tbuckley/cabot-search huggingface dataset:
The effect of MATE1 polymorphisms on cisplatin efficacy in patients with head and neck cancer.
Authors: Daniel Adam Breadner, Mary Mahler, Wendy A. Teft, Nedal Bukhari, Sara Kuruvilla, Anthony Charles Nichols, David A. Palma, Richard B. Kim, Eric Winquist
Journal: Journal of Clinical Oncology (2018)

e18069 Background: MATE1 (multidrug and toxin extrusion protein 1) has an important role in excretion and transport of organic cations including a number of therapeutic drugs. We recently reported that homozygosity for a single nucleotide polymorphism in MATE1 (rs2289669) (A/A) was independently protective for cisplatin-related ototoxicity in patients with head and neck squamous cell carcinoma (HNSCC) receiving cisplatin-based chemoradiation. To evaluate whether MATE1 A/A status had any effect on treatment efficacy we examined cancer outcomes in a subset of our patients with higher risk disease. Methods: Patients were identified from a prospective, single-centre, observational cohort study of 206 HNSCC patients treated with curative intent cisplatin-based chemoradiation. Patients with HPV-associated oropharyngeal and primary unknown cancers were excluded. Germline allelic variants of MATE1 were identified using TaqMan allelic discrimination assays as previously described. The disease specific survival and overall survival of patients with the otoprotective MATE1 homozygous A/A variant were compared to those MATE1 wild type (G/G) and heterozygous (G/A) using the log-rank test. Results: 109 non-HPV-related HNSCC patients were identified and included in the analysis. Median follow up was 33 months. 28 (25.7%) patients had disease progression or recurrence and 30 (27.5%) patients died. 16 (14.7%) patients expressed the MATE1 A/A variant. Median disease specific survival was 46.2 months in the MATE1 A/A patients and not reached in the G/G and G/A patients (hazard ratio 0.66 [95% confidence interval, 0.23 to 1.82]; p = 0.42). Median overall survival was 55.3 months in the MATE1 A/A patients but also not reached G/G and G/A patients (hazard ratio 1.22 [95% confidence interval, 0.46 to 3.27]; p = 0.17). Conclusions: Presence of the MATE1 A/A polymorphism did not compromise treatment efficacy in HNSCC patients receiving cisplatin-based chemoradiation. A small sample size and duration of follow-up are limitations of our data. It appears MATE1 A/A polymorphism is associated with reduced ototoxicity from cisplatin without sacrificing cytotoxic effects, and warrants further investigation in the treatment of HNSCC.
Serum androgens and survival in metastatic castration resistant prostate cancer (mCRPC) patients treated with docetaxel and prednisone: Results from CALGB 90401 (Alliance).
Authors: Charles J. Ryan, Sandipan Dutta, William Kevin Kelly, Rob Middleberg, Carly Russell, Eric Jay Small, Michael J. Morris, Mary-Ellen Taplin, Susan Halabi
Journal: Journal of Clinical Oncology (2017)

5067 Background: Higher baseline androgens have been previously shown to be associated with an improved overall survival (OS) in mCRPC patients treated with the androgen synthesis inhibitors, ketoconazole or abiraterone. The purpose of this analysis was to determine whether baseline serum androgen levels (Testosterone (T), Androstenedione (A) and DHEA (D) are associated with OS in mCRPC patients treated with docetaxel-based chemotherapy. Methods: Data from 1,050 men treated on CALGB 90401 with docetaxel, prednisone and either bevacizumab or placebo were used. Eligibility required progressive mCRPC and no prior chemotherapy. Pre-treatment serum assays for T, A and D were performed via tandem Liquid Chromatography-Mass Spectrometry (LC-MS/MS) at NMS labs. The proportional hazards model was used to assess the prognostic significance of T, A, and D in predicting OS adjusting for known prognostic factors. Results: Median values for T, A, and, D were 1.00, 13.00 and 8.12, ng/dL respectively.Values above the median were defined as low, above as high. Median OS for low vs high levels was 22.7 and 23.1 month for T, 22.4 and 21.7 month for A and 21.8 and 24.0 month for D, respectively, all NS. In multivariable analysis adjusting for 10 known prognostic values and prior keto use in mCRPC (Halabi JCO 2014), A (p-value = 0.013) levels were associated with OS. The HR for A was = 0.99 (95% CI = 0.98-0.99). Conclusions: In multivariate analysis, baseline androstenedione levels are prognostic factors for OS in mCRPC patients receiving chemotherapy. Low or undetectable levels of other androgens are associated with shorter OS, consistent with prior results in androgen synthesis inhibitor treated pts in both the chemotherapy naive and post chemotherapy settings. This relationship may reflect more aggressive tumor biology that evolves in an extreme androgen deprived milieu. Clinical trial information: NCT00110214.
