tbuckley/cabot-search huggingface dataset:
Error in Statistical Code in Cluster Randomized Trial on the Effect of a Breakfast in the Classroom Initiative on Obesity in Urban, School-aged Children
Authors: Gary D. Foster
Journal: JAMA Pediatrics (2019)

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Therapy alteration of solid tumors based on FoundationOne comprehensive genome profiling assay.
Authors: Kirill Karlin, Abdullah Kahraman, Alessandra Curioni Fontecedro, Holger Moch, Martin Zoche, Alexander Rheinhard Siebenhuener
Journal: Journal of Clinical Oncology (2019)

e14742 Background: Molecular profiling assays are becoming widely available and provide valuable information on tumor characteristics, which can identify targeted therapies or immunotherapies for cancer patients. However, the clinical utility of such tests remains unclear. Within our institution, we analyzed the clinical utility and subsequent treatment alterations of the FoundationOne Comprehensive Genome Profiling Test (FOne). Methods: We conducted a retrospective cohort review (2017 - 2018) of patients with solid tumors under standard diagnostic care who received FOne testing. We reviewed the therapies that were proposed by FOne and studied whether they led to a therapeutic alteration. Results: 71 patients were identified, of which the majority presented a progressive disease state (80%). Among the cancer types most frequently tested were adenocarcinoma of the colon (14%), prostate (8%), lung (4%), intrahepatic cholangiocarcinoma (8%) and breast invasive ductal carcinoma (4%). In 16 cases (22%), therapies suggested by FOne were approved in patient’s tumor type while in 30 cases (42%) therapies were approved in another tumor type. For an additional 13 cases (18%) only therapies tested in clinical trials were reported. 4 patients (6%) received a new therapy based on the FOne result: cancer of unknown primary (Everolimus due to a TSC1 mutation), cutaneous angiosarcoma (Pembrolizumab due to a high tumor mutational burden (TMB)), gastrointestinal neuroendocrine carcinoma (Ipilimumab and Nivolumab due to an intermediate TMB) and mucinous adenocarcinoma of the appendix (Talazoparib due to an ATM mutation). For 11 cases (15%), a new therapy option was identified by FOne, which due to the current treatment plan might be considered for later use. 3 cases (4%) were evaluated for potential clinical trial enrollment. Note that for an additional 6 patients (8%), the therapies proposed by FOne were already established on the basis of previous testing (e.g. smaller genomic panels, IHC, FISH). Conclusions: Overall, 18 (25%) patients received a new therapy option by FOne after standard of care diagnostics. Therapeutic alterations were observed particularly in patients with a rare or unknown tumor type.
Performance of FACT-GOG-Ntx to assess chemotherapy-induced peripheral neuropathy (CIPN) in pediatric Hodgkin lymphoma (HL) patients.
Authors: Sharon M. Castellino, Angie Mae Rodday, Qinglin Pei, Rizvan Bush, Frank G. Keller, Tara O. Henderson, Kara M. Kelly, David Cella, Susan K. Parsons
Journal: Journal of Clinical Oncology (2019)

10064 Background: CIPN is a common, but under-recognized complication of tubulin toxins, which are key to curative therapy for HL. In the absence of validated, self- or proxy-report measures for children, CIPN reporting has depended on clinical grading scales. The goal of this study was to assess the psychometric properties of the FACT-GOG-Ntx measure in a pediatric population. Methods: Youth (11+ yrs) and parents of all children (5-18 yrs) with newly diagnosed high risk HL, enrolled on AHOD1331 (NCT02166463), serially completed the FACT-GOG-Ntx, a validated measure of CIPN in adults. Cronbach’s alpha coefficient (reliability) and intra-class coefficients (ICC) were calculated. FACT-GOG-Ntx total scale and 4-item sensory subscale scores (Ntx4) at Cycle 5 (dose peak) and 6-8 weeks after last cycle (End Rx) were compared to mandatory clinical grading, using the Balis Scale with any neuropathy defined as &gt; grade 1 on Balis. Results: 279 youth and 291 parents completed study measures. Cronbach’s alpha exceeded 0.80 for both raters. Inter-rater agreement was strong (ICC=0.89). Sixty (20%) patients had any neuropathy on Balis. Those with CIPN had significantly lower total and Ntx4 scores than those without at cycle 5 and End Rx and for both raters (p&lt;0.05) (Table). Conclusions: This is the first application of the FACT-GOG-Ntx in a pediatric HL trial. We demonstrate that the measure was reliable for both raters and had strong intra-rater agreement. Validity was demonstrated by significantly lower FACT-GOG-Ntx scores among patients with evidence of CIPN on clinical exam. Comparisons between study arms will be evaluated after study accrual is completed. [Table: see text]
Review: Serum biomarkers in idiopathic pulmonary fibrosis and systemic sclerosis associated interstitial lung disease – frontiers and horizons
Authors: Adelle S. Jee, Joanne Sahhar, Peter Youssef, Jane Bleasel, Stephen Adelstein, Maianh Nguyen, Tamera J. Corte
Journal: Pharmacology & Therapeutics (2019)
Opioid–galanin receptor heteromers differentiate the dopaminergic effects of morphine and methadone
Authors: Randal A. Serafini, Venetia Zachariou
Journal: Journal of Clinical Investigation (2019)

