tbuckley/cabot-search huggingface dataset:
Comparison of adverse events beyond cycle 1 between cytotoxic combination and molecularly targeted phase I trials.
Authors: Emma J. Jordan, James F. Spicer, Debashis Sarker
Journal: Journal of Clinical Oncology (2017)

e14028 Background: Traditionally, only grade 3 and 4 adverse events (AEs) occurring during cycle 1 are used for dose escalation decisions in phase I oncology trials. With the shift in cancer drug development away from cytotoxic chemotherapy towards molecularly targeted agents (MTAs), assessment of lower grade AEs and those in later cycles is considered to be of increasing relevance. This study evaluated differences in AE incidence between trial types (combination cytotoxic vs. single MTA) and cycle number (1 vs. 2-6). In line with previous work suggesting ethnic and age related differences in toxicities, we evaluated AE incidence across a range of patient demographics. Methods: Retrospective analysis of toxicity data in patients enrolled onto phase I clinical trials at a single UK centre between 2006 and 2016. All AEs in the first six cycles of treatment deemed at least ‘possibly related’ were recorded. Results: A total of 912 AEs (664, grade 1; 194, grade 2; 54, grade 3 and 4) were identified in 127 patients across 15 different trials (420 treatment cycles). Mean AE totals for patients on cytotoxic combinations and MTAs respectively were 4.51 and 2.94 in cycle 1, 3.47 and 3.04 in cycles 2-6. Patients on cytotoxic combinations experienced a significantly higher mean number of AEs in six cycles compared to those on MTAs (7.98 vs. 5.98, p = 0.0135). Of the patients experiencing grade 3-4 AEs, 57% (cytotoxic combinations) and 75% (MTAs) occurred for the first time after cycle 1. No significant difference in incidence of AEs was found between any subgroups of patient demographic variables. Conclusions: Incidence of AEs is less in MTAs than for cytotoxic combinations across cycles 1-6. The significant incidence of first grade 3-4 AEs occurring from cycle 2 onwards supports incorporation of AE assessment beyond cycle 1 into recommendations for phase II doses in MTAs.
Abstract 13142: Implantable Cardioverter Defibrillators Continue to Offer Mortality Benefit After Improvement in Ejection Fraction to Above 35%: Results From the Sudden Cardiac Death in Heart Failure Trial
Authors: Selcuk Adabag, Kristen K Patton, Thomas Rector, Kristin E Ensrud, Kairav Vakil, Alfred E Buxton, Jeanne E Poole
Journal: Circulation (2016)

Introduction: Patients (pts) discovered to have low ejection fraction (EF ≤ 35%) frequently show increase in EF to &gt; 35% over time. The efficacy of implantable cardioverter defibrillators (ICD) to improve survival is unknown in these pts. Hypothesis: Mortality benefit with ICD therapy is less in pts whose EF improves to &gt; 35% than those whose EF remains ≤ 35%. Methods: A total of 1875 (74%) participants of the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) had a repeat assessment of EF 13.5 ± 6 months after randomization. We stratified them by EF ≤ 35% and &gt; 35% based on the 1 st repeat EF after randomization and compared all-cause mortality of 649 pts randomized to placebo vs. 624 pts randomized to ICD (602 pts randomized to amiodarone were not analyzed). Follow-up started at the time of 1 st repeat EF assessment. Results: Repeat EF was &gt; 35% in 186 (30%) pts in the ICD group and 185 (29%) pts in the placebo group (mean EF increased from 26±7% to 46±8%). The all-cause mortality rate was lower in the ICD group vs. placebo group, both in pts whose EF remained ≤ 35% and in those whose EF improved to &gt; 35% (Table). Compared to placebo, the unadjusted hazard ratio for ICD effect on mortality was 0.72 (95% CI 0.55-0.95) in pts with repeat EF ≤ 35% and 0.58 (95% CI 0.29-1.17) in those with repeat EF &gt; 35%. After adjustment for potential confounders, the estimated effect of ICD was 0.64 (95% CI 0.48-0.85) and 0.62 (95% CI 0.29-1.30) in patients with repeat EF ≤ 35% or &gt; 35%, respectively (Table). We found no evidence of an interaction between treatment assignment and repeat EF for prediction of mortality (p=0.93), suggesting that the ICD effect was similar in patients with EF ≤ 35% or &gt; 35%. Conclusions: Pts with an improvement in EF to &gt; 35% accrued a similar relative reduction in mortality with ICD therapy as those whose EF remained ≤ 35%. However, the absolute benefit of ICD therapy was less in pts with repeat EF &gt; 35% due to the lower mortality risk in this group.
Analysis of nationwide trends and outcomes of percutaneous endoscopic gastrostomy (PEG) tube placement in hospitalized cancer patients over a 13 year period.
Authors: Padma L. Draksharam, Achuta Kumar Guddati, Gagan Kumar, Sireesha Datla, Creticus Petrov Marak, Iuliana Shapira
Journal: Journal of Clinical Oncology (2016)

