tbuckley/cabot-search huggingface dataset:
Additional chemotherapy with 5-FU plus leucovorin between preoperative chemoradiotherapy and surgery improved treatment outcomes in patients with locally advanced rectal cancer.
Authors: Edward Hyunseung Oh, In Gyu Hwang, Song Ee Park, Jin Hwa Choi, Chang Hwan Choi, Beom Gyu Kim, Sang-Cheol Lee
Journal: Journal of Clinical Oncology (2018)

e15682 Background: The aim of the present study was to evaluate the efficacy and safety of 4-week chemotherapy with 5-Fluorouracil (5-FU) and leucovorin (LV) during the resting periods between preoperative chemoradiotherapy (CRT) and surgery in patients with locally advanced rectal cancer (LARC). Methods: Standard preoperative CRT was delivered to the entire pelvis at a total dose of 5040 Gy of radiation with concurrent 5-FU or capecitabine for 6 weeks. Twenty-three patients received additional preoperative chemotherapy with two cycles of 5-FU and LV (LV 200 mg/m2 and 5-FU bolus 400 mg/m2on day 1, and 5-FU infusion 2400 mg/m2 for 46 hrs, every 2 weeks) after preoperative CRT. Surgery was performed at 2–4 weeks following the completion of preoperative chemotherapy. Results: Between May 2013 and January 2015, 23 patients underwent preoperative CRT, with additional chemotherapy and surgery, and 23 patients completed the scheduled treatment. The median follow-up duration was 42.0 months. The tumor down-staging rate was observed in 65.2%, and pathologic complete remission (pCR) was noted in 5 patients (21.7%). T and N down-staging were observed in 16 (69.6%) and 14 (60.9%) patients, respectively. The four-year disease-free survival (DFS) rate was 73.9% and the four-year overall survival (OS) rate was 90.9% in patients who received additional chemotherapy. The four-year DFS rate was 100% in the tumor down-staging group vs. 25.0% in the non-down staging group treated with additional chemotherapy (P < 0.001). There was also a significant difference of the four-year OS rate 100% in the tumor down-staging group compared with 71.4% in the non-down staging group (P = 0.031). Conclusions: The present study showed that additional preoperative chemotherapy with 5-FU and LV during the resting period after 6-week preoperative CRT is tolerable and active and favorably compares with conventional preoperative CRT. We showed a significant improvement in the four-year DFS and four-year OS rates in the tumor down-staging group.
Expression of erythropoietin receptor variant forms is associated with lymphatic invasion and metastasis formation in breast cancer
Authors: Z. Rakosy
Journal: Annals of Oncology (2018)

Background: Anemia not only impairs the quality of life of patients, but it leads to tumor hypoxia, resistance to therapy and reduces survival. Although recombinant Epo has revolutionized the treatment of anemia, clinical trials suggested a potential adverse effect of Epo on tumor recurrence and patient survival. Previously we identified altered EpoR mRNA transcripts in breast cancer cells lacking ligand binding domain exon 1-3 sequences in vitro. Our hypothesis is that altered expression of these proteins may be associated with unique clinicopathologic features. Methods: The expression level of C-and N-terminal portion of EpoR were measured by quantitative RT-PCR in 157 retrospective cohort of archived breast cancers. In order to identify the variant EpoR mRNA forms we have established a SMART RACE PCR assay using EpoR specific primer sets producing large overlapping sequences. Total RNA was frozen sections of 20 primary breast cancers after the H&E diagnoses.The products of the SMART RACE and nested PCR reactions was subjected to sequence analysis. Results: Out of the 157 samples 95 (61%) showed more than 2-fold change between the expression levels of the C and N-terminal regions of EpoR by quantitative RT-PCR. Significant correlation was found between the expression levels of EpoR mRNA variants and lymphatic invasion of the tumors. Logistic regression model demonstrated the association of metastatic capacity and expression differences of extra and intracellular regions of EpoR in primary breast cancers (P < 0.05, greater than 2-fold change). Using a SMART RACE PCR assay a single EpoR mRNA species at ∼1500 kb, corresponding to the full length wild type EpoR mRNA, and several distinct bands at ∼1300 kb, ∼1000 kb and ∼800 kb, lacking exon 1-4 N-terminal ligand binding domain, were seen in the samples. Conclusions: We showed that different variant forms of EPOR present not only in vitro but also in the individual breast tumor samples. These altered forms of EpoR may be responsible for the observed differences in the Epo responsiveness of EpoR bearing breast cancers. Legal entity responsible for the study: Zsuzsa Rakosy. Funding: OTKA PD 116996, 2015-2018. Disclosure: The author has declared no conflicts of interest.