As the opioid addiction crisis reaches epidemic levels, the identification of opioid analgesics that lack abuse potential may provide a path to safer treatment of chronic pain. Preclinical studies have demonstrated that galanin affects physical dependence and rewarding actions associated with morphine. In the brain and periphery, galanin and opioids signal through their respective GPCRs, GalR1-3 and the μ-opioid receptor (MOR). In this issue of the JCI, Cai and collaborators reveal that heteromers between GalR1 and MOR in the rat ventral tegmental area attenuate the potency of methadone, but not other opioids, in stimulating the dopamine release that produces euphoria. These studies help us understand why some synthetic opioids, such as methadone, do not trigger the release of dopamine in the mesolimbic system but still possess strong analgesic properties.
Evaluation of oral S-1 as a first-line chemotherapy for metastatic HER2-negative breast cancer: An analysis of two randomized phase III studies (SELECT BC-CONFIRM and SELECT BC).
Authors: Reiki Nishimura, Hirofumi Mukai, Yukari Uemura, Hiromitsu Akabane, Youngjin Park, Masato Takahashi, Yoshiaki Sagara, Tsutomu Takashima, Tomomi Fujisawa, Yasuo Hozumi, Takuya Kawahara, Takanori Watanabe
Journal: Journal of Clinical Oncology (2019)

1083 Background: Anthracycline regimens and taxane have been first line chemotherapeutic options for HER2 negative metastatic breast cancer. In a previous phase III trial (SELECT BC), non-inferiority of S-1 was demonstrated in terms of overall survival (OS). The SELECT BC-CONFIRM study was designed to confirm the results of the SELECT BC study and to combine the two randomized studies. Methods: Patients (n = 618) in the first trial were randomly assigned (1:1) to the S-1 group or the taxane group. Patients (n = 230) in the second trial (SELECT BC-CONFIRM) were randomly assigned to the anthracycline group or the S-1 group. Treatment continued until tumor progression, unacceptable toxic effects, or completion of six courses in the standard regimen group and four courses in the S-1 group. The primary endpoint was OS and secondary endpoints were progression-free survival (PFS), time to treatment failure, adverse events, HRQOL and cost-effectiveness. A pooled analysis of the two studies was predefined to confirm the results of the SELECT BC study. Results: 1. The HR for the anthracycline group was 1.09 [95%CI 0.80-1.48] in SELECT BC-CONFIRM, and the estimated predictive posterior probability that the HR does not exceed the threshold 1.333 was 90.27%. 2. Median OS was 32.7 months (S-1 group) and 36.3 months (standard treatment group). S-1 was not inferior to standard treatment in terms of OS (p non-inferiority = 0.0062). Median PFS was 11.2 months (S-1 group) and 11.2 months (standard treatment group). 3. Treatment was discontinued due to adverse events (i.e., neutropenia, febrile neutropenia, fatigue and edema) in 5.7% in the S-1 group and 6.6% in the standard treatment group 4. The EORTC QLQ-C30 questionnaire (global health status) revealed that there was no difference between the S-1 and anthracycline groups (p = 0.257), but there was a significant difference between the S-1 and taxane groups (p = 0.0039). Conclusions: S-1 is not inferior to taxane or anthracycline with respect to OS as a first-line treatment for MBC. S-1 should be considered a new option as a first-line chemotherapy for HER2-negative metastatic breast cancer patients. Clinical trial information: UMIN000005449.
Prospective phase II trial in patients with first relapse of high-grade astrocytoma using TVB-2640 in combination with bevacizumab versus bevacizumab alone.
Authors: Brandon Konkel, Laura D Caflisch, Adolfo Enrique Diaz Duque, Joel Michalek, Qianqian Liu, Andrew Jacob Brenner
Journal: Journal of Clinical Oncology (2019)

