tbuckley/cabot-search huggingface dataset:
The Molecular Screening and Therapeutics (MoST) Program: A precision medicine framework for biomarker-driven signal-seeking clinical studies for rare cancers.
Authors: Dominique Hess, Lucille T Sebastian, Katrin Marie Sjoquist, Chee Khoon Lee, Wendy Hague, Danielle Miller, Mark Cowley, Min Ru Qiu, Stephen B. Fox, Anthony M. Joshua, John Simes, David Morgan Thomas
Journal: Journal of Clinical Oncology (2017)

TPS2621 Background: Precision medicine aims to link molecular targets in tumors to cognate therapies and has the potential to yield new treatments for cancer patients with unmet clinical need. With the accelerating pace of discovery and genomic capacity, innovative approaches are needed to translate molecular opportunities into clinical care. The MoST program tests a novel paradigm for evaluation of biomarker-driven treatment of patients with advanced cancer. The key elements of the design are a molecular screening platform to identify ‘actionable’ variants and an overarching protocol for multiple, parallel, signal-seeking clinical substudies. Methods: 1000 patients with advanced solid cancer of any histologic type, having failed all standard therapies will undergo tumor molecular profiling on archival tissue with a 393-gene panel and other molecular assays. Eligibility for biomarker-driven substudies of targeted treatments is based on tumor variants assessed by a Molecular Tumor Board. A novel framework design allows expedited addition of substudies, with ≥12 open-label, single-arm, signal-seeking substudies planned. The primary objective is to identify signals of clinical activity, as measured by objective tumor response or the ratio of time-to-progression on study treatment over the preceding period. Cohorts of 16 patients will be recruited to each substudy. Substudies with ≥3/16 responding patients will be considered sufficiently interesting to investigate further.As of Feb 2017, 65 patients have been screened, and 8 recruited to 2 open sub-studies: CDK4/6 inhibitor (palbociclib) for Rb pathway defects; CTLA-4 plus PD-L1 checkpoint inhibitors (durvalumab + tremelimumab) for patients with no actionable mutations. Additional substudies under development include: PARP plus PD-L1 inhibitors (olaparib + durvalumab) for HR DNA repair defects; SMO inhibitor (vismodegib) for Hh pathway defects. The modular signal-seeking trial design will be evaluated and is intended to expedite testing of biomarker-based therapies for rare cancers. Clinical trial information: ACTRN12616000908437; ACTRN12616000931471; ACTRN12616001019493.
A pilot study using hyperbaric oxygen therapy to improve umbilical cord blood stem cell engraftment: 6-months follow up results.
Authors: Alain Mina, Amy Cantilena, Tara L. Lin, Siddhartha Ganguly, Leyla Osman Shune, Amanda L. Wise, Anurag Singh, Sunil H. Abhyankar, Joseph McGuirk, Dennis Allin, Omar Salah Aljitawi
Journal: Journal of Clinical Oncology (2016)

7048 Background: Umbilical cord blood (UCB) transplantation has a major drawback related to delayed or failed engraftment which increases post-transplant mortality. In a pilot clinical trial, we have demonstrated that hyperbaric oxygen (HBO) therapy prior to UCB transplantation was associated with improved day +100 outcomes. Herein, we report 6-months outcome of our HBO treated patients. Methods: We retrospectively evaluated patients who were enrolled in our pilot clinical trial and received HBO therapy and compared their outcomes to our historic patients who received UCB transplantation within 5 years. Results: Fifteen patients with a median age of 45 (range: 17-70, 60.0%M) underwent HBO therapy. Their outcome was compared to that of 45 control patients with a median age of 47 (range: 18-71, 55.6%M). Most of patients had AML (80.0% in the HBO group vs 71.1% in the control group). In terms of graft versus host disease (GVHD), 92.8% of the HBO group had acute GVHD compared to 72.5% of the control group. Nonetheless, GVHD was far less severe in the HBO group, with only 15.3% of HBO patients having a grade III/IV GVHD compared to 48.3% in the control group. Of the HBO patients, 85.7% were steroid free at 6 months compared to 77.8% of the control group. There were no deaths in the HBO group in the first 6 months post- transplant, while 14 (31.1%) of the control group died. Deaths were secondary to relapse, graft failure, infections, severe refractory GVHD, and preparative regimen (Table). Six months survival was 100.0% in the HBO group, compared to 68.9% in the control group (p=0.0195). Conclusions: Extended follow up of our HBO pilot study shows improved clinical outcomes compared to our historic data. Prospective studies are needed to determine HBO effects on UCB transplantation outcomes. Post-transplant outcomes. Variables HBO GROUP (N=15) CONTROL (N=45) p-value GVHD Incidence Acute 13 (92.8%) 29 (72.5%) NS Chronic 4 (28.6%) 11 (40.7%) NS % Steroid Free at 6 months 12 (85.7%) 21 (77.8%) NS Mortality at 6 months 0 (100.0%) 14 (100%) 0.013 Relapse 6 (42.9%) Graft Failure 2 (14.3%) Infection 4(28.6%) GVHD 1 (7.1%) Preparative Regimen 1 (7.1%) Survival at 6 months 15 (100.0%) 31 (68.9%) 0.0195
Treatment of rectal cancer patients with synchronous liver metastases.
Authors: Alexey Privalov, Andrey Antonov, Andrey Vazenin
Journal: Journal of Clinical Oncology (2018)