The application of cognitive computing technology in genomics in precision oncological medicine: The Sistemas Genomicos Experience.
Authors: Lucía Pérez, Diego Cantalapiedra, Diana Valero-Hervas, Ignacio Duran, Oriol Calvete, Ching-Kun Wang, Carolina Martinez-Laperche, Anna Gonzalez-Neira, Vanesa Felipe-Ponce, Sergio Lois Olmo, Jaime Garcia, Carmen Collado Mico, Victoria Fernandez Pedrosa, Rebeca Miñambres, Ismael Buño Borde, Sonia Santillan, Alexandra Urman, Fernando Jose Suarez Saiz, Christian Martin Moya
Journal: Journal of Clinical Oncology (2018)

e18544 Background: Genomics shows promise for improving outcomes for personalized medicine in cancer. However, barriers exist, including cost, time needed for interpretation, and interpretation of the results. Cognitive computing technologies may help overcome these challenges. This study tested the robustness and feasibility of such technology, called IBM Watson for Genomics (WFG), which uses natural language processing (NLP) to obtain evidence-based targeted therapy and clinical trial options in an automated manner. Methods: Next Generation Sequencing (NGS) was used on 17 samples from 8 diagnoses. Samples were studied using 3 clinically relevant platforms and included, 1 glioblastoma, 2 primary cardiac angiosarcomas, 1 renal cell carcinoma, 1 renal angiomyolipoma, 1 triple negative breast cancer and 1 chronic myeloid leukaemia. They were sequenced using Illumina Hi-seq with a TruSight 170 gene panel. A second set using Illumina Mi-Seq and a 63 custom Acute Myeloid Leukemia (AML) gene panel was used to test 2 AML cases (diagnosis and relapse samples). Lastly, a Chronic Lymphocytic Leukemia (CLL) panel using Hi-Seq was used to test 3 CLL samples and a Hairy Cell leukaemia. The resulting files were interpreted by WFG. Results: In most cases investigational options were identified. Of note is a case of glioblastoma, treated with Temozolomide, analysis found a KIT, EGFR and PDGFRA amplification, as well as 2 TP53 mutations. The system displayed options in the context of these findings, namely Pazopanib, Imatinib, and Panotinib for intervention in KIT amplified cases. In addition, we found different genomic profiles for patients with primary cardiac angiosarcomas, one with alterations in KIT and CDKN2A and TP53 mutations detected in both cases. Different therapeutic options have been suggested in the same type of rare tumor. Conclusions: Implementing tumour molecular characterization from NGS studies complemented by evidence-based options for interventions, may provide a precise molecular diagnosis, tumor sub-classification and treatment options. Finally, this strategy provides new information for clinicians to consider with their patients.
Novel T cell exhaustion marker to predict monotherapy PD-1 compared to combination CTLA-4 and PD-1 response in melanoma.