10135 Background: The decision to provide enteral feeding in cancer patients is complex and is based on several factors. Outcomes of PEG tube placement in cancer patients have not been studied and compared with non-cancer patients over an extended period on a national basis. We have analyzed a database with nationwide representation for outcomes in these patients over a 13 year period. Methods: Data regarding cancer and non-cancer patients who underwent PEG tube placement was extracted from the Nationwide Inpatient Sample (NIS) from 2000 to 2012 using ICD-9-CM codes. NIS variables were used to identify in-hospital mortality, discharge dispositions. We also examined the admissions related to complications from PEG tube placement. Chi square test and Wilcoxon rank test were used to compare categorical and continuous variables respectively. Results: 2,325,603 hospitalized patients underwent PEG tube placement from 2000 to 2012. Of these, 465,049 (20%) were cancer patients. Of all cancer related admissions, 0.86% received PEG tube placement. The rate of PEG tube placement in cancer patients has gradually increased from 2000 to 2012 (p = 0.007). The number of hospital admissions with PEG tube-related complications have increased from 6696 in 2000 to 9640 in 2012. The in-hospital mortality in non-cancer patients who received PEG tube was higher than in those who did not get PEG tube (9.85% vs. 8.05%, p = 0.0000). Cancer patients who underwent PEG tube placement were discharged to nursing homes less often than non-cancer patients (47% vs. 80%, p < 0.001). Conclusions: The rates of PEG tube placement in cancer patients and related complications have increased in the last decade. The in-hospital mortality of non-cancer patients who received PEG tube placement was higher and these patients were discharged to nursing homes more often than cancer patients who received PEG tube placement. The decision to place PEG tube in cancer patients should be individualized taking into consideration the effect of possible PEG tube-related complications, availability of support systems, prognosis of the underlying malignancy and the desired quality of life.
Epidural Spinal Cord Stimulation Training and Sustained Recovery of Cardiovascular Function in Individuals With Chronic Cervical Spinal Cord Injury
Authors: Susan J. Harkema, Bonnie Legg Ditterline, Siqi Wang, Sevda Aslan, Claudia A. Angeli, Alexander Ovechkin, Glenn A. Hirsch
Journal: JAMA Neurology (2018)

This cohort study evaluates the feasibility of daily customized epidural stimulation configurations targeted for cardiovascular function in individuals with chronic, cervical motor-complete spinal cord injury.
A randomized, double-blind phase II study of pembrolizumab versus placebo in patients with head and neck cancers at high risk for recurrence or low-volume residual disease: The PATHWay Study.
Authors: Joshua Bauml, Theodore Karrison, Everett E. Vokes, Roger B. Cohen, Jonas A. De Souza, Charu Aggarwal, Vassiliki Saloura, Nishant Agrawal, Nabil F. Saba, Corey J. Langer, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2017)