e15567 Background: Synchronous Liver Metastases occur in approximately 20% of patients with Rectal Cancer. Patients with SCRLM are a heterogeneous group. Potential cure is dependent on the ability to resect all disease and requires a multidisciplinary approach, SCRM is initially addressed with chemotherapy. The optimal sequence of multimodality treatment is under active investigation. Methods: In 2015 and 2016, 82 patients with rectal cancer with synchronous liver metastases were treated in our center. There were 48 men and 36 women with mean age of 62.5. The criteria of inclusion to the group of surgical treatment were the presence of complications such as bleeding, bowel obstruction and oligometastatic liver lesion. The group of surgical treatment was 50 patients. Surgical treatment consisted of low anterior resection and later was followed by chemotherapy in FOLFOX regimen for 6 months. 12 patients (24 % ) underwent resection of liver metastases after completion of chemotherapy. Patients without of complications and with multiple liver lesions firstly received chemotherapy in FOLFOX or FL regimens. Only in case of multiple liver lesion and bowel obstruction symptoms loop colostomy was performed before the chemotherapy start. Results: The patients of the surgical group, that underwent liver metastases resection are all alive. 15 of 38 patients (30%) who had been operated on the primary tumor, died of distant tumor progression, 70 % of patients are receiving second and third lines of chemotherapy. In the group of chemotherapy alone 20 patients (62.5%) are died because of progression. Conclusions: The early data show that primary tumor resection in patients with rectal cancer with synchronous liver metastases can definitely benefit the subgroup of patients that can undergo liver mets resection afterwards. The outcomes of rectal surgery in patients with unrespectable liver metastases followed by chemotherapy compared to those of patients undergoing chemotherapy alone are still to be evaluated.
Reply
Authors: Vinod Arora, Shiv Kumar Sarin
Journal: Hepatology (2018)

Reply: We would like to thank the reader for carefully reviewing our study and providing a valuable critique. We do agree that noradrenaline is a potent drug in hepatorenal syndrome‐acute kidney injury (HRS‐AKI) in patients with decompensated cirrhosis and is comparable to terlipressin.1 Acute on chronic liver failure (ACLF) is a sicker cohort of patients, with a different underlying pathophysiology from AKI and higher incidence and greater progression to HRS‐AKI.2 There are no head‐to‐head trials comparing terlipressin with noradrenaline in ACLF. Development of HRS‐AKI in ACLF patients is associated with low response rates of around 35% to terlipressin, as shown by Jindal et al.3 This was also recently reported by Piano et al.4 Our study included a sick cohort of ACLF patients with high Model for End‐Stage Liver Disease score. The mortality rate was 80%, with a 51.7% rate in noradrenaline and terlipressin nonresponders. Because we had used continuous infusion of terlipressin, the frequency of adverse effects requiring discontinuation of the drug was not significantly different between the two groups (P = 0.39). We did not have a crossover study design, but it seems improbable that terlipressin nonresponders would have benefited from noradrenaline. In another study, we had used a combination of noradrenaline and terlipressin as vasoconstrictors in patients with cirrhosis and septic shock.5 There was no added advantage of the combination therapy as a rescue approach, probably owing to a preexisting high sympathetic drive in such sick patients. In this context, we disagree with the reader that using noradrenaline in a patient who is terlipressin‐intolerant or nonresponsive is likely to be rewarding and that these patients should be counseled for early liver transplantation. Potential conflict of interest Nothing to report.
High concordance in advanced cancer patient paired testing by commercially available tumor tissue NGS assays and a liquid biopsy NGS assay.
Authors: Rebecca Christian Arend, Angelina Londono, Alba Martínez, Andrew Ford, Charmaine Brown, Chen-Hsiung Yeh, Nader Javadi, Glen J. Weiss
Journal: Journal of Clinical Oncology (2018)