Authors: Kimberly Loo, Katy K. Tsai, Mariela Pauli, Priscila Munoz Sandoval, Michael Alvarado, Alain Patrick Algazi, Michael Rosenblum, Adil Daud
Journal: Journal of Clinical Oncology (2016)

9520 Background: The identification of a robust biomarker to determine potential responses to checkpoint mono- or combination therapy is critical in order to stratify patients and rationally select therapy. We explored the utility of proportion “exhausted” antigen experienced T cells (TEx)/Total CD8+ cells to predict response. Methods: Freshly isolated tumor samples were digested and tumor infiltrating lymphocytes (TILs) were extracted and stained with T cell myeloid and activation markers, and analyzed with 14 color FACS. Patients were treated with the combination therapy Ipilimumab 3 mg/kg q3 week x 4 and Nivolumab 1 mg/kg q3 week (Ipi/Nivo), or monotherapy of either Nivolumab 3 mg/kg q2 week or Pembrolizumab 2 mg/kg q3 week. TEx was calculated as % CD8+, PD-1+, CTLA-4+ cells divided by total CD8+ T cells in the tumor sample. Results: A total of 53 patients were evaluable for both response and T cell phenotype, 15 patients were treated with combination Ipi/Nivo, and 38 with monotherapy PD-1. For monotherapy, 0/12 (0%) responders had a TEx ≤20%, while 21/26 (81%) of the responders had a TEx >20%. For responders, median TEx=40.3%, for non-responders, median TEx= 16%, p<0.0001. At this threshold, the negative predictive value (NPV) was 100% and the positive predictive value (PPV) was 81%. For patients treated with combination Ipi/Nivo, the threshold for response was much lower. Responses to the combination therapy were seen at all levels with NPV=50% and PPV=80%, with responders median TEx=19.7% and non-responders median TEx=7.8%, p=0.13. Conclusions: Comprehensive tumor T cell profiling with FACS reveals interesting insights into tumor response to checkpoint inhibitors. % TEx is an accurate predictor of response to monotherapy but not combination checkpoint therapy. Combination Ipi/Nivo therapy produces responses at a much lower TEx threshold, suggesting enhanced rescue and/or recruitment of T cells into the tumor microenvironment. % TEx Monotherapy PD-1, ORR NPV % PPV % > 20% 81% 100 81 ≤20% 0% Ipi/Nivo, ORR 50 80 >20% 80% ≤20% 50%
P01.012 Tumor Treating Fields (TTFields) in combination with lomustine (CCNU) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM)
Authors: L Lazaridis, N Schäfer, S Kebir, J Weller, T Tzaridis, B Scheffler, D Pierscianek, C Kleinschnitz, M Stuschke, U Sure, U Herrlinger, M Glas
Journal: Neuro-Oncology (2018)

TTFields in combination with TMZ showed significant survival benefit for newly diagnosed glioblastoma patients in the EF-14 trial, compared to TMZ standard therapy; independent of MGMT-promotor methylation-status, age and performance status. Recently, the CeTeG trial (NOA-09) demonstrated improved efficacy of lomustine (CCNU)/TMZ compared to TMZ standard therapy in newly diagnosed MGMT-promotor methylated GBM patients. Given that TTFields demonstrated a strong safety profile as well as a high potential being combined with other modalities and the very promising results for GBM patients with methylated MGMT-promotor in the CeTeG trial, there is a strong rationale in combining these modalities. This is the first report on patients, treated with a combination of both treatment regimens, TTFields and CCNU/TMZ. Patients with newly diagnosed GBM and MGMT-promoter methylation were treated after surgery and radiochemotherapy with a combination of TTFields plus CCNU/TMZ at our institutions. Patients with complete resection (N=4), partial resection (N=3) as well as biopsy (N=1) were included in the analysis. We assessed safety and feasibility of this combined therapy. Currently, eight patients (medians: age 49, [39–69]; KPS 90, [70–100]) have been treated and analyzed: GBM IDH mutant (N=2), IDH wild-type (N=6). To-date, CTCAE grade 3 hematotoxicities were observed in two patients, but were not considered to be related to the addition of TTFields to CCNU/TMZ. No further non-hematologic toxicity was observed. In one patient a grade 3 event (herpes zoster) emerged. Regarding medical device site reactions, low-grade skin irritations were detected in four patients (50%), corresponding to the safety analysis from the EF-14 trial with low-grade skin irritations in 52% of the patients. These data provide first indications that the combination of TTFields and CCNU/TMZ is probably safe and feasible. Additional follow-up and a higher sample size are needed for further toxicity analysis and efficacy assessment of this combination.
