tbuckley/cabot-search huggingface dataset:
Glycogen synthase kinase-3 beta (GSK-3β) blockade with 9-ing-41 in gastrointestinal cancers: The 1801 phase Ib/II study.
Authors: Howard Safran, Mallika Sachdev Dhawan, Ludimila Cavalcante, Andre Luiz De Souza, Steven Francis Powell, Daniel D. Billadeau, Francis J. Giles, Pamela N. Munster, Benedito A. Carneiro
Journal: Journal of Clinical Oncology (2020)

827 Background: 9-ING-41 is a selective GSK-3β inhibitor with significant pre-clinical antitumor activity in a broad spectrum of malignancies as a single agent and in combination with cytotoxic agents. GSK-3β is a serine/threonine kinase whose overexpression is associated with advanced stage, aggressive tumor growth, and chemotherapy resistance. We report the preliminary results of patients (pts) with gastrointestinal (GI) malignancies. Methods: Phase 1b/2 study evaluating safety and efficacy of 9-ING-41 as monotherapy and combination therapy in pts with refractory cancers. 9-ING-41 is administered intravenously twice-weekly as a single agent (21-day-cycle) or combined with chemotherapy agents, including gemcitabine (GEM), nab-paclitaxel + GEM, carboplatin, or paclitaxel. Study parts 1 and 2 evaluate the safety, describe dose-limiting toxicities (DLTs), determine the maximum tolerated dose and the recommended phase 2 study dose (RP2D) for 9-ING-41 as monotherapy (Part 1) and as combination therapy (Part 2). Part 3 (Simon 2-Stage Phase 2) assess clinical benefit in pts treated with 9-ING-41-based combinations at the RP2D established in Part 2. Response is assessed by RECIST 1.1 criteria in the evaluable lesions. Results: To date, the study accrued 63 pts. Five dose levels (1, 2, 3.3, 5 and 7 mg/kg) have been completed without DLTs. Part 2 of the study evaluating 9-ING-41-based chemotherapy combinations is ongoing. Five out of nine pts with pancreas cancer (PCa) enrolled had stable disease (SD) as the best response; 2 out of 9 pts had a 40-45% decline of CA 19-9. One pt completed 6 cycles with 9-ING-41, two pts completed 4 cycles with 9-ING-41/GEM. Two active pts are receiving 9-ING-41/GEM with SD after 3 and 4 cycles. Three out of four pts with adenocarcinoma of the appendix enrolled had SD as the best response; two pts in active treatment are receiving cycles 5 and 6. One out of 13 pts with colorectal cancer had SD. 9-ING-41-attributable AE to date are reversible grade 1 transient visual changes (color perception). Conclusions: 9-ING-41 is well-tolerated with encouraging SD among heavily pretreated pts with carcinoma of the pancreas and appendix. Clinical trial information: NCT03678883.
NuTide: 302—A phase Ib study of the ProTide NUC-3373 in combination with standard therapies in advanced colorectal cancer.
Authors: Kristen Keon Ciombor, Janet Shirley Graham, Francesca Aroldi, Andrew L. Coveler, Benjamin L. Schlechter, Jeffrey William Clark, Jill Graham, Lisa Jane Rodgers, Aimery De Gramont, Josep Tabernero, Jordan Berlin, Sarah Patricia Blagden, T.R. Jeffry Evans
Journal: Journal of Clinical Oncology (2020)