e24169 Background: Next-generation sequencing (NGS) assays are increasingly being used in oncology clinical practice. With the recent FDA approval of a commercially available tumor tissue NGS assay and reports of low concordance across different platforms, we sought to evaluate the concordance of DNA mutations and PD-L1 testing results from Caris Molecular Intelligence testing (CMI) or FoundationOne (F1) on tumor tissue and Circulogene Theranostics Personalized Gene Profile (CGP, 50-gene panel) on cell-free circulating DNA and RNA. Methods: We conducted a two center retrospective analysis of stage 3/4 solid tumor patients that had matched paired testing. Concordance was calculated as the number of shared genes with or without mutations (mut) identified divided by the total number of identical genes common to the assays being compared. For example, for a specific patient, if NGS assay reported a KRAS mut and the other NGS assay reported a KRAS and APC mut and both assays tested 50 of the same genes, the concordance rate would be 49/50 (98%). Results: One hundred eighteen patients (median age 66 years, range 25-88); 18M:100F) underwent either CMI (between 06/14-09/17) or F1 (between 03/16-04/17) and CGP (between 05/15-08/17) testing. The majority of cancer types were ovarian, uterine, breast, non-small cell lung, and colon. All F1/CGP pairs were performed on gynecologic malignancies, and F1 sampling was from surgical resection while CGP sampling was a median of 692 days (range 8-3859 days) subsequent to date of specimen sent for F1 testing. Overall concordance at the gene level between CMI and CGP was 1009/1119 (90.2%) and F1 and CGP was 3408/3604 (94.6%). None of the mut were at the same exon. There were four paired samples with PD-L1 results, and concordance was 3/4 (75%). When limiting analysis to paired cases with tumor and blood NGS collected within the preceding 60 days of each other (n = 19), the overall concordance at the gene level between CMI and CGP was 87.9% and F1 and CGP was 93.6%. Conclusions: This analysis indicates there is high concordance at the gene level between a liquid biopsy NGS assay and two different tumor NGS assays.
Prognostic significance of t(11;14) expression by FISH in patients with newly diagnosed multiple myeloma in the era of novel therapies.
Authors: Miguel Gonzalez Velez, Ricardo Daniel Parrondo, Tracy Andrews, Narjust Duma, Joshua Ryan Richter, David H. Vesole, David Samuel DiCapua Siegel, Noa Biran
Journal: Journal of Clinical Oncology (2017)

e19525 Background: Rearrangements of the immunoglobulin heavy chain (IGH) on chromosome 14 are identified by FISH in about 15-20% of patients (pts) with newly diagnosed multiple myeloma (MM). Historically there is variation on the significance on prognosis of these rearrangements: typically, t(4;14), t(14;16) and t(14;20) have high risk (HR), and t(11;14) have standard risk (SR). A recent study (Kaufman et al, Leukemia. 2016 30:633-9) suggests that t(11;14) may confer a worse prognosis We report the prognostic significance of t(11;14) in a single-institution MM cohort. Methods: 87 pts with t(11;14) by CD 138 selected FISH at diagnosis were identified, pts without symptomatic MM were excluded. Cox regression was used for statistical analysis. Progression free survival (PFS), and overall survivals (OS) from diagnosis and post autologous stem cell transplant (ASCT) were analyzed by Kaplan-Meier. Results: Median age at diagnosis was 62 years, 45 pts (52%) were male, and 24 pts (27%) had ISS 3. All pts received either a proteasome inhibitor or an immunomodulatory agent, and 42 (48%) received triplet treatment as induction. Sixty-nine (79%) pts had ASCT, and overall response rate (ORR, partial response or better) post ASCT was 73%. For pts with HR FISH (defined as t(14;16), p53 del, 1q21 gain or 1p del) compared to SR FISH, the ORR post ASCT was 70% vs 77% (p = 0.67). OS from diagnosis was 93% at 3 years, 74% at 4 years and 51% at 5 years. Seven patients (8%) developed plasma cell leukemia, and there was no association between HR and SR FISH (p = 0.66). In multivariate analysis, ISS stage was an independent risk factor for mortality; pts with stage 3 had 7.3 times (CI: 1.16-36.4) and 5.7 times (CI: 1.63-20.0) the risk of mortality than pts with stage 1 and 2. Having an ASCT reduced mortality by 87% (CI: 0.04-0.41). Conclusions: Despite the use of novel therapies the OS at 5 years of our pts with MM was not significantly improved compared to SEER data from 1992-2013 (51% vs 48.5%). Pts with t(11;14) who had ASCT had increased survival compared to those who did not. Our results suggest that t(11;14) may confer a worse prognosis. Further prospective studies evaluating the risk of t(11;14) are warranted.
Immunotherapy (IO) versus targeted therapy triage in endometrial adenocarcinoma (EA) by concurrent assessment of tumor mutation burden (TMB), microsatellite instability (MSI) status, and targetable genomic alterations (GA).
Authors: Alessandro Santin, Kathleen N. Moore, Camille Gunderson, Kyle Gowen, David Fabrizio, Garrett Michael Frampton, Jo-Anne Vergilio, James Suh, Laurie M Gay, Shakti Ramkissoon, Siraj Mahamed Ali, Vincent A. Miller, Phil Stephens, Jeffrey S. Ross, James Sun, Julia Andrea Elvin
Journal: Journal of Clinical Oncology (2016)

