tbuckley/cabot-search huggingface dataset:
Oral Rehydration Solution—An Essential Therapy for Childhood Gastroenteritis
Authors: Alfredo Guarino, Eugenia Bruzzese, Andrea Lo Vecchio
Journal: JAMA Pediatrics (2018)

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Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis
Authors: Kim Papp, Kenneth Gordon, Diamant Thaçi, Akimichi Morita, Melinda Gooderham, Peter Foley, Ihab G. Girgis, Sudeep Kundu, Subhashis Banerjee
Journal: New England Journal of Medicine (2018)

Tyrosine kinase 2 (TYK2) signaling pathways, which mediate cytokine signaling, are implicated in the pathophysiology of psoriasis. Selective inhibitors of TYK2 may be effective in treating psoriasis.
Survival in patients with hepatocellular carcinoma (HCC): A report of 1444 patients treated within a multidisciplinary program.
Authors: Mary A. Maluccio, Yong Zang, Wenhu Pi, Mark Tann, Chandrashekhar Kubal, Marco A Lacerda, Bert H. O'Neil, David M Agarwal, Feng-Ming (Spring) Kong
Journal: Journal of Clinical Oncology (2017)

e15652 Background: The evolution of treatment for HCC has seen novel therapies emerge as front line treatment alternatives. The aim of this study was to report survival in HCC patients treated within the context of a robust multidisciplinary program and to identify patient and tumor specific factors that direct patient centered treatment decisions and optimize outcome. Methods: This is retrospective analysis of medical records identified through the cancer registry at our institution from 2000 to 2016. Variables analyzed for survival significance included patient factors (age, gender, race, tobacco history, alcohol history, and marital status) and tumor factors (tumor size, histology grade, AFP level, SEER stage, clinical and pathologic stage). Survival was estimated from the time of diagnosis to the last contact. Results: A total of 1444 consecutive patients with confirmed HCC were eligible for this analysis. Median follow-up was 45 months. Median survival was 18 months (95% CI: 11-25 months). The overall 1-, 3-, and 5-year survival rates were 63, 40, and 35%, respectively. Significant prognostic parameters were SEER stage (HR = 2.3, p = 2x10 -16 local as the reference), pathologic stage (HR = 1.2, p = 3×10 -9 ), tobacco history (HR = 1.2, p = 0.03), , and clinical stage (HR = 1.1, p = 4x10 -5 ). Of a total of 380 patients resected, median and 3-year survival were 75 months and 63% (95% CI: 58-69%). The only significant prognostic parameter associated with survival in resection patients was SEER stage (HR = 1.7, p = 0.002). The 5 year survival for all patients versus those resected were 44% (95% CI: 40-48) /59% (95% CI: 53-65), 21% (95% CI: 17-27) /36% (95% CI: 24-54), and 11% (95% CI: 5-20) /25% (95% CI: 6-100) for localized, regional, and distant disease, respectively. Conclusions: Survival has improved for patients with HCC due to an increased number of available options and better methods to identify tumor and patients specific variables that individualize care. The significance of SEER stage suggests that early detection remains critical for survival.
Individualization of high dose carboplatin based on therapeutic drug monitoring (TDM) for the treatment of testicular germ cell tumors (TICE protocol): Results of a multicenter phase II study.
Authors: Fabienne Thomas, Sotheara Moeung, Sophie Broutin, Jerome Guitton, Michele Boisdron-Celle, Joseph Ciccolini, Christophe Massard, Aude Flechon, Remy Delva, Gwenaelle Gravis, Jean-Pierre Lotz, Jacques-Olivier Bay, Marine Gross-Goupil, Angelo Paci, Vianney Poinsignon, Karim Fizazi, Thierry Lafont, Isabelle Lochon, Christine Chevreau, Etienne Chatelut
Journal: Journal of Clinical Oncology (2017)