TPS274 Background: Although 5-FU-based regimens such as FOLFOX and FOLFIRI remain the cornerstone of treatment for patients (pts) with colorectal cancer (CRC), their clinical utility is limited by resistance mechanisms and toxicity. Anti-cancer activity of 5-FU is dependent on conversion to an active metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), which binds to and inhibits thymidylate synthase (TS), a critical enzyme in de novo nucleotide synthesis and cell survival. However, due to multiple limitations including: reliance on enzymatic activation; catabolism by dihydropyrimidine dehydrogenase (DPD) and a short plasma half-life, 5-FU is not efficiently converted to FUDR-MP. NUC-3373, a phosphoramidate transformation of FUDR-MP, was designed to bypass the key resistance mechanisms that limit the clinical utility of 5-FU. NUC-3373 demonstrated a favorable PK/PD profile and promising efficacy signals in the first-in-human study (NuTide:301) in pts with advanced solid tumors. NUC-3373 has a longer plasma t 1/2 (9.7 hours) than 5-FU (8-14 minutes) and generates high intracellular levels of FUDR-MP (Ghazaly et al ESMO, 2017). TS is efficiently inhibited and sequestered into TS-ternary complexes, depleting the pool of deoxythymidine monophosphate (dTMP) within 2-4 hours. Methods: NuTide:302 is a three-part, Phase Ib study in pts with advanced CRC who have relapsed after ≥2 prior lines of 5-FU-containing therapies. Primary objective is to identify a RP2D of NUC-3373 when administered weekly and q2w in combination with standard agents used in CRC treatment. Secondary objectives include safety, PK/PD and anti‐tumor activity. In Part 1, patients are receiving NUC-3373 with leucovorin (LV) to determine if LV augments TS inhibition. In Part 2, NUC-3373 (±LV) will be administered in dose escalating cohorts, in a modified 3+3 design, with either oxaliplatin (NUFOX) or irinotecan (NUFIRI). In Part 3, the NUFOX and NUFIRI regimens selected in Part 2 will be combined with biologics targeting VEGF or EGFR pathways. To date, 22 pts have received study treatment. Recruitment is ongoing in the US and Europe. Clinical trial information: NCT03428958.
An Acetylation Switch of the NLRP3 Inflammasome Regulates Aging-Associated Chronic Inflammation and Insulin Resistance
Authors: Ming He, Hou-Hsien Chiang, Hanzhi Luo, Zhifang Zheng, Qi Qiao, Li Wang, Mingdian Tan, Rika Ohkubo, Wei-Chieh Mu, Shimin Zhao, Hao Wu, Danica Chen
Journal: Cell Metabolism (2020)
Stage-specific conditional survival among young versus older adults with colorectal cancer in the United States, 2004-2010.
Authors: Nina Niu Sanford, Chul Ahn, Michael Ryan Folkert, Todd Anthony Aguilera, David J. Sher
Journal: Journal of Clinical Oncology (2020)

257 Background: Conditional survival (CS) is a relevant prognostic measure for cancer survivors and physicians and may be particularly important for young adult patients with CRC (colorectal cancer), whose incidence is rising. We sought to compare CS among young versus older adults with CRC. Methods: Patients diagnosed with colon or rectal adenocarcinoma between 2004-2010 were identified from the Surveillance, Epidemiology and End Results (SEER) registry. Overall survival (OS) and cancer-specific survival (CSS) were estimated, along with smoothed yearly hazards of death due to CRC, other causes and any cause, stratified by age at diagnosis ( &lt; 50 vs. &gt;50 years). Stage-specific conditional 5-year OS and 5-year CSS given that patients had already survived 1, 2, 3, 4 or 5 years after diagnosis was calculated, also stratified by age. Results: Among 161,859 patients with median follow-up of 54 months, 35,411 (21.9%) were aged &lt; 50 years. Both OS and CSS were superior among younger adult as compared to older adult patients (p &lt; 0.001). For older adults with rectal cancer, hazards of death due to non-cancer causes exceeded that of rectal and colon cancer approximately 6 and 4.5 years after diagnosis, respectively. Among younger adults, hazard of death from cancer remained greater than death from other causes throughout the entire study interval. Patients experienced improved conditional survival over time with greater improvement seen for more advanced stages. However, young adults had less CS improvement over time than older adults. For example, the 5-year overall and CSS for Stage IV colon cancer improved from 7.4% to 52.4%% (OS) and 15.1% to 78.5% (CSS) 0 to 5 years after diagnosis for older adults. In contrast, for younger adults, the 5-year overall and CSS for Stage IV colon cancer improved from 15.6% to 57% (OS) and 19.3% to 68.4% (CSS). Conclusions: Prognosis for CRC improves over time for all patients, although the increase in survival appears to be less for younger than older adults. Up to 10 years after diagnosis, the primary cause of death in younger adults with CRC remains their incident cancer.
A Common Rule for Resection of Glioblastoma in the Molecular Era
Authors: Bryan D. Choi, Elizabeth R. Gerstner, William T. Curry
Journal: JAMA Oncology (2020)