2064 Background: Recurrent glioblastoma (rGBM) following chemoradiation is associated with a poor prognosis. While bevacizumab is the most common salvage therapy, responses remain brief and without an associated survival benefit. Resistance may involve overexpression of Fatty Acid Synthase (FASN). Our institution is conducting a phase 2 study of bevacizumab with FASN inhibitor TVB-2640 in patients with GBM in first relapse. Methods: This is a prospective, phase 2 study of bevacizumab with TVB-2640 in patients with GBM in first relapse. Primary end point is progression free survival (PFS). Inclusion criteria are: age ≥ 18, ECOG 0 to 2, GBM progression following standard combined modality treatment. Randomization into two arms for the first 28 days is included for exploratory biochemical analysis: patients in arm 1 receive bevacizumab every 2 weeks in combination with TVB-2640; those in arm 2 receive bevacizumab alone every 2 weeks. MR-Spectroscopy (MRS) and serum sampling for exosome analysis are obtained on patients at day 1 and 28 of first cycle. Starting on cycle 2 day 1, all patients converge to a single arm and continue to receive bevacizumab in combination with TVB-2640. Results: We have enrolled 24 patients to date; 23 have started treatment. Of those 23 patients, 10 have died, 4 have progressed but are still alive, 2 withdrew, and 7 are still active on trial. The PFS6 is and OS9 are both currently 50%, which compares favorably with historical controls. There have been no reports of grade 4 or 5 treatment-related AEs (of note, 2 deaths were thought definitely unrelated to treatment, including 1 case of intracerebral hemorrhage, and 1 case of sepsis). There have been two cases of grade 3 hand-foot syndrome thought definitely related to treatment. Updated results will include PFS, response, and biomarker analysis (exosome, MRS). Conclusions: The combination of TVB2640 with bevacizumab appears be well tolerated. PFS6 and OS9 are both currently 50%. The study has completed accrual with final data expected later in 2019. Clinical trial information: NCT03032484.
Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: CAO/ARO/AIO-12
Authors: Emmanouil Fokas, Michael Allgäuer, Bülent Polat, Gunther Klautke, Gerhard G. Grabenbauer, Rainer Fietkau, Thomas Kuhnt, Ludger Staib, Thomas Brunner, Anca-Ligia Grosu, Wolff Schmiegel, Lutz Jacobasch, Jürgen Weitz, Gunnar Folprecht, Anke Schlenska-Lange, Michael Flentje, Christoph-Thomas Germer, Robert Grützmann, Matthias Schwarzbach, Vittorio Paolucci, Wolf O. Bechstein, Tim Friede, Michael Ghadimi, Ralf-Dieter Hofheinz, Claus Rödel
Journal: Journal of Clinical Oncology (2019)