4554 Background: We conducted a national phase II multicenter trial that aimed at evaluating the efficacy and tolerance of Paclitaxel plus Ifosfamide followed by high-dose carboplatin plus etoposide treatment (TICE) in previously treated germ cell tumors. The particularity of our study (in comparison with the standard protocol [Motzer RJ, et al. J Clin Oncol 2000 Mar; 18(6): 1173-1180.]) is that the carboplatin dose was individualized for each patient according to therapeutic drug monitoring (TDM) in order to reach the target AUC of 24 mg.min/ml over 3 days. Methods: In total, 89 patients were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/ml over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC and the intra- and inter-cycle clearance variability. Secondly, a population pharmacokinetic analysis was also performed on 59 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future patients treated with the TICE protocol. The performance of this new equation was then prospectively evaluated on the other 30 patients along with different methods of carboplatin clearance prediction. Results: TDM allowed us to control the carboplatin exposure with a mean actual AUC of 24.5 mg.min/ml (22.2 and 28.0 for 5 th and 95 th percentile respectively) per cycle. We observed a modest but significant decrease of carboplatin clearance over cycles (median value of change of -11.8% from cycle 1 to cycle 3, maximum value of -36%). The new covariate equation allows unbiased and more accurate prediction of carboplatin clearance in the prospective validation cohort compared to other equations. Conclusions: Carboplatin TDM allowed the target AUC to be accurately reached and thereby avoid over- or under-exposure. We propose a new equation to predict carboplatin clearance more adapted to these particular patients (young males) that could be used as an alternative if the TDM cannot be organized. Clinical trial information: 2008-005068-14.
A phase 1/2 study to evaluate safety and efficacy of nivolumab plus brentuximab vedotin in patients with CD30-expressing relapsed/refractory non-Hodgkin lymphomas (NHLs).
Authors: Philippe Armand, Joshua Brody, Paul M. Barr, Andrei R. Shustov, Alison J. Moskowitz, Justin Paul Kline, Kerry J. Savage, John Kuruvilla, Neil C. Josephson, Pier Luigi Zinzani, Gilles A. Salles, Aisha Masood, Stephen Maxted Ansell
Journal: Journal of Clinical Oncology (2016)

TPS7576 Background: Nivolumab (nivo) is a fully-human immunoglobulin G4 monoclonal antibody immune checkpoint inhibitor that targets programmed death receptor-1 (PD-1) to restore active T-cell immune responses against the tumor. While PD-1 blockade has shown encouraging activity in aggressive B-cell and T-cell NHL,1 the majority of patients (pts) either do not respond or progress after an initial response. Combination therapy with therapeutic agents such as antibody-drug conjugates may increase the frequency and durability of responses, through both direct cell killing and immunogenic consequences of cell death. Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate that has shown anti-tumor activity in a wide range of lymphoid malignancies. BV works primarily by inducing cell cycle arrest and apoptotic death in CD30-expressing cells. As BV may also mediate immunogenic cell death, it could synergize with PD-1 blockade.2 We hypothesize that nivo and BV may induce frequent and durable responses in pts with CD30+ relapsed, refractory T-cell NHL and diffuse large B-cell lymphoma (DLBCL). Methods: This phase 1/2 open-label, international, multicenter study (NCT02581631), investigates the safety and efficacy of nivo combined with BV in pts with relapsed/refractory NHL. Pts (aged ≥ 18 yrs) with relapsed/refractory DLBCL, peripheral T-cell lymphoma (excluding anaplastic large cell lymphoma), or cutaneous T-cell lymphoma (mycosis fungoides/Sézary syndrome) are eligible. All pts must have expression of CD30 on ≥ 1% of tumor cells (by IHC analysis). In the ph1 portion, pts will receive nivo + BV with dose de-escalation for excessive toxicity. In the ph2 portion, an extra 90 pts will be enrolled across the 3 histologic subgroups. Primary endpoints: safety, tolerability, and objective response rate. Secondary endpoints: duration of response, complete response rate, duration of complete response, progression-free survival, overall survival, and biomarker analyses. Accrual is ongoing. References: 1. Armand P et al. Haematologica 2015;100(Suppl 1):S808 [abstract] 2. Gardai SJ et al. Cancer Res 2015;75(15 Suppl):2469 [abstract] Clinical trial information: NCT02581631.
TCT-288 Early Thoracic Endovascular Aortic Repair (TEVAR) of Uncomplicated Type B Thoracic Aortic Dissection in the Cardiac Catheterization Laboratory: The Rise of the Cardio-Vascular Interventionalist
Authors: Matthew McDiarmid, Khawaja Afzal Ammar, Lauren Richards, Mirza Nubair Ahmad, Jayant Khitha, M. Fuad Jan, Tonga Nfor, Suhail Q. Allaqaband, Tanvir Bajwa, Eric Weiss
Journal: Journal of the American College of Cardiology (2018)
Efficacy of a repeat dose injection of CLR 131 (I-131-CLR1404) in U87-MG tumor-bearing athymic nude mice.
Authors: Katherine Oliver, Jarrod Longcor, Irawati Kandela
Journal: Journal of Clinical Oncology (2017)

