tbuckley/cabot-search huggingface dataset:
A phase I/II study of live biotherapeutic MRx0518 in combination with pembrolizumab in patients who have progressed on prior anti-PD-1 therapy.
Authors: Shubham Pant, Imke Mulder, Amishi Yogesh Shah, Pavlos Msaouel, Mehmet Altan, John Weinberg, Alex Stevenson, Funda Meric-Bernstam, Timothy A Yap, Vivek Subbiah, Jordi Rodon Ahnert
Journal: Journal of Clinical Oncology (2019)

TPS2670 Background: The gut microbiome has emerged as a new therapeutic target to augment the efficacy of immune checkpoint blockade. MRx0518 is a novel, gut microbiome-derived, oral live biotherapeutic, designed to induce a broad immunostimulatory response to re-engage PD-1 inhibitor activity. Preclinical studies showed that MRx0518 reduced tumour growth in models of kidney, lung and breast cancer. MRx0518 increased CD4 and CD8 T cell and NK cell infiltration into the tumour and decreased Tregs. Upregulation of tumour TLR5 was observed and linked to the bacterial flagellin moiety, which was shown to strongly induce NFκB, cytokine responses and IFNγ+ CD4 and CD8 T cells. The study, one of the first oncology trials conducted with live biotherapeutics, is a single center, open label, safety and preliminary efficacy study of MRx0518 in combination with pembrolizumab in patients with solid tumors who have progressed on PD-1 inhibitors. Methods: Trial consists of 2 parts. In Part A, 12 patients receive pembrolizumab 200 mg every 3 weeks plus 1 capsule (bid) of MRx0518 with a DLT period of 1 cycle (21 days). In Part B, up to 30 patients per cohort (NSCLC, Urothelial, Renal and Melanoma) will receive pembrolizumab 200 mg every 3 weeks plus 1 capsule (bid) of MRx0518 for up to 35 cycles or until disease progression per RECIST 1.1. The primary end points are safety and tolerability of MRx0518 in combination with pembrolizumab (Parts A and B) and clinical benefit of MRx0518 in combination with pembrolizumab (Part B). Secondary end points are objective response rate, duration of response, disease control rate, and progression-free survival. Exploratory end points include biomarkers of treatment effect, effect on microbiota and overall survival. Recruitment is ongoing. Clinical trial information: NCT03637803.
Oncology Associated Symptoms and Individualized strategies (OASIS): Precision symptoms management for rural patients with advanced cancer.
Authors: Praveen Vikas, Stephanie Gilbertson-White, Tannaz Saeidzadeh, Yelena Perkhounkova
Journal: Journal of Clinical Oncology (2019)

e23155 Background: Rural cancer patients have limited access to symptom management specialists. OASIS is an 8-week, web-based intervention addressing this access gap by providing the right symptom management to the right patients at the right time. This feasibility study seeks to describe recruitment and retention patterns and evaluate symptom severity, distress, and interference at 4, 8, and 12 weeks. Methods: Eligibility included: advanced cancer diagnosis, &gt; 18 years old, and living in small town or rural area. Reasons for non-enrollment and dropout were collected. Descriptive statistics were calculated to evaluate recruitment and retention rates along with symptom severity and interference at each time point. The mean severity and distress scores using the 0-10 NRS of the five symptoms with the highest rating was computed for each time point (i.e., baseline, week 4, and week 8). By averaging the five highest rated symptoms, we evaluated the worst symptoms the individual is experiencing at each data point. Results: Fifty-nine people were approached about the study over 18 months, 38 people signed consents, 12 dropped before completing baseline questionnaires, and 9 completed baseline questionnaires but did not start the intervention. Seventeen people completed baseline questionnaires and started the intervention. The recruitment rate was 66%, the retention rates were 50% and 33% at 4 and 12 weeks.Reasons for drop out included lack of bothersome symptoms, too busy, and generally overwhelmed. Mean age of sample was 62 years and majority men (62.5%). Fatigue (M = 6.4), drowsiness (M = 5.4), numbness/tingling (M = 4.4), and sleep disturbance (M = 4.4) were the most severe symptoms at baseline. Mean symptom severity was M = 3.03 and mean interference was M = 2.53 at baseline. For participants who received the full OASIS-WN intervention, between baseline and week 8, the mean interference rating decreased by 1.6±2.1 points (p = .019), mean severity and distress ratings for the five worst symptoms decreased by 1.72±1.72 (p = .004) and 2.2±2.4 (p = .006), respectively. Conclusions: Symptom severity, distress, and interference improved for participants who received the full intervention. Reasons for early drop out suggest symptom management ought to be provided when the situation is optimal for learning. Future research will evaluate the efficacy of OASIS.
