity of axi-cel and result in improved clinical outcomes. This study will evaluate safety and efficacy of axi-cel when given with atezolizumab (anti–PD-L1 antibody), delivered sequentially, in patients with refractory DLBCL. Methods: Phase 1 will enroll ~3-9 patients to estimate the incidence of dose-limiting toxicities. Phase 2 will enroll ~22 patients to evaluate safety and efficacy, with a primary endpoint of complete response (CR) rate (Cheson 2007). Secondary endpoints include key efficacy outcomes such as objective response rate (CR+partial response [PR]), duration of response, progression-free and overall survival, and safety and biomarker outcomes. Eligible adult patients will have received prior adequate therapy (including anti-CD20 monoclonal antibody and an anthracycline-based regimen) and have an ECOG PS of 0-1 and adequate bone marrow and organ function. Patients with a history of Richter transformation, transformed follicular lymphoma, CNS disease, or active infection are not eligible. Patients will receive fludarabine 30 mg/m 2 /d and cyclophosphamide 500 mg/m 2 /d × 3 d, followed by a single infusion of axi-cel (target dose, 2 × 10 6 anti-CD19 CAR T cells/kg) followed by atezolizumab 1200 mg given every 21 d for 4 doses (phase 1, first dose to occur 21, 14, and 1 d after axi-cel infusion in cohorts 1, 2, and 3, respectively). The study opened to accrual in September 2016. Clinical trial information: NCT02926833.
Changing cancer survival in China during 2003–15: a pooled analysis of 17 population-based cancer registries
Authors: Hongmei Zeng, Wanqing Chen, Rongshou Zheng, Siwei Zhang, John S Ji, Xiaonong Zou, Changfa Xia, Kexin Sun, Zhixun Yang, He Li, Ning Wang, Renqiang Han, Shuzheng Liu, Huizhang Li, Huijuan Mu, Yutong He, Yanjun Xu, Zhentao Fu, Yan Zhou, Jie Jiang, Yanlei Yang, Jianguo Chen, Kuangrong Wei, Dongmei Fan, Jian Wang, Fangxian Fu, Deli Zhao, Guohui Song, Jianshun Chen, Chunxiao Jiang, Xin Zhou, Xiaoping Gu, Feng Jin, Qilong Li, Yanhua Li, Tonghao Wu, Chunhua Yan, Jianmei Dong, Zhaolai Hua, Peter Baade, Freddie Bray, Ahmedin Jemal, Xue Qin Yu, Jie He
Journal: The Lancet Global Health (2018)

From 2003 to 2005, standardised 5-year cancer survival in China was much lower than in developed countries and varied substantially by geographical area. Monitoring population-level cancer survival is crucial to the understanding of the overall effectiveness of cancer care. We therefore aimed to investigate survival statistics for people with cancer in China between 2003 and 2015.
Phase II Study of Two Weeks on, One Week off Sunitinib Scheduling in Patients With Metastatic Renal Cell Carcinoma
Authors: Eric Jonasch, Rebecca S. Slack, Daniel M. Geynisman, Elshad Hasanov, Matthew I. Milowsky, W. Kimryn Rathmell, Summer Stovall, Donna Juarez, Troy R. Gilchrist, Lisa Pruitt, Moshe C. Ornstein, Elizabeth R. Plimack, Nizar M. Tannir, Brian I. Rini
Journal: Journal of Clinical Oncology (2018)

Purpose Standard frontline treatment of patients with metastatic renal cell carcinoma currently includes sunitinib. A barrier to long-term treatment with sunitinib includes the development of significant adverse effects, including diarrhea, hand-foot syndrome (HFS), and fatigue. This trial assessed the effect of an alternate 2 weeks on, 1 week off (2/1) schedule of sunitinib on toxicity and efficacy in previously untreated patients with metastatic renal cell carcinoma. Methods Patients started with oral administration of 50 mg sunitinib on a 2/1 schedule and underwent schedule and dose alterations if toxicity developed. The primary end point was &lt; 15% grade ≥ 3 fatigue, diarrhea, or HFS. With 60 patients, the upper bound of the CI would fall below the published 4/2 schedule grade ≥ 3 toxicity rate of 25% to 30%. Results Fifty-nine patients were treated between August 2014 and March 2016. Seventy-seven percent were intermediate or poor risk per Memorial Sloan Kettering Cancer Center criteria. With a median follow-up of 17 months, 25% of patients experienced grade 3 fatigue, HFS, or diarrhea; 37% required a dose reduction, and 10% discontinued because of toxicity. The overall response rate was 57%, median progression-free survival was 13.7 months, and median overall survival was not reached. At 12 weeks, Functional Assessment of Cancer Therapy–General scores dropped between 0% and 10% from baseline, with less reduction in patients who continued treatment longer. Conclusion The primary end point of decreased grade 3 toxicity was not met; however, treatment with a 2/1 sunitinib schedule is associated with a lack of grade 4 toxicity, a low patient discontinuation rate, and high efficacy.
Public health or research—money matters
Authors: Cat Chatfield
Journal: BMJ (2018)

The UK introduced its first sugar tax this week. Soft drink manufacturers will now have to pay tax linked to a product’s sugar content, and some companies are already taking action.1 Whether it will have any impact on the obesity crisis remains to be seen,2 but growing evidence shows that taxes on alcohol, tobacco, and soft drinks have been effective in reducing non-communicable diseases, as found in a …