Rate of complete metabolic responses to immune checkpoint inhibitors in extremely heavily pre-treated patients with classical Hodgkin’s lymphoma and immunoepigenetic priming.
Authors: Lorenzo Falchi, Ahmed Sawas, Changchun Deng, Jennifer Effie Amengual, Donald Steven Colbourn, Emily Lichtenstein, Karen Khan, Michael J. Smith, Heather Dials, Owen A. O'Connor
Journal: Journal of Clinical Oncology (2016)

e19012 Background: Options for relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) after failure of brentuximab vedotin (Bv) and ASCT are limited. cHL is associated with genetically determined overexpression of PD-L1 and PD-L2. The anti-PD-1 antibodies (Abs) nivolumab and pembrolizumab have shown remarkable activity in this population. However, only 16-17% of patients achieved CR to either agent Methods: Ten consecutive patients with heavily pretreated R/R cHL received either pembrolizumab (n = 8) 2 mg/kg Q3 weeks, or nivolumab (n = 2) 3 mg/kg Q2 weeks. Response was assessed by PET/CT. Treatment beyond progression was allowed in the absence of toxicity Results: Median age was 35 [24-57]; median ECOG PS 1; median number of prior treatments 11 [3-16]. All patients had received ASCT and Bv. Five patients had been exposed to azacitidine on study. Median duration of treatment was 25.5 weeks [2-52]. There were two episodes of treatment delay: one of 4 weeks due to lack of insurance coverage and one of 2 weeks due to intercurrent MDS diagnosis. There were 5 G ≥ 3 adverse events (AE) in 4 patients: G3 thrombocytopenia, G5 shock after the first infusion, MDS evolved into acute leukemia in 2 patients heavily exposed with radiation and alkylating agents (one fatal), and acute on chronic kidney injury. G1-2 AE included: infusion reaction (4 patients), hypothyroidism (2), and diarrhea (1). Eight patients were evaluable for response: 7 patients achieved metabolic CR and 1 mixed response with overall reduction of tumor burden, at first evaluation (6-16 weeks). At a median follow-up of 8.9 months [0.5-11.5], 8 patients are alive. Five patients are still receiving treatment, and 4 are in continued CR. One transitioned to allogeneic transplantation in CR after 9 weeks. Three patients progressed at 6.5, 8, and 8.4 months Conclusions: Our experience shows an unprecedented rate of CR to anti-PD-1 Abs. Interestingly, all 5 patients who received azacytidine prior to anti-PD-1 Abs achieved CR. Prior exposure to hypomethylating agents may ‘prime’ these patients to immune checkpoint inhibitors, which is being followed up in a dedicated study
Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer
Authors: G.V. Long, S.S. Tykodi, J.G. Schneider, C. Garbe, G. Gravis, M. Rashford, S. Agrawal, E. Grigoryeva, A. Bello, A. Roy, L. Rollin, X. Zhao
Journal: Annals of Oncology (2018)

A nivolumab monotherapy flat-dosing regimen of 480 mg every 4 weeks (Q4W) has been approved in several markets, including the United States, Canada, and European Union, as an alternative dosing regimen for several indications. Approvals of this Q4W regimen were based on population pharmacokinetic (PK) analyses, established flat exposure-response relationships, and clinical safety. The objective of this study was to compare the PK exposure of 480 mg Q4W with 3 mg/kg every 2 weeks (Q2W) and 240 mg Q2W using modeling and simulation, and to evaluate clinical safety of the Q4W regimen.Nivolumab PK exposure for the 480 mg Q4W schedule was simulated for 3817 patients across multiple tumor types and compared with those for the 3 mg/kg Q2W and 240 mg Q2W schedules. The safety profile of the Q4W schedule was assessed by analysis of clinical data from 