Total neoadjuvant therapy is a new paradigm for rectal cancer treatment. Optimal scheduling of preoperative chemoradiotherapy (CRT) and chemotherapy remains to be established. We conducted a multicenter, randomized, phase II trial using a pick-the-winner design on the basis of the hypothesis of an increased pathologic complete response (pCR) of 25% after total neoadjuvant therapy compared with standard 15% after preoperative CRT. Patients with stage II or III rectal cancer were assigned to group A for induction chemotherapy using three cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy) or to group B for consolidation chemotherapy after CRT. Secondary end points included toxicity, compliance, and surgical morbidity. Of the 311 patients enrolled, 306 patients were evaluable (156 in group A and 150 in group B). CRT-related grade 3 or 4 toxicity was lower (37% v 27%) and compliance with CRT higher in group B (91%, 78%, and 76% v 97%, 87%, and 93% received full-dose radiotherapy, concomitant fluorouracil, and concomitant oxaliplatin in groups A and B, respectively); 92% versus 85% completed all induction/consolidation chemotherapy cycles, respectively. The longer interval between completion of CRT and surgery in group B (median 90 v 45 days in group A) did not increase surgical morbidity. A pCR in the intention-to-treat population was achieved in 17% in group A and in 25% in group B. Thus, only group B (P < .001), but not group A (P = .210), fulfilled the predefined statistical hypothesis. Up-front CRT followed by chemotherapy resulted in better compliance with CRT but worse compliance with chemotherapy compared with group A. Long-term follow-up will assess whether improved pCR in group B translates to better oncologic outcome.
A Simple RNA Target Capture NGS Strategy for Fusion Genes Assessment in the Diagnostics of Pediatric B‐cell Acute Lymphoblastic Leukemia
Authors: Andrea Grioni, Grazia Fazio, Silvia Rigamonti, Vojtech Bystry, Giulia Daniele, Zuzana Dostalova, Manuel Quadri, Claudia Saitta, Daniela Silvestri, Simona Songia, Clelia T. Storlazzi, Andrea Biondi, Nikos Darzentas, Giovanni Cazzaniga
Journal: HemaSphere (2019)

Acute lymphoblastic leukemia (ALL) is the most frequent pediatric cancer. Fusion genes are hallmarks of ALL, and they are used as biomarkers for risk stratification as well as targets for precision medicine. Hence, clinical diagnostics pursues broad and comprehensive strategies for accurate discovery of fusion genes. Currently, the gold standard methodologies for fusion gene detection are fluorescence in situ hybridization and polymerase chain reaction; these, however, lack sensitivity for the identification of new fusion genes and breakpoints. In this study, we implemented a simple operating procedure (OP) for detecting fusion genes. The OP employs RNA CaptureSeq, a versatile and effortless next-generation sequencing assay, and an in-house as well as a purpose-built bioinformatics pipeline for the subsequent data analysis. The OP was evaluated on a cohort of 89 B-cell precursor ALL (BCP-ALL) pediatric samples annotated as negative for fusion genes by the standard techniques. The OP confirmed 51 samples as negative for fusion genes, and, more importantly, it identified known (KMT2A rearrangements) as well as new fusion events (JAK2 rearrangements) in the remaining 38 investigated samples, of which 16 fusion genes had prognostic significance. Herein, we describe the OP and its deployment into routine ALL diagnostics, which will allow substantial improvements in both patient risk stratification and precision medicine.
A phase II study of dual immune checkpoint blockade (ICB) plus androgen receptor (AR) blockade to enhance thymic T-cell production and immunotherapy response in metastatic breast cancer (MBC).
Authors: David B. Page, Isaac K Kim, Brie Chun, William L Redmond, Maritza Martel, Motomi Mori, Dottie Wadell, Nicole Moxon, Staci L. Mellinger, Walter John Urba, Ayca Gucalp, Tiffany A. Traina
Journal: Journal of Clinical Oncology (2019)