TPS6095 Background: Head and neck squamous cell carcinoma (HNSCC) is a major medical problem worldwide. While some patients may be cured with a combination of surgery, radiation, and systemic therapies, a significant percentage of patients will have recurrent and incurable disease. Despite our epidemiologic understanding of which patients are likely to recur, there are no consolidative therapies that have been shown to improve outcomes in this high-risk population. Pembrolizumab is a PD-1 inhibitor that has shown significant single agent activity in recurrent/metastatic HNSCC after treatment with other systemic therapies. While drug development of pembrolizumab is ongoing in Phase III studies in the 2 nd and 1 st line recurrent/metastatic disease settings, the ultimately the biggest potential impact based on patient volume and survival will potentially be in the curative intent setting. This randomized study is intended to explore the incorporation of pembrolizumab into the treatment of patients with locally advanced HNSCC at high risk for recurrence. Methods: Eligible patients must have HNSCC, completed therapy with definitive intent, and have an estimated risk of recurrence ≥40-50% (including tumors with extensive lymphadenopathy, extracervical lymphadenopathy, indeterminate residual local or distant mass after treatment, non-responders to induction chemotherapy, incomplete definitive therapy, receipt of salvage therapies, or oligometastatic disease treated definitively). Patients will be randomized to 1 year of either pembrolizumab 200 mg or placebo, administered intravenously day 1 of each 3-week cycle. The primary hypothesis of the study is that the addition of pembrolizumab will improve the 2-year progression-free survival (PFS) rate, compared to placebo. A sample size of 90 (45 patients per treatment arm, assuming 10% loss of follow up in N = 100 patient trial) will achieve 92.7% power at alpha = 0.10 (one-sided) to detect a difference between 50% and 72.5% PFS at 2 years. Approximately 51 events are required to detect such a difference. Patient screening and enrollment are expected to begin spring 2017.
Novel anti-PD-1 antibodies not acting through PD-1/pdl-1 blockade that enhance tumor clearance.
Authors: Craig Fenwick, Juan-Luis Loredo-Varela, Victor Joo, Celine Pellaton, Alex Farina, Navina Rajah, Thibaut Decaillon, Line Esteves-Leuenberger, Madeleine Suffiotti, Khalid Ohmiti, Raphael Gottardo, Winfried Weissenhorn, Giuseppe Pantaleo
Journal: Journal of Clinical Oncology (2018)

e15118 Background: Monoclonal antibodies (Abs) that act through PD-1 blockade have had significant clinical success in cancer immunotherapeutic agents with current Abs relying on the blockade of the PD-1/PD-L1 interaction. Given the success of anti-PD-1 immunotherapies, our goal was to identify novel Abs with more potent anti-tumor activity, and/or acting through a mechanism independent of PD-1/PDL-1 blockade that would synergize with classical PDL-1 blocker Abs. Methods: Abs targeting human PD-1 were identified from a mouse immunization campaign and screened for the ability to block the PD-1/PDL-1 interaction and to recover antigen-specific CD8 T cells from functional exhaustion. An Ab family that was non-blocking of the PD-1/PDL-1 interaction showed antagonistic activity comparable to Pembrolizumab and Nivolumab. The binding epitope of these Abs was mapped through PD-1 site directed mutation and co-crystal structural studies. Functional synergies between blocking and non-blocking anti-PD-1 Abs was evaluated in both in vitro functional assays and in an in vivo mouse tumor model. Results: Structural studies showed that non-blocking Abs recognize PD-1 epitopes located on the opposing face of the PDL-1 interaction and overlap with a newly identified evolutionarily conserved patch. Importantly, combination of blocking and non-blocking Abs synergizes in the functional recovery of antigen specific exhausted CD8 T cells beyond levels achieved by either individual Ab. Mode of action studies showed that non-blocking Abs act primarily through restoring signaling to the AKT pathway and calcium mobilization during T cell stimulation. In vivo studies in a mouse tumor model demonstrated that non-blocking anti-PD-1 Abs have equivalent anti-tumor activity compared to blocker Abs. Combination therapy using both anti-PD-1 Ab classes significantly suppressed tumor growth and showed a 2.4-fold increase in mice with tumor control relative to anti-PD-1 monotherapies. Conclusions: The identification of the novel non-blocker anti-PD-1 Abs and their synergy with classical blocker anti-PD-1 Abs may have an important place in potentiating anti-tumor activity of classical blocker anti-PD-1 Abs in patients with cancer.
Comparison of guidelines, BRCAPRO, and genetic counsellors estimates for the identification of BRCA1 and BRCA2 mutations in pancreatic cancer.
Authors: Robert C Grant, Spring Holter, Ayelet Borgida, Melania Pintile, Mohammad R Akbari, George Zogopoulos, Steven Gallinger
Journal: Journal of Clinical Oncology (2017)