P05.09 Detection of clinically relevant mutations in the cerebrospinal fluid of patients with central nervous system metastases
Authors: I Moya, S Villatoro, C Mayo, A Balada, S Viteri, M González-Cao, N Karachaliou, F Pons, X González, R Rosell
Journal: Neuro-Oncology (2018)

Mutation analyses in solid tumors are usually performed in tissue biopsies. However, in a significant number of patients, the availability of biopsies is limited, particularly at relapse. Liquid biopsies can be an alternative in this setting. In patients with central nervous system (CNS) metastases, the collection of cerebrospinal fluid (CSF) is challenging but it can be a better material for genetic analyses than blood. In addition, diagnosis of CNS metastases is based on clinical, radiological and cytological data, but CSF is often negative for tumor cells and can lead to a misdiagnosis. Mutational testing in CSF can help to avoid this problem. Patients with EGFR (n=7) or KRAS-mutant (n=1) lung adenocarcinoma and BRAF-mutant melanoma (n=2) were included in the study. CSF was collected at initial diagnose (n=1) or at progression to systemic therapies (n=9) and paired blood samples were simultaneously drawn in all cases. All 10 patients had CNS metastases at the time of CSF collection, and 3 also presented extra-CNS tumor involvement. CSF was centrifuged, circulating-free DNA was isolated using an automatic extractor (Qiasymphony) and mutation testing was performed by Taqman® in presence of PNAs. EGFR, KRAS or BRAF mutations were identified in the cfDNA isolated from CSF in all the 10 patients included in the study. In the three patients with additional extra-CNS metastases, mutations were also identified in blood, although allelic fractions were lower than in CSF. In contrast, the 7 patients with no extra-CNS involvement were negative in blood. In two EGFR-mutant patients progressing to EGFR TKIs, a T790M mutation was detected exclusively in CSF. Finally, in a KRAS-mutant NSCLC patient repeated CSF samples could be obtained and the evolution of the KRAS mutation related to the clinical outcome. Mutation analysis in CSF is feasible in patients with CNS metastases and provides useful clinical information.
Challenges in Adopting Level 1 Evidence for Multiparametric Magnetic Resonance Imaging as a Biomarker for Prostate Cancer Screening
Authors: Soo Jeong Kim, Andrew J. Vickers, Jim C. Hu
Journal: JAMA Oncology (2018)

This Viewpoint addresses whether there is sufficient evidence to support routine use of multiparametric magnetic resonance imaging as an adjunctive test for men with elevated prostate-specific antigen level and considers the practical implications of its widespread implementation.
Median 3.5-Year Follow-up of Ibrutinib Treatment in Patients with Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis
Authors: Simon Rule, Martin Dreyling, Andre Goy, Georg Hess, Rebecca Auer, Brad S Kahl, Jose Angel Hernandez-Rivas, Anil Londhe, Fong Clow, Sanjay Deshpande, Lori Parisi, Michael Wang
Journal: Blood (2017)
First-in-human study of ABBV-075 (mivebresib), a pan-inhibitor of bromodomain and extra terminal (BET) proteins, in patients (pts) with relapsed/refractory (RR) acute myeloid leukemia (AML): Preliminary data.