TPS1106 Background: ICB (atezolizumab, anti-PD-L1) is known to improve survival when added to chemo, however only in PD-L1-positive, triple-negative MBC. ICB is less effective in hormone receptor positive (HR+) MBC, or when administered following palliative chemo. Novel approaches are required to broaden clinical benefit of ICB, particularly in PD-L1-negative, HR+, or chemo-experienced MBC. Dual ICB with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab) is associated with enhanced activity in melanoma other malignancies, but has not been explored extensively in MBC. Androgen receptor (AR) blockade, in addition to known direct cytostatic effects in AR-expressing MBCs (50% of TNBC, &gt; 75% of HR+ MBC), may also modulate immune response. AR blockade has been shown experimentally to stimulate thymic production of naïve T-cell clones, which in turn can facilitate de novo anti-tumor immune responses. Concurrent ICB can enhance the activity of these T-cell clones by interfering with PD-1-mediated peripheral tolerance. This combination approach is promising in MBC in light of known AR positivity, and the routine use of lymphodepleting chemo regimens in the curative-intent setting. Methods: This is a phase II trial of dual immune checkpoint blockade (nivolumab 240mg IV q2w; ipilimumab 1mg/kg IV q6w) plus AR blockade (bicalutamide, 150mg PO daily, dose reduction allowed) in triple-negative MBC (cohort A: AR-positive [ &gt; 1% by IHC]; cohort B: AR-negative) or HR+ MBC (cohort C) in subjects who received 0/1 prior chemotherapies in the non-curative setting. Objectives include 24-week clinical benefit rate by iRECIST (primary), safety (CTCAE v4.0), and other response measures (RECIST1.1, PFS, OS). Efficacy for each cohort is defined as &gt; 20% improvement in response over historical control (30% per EMBRACE clinical trial) employing a Simon 2-stage design to minimize futility (n = 46/cohort, stage I n = 15). Thymic generation of T-cells will be measured via quantitative deep sequencing of T-cell receptors (TcR, ImmunoSEQ assay) and TcR excision circles (TRECs), as well as real-time flow cytometry using surrogate cell surface markers of recent thymic emigration. Enrollment has commenced, sites: Earle A. Chiles Research Institute (Portland, OR), Memorial Sloan Kettering Cancer Center (New York, NY). Clinical trial information: NCT03650894.
Abstract 11400: Nitric Oxide Exerts Organoprotective Effects in Cardiac Surgery
Authors: Nikolay O Kamenshchikov, Irina A Mandel, Yuri K Podoksenov, Yulia S Svirko, Vladimir V Lomivorotov, Sergey L Mikheev, Boris N Kozlov, Aleksandra A Nenakhova, Yana Anfinogenova, Vladimir M Shipulin, Dmitriy N Atochin
Journal: Circulation (2018)

Introduction: Nitric oxide (NO) signaling is involved in the mechanisms of organoprotection during ischemia and reperfusion. Hypothesis: We assessed the hypothesis that NO supply to the extracorpor...
Balixafortide (a CXCR4 antagonist) + eribulin in HER2-negative metastatic breast cancer (MBC): Survival outcomes of the phase I trial.
Authors: Peter A. Kaufman, Sonia Pernas Simon, Miguel Martin, Marta Gil-Martin, Patricia Gomez Pardo, Sara Lopez-Tarruella, Luis Manso, Eva Ciruelos, Jose Alejandro Perez-Fidalgo, Cristina Hernando, Foluso Olabisi Ademuyiwa, Katherine N. Weilbaecher, Ingrid A. Mayer, Timothy J. Pluard, Maria Martinez Garcia, Linda T. Vahdat, Debra Barker, Barbara Romagnoli, Javier Cortes
Journal: Journal of Clinical Oncology (2019)

2606 Background: Balixafortide (B) is a potent antagonist of the chemokine receptor CXCR4. Preclinical evidence suggests that disrupting CXCR4 dependent pathways prevents development of breast cancer metastases, enhances the cytotoxic effect of chemotherapy and immunotherapy, and counteracts tumor cell evasion of the immune system. Encouraging safety and efficacy data were published recently from the ongoing Phase 1 trial investigating B + eribulin (E) in patients with HER2 negative MBC (Pernas S. et al. Lancet Oncol. 2018; 19: 812−24). The objective response rate, median progression free survival and median overall survival (OS) for the expanded cohort (EC) and the overall efficacy population (OEP) were 37.5% and 29.6%, 6.2 months and 4.5 months, and 18 months and 16.8 months, respectively. Here we report the 18 and 24 months landmark OS data from this trial. Methods: This trial enrolled 56 patients with HER2-negative, CXCR4-positive MBC, previously treated with 1−3 chemotherapy regimens for MBC. A 3+3 dose escalation design was used, followed by an EC. All cohorts received E on days 2 and 9, and B on days 1−3 and 8−10 of 21 day cycles. The association between various baseline biomarkers and treatment outcomes including OS is currently being investigated in a multivariate analysis (MVA). Results: Landmark survival data for the trial are shown in the table. Clinical trial information: NCT01837095. Conclusions: Landmark 18 months and 24 months OS data are consistent with the positive trend of all efficacy read-outs observed in this study and safety information is consistent with what was previously reported. Although inter-trial comparisons should be interpreted with caution, these survival rates, especially for the EC, are higher than those reported for eribulin monotherapy in similar MBC populations. These promising results suggest that B + E could potentially provide a new treatment option in heavily pre-treated patients with HER2 negative MBC and this is currently being investigated in a pivotal, randomized trial.[Table: see text]