e15784 Background: Germline BRCA1 and BRCA2 (BRCA) mutation carriers with pancreatic adenocarcinoma (PDAC) are eligible for precision therapy trials and their relatives should undergo genetic testing and tailored cancer prevention. We assessed the performance of strategies to identify BRCA mutation carriers in PDAC. Methods: Incident cases of PDAC were prospectively recruited for BRCA sequencing in a multidisciplinary PDAC clinic. Probands were evaluated according to the National Comprehensive Cancer Network 2017 (NCCN) and the Ontario Ministry of Health and Long-Term Care (MOHLTC) guidelines for BRCA testing. The probability of each proband carrying a BRCA mutation was estimated using BRCAPRO and by surveying genetic counsellors. Guidelines were compared across sensitivity, specificity, and positive and negative predictive values (PPV and NPV). Estimates from BRCAPRO and the genetic counsellors were compared using the area-under-the-curve (AUC) for discrimination and the Hosmer-Lemeshow test for calibration. Results: 22/484 (4.5%) of probands carried a BRCA mutation. The mutation rate was higher in probands with Ashkenazi Jewish ancestry (7/57, p=0.009) or a first-degree relative with breast cancer (8/83, p=0.036). 119 genetic counsellors responded to the survey and each proband was assessed by a mean of 5.9 genetic counsellors. The Table displays the performance of the guidelines. Discrimination was similar for the estimates from genetic counsellors and BRCAPRO (AUC 0.755 and 0.775, respectively, p=0.701). Genetic counsellors generally overestimated (p=0.008), whereas BRCAPRO severely underestimated (p&lt;0.001), the probability that each proband carried a mutation. Conclusions: The NCCN 2017 guidelines and estimates from genetic counsellors accurately identify BRCA mutations in PDAC. The MOHLTC guidelines and BRCAPRO should be updated to account for the association between PDAC and BRCA mutations. [Table: see text]
Abstract 10765: Dilated and Tilted Mitral Annulus by Left Atrial Dilation May Cause Mitral Regurgitation in Nonvalvular Atrial Fibrillation
Authors: Tatsuji Kono, Kaoru Otsuka, Akiko Soyama, Tomohiro Matsuoka, Shogo Murakami, Eimei Tsuda
Journal: Circulation (2015)

Background: Although mitral annular dilation has been considered to be the primary mechanism of mitral regurgitation (MR) in patients with nonvalvular atrial fibrillation (AF), whether a stretched mitral annulus is sufficient to cause significant MR remains controversial. The aim of this study was to clarify it. Methods: The presence of MR and left atrial dimension (LAD) were evaluated by echocardiography. Cardiac magnetic resonance imaging was performed in patients with AF and MR (AF-MR; n=23) or without MR (AF-noMR; n=56) and in controls with normal sinus rhythm (n=130). Using 4-chamber view, we quantified the end-systolic septolateral mitral annular diameter (MAD), angle (Angle) between the mitral annulus and the perpendicular line of the long axis of the left ventricle passing through the base of the anterior leaflet (Line), and the distance (Distance) between the mitral leaflets coaptation point and the Line (Figure). Results: LAD was significantly increased in AF-MR compared to AF-noMR and controls (50±9 mm, 41±7 mm, 36±5 mm, respectively, AF-MR vs. AF-noMR, P&lt;0.001, AF-MR vs. controls, P&lt;0.001). MAD, Angle and Distance were significantly increased in AF-MR compared to AF-noMR and controls (Figure). CONCLUSIONS: In concert with mitral annular dilation, tilted mitral annulus by left atrial dilatation may cause incomplete coaptation of the mitral leaflets resulting in the development of MR in nonvalvular AF.
The ASCENT trial: A phase II study of neoadjuvant afatinib, chemoradiation and surgery for stage III EGFR mutation-positive NSCLC.
Authors: Lecia V. Sequist, Henning Willers, Michael Lanuti, Alona Muzikansky, Aileen B. Chen, Pasi A. Janne, Noah C. Choi, Mari Mino-Kenudson, Scott Swanson, Cameron D Wright, J Paul Marcoux, Zofia Piotrowska, Geoffrey R. Oxnard, Raymond H. Mak
Journal: Journal of Clinical Oncology (2018)