Authors: Gautam Borthakur, Johannes E. Wolff, Ibrahim Aldoss, Beibei Hu, Minh Dinh, Alison Torres, Xiaotian Chen, David Rizzieri, Anjla Sood, Olatoyosi Odenike, Brian Andrew Jonas
Journal: Journal of Clinical Oncology (2018)

7019 Background: Pts with RR AML have a poor prognosis. BET proteins bind acetylated histone tails, leading to the upregulation of oncogenic target genes; their inhibition can block aberrant transcription in tumor models. ABBV-075 is a pan-BET inhibitor with antitumor activity in vitro and in xenograft models of AML. This 2-part first-in-human study assesses the safety and PK of ABBV-075 at various monotherapy or combination dosing schedules (NCT02391480). In part 1, the recommended phase 2 dose for ABBV-075 monotherapy in pts with solid tumors was identified. Here, we report preliminary data from part 2 in pts with RR AML. Methods: Adult pts with RR AML received daily ABBV-075 as monotherapy (ABBV075-mono) or combined with venetoclax (ABBV075-VEN). The dose-limiting toxicity (DLT) period was 28 d (ABBV075-mono) or 21 d (ABBV075-VEN). Thrombocytopenia was not considered a DLT. Results: As of 1 Jan 2018, 19 pts (median age: 65 y [range, 30–78]; 14 pts had ≥3 prior therapies) were enrolled: 12 pts in ABBV075-mono, 7 in ABBV075-VEN cohorts. Median time on treatment was 39 d (range, 3–213). There were no DLTs; 16 pts experienced AEs. AEs irrespective of causality in > 3 pts were: anemia (11), fatigue (11), dysgeusia (10), nausea (9), diarrhea (7), decreased appetite (7), febrile neutropenia (6), thrombocytopenia (6), and dry mouth, vomiting, contusion, decreased platelet count, decreased weight, hyponatremia, and hemoptysis (4 each). 15 pts had grade ≥3 AEs (anemia [11]); 13 pts had serious AEs (febrile neutropenia [4]). 10 pts died of causes unrelated to ABBV-075, 5/10 pts due to AML progression. In ABBV075-mono cohorts, bone marrow blast count was ≤50% of baseline in 4/11 evaluable pts. 1 pt (female; normal cytogenetics; STAG2 mut) reached complete remission with incomplete hematologic recovery (thrombocytopenia) in cycle 5, still maintained at 8 m from treatment start. At cutoff date, the median overall survival for all pts was 3.2 m, and 4 pts were still in treatment without progression for 1, 6, 20, and 24 w. Enrollment is ongoing. Conclusions: ABBV-075 was well tolerated and showed antileukemic effects in pts with RR AML. Clinical trial information: NCT02391480.
TCT-316 Percutaneous Coronary Intervention Before Transcatheter Aortic Valve Replacement
Authors: Franco Fabbiocchi, Paolo Olivares, Giuseppe Calligaris, Giovanni Teruzzi, Stefano Galli, Stefano De Martini, Paolo Mario Ravagnani, Luca Grancini, Daniela Trabattoni, Antonio Bartorelli
Journal: Journal of the American College of Cardiology (2018)
The EASI-SWITCH trial: Early switch to oral antibiotic therapy in patients with low risk neutropenic sepsis.
Authors: Caroline Forde, Ronan McMullan, Mike Clarke, Richard H. Wilson, Elizabeth R. Plummer, Anne L. Thomas, Rosemary A Barnes, Richard A. Adams, Ian Chau, Margaret Grayson, Cliona McDowell, Ashley Agus, Ewan Brown, Dawn Jane Storey, Danny McAuley, Victoria Coyle
Journal: Journal of Clinical Oncology (2016)

TPS10143 Background: Neutropenic sepsis is a common complication of systemic anti-cancer treatment (SACT) with management determined by the risk of developing septic complications. The UK National Institute for Health and Care Excellence were unable to recommend switching from empirical intravenous (IV) to oral antibiotics at < 48 hours in low-risk patients, because of uncertainty about whether this achieved comparable outcomes to current practice of longer IV antibiotics.1 The UK National Institute for Health Research funded the EASI-SWITCH trial to tackle this uncertainty. This phase IV, pragmatic, randomised, non-inferiority trial aims to establish the clinical and cost effectiveness of early switching to oral antibiotics, with potential patient quality of life benefits and resource savings. Methods: Patients ≥ 16 years are eligible if receiving SACT (acute leukaemics/stem cell transplants excluded), temperature > 380C, neutrophil count ≤ 0.5x109/l, MASCC (Multinational Association of Supportive Care in Cancer) score ≥ 21 and receiving IV piperacillin/tazobactam or meropenem for < 24 hours. Patients are randomised 1:1 to either (i) switch to oral ciprofloxacin and co-amoxiclav within 12-24 hours of commencing IV antibiotics, completing at least 5 days total antibiotics (intervention) or (ii) continue IV antibiotics for at least 48 hours, with ongoing antibiotics then at physician’s discretion (control). Patients are discharged when physicians deem it appropriate. The primary outcome measure is a composite of treatment failure assessed at Day 14. Criteria include fever persistence/recurrence after 72 hours of starting IV antibiotics, escalation from protocolised antibiotics, hospital readmission related to infection/antibiotics, critical care support or death. Research blood samples will be analysed for potential biomarkers capable of enhancing risk stratification. Enrolment began in February 2016 with 4 pilot sites assessing recruitment and protocol adherence. The recruitment target is 628 patients over 36 months in 12 UK cancer centres, based on a 15% treatment failure rate in the control group and a 10% non-inferiority margin. 1. https://www.nice.org.uk EudraCT Number 2015-002830-35 Clinical trial information: 84288963.