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
DPX-Survivac, a novel T-cell immunotherapy, to induce robust T-cell responses in advanced ovarian cancer.
Authors: Oliver Dorigo, Stephan Fiset, Lisa Diana MacDonald, Yogesh Bramhecha, Olga Hrytsenko, Brennan Dirk, Gabriela Nicola Rosu, Marianne Stanford
Journal: Journal of Clinical Oncology (2020)

6 Background: Survivin has emerged as an attractive target for T cell-based immunotherapy because of its essential role in tumor biology and its tumor-specific expression in multiple tumor types. DPX-Survivac is a novel T cell immunotherapy that uses the DPX platform to elicit strong and sustained survivin-specific T cell responses against tumor cells. DPX is designed to extend the duration and robustness of targeted immune responses by requiring active uptake of antigens by antigen presenting cells at the injection site. DPX-Survivac incorporating survivin targets within the DPX platform is therefore a relevant approach for treatment of survivin-expressing cancers to generate strong T cell responses that infiltrate tumors and result in measurable anti-tumor responses. Methods: 121 patients with platinum sensitive or resistant, advanced ovarian, fallopian tube or peritoneal cancer were treated with DPX-Survivac with or without drug combinations. Data from 3 different clinical trials were analyzed for systemic immune responses, tumor immune infiltrates and clinical tumor responses. Patients were enrolled in both the maintenance (N = 56) and recurrent (N = 65) disease settings. Results: DPX-Survivac generated survivin-specific T cells in 80% of patients as demonstrated by IFN-γ ELISPOT of PBMCs. Paired pre- and post-treatment tumor samples were collected from 37 patients. Survivin-specific T cells were found in the tumor microenvironment post-treatment using TCR-β sequencing. Clinical anti-tumor responses were correlated with increased infiltration of T cells into tumors following treatment with DPX-Survivac. An increase in T cell signaling in post-treatment tumor tissue was shown by RNAseq along with upregulation of cytotoxic markers, NK and B cell markers. Importantly, the antigen-specific T cells retain their functionality throughout the duration of treatment. Conclusions: DPX-Survivac stimulates significant clinical anti-tumor responses by inducing strong and sustained survivin-specific T cell responses and increasing infiltration of target-specific T cells into tumors. Clinical trial information: NCT01416038; NCT03332576; NCT02785250.
Efficacy of pembrolizumab (pembro) monotherapy versus chemotherapy for PD-L1–positive (CPS ≥10) advanced G/GEJ cancer in the phase II KEYNOTE-059 (cohort 1) and phase III KEYNOTE-061 and KEYNOTE-062 studies.
Authors: Zev A. Wainberg, Charles S. Fuchs, Josep Tabernero, Kohei Shitara, Kei Muro, Eric Van Cutsem, Yung-Jue Bang, Hyun Cheol Chung, Kensei Yamaguchi, Eniko Varga, Jen-Shi Chen, Daniel Hochhauser, Peter C. Thuss-Patience, Salah-Eddin Al-Batran, Marcelo Garrido, Uma Kher, Chie-Schin Shih, Sukrut Shah, Pooja Bhagia, Joseph Chao
Journal: Journal of Clinical Oncology (2020)