8544 Background: The stage III NSCLC paradigm now includes immunotherapy (IO), but advanced EGFR-mutant (EGFR+) pts typically don’t respond to IO. In 2011 we began a phase II trial of neoadjuvant afatinib (NeoAfat) and standard of care (SOC) curative intent treatment for EGFR+ stage III NSCLC, NCT01553942. We present an interim analysis given the evolving SOC landscape. Methods: EGFR+ stage III pts amenable to curative-intent chemoradiation (CRT) ± surgery were treated with NeoAfat 40mg po QD x2mo, then concurrent CRT: cisplatin 75mg/m2 + pemetrexed 500mg/m2 IV q3wk up to 4 cycles and 3D conformal RT or IMRT personalized to tumor size, site, operability. Surgery and adjuvant afatinib (AdjAfat) x2yr were optional. Primary outcome was objective response rate (ORR) to NeoAfat. Results: 13 pts were treated (10F/3M); med age 56 (range 34-75). EGFR mutations: del19 (n = 9); L858R (n = 4). Stage: operable IIIA (n = 7); inoperable IIIA/B (n = 6). NeoAfat ORR = 69% (95% CI 39-91); 5 (38%) pts dose reduced NeoAfat. All pts proceeded to CRT with pre-op med RT dose of 54 Gy (range 45-66; n = 7), definitive med dose of 65 Gy (range 63-72; n = 6). 5 (71%) of the 7 surgical pts had major (4) or complete (1) pathologic response. 7 (54%) pts started AdjAfat at med dose of 30mg QD; 4 completed 2yr, 2 aborted early, 1 ongoing . Key grade 3/4 toxicities: rash 5), diarrhea (5), esophagitis (3), nausea (3), pneumonitis (2 gr 3) and febrile neutropenia (1); no treatment-related deaths. With med follow-up of 24.1 mo (range 5.0-64.2), 6 (46%) pts have recurred; including 4/6 inoperable pts, 2/7 who had surgery, 1/5 with major path response (CNS-only recurrence). Med PFS is 34.6 mo (95% CI 12.6-NR). 2-yr OS is 85% (95% CI 33-98). Conclusions: Neo-adjuvant afatinib achieves high ORR and major surgical path responses, and doesn’t impair receipt of SOC, curative CRT ± surgery in EGFR+ stage III NSCLC. Feasibility of NeoAfat exceeds AdjAfat in stage III setting. The prolonged PFS compares favorably to PACIFIC IO arm; more data is needed about optimal strategy for stage III EGFR+ pts. ASCENT is still ongoing, but it and similar randomized RTOG 1306 have accrued slowly, highlighting the challenge of studying curative approaches in genotype-defined subgroups. Clinical trial information: NCT01553942.
Bcl-2 family pro-death and pro-survival proteins in Ph-like B cell precursor acute lymphoblastic leukemia.
Authors: Muhammad Omair Kamal, Cornelia Stoian, Shania Aponte-Paris, Micheal Brandon Reed, Hannah Choi, Jacquelyn Coats, Evgeny Chirshev, Chien-Shing Chen, Kimberly J Payne
Journal: Journal of Clinical Oncology (2016)