Abstract 019: Cost-effectiveness of the FDA Sodium Reduction Targets for the Processed Food Industry: Are There Internal Incentives to Reformulate?
Authors: Brendan Collins, Chris Kypridemos, Jonathan Pearson-Stuttard, Yue Huang, Piotr Bandosz, Parke Wilde, Rogan Kersh, Simon Capewell, Dariush Mozzafarian, Laurie Whitsel, Renata Micha, Martin O'Flaherty
Journal: Circulation (2018)

Introduction: In 2016, the US Food &amp; Drug Administration (FDA) proposed voluntary industry reductions in sodium, a major modifiable risk factor for CVD, for processed foods. Yet, reformulation could cost the food industry up to $16bn over 10 years, perhaps partly explaining why in 2017 Congress blocked the FDA from implementing these long-term voluntary targets. Aim: To estimate the potential health gains and health-related cost savings for food industry employees from the FDA sodium targets. We defined the industry perspective as including all costs to the food industry and all health-related costs and health benefits to people working in the industry. Methods: Utilizing the validated US IMPACT Food Policy dynamic microsimulation model, we estimated QALYs gained, costs, and incremental cost effectiveness ratios (incremental cumulative cost per QALY gained, with costs and QALYs discounted at 3%) from 2017-2036 in individuals working in the wider food system (food services and drinking places; food and beverage stores; food manufacturing) and the subset of food manufacturing. Data sources included NHANES, matched to demographic data for workers from the American Community Survey, and meta-analyses of sodium effects on blood pressure and blood pressure on CVD. Costs included industry reformulation costs, government costs, and health-related costs (healthcare, productivity, informal care) for individuals working in the industry. We modelled the FDA sodium targets under 2 scenarios: a) Short-term, 100% compliance of 2-year reformulation targets with no further progress. b) Long-term, 100% compliance of 10-year reformulation targets We tested our assumptions with probabilistic sensitivity analysis. Results: Achieving the short-term, 2-year reformulation targets would generate net discounted industry costs of ~$7bn, health-related cost savings of ~$1.7bn (95% UI: $1.0bn, $2.9bn) and health gains of ~60,000 QALYs (50,000, 77,000) over 20 years, with an ICER of ~$85,000 ($12,000, $243,000) per QALY gained. Achieving the long-term sodium reduction targets could result in industry costs of ~$16bn, health-related cost savings of approximately $5.1bn ($3.4bn, $8.3bn), and industry health gain of ~180,000 (149,000, 209,000) QALYs, with an ICER of ~$60,000 ($2,000, $168,000). For the subset of food manufacturing, the long-term sodium reduction targets would lead to health-related savings of ~$1bn ($0.6bn, $1.6bn) and ~32,000 (27,000, 37,000) QALYs gained with an ICER of $489,000 ($160,000, $1,052,000). Conclusions: Sustained sodium reduction is estimated to benefit the overall food industry with a healthier workforce and partly offset the reformulation costs for the subset of the processed food industry.