5591 Background: IO holds promise for EA with mismatch repair (MMR) or MSI-H phenotype, while trials of targeted agents matched by histology/single biomarkers have yet to meet clinical endpoints. We hypothesized a single comprehensive genomic profiling (CGP) assay could better match EA subsets to treatment modalities by simultaneously assessing MSI status, TMB, and targetable GAs. Methods: CGP of 717 FFPE EA clinical specimens by hybridization-capture of up to 315 cancer-related genes (FoundationOne) provided GA (SV, indels, CNA, rearr), TMB, and MSI status. TMB was calculated by counting mutations across a 1.25Mb region and classified as high (TMB-H; range 10.4-541 mut/Mb) or low (TMB-L; 0-10.3 mut/Mb) using the top quartile threshold. MSI high (MSI-H) or stable (MSS) status was assigned by a computational algorithm examining 114 intronic homopolymer loci. Results: Median patient age for 717 advanced or recurrent, treatment refractory EAs was 65 yrs (range 24-92 yrs). 16.9% were MSI-H, which correlated with non-serous/clear cell histology (representing 28.9% of total endometrioid, 18.8% mixed/NOS, 7.1% clear cell, and 1.5% serous cases; p < 0.0001). MMR GA (in MLH1, MSH2, MSH6, PMS2) were identified in 33% of MSI-H cases, compared to 1.9% MSS cases (p < 0.0001). Of the 173 TMB-H cases, 73% were MSI-H while 27% had a hypermutated, non-indel MSS signature (POLE GA in 16.3%). 7.4% of all MSS (43/481) samples were TMB-H and were distributed across histologies: 35% endometrioid, 40% mixed/NOS, 19% serous, 7% clear cell. GA co-occurrence frequencies differed significantly between MSI-H and TMB-H MSS EA for PTEN, MLL2, ARID1A, TP53, and KRAS (p < 0.0001). Patients with MSI-H and MSS TMB-H EA responding to IO, including 2 cases initially excluded by standard testing, will be presented. Conclusions: MSI status by CGP identified 3 times as many potentially IO-relevant cases as MMR GA, and TMB identified an additional 35% of MSS EA, including non-endometrioid subtypes. Co-occurring GA differ between TMB-L, MSI-H TMB-H, and MSS TMB-H, suggesting molecular subgroups relevant to targeted agent efficacy.
Tenalisib, a dual PI3K δ/γ inhibitor: Safety and efficacy results from an on-going phase I/Ib study in relapsed/refractory T-cell lymphoma.
Authors: Yasuhiro Oki, Bradley Haverkos, Jasmine M. Zain, Mary Jo Lechowicz, Sumana Devata, Neil J Korman, Rod Ramchandren, Lauren C. Pinter-Brown, Prajak J. Barde, Ajit Nair, Auris Huen
Journal: Journal of Clinical Oncology (2018)