7030 Background: B cell acute lymphoblastic leukemia with overexpression of CRLF2 (CRLF2 B-ALL) is a Ph-like leukemia with poor outcome in children, as well as in adults. Activation of the CRLF2 receptor by the cytokine, TSLP, results in activation of the JAK/STAT and PI3K/AKT/MTOR pathways. Activation of these pathways has been associated with oncogenesis and chemoresistance and their downstream targets include members of the Bcl-2 family. Our objective here was to determine the effect of TSLP on expression of Bcl-2 family proteins and the efficacy of targeting Bcl-2 family pro-survival proteins in CRLF2 B-ALL. Methods: Human CRLF2 overexpressing B-ALL cell lines (MUTZ5 and CALL4) were cultured with and without TSLP and evaluated for expression of Bcl-2 family pro-survival and pro-death proteins by flow cytometry. Flow cytometry was also used to assess for Annexin V/7-AAD and Caspase 3/7 assays of apoptosis following treatment of CRLF2 B-ALL cells with the Mcl-1 inhibitor (Mim-1). Results: Our data show that TSLP induces CRLF2 B-ALL cells to increase expression of the Bcl-2 family pro-survival proteins Bcl-XL and Mcl-1, but not Bcl-2. TSLP also increased the expression of several Bcl-2 family pro-death proteins including Bim, Bak, Bax, and Bad. Treatment with Mcl-1 inhibitor (Mim-1) reduced cell counts by > 90% and this reduction was maintained in the presence of TSLP. Reductions in cell number were due to a dose-dependent increase in caspase-mediated apoptosis reaching > 95% cell death after 3 days in concentrations of Mim-1 over 15 uM, even when TSLP was present. Conclusions: These data suggest that in patients where TSLP stimulates CRLF2 B-ALL cells, leukemia cells are likely to express high levels of pro-survival molecules to sequester the high levels of pro-death molecules contributing to the survival of leukemia cells. These data also suggest that therapies which can inhibit Bcl-2 family pro-survival proteins (inhibitors of Mcl-1 and/or Bcl-XL) are likely to make CRLF2 B-ALL cells highly susceptible to apoptosis, due to the elevated levels of pro-death molecules induced by TSLP.
Pelareorep to promote the expression of a IFN-gamma-related gene signature that predicts response to checkpoint blockade therapy.
Authors: Grey A Wilkinson, Aine Piar, Christopher Resnyk, M. Jordan Humphrey, Keith Glendinning, Hue Tran, Romit Chakrabarty, Andres Gutierrez, Matthew C. Coffey
Journal: Journal of Clinical Oncology (2018)

3089 Background: A clinical study in patients (pts) with metastatic breast cancer (mBC) treated with pelareorep resulted in significant improvements in overall survival. Clinical studies with checkpoint blockade inhibitors (CBIs) have also resulted in noteworthy clinical responses in a small subset of mBC pts. In pts who do not respond to CBIs, the absence of IFN-γ signalling in the tumor microenvironment has been proposed as a key mediator of innate resistance. IFN-γ signalling upregulates the expression of checkpoint ligands and promotes lymphocyte activation and infiltration to the tumor microenvironment. Thus, the expression of IFN-ɣ-related genes can be used to both facilitate and predict response to CBIs. Given pelareorep’s known capacity to promote an inflamed tumor phenotype, we hypothesised that pelareorep could also stimulate the expression of IFN-ɣ-related genes associated with response to CBIs. Methods: Cell lines derived from breast cancer (BC: MCF7, T47D, MD-231), colorectal cancer (CRC: HT-29, SW620), hepatocellular carcinoma, (HCC: SNU-387) and non-small cell lung cancer (NSCLC: H522) were infected with pelareorep at a multiplicity of infection equal to 50. We examined changes in gene expression and conducted cell viability assays at 6, 12, and 18 hours post-infection (including a non-infected control). To monitor changes in gene expression we employed a 780-gene panel (nanoString) to monitor for changes in the expression of key IFN-ɣ-related and other immunity-related genes. Results: All cell lines were susceptible to pelareorep induced cytopathic effect. Strikingly, BC and HCC cells lines significantly upregulated IFN-ɣ-related genes while CRC and NSCLC cell lines demonstrated only a modest and variable ability to promote IFN-ɣ pathway activation. Moreover, BC and HCC cells lines also upregulated key chemokines that are known to promote response to immunotherapy. Conclusions: These results suggest that various tumor types are amenable to immune priming for CBIs therapy with pelareorep. The role of pelareorep in the treatment of BC and HCC deserves further investigation, particularly in combination with other immunotherapies.