Association of Trajectory of Cardiovascular Health Score and Incident Cardiovascular Disease
Authors: Shouling Wu, Shasha An, Weijuan Li, Alice H. Lichtenstein, Jingsheng Gao, Penny M. Kris-Etherton, Yuntao Wu, Cheng Jin, Shue Huang, Frank B. Hu, Xiang Gao
Journal: JAMA Network Open (2019)

The American Heart Association 2020 Strategic Impact Goals target an improvement in overall cardiovascular health, as assessed by 7 health metrics (smoking, body weight, physical activity, diet, plasma glucose level, plasma cholesterol level, and blood pressure).To examine whether trajectories of overall cardiovascular health over time, as assessed by the cardiovascular health score (CHS) in 2006, 2008, and 2010, are associated with subsequent risk of CVD.The Kailuan study is a prospective, population-based study that began in 2006. The cohort included 74 701 Chinese adults free of myocardial infarction, stroke, and cancer in or before 2010. In the present study, CHS trajectories were developed from 2006 to 2010 to predict CVD risk from 2010 to 2015. Data analysis was performed from January 1, 2006, to December 31, 2015.The CHS trajectories during 2006-2010 were identified using latent mixture models.Incident CVD events (myocardial infarction and stroke) during 2010-2015 were confirmed by review of medical records. The CHS trajectories were determined using 7 cardiovascular health metrics scored as poor (0 points), intermediate (1 point), and ideal (2 points); total score ranges from 0 (worst) to 14 (best). Based on the baseline CHS and patterns over time, 5 trajectories were categorized (low-stable, moderate-increasing, moderate-decreasing, high-stable I, and high-stable II).Of the 74 701 adults included in the study (mean [SD] age at baseline, 49.6 [11.8] years), 58 216 (77.9%) were men and 16 485 (22.1%) were women. Five CHS trajectories were identified from 2006 to 2010: low-stable (n = 4393; range, 4.6-5.2), moderate-increasing (n = 4643; mean increase from 5.4 to 7.8), moderate-decreasing (n = 14 853; mean decrease from 7.4 to 6.3), high-stable I (n = 36 352; range, 8.8-9.0), and high-stable II (n = 14 461; range, 10.9-11.0). During 5 years of follow-up, 1852 incident CVD cases were identified. Relative to the low-stable trajectory, the high-stable II trajectory was associated with a lower subsequent risk of CVD (adjusted hazard ratio, 0.21; 95% CI, 0.16-0.26, after adjusting for age, sex, educational level, income, occupation, alcohol intake, and serum high-sensitivity C-reactive protein concentration at baseline).Cardiovascular health trajectories may be associated with subsequent CVD risk.
Phase II study of spartalizumab (PDR001) and LAG525 in advanced solid tumors and hematologic malignancies.