61 patients who transitioned to nivolumab 480 mg Q4W from 3 mg/kg Q2W during four phase III clinical trials.Compared with 3 mg/kg Q2W, nivolumab 480 mg Q4W produced similar time-averaged concentration, approximately 16% lower trough concentration, and 45% higher peak concentration at steady state. The peak concentration for 480 mg Q4W was significantly lower than that of 10 mg/kg Q2W, a dose previously shown to have an acceptable tolerability and safety profile. Treatment-related adverse events (TRAEs) that started after transitioning from 3 mg/kg Q2W to 480 mg Q4W were reported in 14.8% of patients, with 1.6% of patients reporting grades 3-4 TRAEs. Pooled safety data for these patients are consistent with those for the 3 mg/kg Q2W schedules, and no new safety signals were identified.The time-averaged steady-state exposure and safety profile of nivolumab 480 mg Q4W are consistent with that of 3 mg/kg Q2W across multiple tumor types. Nivolumab 480 mg Q4W represents a new dosing schedule option, and in addition to 240 mg Q2W, provides convenience and flexibility for patient care.NCT01721772, NCT01668784, NCT01673867, NCT01642004.
P01.109 Tumor treating fields treatment for patients with newly diagnosed glioblastoma: a cost-effectiveness analysis for Sweden
Authors: G F Guzauskas, B C M Wang, A Kinzel, C Proescholdt
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most aggressive form of primary brain cancer in adults. The EF-14 Trial in GBM patients reported a 5-year survival rate of 13% for newly diagnosed GBM patients treated with TTFields and maintenance temozolomide (TMZ) chemotherapy. The cost-effectiveness of adding TTFields to the maintainance phase of the first line treatment protocol for GBM patients was assessed in Swedish Krona. The primary economic endpoint was the projected incremental cost-effectiveness ratio (ICER) for treatment of newly diagnosed GBM with TTFields and TMZ versus TMZ monotherapy alone during the maintenance phase of treatment. Patient outcomes were simulated using a 3-state area under the curve model including alive without progression, progressed disease, and death. Survival was modelled over a lifetime horizon by integrating the 5-year survival results reported in the EF-14 trial with long-term GBM epidemiology data and background mortality rates. Data on patient utilities used to calculate quality-adjusted life years (QALYs) were based on the single previous analysis of GBM-specific health-state preferences from Garside. Costs and frequency of adverse events associated with TTFields and TMZ were estimated from the EF-14 trial. Supportive care cost estimates were derived from published literature. Future survival benefits and costs were discounted to present value at a rate of 3%. One-way and probabilistic sensitivity analyses were performed to assess result uncertainty due to parameter variability. Use of TTFields plus TMZ were projected to increase in undiscounted mean survival of 1.8 life years versus TMZ alone. The resulting life years gained (LYG) and quality-adjusted life years (QALYs) were 1.3 and 1.0, respectively, after discounting. The incremental total cost was SEK 1,65 Million. The ICER was SEK 1,31 Million per LYG and SEK 1,72 Million per QALY gained. Treating newly diagnosed GBM patients with TTFields and TMZ has the potential to increase mean lifetime survival and quality-adjusted survival substantially compared to treatment with TMZ alone. TTFields therapy was deemed to be within the range of potential cost-effectiveness based on evaluation at its full list price. After negotiation the product was recommended for reimbursement in Sweden.