7510 Background: Tenalisib is a novel, next generation, highly specific, dual equi-potent PI3K δ/γ inhibitor. Early results demonstrated an acceptable safety profile with encouraging clinical activity in relapsed/refractory TCL (NCT02567656). Methods: An open-label, Phase 1/1b study consists of dose escalation cohorts followed by two expansion cohorts enrolling patients with peripheral TCL (PTCL) and with cutaneous TCL (CTCL). The primary objective is to determine the MTD, and to describe the safety and pharmacokinetic profiles. The secondary objectives are assessment of the overall response rate (ORR) and duration of response (DoR). Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2007) and the mSWAT respectively. Results: As of January 10, 2018, a total of 55 patients (27 PTCL and 28 CTCL) have been enrolled. 19 patients across dose escalation (200 mg - 800 mg BID) and 36 patients in dose expansion (at MTD, 800 mg BID Fasting) were enrolled and the results presented are the pooled data across both parts. At the time of analysis, safety assessment of 55 patients receiving at least one dose of Tenalisib demonstrated an acceptable safety profile. The most common drug related AEs were transaminitis, diarrhea, and fatigue. Related Grade ≥ 3 AE (≥ 5%) includes transaminitis (20%) and rash (5%). These events were reversible and managed by withholding study drug. Seven of 14 patients who had transaminitis were treated with steroids and only one patient discontinued therapy due to a drug related transaminitis. Drug related SAEs were pyrexia, elevated INR, sepsis, and diplopia secondary to neuropathy. Efficacy assessments of the 32 evaluable patients receiving at least two cycles of tenalisib showed an ORR of 47% (15/32, 3 CR, 12 PR and 10 SD). Indication specific analysis showed an ORR of 50% (7/14, 3 CR, 4 PR) in PTCL and 44% (8/18, 8 PR) in CTCL. Twelve patients discontinued treatment due to a rapid progression before the first efficacy assessment. Conclusions: Tenalisib shows acceptable safety and encouraging clinical activity in relapsed/refractory TCL. Recruitment in the expansion cohort is close to completion. Clinical trial information: NCT02567656.
P01.037 Quality criteria for glioma care, use in clinical practice: results of a national survey
Authors: M A de Peuter, L van Baest, H P Bienfait, K Dujardin, M C J Hanse, M J Vos, F Y F L de Vos, V K Y Ho, J M M Gijtenbeek
Journal: Neuro-Oncology (2018)

The Dutch Society for Neuro-Oncology (LWNO) in collaboration with the patients' association, developed quality criteria for glioma care. The criteria encompass the phases of diagnosis, treatment and follow-up. Following the approval of the criteria in 2014, a baseline questionnaire regarding glioma care was sent to all Dutch hospitals. In 2017, the implementation of the criteria in daily clinical practice was evaluated and compared with the baseline questionnaire. We describe the current implementation of the criteria as well as changes observed over the last three years. A survey was sent to neurology departments of all Dutch hospitals. The surveys of 2014 and 2017 both addressed topics on type of care provided, organisation of the neuro-oncology tumour working group, number of patients discussed annually and collaboration amongst hospitals. In addition, the 2017 survey evaluated criteria such as availability of a predefined clinical pathway, access to a neuro-oncology nurse, regular screening on physical, cognitive, and behavioural limitations and regular screening on the need for psychosocial support for themselves as well as their proxies. Important changes in care resulting in centralization, professionalization and collaboration within the neuro-oncology field followed the implementation of the 2014 criteria. While 78% of responding hospitals provided care to glioma patients in 2014, this percentage reduced to 46% in 2017. By now, in all hospitals providing glioma care patients are being discussed at time of diagnosis and relapse in a multidisciplinary neuro-oncology tumour working group, and the number of tumour working groups that discuss at least 50 new glioma patients annually increased from 56% to 78%. Regular screening of the majority of patients on physical, cognitive, emotional and behavioural limitations is done in 26% - 44% of hospitals providing glioma care. Regular screening on the need for psychosocial support for patients and for their proxies is provided by respectively 44% and 26% of hospitals. Also, the use of predefined clinical pathways and access to a neuro-oncology nurse with regular consultation hours is suboptimal. The introduction of quality criteria for glioma care has resulted in centralization, professionalization and increased collaboration within the neuro-oncology field. Still, some aspects of care need further improvement. Strategies to enhance these aspects are currently being initiated; For example, in-depth insights into routine practice are collected amongst neuro-oncology nurses.