Authors: Nataliya Volodymyrivna Uboha, Mohammed M. Milhem, Christina Kovacs, Alpesh Amin, Andrea Magley, D. Das Purkayastha, Sarina Anne Piha-Paul
Journal: Journal of Clinical Oncology (2019)

2553 Background: Spartalizumab and LAG525 are monoclonal antibodies targeting PD-1 and LAG-3, respectively. Dual blockade of PD-1 and LAG-3 has shown synergistic antitumor activity in preclinical models. Here we describe preliminary efficacy of spartalizumab + LAG525 across seven tumor types. Methods: Phase II, open-label, parallel-cohort study was conducted in pts with solid or hematologic malignances relapsed and/or refractory to standard-of-care therapies. Prior immunotherapy was prohibited. LAG525 (400 mg) and spartalizumab (300 mg) were dosed intravenously every 3 weeks. Primary endpoint was clinical benefit rate at 24 weeks (CBR24), assessed using a Bayesian hierarchical model-based futility analysis. Posterior probability that clinical benefit exceeds historical control (Pr) was estimated to determine futility at interim against prespecified thresholds. Results: As of January 7 2019, 76 pts received spartalizumab + LAG525; 72 pts were eligible for analysis (Table). The Pr cut-off for all arms was &gt; 0.70. Hence, neuroendocrine tumors (NET), small cell lung cancer (SCLC) and diffuse large B-cell lymphoma (DLBCL) cohorts all met the expansion criteria with Pr of 0.971, 0.975 and 0.804 respectively. CBR24 were as follows; NET: 0.86, SCLC: 0.27, DLBCL: 0.43. Prostate, sarcoma and ovarian cohorts did not meet the expansion criterion (Pr &gt; 0.70) but were not declared futile; enrollment was paused pending results of next analysis. Gastroesophageal (GE) cancer cohort was stopped for futility due to Pr (0.071) below the futility threshold. Conclusions: Spartalizumab and LAG525 showed promising activity in NET, SCLC and DLBCL that met expansion criteria. The GE cohort was declared futile. Remaining cohorts are paused pending further analysis. Clinical trial information: NCT03365791. [Table: see text]
AB0074 INTERRELATIONSHIP BETWEEN NICOTINIC ACETYLCHOLINE RECEPTOR AND CYTOKINE PRODUCTION NOTED FOLLOWING T-CELL ANTIGEN RECOGNITION AND ACTIVATION
Authors: Nicholas Manolios, Kevin Hou, Han-Shen Tae, David Adams
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> T cells express muscarinic and nicotinic acetylcholine receptors (mAChRs, nAChRs) that increase intracellular Ca<sup>2+</sup> [1] on stimulation. The expression of these receptors on macrophages and their activation by vagal stimulation has recently been the focus for novel arthritis treatment [2]. <h3>Objectives</h3> Our aim in the present study was to assess the effect of various peptides, on cytokine production and nAChRs inhibition. <h3>Methods</h3> nAChR heterologous subunits were expressed in <i>Xenopus</i> oocytes and the inhibitory activity of various peptides at ACh-evoked currents were assessed. The effect of these peptides on T-cell antigen recognition and subsequent cytokine production was assessed using an antigen presentation assay (APA). Briefly, the 2B4.11 murine T cell hybridoma recognizing cytochrome c as the antigen was co-cultured with the antigen presenting B cell hybridoma line LK35.2 (I-Ek bearing) and pigeon cytochrome c in the absence or presence of peptide or several nAChRs antagonists, including mecamylamine (broad nAChR antagonist), waglerin-1 (α1β1εδ), α-bungarotoxin (α7), RgIA (α9α10), Vc1.1 (α9α10) and dihydro-β-erythroidine hydrobromide (α4β4 and α4β2). ELISA and real-time PCR were performed to measure cytokine protein levels and nAChRs T-cells mRNA express levels separately. <h3>Results</h3> At 10μM, peptide W32052 had modest 50-55 % inhibition of human (h) α3β2 and hα4β2 nAChR subtypes, and 35% inhibition at hα9α10. W32052 greatly inhibited chimeric rat α1β1δ-mouse ε (85%) at 10μM. W32052 also inhibited IL-2, IL-6, TNF-α and GM-CSF production at 50μM in the APA. nAChRs antagonists, mecamylamine (100μM), RgIA (10nM), Vc1.1 (17.5μM) and dihydro-β-erythroidine hydrobromide (10μM) could decrease IL-2 production. However, waglerin-1 and α-bungarotoxin did not affect IL-2 production in the APA. <h3>Conclusion</h3> W32052, an antagonist of nAChR, inhibits cytokine production following antigen recognition suggesting that there is a close link between T-cell antigen activation, ion channel regulation mediated by AChR and cytokine production. Further experiments are in progress. <h3>References</h3> [1] Masato M, Yukari I, Takeshi FJ, et al. Acetylcholine released from T cells regulates intracellular Ca2+, IL-2 secretion and T cell proliferation through nicotinic acetylcholine receptor, Life Science, 2017, 172: 13-18. [2] Koopman FA, Chavan SS, Tak PP, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis, PNAS, 2016, 113(29):8248-9. <h3>Disclosure of Interests</h3> None declared