e14089 Background: CLR 131 is a novel radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Study was to evaluate the therapeutic effect of CLR 131 when administered as a repeat dose intravenous injection in U87-MG tumor bearing mice. Malignant gliomas are associated with a low survival rate, and treatment with chemotherapy, external beam radiation, or surgery have shown limited effectiveness. In this study, therapeutic effect was evaluated by measurement of tumor volume increase and by survival of CLR 131 treated animals compared to animals dosed with a I-127-CLR1404 control. Methods: The U87-MG cell line (human glioma) was purchased from American Type Culture Collection (ATCC, Rockville, MD) and maintained in MEM media supplemented with 10% fetal bovine serum. Twenty female athymic nude mice (Harlan, Indianapolis, IN) weighing between 16-20 g were anaesthetized with isofluorene and inoculated subcutaneously in the right flank with 1 x 10 6 U87-MG tumor cells suspended in 50 μL PBS. The mice were given potassium iodide at a concentration of 0.1% in their drinking water to block possible free iodide in the drug formulation, with the addition of 0.4% (w/v) sweetener (Sweet and Low) to aid palatability, three days prior to injection and continuing through two weeks post injection. Doses of 95.7µCi and 109.0 µCi of CLR 131were given at Day 0 and Day 7 (N = 8 per group). Control doses of I-127-CLR1404 were given at the indicated dose and was injected via tail vein on Day 0 and Day 7. Results: The control group’s tumors increased 25-fold over a period of four weeks and the treatment group’s tumors increased 12-fold over the same period. There was a significant difference between the control and treatment tumor volumes. Mean survival time was 24.5 days and 31.9 days post injection, respectively. Conclusions: CLR 131 represents a unique, first in class targeted radiotherapeutic currently in clinical development. This study shows that CLR 131 dosed twice provides significant inhibition of tumor growth in a U87-MG tumor model which is known for very aggressive growth. Additionally, CLR 131 provided an overall survival benefit over the control group.
P03.06 Introduction of post neuro oncology multidisciplinary team meeting clinic to improve patient pathway within a tertiary care centre
Authors: F R Berki
Journal: Neuro-Oncology (2018)