Post-transplant cyclophosphamide (PT-Cy) based haploidentical transplantation (haploHCT) versus matched sibling (MSD) or matched unrelated donor (MUD) reduced intensity conditioning (RIC) HCT for diffuse large b-cell lymphoma (DLBCL): A CIBMTR and EBMT analysis.
Authors: Mehdi Hamadani, Kwang Woo Ahn, Carlos Litovich, Finel Herve, Sonali M. Smith, Timothy S Fenske, Ariane Boumendil, Sascha Dietrich, Stephen Robinson, Silvia Montoto, Peter Dreger, Anna M. Sureda
Journal: Journal of Clinical Oncology (2018)

7056 Background: The outcomes of DLBCL patients undergoing PT-Cy based haploHCT have not been compared to those receiving MSD or MUD HCT Methods: Adult (≥18yr) DLBCL pts (n = 1438) undergoing RIC allogeneic HCT during 2008-15 were identified in the CIBMTR or EBMT registries. Pts were divided into 4 groups; haploHCT, MSD, MUD with (w) ATG/campath (A-C) and MUD without (w/o) A-C. Overall survival (OS) was primary endpoint. Secondary endpoints included acute (a) and (c) GVHD, non-relapse mortality (NRM), relapse/progression (R/P) and progression-free survival (PFS). Results: The baseline characteristics are shown in Table. The cumulative incidence of day 180 grade 3-4 aGVHD and 1 year cGVHD was 7%, 11%, 13% and 19% (p < 0.001) and 15%, 41%, 23% and 48% (p < 0.001) in the haploHCT v MSD v MUD w A-C v MUD w/o A-C groups, respectively. The 3 year post HCT univariate outcomes for the haploHCT, MSD, MUD w A-C and MUD w/o A-C cohorts were as follows: NRM (22% v 17% v 26% v 30%), R/P (41% v 47% v 38% v 34%), PFS (38% v 37% v 36% v 37%) & OS (46% v 50% v 43% v 46%). On multivariate analysis (MVA) compared to haploHCT, MSD (RR 3.1), MUD w A-C (RR 2.0) and MUD w/o A-C (RR 4.0) were associated with significantly higher risk of cGVHD (p < 0.001). Relative to haploHCT the 3 other groups did not have a significantly different R/P risk, but compared to MSD, the MUD w A-C pts had a significantly higher R/P risk (RR 1.45; p = 0.0008). MVA showed no significant difference between the 4 cohorts in terms of NRM (p = 0.08), PFS (p = 0.45) and OS (p = 0.53). Conclusions: Survival outcomes are comparable between RIC MSD, MUD and PT-Cy based haploHCT in DLBCL. cGVHD was significantly lower with haploHCT. HaploHCT (N 132) MSD (N 525) MUD w A-C (N 403) MUD w/o A-C (N 378) Median age (range) 58 (20-75) 55 (19-73) 55 (19-75) 56 (23-73) Male sex 86 323 259 218 KPS ≥90 96 325 249 216 HCT-CI ≥ 3 36 137 85 125 Median time from diagnosis to HCT, mos 22 26 24 28 % with Prior autoHCT 42 55 59 61 Chemosensitive @ HCT (%) 108 (72) 398 (75) 312 (77) 304 (80) Marrow graft 100 10 30 20 GVHD prophylaxis PT-Cy+CNI+MMF 132 - - - CNI+other - 525 403 378 Median follow up, mos 49 48 49 39
Genomic instability and DNA damage repair in clear cell renal cell carcinoma.