Thromboelastography‐Guided Blood Component Use in Patients With Cirrhosis With Nonvariceal Bleeding: A Randomized Controlled Trial
Authors: Manoj Kumar, Juned Ahmad, Rakhi Maiwall, Ashok Choudhury, Meenu Bajpai, Lalita G. Mitra, Vandana Saluja, Prashant Mohan Agarwal, Chhagan Bihari, Saggere Muralikrishna Shasthry, Ankur Jindal, Ankit Bhardwaj, Guresh Kumar, Shiv K. Sarin
Journal: Hepatology (2019)

Thromboelastography (TEG) provides a more comprehensive global coagulation assessment than routine tests (international normalized ratio [INR] and platelet [PLT] count), and its use may avoid unnecessary blood component transfusion in patients with advanced cirrhosis and significant coagulopathy who have nonvariceal upper gastrointestinal (GI) bleeding. A total of 96 patients with significant coagulopathy (defined in this study as INR >1.8 and/or PLT count < 50 × 109 /L) and nonvariceal upper GI bleed (diagnosed after doing upper gastrointestinal endoscopy, which showed ongoing bleed from a nonvariceal source) were randomly allocated to TEG-guided transfusion strategy (TEG group; n = 49) or standard-of-care (SOC) group (n = 47). In the TEG group, only 26.5% patients were transfused with all three blood components (fresh frozen plasma [FFP], PLTs, and cryoprecipitate) versus 87.2% in the SOC group (P < 0.001). Although 7 (14.3%) patients in the TEG group received no blood component transfusion, there were no such patients in the SOC group (P = 0.012). Also, there was a significantly lower use of blood components (FFP, PLTs, and cryoprecipitate) in the TEG group compared with the SOC group. Failure to control bleed, failure to prevent rebleeds, and mortality between the two groups were similar. Conclusion: In patients with advanced cirrhosis with coagulopathy and nonvariceal upper GI bleeding, TEG-guided transfusion strategy leads to a significantly lower use of blood components compared with SOC (transfusion guided by INR and PLT count), without an increase in failure to control bleed, failure to prevent rebleed, and mortality.
HIV associated head and neck cancers in an inner-city minority population.
Authors: Vatsala Katiyar, Tiago Araujo, Shweta Gupta, Paul G. Rubinstein, Fred R. Rosen
Journal: Journal of Clinical Oncology (2019)

e13124 Background: Head and Neck Cancer (HNC) is a common non-AIDS defining malignancy and its risk increases by 1.7 to 4-fold with HIV infection. Little is known about the epidemiology and outcomes in this subset of patients. This study was undertaken to evaluate the characteristics of HIV+ HNC in an inner city minority population. Methods: All patients with a diagnosis of HNC from January 2008 to December 2017 were identified from the Tumor Registry Database of Cook County Health. We screened patients for HIV+ status at the time of HNC diagnosis. Retrospective chart review of those with Squamous cell carcinoma (SCC) was performed and compared to the largest reported HIV+ HNC cohort (SPORE consortium – J Acquir Immune Defic Syndr. 2015; 65(5):603-10). Other histologies were not included. Results: A total of 1379 charts were screened and 38 unique HIV+ patients with SCC were identified. The most common tumor sites were oral cavity (34%), larynx (26%) and oropharynx (26%), similar to SPORE. However, our cohort had a higher number of African Americans (AA) and a greater proportion of female patients. The median age of diagnosis was 52 years, which is similar in both studies but much lower than the non-HIV population (SEER database - median age 65). Over 63% had an undetectable viral load (VL) compared to 1.4% in SPORE, but the median CD4 count did not differ (298 vs 300 cells/µL). Survival information was available for 27 patients, with a median of 21 months (mo) versus 49 mo in SPORE. Overall survival (OS) was higher in non-smokers (34.5 mo vs 21 mo) and those with CD4&gt;500 when compared to CD4&lt;100 (42mo vs 15mo) Table summarizes the comparison of data. Conclusions: HIV+ HNC was predominantly seen in AA males. When compared to the SPORE cohort, OS was much poorer in the inner city minority, despite similar median age and CD4 counts. In addition, smokers and those with CD4 &lt;100 cells/µL at diagnosis seem to have worse outcomes. [Table: see text]
First-line (1L) ribociclib (RIB) plus letrozole (LET) for postmenopausal women with hormone receptor-positive (HR+), HER2- advanced breast cancer (ABC): MONALEESA-2 long-term safety results.