Patients with suspected newly presenting or recurrent neurological malignancy are discussed at the regional neuro-oncology multi-disciplinary team meeting (MDTM). Following discussion, patients would wait for a slot to see their consultant or attend one of the wards on an ad hoc basis. This system could potentially result in delays formulating appropriate oncological plans; resulting in increased patient/carer anxiety and a complicated pathway to definitive treatment. A number of initiatives were introduced in August 2017 including dedicated theatre lists with core neuro-oncology neurosurgeons and a specific one-stop clinic for patients discussed at the MDTM; with the aim of expediting early review and implementation of definitive management. Patients are seen within 48 hours of MDTM discussion by a core member with a neuro-oncology Clinical Nurse Specialist present. We aimed to review the utilisation of this clinic to date. Materials and Methods: Attendances at the multi-disciplinary neuro-oncology clinic between August 2017 and May 2018 are prospectively recorded in a database. We reviewed the number of patient attendances and whether a definitive decision had been made in that clinic. 2233 patients have been discussed in total in a 12 month period ending in April 2018. Since introduction of the clinic in August 2017 until present (May 2018), 270 patients have been seen. 142 of these were patients with newly presented suspected neurological malignancy. The majority of these patients were seen within 48 hours of MDTM discussion. Of these 81 (57%) were listed for radical surgery (craniotomy), 51 (36%) were listed for a surgical procedure other than a craniotomy including biopsy, insertion of shunt etc, and 10 (7%) were deemed to be for best supportive care only. The specialist neuro-oncology multi-disciplinary clinic has been utilised well. Patients are seen within a timely fashion with appropriate members of the team present and definitive management plans are made. Further work will be carried out including a survey of patient satisfaction and an audit of patient pathway timings with the aim of comparing patient waiting times from MDTM to definitive oncological management plan being made pre- and post-introduction of the clinic.
Phase 1b/2 study of intratumoral Ad-RTS-hIL-12 + veledimex in patients with chemotherapy-responsive locally advanced or metastatic breast cancer.
Authors: Heather L. McArthur, David B. Page, Tracy Ann Proverbs-Singh, Stephen Barnett Solomon, Clifford A. Hudis, Larry Norton, Sujata Patil, John A Barrett, Francois M. Lebel
Journal: Journal of Clinical Oncology (2016)

TPS3097 Background: Immune-based strategies involving T-cell activation have shown significant activity in multiple tumor types. The presence of immune elements in breast cancers has prognostic and predictive impact. Thus, strategies that optimize the interplay between breast cancer and the effected individual’s immune system may be therapeutic. Interleukin-12 (IL-12), a pro-inflammatory cytokine, reverses immune escape mechanisms induced by myeloid derived suppressor and dendritic cells which, in turn, improves the function of activated CD8+ T cells and promotes tumor stroma collapse. Because tumor neoantigens may be generated in response to chemotherapy, IL12-mediated immune modulation may be optimal in patients with chemotherapy-sensitive metastatic breast cancer. Ad-RTS-hIL-12 (Ad) is a novel gene therapy candidate expressing IL-12 under the control of an orally-administered activator ligand, veledimex (V) through the proprietary RheoSwitch Therapeutic System (RTS). Methods: Open-label, phase 1b/2, single-arm, single-center study to evaluate the safety and tolerability of Ad+V in women with stable or responsive disease after ≥ 12-weeks of 1st or 2nd-line chemotherapy. Up to 40 patients, including up to 8 HER2+patients will be placed on chemotherapy-holiday and enter the immunotherapy phase, consisting of a single cycle of Ad administered intratumorally (Day 1), along with V (80 mg QDx7). HER2-directed antibody therapy may be continued during the immunotherapy phase for women with HER2- disease. Women ≥ 18 years with histologically-confirmed locally advanced or metastatic breast cancer who have achieved a partial response (PR) or stable disease (SD) to 1st or 2nd-line chemotherapy are eligible. Secondary endpoints include 12 week overall response rate, disease control rate and impact on exploratory immune biomarkers. Summary: Ad+V is a novel gene therapy which controls local expression of IL-12 and may stimulate an anti-cancer T cell immune response. The ability to regulate the production of IL-12 by modulating V dosing may result in an improved therapeutic index in combination with standard of care. Clinical trial information: NCT02423902.
Treatment-related dietary changes and management of nutrition-related treatment side effects: Experiences and perspectives of individuals with cancer and their caregivers.
Authors: Brandy-Joe Milliron, Dan Dychtwald, Jonathan Deutsch, Yuxi Zeng, Kira Sy, Byron Barksdale, Ochi Ogbogu, Lora Packel
Journal: Journal of Clinical Oncology (2018)