427 Background: Pts with advanced gastric/gastroesophageal junction (G/GEJ) cancer received pembro monotherapy (200 mg Q3W) 3L+ in cohort 1 of KEYNOTE-059 (NCT02335411), 2L in KEYNOTE-061 (NCT02370498), or 1L in KEYNOTE-062 (NCT02494583). We present efficacy data for patients with PD-L1 combined positive score (CPS) ≥10 tumors in these trials. Methods: In study 059, 46 pts in cohort 1 with PD-L1 CPS ≥10 received pembro. In study 061, 108 pts with PD-L1 CPS ≥10 received pembro (n=53) or chemotherapy (chemo; n=55). In study 062, 182 pts with CPS ≥10 received pembro (n=92) or placebo + chemo (n=90). Efficacy end points included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR). Results: Median follow-up in study 059 was 5.6 mo. Median OS with pembro was 7.9 mo (95% CI, 5.8-11.1), and 12-mo OS was 32.6%. PFS at 6 mo was 17.4%, ORR was 17.4%, and median DOR was 20.9 mo (2.8+ to 34.9+). In study 061, after a median follow-up of 8.8 mo, pembro prolonged OS vs chemo (median 10.4 vs 8.0 mo; HR, 0.64; 95% CI, 0.41-1.02); 12-mo OS was 45.3% for pembro and 23.6% for chemo. Median PFS was 2.7 mo for pembro and 3.4 mo for chemo (HR, 0.86; 95% CI, 0.56-1.33). ORR was 24.5% vs 9.1%, and median DOR was NR (4.1-26.0+) and 6.9 mo (2.6-6.9) for pembro vs chemo. In study 062, median follow-up was 17.4 mo for pembro and 10.8 mo for chemo. Pembro prolonged OS vs chemo (median 17.4 vs 10.8 mo; HR, 0.69; 95% CI, 0.49-0.97); 12-mo OS was 56.5% vs 46.7%. Median PFS was 2.9 mo vs 6.1 mo (HR, 1.09, 95% CI, 0.79-1.49). ORR was 25.0% vs 37.8%, and median DOR was 19.3 mo (1.4+ to 33.6+) vs 6.8 mo (1.5+ to 30.4+) for pembro vs chemo, respectively. Conclusions: Collectively, these data indicate that 1L, 2L, and 3L+ pembro monotherapy showed clinically meaningful efficacy in CPS ≥10, with a more durable response than chemotherapy. Clinical trial information: NCT02335411, NCT02370498, and NCT02494583. [Table: see text]
Association of sarcopenia and myosteatosis with the systemic inflammatory response and tumor stage in patients undergoing surgery for colorectal cancer (CRC).
Authors: Tanvir Abbass, Ross Dolan, Stephen Thomas McSorley, Paul G. Horgan, Donald C. McMillan
Journal: Journal of Clinical Oncology (2020)

130 Background: There is now good evidence that sarcopenia and myosteatosis, measured as low skeletal muscle index (SMI) and low skeletal muscle density (SMD) from CT scans, are associated with poor survival in patients undergoing surgery for CRC. However, this is not clear whether this is as a result of tumour burden or chronic inflammation. Methods: The relationship between tumour stage, systemic inflammatory response using modified Glasgow prognostic score (mGPS), neutrophil lymphocyte ratio (NLR) and sarcopenia and myosteatosis using defined SMI/SMD was examined in 840 patients undergoing CRC resection from a prospectively maintained database. Results: The majority of patients were &gt; 65 years of age (64.5%), male (55%) and did not have sarcopenia (51%) but had myosteatosis (65%). In those patients with a mGPS = 0 (n = 617), mGPS = 1 (n = 99), mGPS = 2 (n = 124), TNM stage of 0-I, II and III was not associated with sarcopenia (p = 0.260, p = 0.869 and p = 0.458 respectively) or myosteatosis (p = 0.136, p = 0.879 and p = 0.06 respectively). In those patients with TNM stage of 0-I (n = 202), stage II (n = 346) and stage III (n = 292), mGPS (0,1,2) was significantly associated with sarcopenia (p = 0.329, p = 0.001 and p = 0.002 respectively) and myosteatosis (p = 0.329, p &lt; 0.001 and p = 0.001 respectively). In patients with TNM stage of 0-I, stage II and stage III, NLR was significantly associated with sarcopenia (p = 0.492, p = 0.299 and 0.027 respectively) and myosteatosis (p = 0.870, p = 0.012 and p = 0.019 respectively). Conclusions: Compared with tumour burden, the systemic inflammatory response (particularly mGPS) appears to have a greater influence on the development of sarcopenia and myosteatosis. These results have implications for the treatment of sarcopenia and myosteatosis in patients undergoing surgery for CRC.
Dermatologic adverse events with immune checkpoint blockade: Systematic review and meta-analysis.
Authors: Kushal Naha, Lakshmi Manogna Chintalacheruvu, Donald C. Doll, Sowjanya Naha
Journal: Journal of Clinical Oncology (2020)