Authors: Joyce O'Shaughnessy, Mario Campone, Fabrice Andre, Arnd Nusch, Eva-Maria Grischke, Cristian Villanueva, Norbert Marschner, Eric P. Winer, Shani Paluch-Shimon, Karen Rodriguez-Lorenc, Annie Hilliard, Fabienne Le Gac, Antonia Ridolfi, Gabriel N. Hortobagyi
Journal: Journal of Clinical Oncology (2019)

1078 Background: In the phase III MONALEESA-2 study (NCT01958021), 1L treatment (Tx) with RIB (cyclin-dependent kinase 4/6 inhibitor) plus LET significantly prolonged PFS vs placebo (PBO) + LET in patients (pts) with HR+/HER2– ABC (HR 0.56; P&lt;0.0001). In the primary publication (data cutoff, Jan 2016), the median duration of exposure was 13.0 mo (RIB + LET) and 12.4 mo (PBO + LET), and the most common all-grade adverse events (AEs) in the RIB + LET arm were neutropenia (74.3%), nausea (51.5%), infections (50.3%), fatigue (36.5%), and diarrhea (35.0%; Hortobagyi GN, et al. N Engl J Med. 2016;375:1738-48). Here we present long-term safety data from MONALEESA-2. Methods: Pts received either RIB + LET (n=334) or PBO + LET (n=330). AEs were graded per CTCAE v4.03. Results: As of data cutoff (Oct 2018), 79 (24%) pts (RIB + LET) and 39 (12%) pts (PBO + LET) remained on Tx. The median duration of exposure was 20.2 mo (range, 0-54) for RIB + LET and 14.1 mo for PBO + LET, and 30% and 17%, respectively, had ≥ 36 mo of exposure. Neutropenia was the most common exposure-adjusted any-grade AE of special interest (AESI) in the RIB + LET arm (Table). AEs were the most common reason for RIB dose reductions (56.6%) and interruptions (73.4%). Discontinuations due to AEs occurred in 19.2% and 4.2% of pts in the RIB + LET and PBO + LET arms, respectively, and the most common AEs leading to discontinuation in the RIB + LET arm were increased ALT (4.5%), GI disorders (3.3%), and increased AST (2.7%). Prolonged QT led to dose interruption in 0.9% of patients (no discontinuations), and the additional follow-up did not reveal any sudden deaths related to prolonged QT interval beyond the 1 identified in the primary analysis. Conclusions: AEs occurring with 1L RIB + LET in postmenopausal pts with HR+/HER2– ABC were manageable and the safety profile was comparable to that in the primary report. Clinical trial information: NCT01958021. [Table: see text]
Collagen affinity improves efficacy and safety of antibody and cytokine cancer immunotherapy.