e22058 Background: Treatment-related changes in taste perception, food preferences, and food-related quality of life are significant challenges among individuals with cancer and their caregivers, but the extent to which these disturbances affect dietary behaviors is not clear. The objectives were to characterize treatment-related dietary changes and their impact on dietary behaviors among individuals with cancer, and related challenges among cancer caregivers. Methods: A convergent mixed methods design was used. Individuals with cancer and their caregivers were recruited from American Cancer Society’s Philadelphia Hope Lodge to complete surveys and in-depth interviews. Questions regarding treatment side effects and food preferences were adapted from a previously tested questionnaire. Descriptive statistics were calculated. Interviews were recorded, transcribed verbatim, and analyzed using inductive thematic analysis. Results: Thirty-nine patients (n = 19, 67% male, 73% ≥55 yrs) and caregivers (n = 20, 31% male, 63% ≥55 yrs) completed study activities. Three themes emerged: nutrition-related side effects, challenges in side effect management, and lack of nutrition support. Nearly 90% of patients reported one or more treatment-induced side effects, including fatigue (67%), dry mouth (47%), mouth ulcers (33%), difficulty swallowing (27%), nausea (20%), persistent after- taste (20%), diarrhea (20%), constipation (20%), and difficulty chewing (13%). Participants reported changes in taste and diet, reduced interest in food, and weight loss. Caregivers reported challenges in providing nutritional support for their loved one and changes in their own dietary behaviors. Both groups reported lack of nutritional counseling and insufficient treatment options for anticipated dietary side effects of treatment. Conclusions: A lack of information and intervention strategies for dietary issues were salient issues in both people with cancer and their caregivers. Additional research is critical to test new strategies to alleviate the effects of nutrition-related side effects and provide tailored nutrition intervention.
A randomised, double-blind, placebo-controlled phase IIa trial of AMG319 given orally as neoadjuvant therapy in patients with human papillomavirus (HPV) positive and negative head and neck squamous cell carcinoma (HNSCC).
Authors: Christian H.H Ottensmeier, Terry Jones, Joseph J Sacco, James Anthony McCaul, Peter Brennan, Claire Paterson, Andrew Graeme Schache, Richard Shaw, Rabindra P Singh, Joseph H. Davies, Lindsey Chudley, Danielle Jeffrey, Gareth Thomas, Paul Loadman, Nicola A Dobbs, Louisa Essame, Gary Acton, Sidath Katugampola, Bart Vanhaesebroeck, Emma King
Journal: Journal of Clinical Oncology (2018)

6068 Background: AMG319 is a PI3Kδ inhibitor. Preclinically, target inhibition abrogates Treg mediated immunosuppression, augmenting CD8+ T-cell anti-tumour activity. This study aims to quantify the immunological effects of AMG319 on the tumour microenvironment in HNSCC patients (pts). Methods: The trial is a neoadjuvant window study of 54 pts, randomised 2:1 to AMG319/placebo for 20-29 days. Eligible pts have operable HNSCC, ECOG 0/1, adequate organ function and no active autoimmune disease. Primary endpoints are changes in tumour-infiltrating immune cell density, safety and toxicity. Changes in circulating immune markers, pAKT and change in tumour volume (pre-dosing vs immediately pre-surgery) are also assessed. Steady state plasma concentrations of AMG319 are determined at days 8, 15 and 22. Humoral and cellular immune responses to a tetanus vaccine are employed to confirm non-tumour immunocompetence. Results: Blinded clinical and laboratory data have been reviewed for 22 pts who received 400mg/day of AMG319/placebo. Ten pts experienced grade 2/3 treatment related adverse events (AEs): rash, diarrhoea/colitis, vomiting, fever, flu-like symptoms (days 7-11). AEs resolved with withdrawal of IMP and supportive treatment but led to early discontinuation in 9 pts; 8 pts received less than 80% of the intended dose. pAkt levels on both day 1 and 15 show inhibition of PI3K (51.6-88.9%) 4h post dosing in a proportion of pts. A ≥ 2-fold increase was seen in anti-tetanus antibody response in 5/10 pts analysed. One patient experiencing immune-like toxicity with a T1 oral cavity squamous cell carcinoma achieved a complete pathological response. Conclusions: The percentage inhibition demonstrated in the pAkt assay and observed in HNSCC is similar in magnitude to that seen previously with AMG319 in patients with advanced B cell malignancies, thereby supporting target inhibition. Cutaneous and GI toxicities are consistent with Treg depletion suggesting that efficacy and toxicity may be mechanistically interrelated. The trial is ongoing to further explore AMG319 solid tumour dosing regimens. Clinical trial information: NCT02540928.