84 Background: Immune checkpoint blockade is known to be associated with various dermatologic adverse events. However, these adverse effects have not been studied in a systematic manner. This is especially relevant considering the rapidly increasing number of immune checkpoint inhibitors that are now available. Methods: We searched for eligible studies in PubMed and Google scholar. We reviewed randomized controlled trials involving cancer patients treated with immune checkpoint inhibitors - PD1 inhibitors, PDL1 inhibitors and CTLA4 inhibitors and for dermatologic adverse effects. A total of 47 randomized controlled trials involving 11875 patients met eligibility criteria for our study. Results: Incidence rate of all grade dermatologic adverse effects was 40.6% (95% confidence interval [CI], 39.4-41.7%). Most common adverse effects included pruritus (17.3%) (95% confidence interval [CI] 16.6-18.1%), undifferentiated rash (15.1%) (95% confidence interval [CI] 14.4-15.9%), vitiligo (3.6%) (95% confidence interval [CI] 3.2-3.9%), maculopapular rash (2.3%) (95% confidence interval [CI] 2.1-2.6%), stomatitis (0.7%) (95% confidence interval [CI] 0.55-0.92%) and dry skin (0.7%) (95% confidence interval [CI] 0.5-0.8%). Less common adverse events include palmoplantar erythrodysesthesia, pemphigoid skin reactions, lichen planus and hyperhidrosis. Grade 3 and higher adverse effects were seen in 1.3% of patients (95% confidence interval [CI] 1.1-1.6%). Conclusions: A wide range of dermatologic adverse effects can be seen with immune checkpoint blockade. While the majority of these events are of grade 1-2, they can occasionally be severe and even life threatening. Patients receiving immune checkpoint blockade should be closely monitored for dermatologic adverse effects.
The relevance of neuropilin-1 expression with prognosis according to the histology of gastric cancer.
Authors: Ho Seok Seo, Han Hong Lee
Journal: Journal of Clinical Oncology (2020)

442 Background: Neuropilin-1 (NRP-1) is known to be related with various types of cancer and considered as a novel tumor marker or a therapeutic target. The aim of the study is to identify the clinical implication of NRP-1 expression in terms of prognosis in gastric cancer. Methods: A total of 265 patients who underwent radical gastrectomy for the treatment of gastric cancer from 2008 to 2011 were included. NRP-1 expression of tumors was determined by immunohistochemistry. Patients’ clinicopathologic characteristics, operation details, and long-term outcomes were retrospectively analyzed. Results: 181 (68.3%) patients showed NRP-1 expression. There was no survival difference according to the NRP-1 expression in all patients. The patients were divided into gland formation (GF) type and no gland formation (nGF) type according to histologic type. NRP-1 expression rates were 65.6% (84/128) and 70.8% (97/137), respectively. In the group of GF, NRP-1 expression was not independent prognostic factor, although patients with NRP-1 expression had better survival outcome. In contrast, patients with NRP-1 expression had worse 5-year survival rate in the group of nGF (p = 0.027) and it was an independent prognostic factor multivariate analysis (HR, 1.923; 95% CI, 1.041 - 3.551). Conclusions: NRP-1 expression in the nGF type gastric cancer predicts a poor prognosis.
The impact of biologic agents in patients with metastatic colorectal cancer by race/ethnicity.
Authors: Seda Serra Tolu, Adel Chergui, Devika Rao, Meghan Kaumaya, Ana Acuna-Villaorduna, Andreas Kaubisch, Jennifer W. Chuy, Lakshmi Rajdev, Tarek N. Elrafei, Sanjay Goel
Journal: Journal of Clinical Oncology (2020)