Authors: Ako Ishihara, Jun Ishihara, Jeffrey A Hubbell, Melody A Swartz
Journal: Journal of Clinical Oncology (2019)

e14232 Background: Cancer immunotherapy with immune checkpoint inhibitors (CPI) and interleukin (IL)-2 have demonstrated clinical antitumor efficacy but is frequently accompanied with severe side-effects caused by excessive and systemic immune system activation. Methods: We addressed this need by targeting both the CPI antibodies anti-CTLA4 (aCTLA4) + anti-PD-L1 (aPD-L1) and the cytokine IL-2 to tumors via conjugation (for the antibodies) or recombinant fusion (for the cytokine) to a collagen-binding domain (CBD) derived from the blood protein von Willebrand factor (VWF) A3 domain. This approach harnesses the exposure of tumor stroma collagen to blood components due to the leakiness of the tumor vasculature. Results: We show that intravenously (i.v.) administered CBD protein accumulated in tumors in an orthotopic MMTV-PyMT breast tumor model. CBD conjugation or fusion decreased the systemic toxicity of both aCTLA4+aPD-L1 combination therapy and IL-2. CBD-conjugation to CPI abolished T cell infiltration into the liver and eliminated hepatotoxicity as well as decreased systemic cytokine release in the blood serum. CBD-fusion to IL-2 ameliorated capillary leak syndrome and pulmonary edema. These side-effects have been reported in the clinic. CBD-CPI and CBD-IL-2 significantly suppressed tumor growth compared to their unmodified forms in B16F10 melanoma, CT26 colon carcinoma and MMTV-PyMT slow growing breast cancer models, and both CBD-CPI and CBD-IL-2 increased tumor-infiltrating CD8+ T cells; increases in the ratio of effector CD8 + T cells to T regulatory cells were observed. In an orthotopic breast tumor model, combination treatment with CPI and IL-2 eradicated tumors in 9/13 animals with the CBD-modified drugs, whereas it did so in only 1/13 animals with the unmodified drugs. Conclusions: Our data suggest that the A3 domain of VWF can be used to engineer immunotherapies (e.g. CPI and cytokine) with high translational promise as systemically-administered tumor targeting drugs with improved safety and efficacy compared to their native forms.
Neighborhood effects and obesity in adult survivors of pediatric cancer: A report from the St. Jude Lifetime Cohort Study.
Authors: Carrie R. Howell, Carmen Louise Wilson, Yutaka Yasui, Deo Kumar Srivastava, Wei Liu, Kari L. Bjornard, Matthew J. Ehrhardt, Tara M. Brinkman, Wassim Chemaitilly, Jason R. Hodges, Jennifer Q. Lanctot, Leslie L. Robison, Melissa M. Hudson, Kirsten K. Ness
Journal: Journal of Clinical Oncology (2019)

e23051 Background: Survivors of childhood cancer are at risk for obesity and associated chronic health conditions - risks that are potentially modifiable if survivors adopt a lifestyle with adequate physical activity and a healthy diet. Neighborhoods where survivors reside may influence uptake of health behaviors. We examined associations between neighborhood factors and obesity in survivors. Methods: Adult survivors participating in the St. Jude Lifetime cohort with addresses available for geocoding were eligible for analysis [N = 2265, mean assessment age 32.5 (SD 9.1) years, 46% female, and 85% white]. Survivors completed questionnaires regarding individual behaviors; percent body fat was assessed via dual x-ray absorptiometry (obesity: ≥25% males; ≥35% females); and neighborhood effects were characterized using census tract of residence (e.g. neighborhood socioeconomic status (SES), rurality). Structural equation modeling (SEM) was used to determine associations between neighborhood effects, physical activity, diet, smoking, treatment exposures, and obesity. Results: Obese survivors (n = 1420, 62.7%) lived in neighborhoods with less access to exercise opportunities (63% vs 66%, p = 0.01) and lower SES (22% vs 18%, p &lt; 0.001); and were more likely to live in small town/rural areas (14% vs 10%, p = 0.04) compared to non-obese survivors. Obese survivors who lived in the lowest SES neighborhoods were more likely to be CNS tumor survivors (17% vs 12%, p = 0.02) and received higher mean doses of cranial radiation (CRT) (15Gy vs 11Gy, p = 0.02) than obese survivors living in higher SES neighborhoods. Resource poor neighborhoods (standardized effect: 0.09, p &lt; 0.001) and CRT (0.14, p &lt; 0.001) had direct effects on percent body fat. Associations between neighborhood of residence and percent body fat were attenuated (-0.02, p &lt; 0.001) among individuals with a better diet. Conclusions: The neighborhood in which a childhood cancer survivor resides as an adult is associated with obesity, and obese survivors treated with CRT are more likely to live in neighborhoods with lower SES. Interventions targeting survivors should incorporate strategies that address environmental influences on obesity.