156 Background: Biologic agents have shown to improve overall survival (OS) in patients with metastatic colorectal cancer (mCRC). However, minority racial/ethnic groups were underrepresented in clinical trials. A retrospective study in a racially-diverse population diagnosed between 2000 - 2011, done by our group, reported a survival benefit with biologics; but, a subgroup analysis suggested that it was restricted to Non-Hispanic whites (NHW) only. This study aims to compare OS in patients with mCRC treated with chemotherapy and biologic agents (CBT) among racial/ethnic groups. Methods: Patients diagnosed with mCRC between 2012-2018 and treated with CBT at 3 cancer centers in the Bronx, NY were identified. Clinical data was collected by retrospective review for demographics (age at metastasis, gender and race/ethnicity categorized as Non-hispanic Black (NHB), NHW or Hispanic), pathological/ treatment characteristics (tumor grade, primary location, chemotherapy regimen, biologic agent). Cases without available race/ethnicity were excluded. OS was measured as time from mCRC diagnosis to death (verified from the National Death Index) and was compared among racial/ethnic groups using Kaplan-Meier curves. Results: A total of 278 patients; of whom 84 (42.4%) were Hispanic, 70 (35.4%) NHB and 44 (22.2%) NHW were included. The median age at diagnosis was 60 years and did not differ among racial/ethnic groups (62.5 vs 55.5 vs 56 years, p=0.07). There was a female predominance in NHB and Hispanics. Bevacizumab was more frequently used in Hispanics and NHB compared to NHW (95.2% vs. 92.9% vs. 77.3%, p=0.003, respectively). There were no differences in the frequency of cetuximab and panitumumab use. Median OS did not differ by racial/ethnic groups (21 in NHW vs. 22.8 in Hispanics and 28.6 months in NHB, p=0.40). Conclusions: Minority groups attain a similar survival benefit from the addition of biologics compared to NHW. Population-based studies are required to confirm these results.
Mitochondria Do Not Survive Calcium Overload During Transplantation
Authors: Edoardo Bertero, Brian O’Rourke, Christoph Maack
Journal: Circulation Research (2020)

utologous mitochondrial transplantation was recently proposed as a novel therapeutic strategy to restore cardiac function after myocardial infarction. 1 For this intervention, functional mitochondria are isolated from skeletal muscle and then injected directly into the ischemic heart or coronary arteries of the same subject. 1he declared treatment goal is to replace mitochondria in cardiac myocytes damaged by ischemia with respiration-competent mitochondria, whose ATP formation supposedly sustains cardiac vitality and contraction.This approach was tested in preclinical models of ischemia/ reperfusion injury 1 and subsequently applied to pediatric patients with myocardial ischemia in an open-label, single-armed clinical trial (NCT02851758).We recently argued that the translation of this approach to the clinical arena may be premature, since it appears unlikely that injected mitochondria withstand high Ca 2+ concentrations in the extracellular environment. 2In response to our article, McCully et al, 1 who had introduced this approach, emphasized that "donor mitochondria are viable in both the isolated perfused heart, where Ca 2+ concentration was 1.7 mmol/L and in in vitro cell studies where Ca 2+ concentration was 1.8 mmol/L." 3 It is widely accepted that upper micromolar Ca 2+ concentrations induce mitochondrial Ca 2+ overload with fatal activation of the permeability transition pore.However, high extramitochondrial Na + concentrations in the bloodstream or extracellular fluid may potentially protect mitochondria from Ca 2+ overload by inducing Ca 2+ efflux via the mitochondrial Na + /Ca 2+ exchanger.To address this hypothesis, we isolated skeletal muscle mitochondria (as used in the studies by McCully et al) 1 from mice and Meet the First