Authors: Patrick Glen Pilie, Lijun Zhou, Pan Tong, Surena F. Matin, Kanishka Sircar, Pheroze Tamboli, Jose A. Karam, Christopher G. Wood, Anh Hoang, Eric Jonasch
Journal: Journal of Clinical Oncology (2017)

4581 Background: Kidney cancer accounts for 2-3% of all new cancers with clear cell renal cell carcinoma (ccRCC) the most common subtype. ccRCC is characterized by a high level of genomic instability, suggesting defective DNA damage repair (DDR). The most frequent genomic alteration in ccRCC involves loss of the 3p chromosomal arm which harbors the von Hippel Lindau gene ( VHL), in addition to nearby genes SETD2, BAP1, and PBRM. We hypothesized that VHL loss leads to defective DDR as an early event in ccRCC carcinogenesis, giving way to a mutator phenotype. We posited that assessment of very early ccRCC tumors would inform us regarding the core mutations required to drive tumorigenesis in ccRCC, and that we could confirm these findings in appropriate model systems. Methods: We performed whole-exome (WES) DNA sequencing on 11 early-stage ccRCC tumors from 5 individuals, along with their matched normal DNA. We then analyzed ccRCC samples with and without somatic VHL mutations from the Cancer Genome Atlas (TCGA) for mutational load. Finally we assessed DDR signaling activity in renal proximal tubular cell lines (RPTEC) with VHL/SETD2 knockdown and in murine embryo fibroblasts (MEFs) from Vhl and Setd2knockout mice treated with etoposide via γH2AX expression and direct repeat-green fluorescent protein reporter assay. Results: All 11 samples revealed loss of 3p with pathogenic germline or somatic mutation in remaining VHL allele. No mutations were found in genes frequently mutated in larger ccRCC, including PBRM1, BAP1 or SETD2. WES revealed ~100 mutations/tumor, with no shared mutations across samples, even within the same individual. TCGA analysis showed similar mutational loads across ccRCC samples. MEFs with biallelic loss of Vhl and monoallelic loss of Setd2 and RPTEC with VHL and SETD2knockdown displayed increased DNA damage with impaired homologous repair and increased non-homologous end joining (NHEJ). Conclusions: Early stage ccRCC tumors with loss of VHL and chr 3p demonstrate genomic instability and a mutator phenotype similar to more advanced ccRCC. Cell line models of early ccRCC show increased DNA damage with a greater reliance on error-prone NHEJ machinery. These defects could be targeted for synthetic lethal treatment strategies.
Cancer screening among patients with metastatic cancer.
Authors: Debra E. Irwin, Liisa A Palmer
Journal: Journal of Clinical Oncology (2016)

e18178 Background: Cancer screening is an integral component of preventive medicine; however, these services likely have little or no benefit in metastatic cancer patients due to limited life expectancy. The objective of this analysis was to evaluate the extent to which patients with metastatic cancer are screened for new cancers. Methods: A retrospective analysis was conducted using administrative claims data from the MarketScan Commercial and Medicare databases (1/1/2005-3/30/2014). Patients were included if they were diagnosed with metastatic lung, pancreatic, esophageal or gastric cancer. Patients were excluded if they had evidence of another primary malignancy. Outcomes included utilization of cancer screening including colonoscopy, prostate specific antigen (PSA), mammography, and Papanicolaou (PAP) screening over a 6 month time period after the first metastatic cancer diagnosis. The analysis was conducted in patients who were continuously enrolled in the health plan and survived at least 6 months (lung 53%; pancreatic 47%; gastric 53%; esophageal 54%) with the final sample sizes as follows: lung (males n=26,890; females n=24,900), pancreatic (males n=4,232; females n=4,214), esophageal (males n=4,027; females n=914) or gastric cancer (males n=3,731; females n=1,665). The proportion of patients screened was examined among the recommended age groups based on national screening guidelines. Results: Cancer screening was performed on metastatic cancer patients during the 6 months following a metastatic cancer diagnosis (Table). Conclusions: A consistent proportion of metastatic cancer patients continue to have cancer screening for new cancer diagnoses during the first 6 months after their metastatic diagnosis. The benefit of these screening services is questionable. Cancer Type Colonoscopy PSA Mammography PAP Smears Lung - Males 4% 8% NA NA Lung - Females 4% NA 10% 6% Pancreatic - Males 5% 7% NA NA Pancreatic - Females 4% NA 9% 6% Esophageal - Males 5% 7% NA NA Esophageal - Females 6% NA 11% 6% Gastric - Males 6% 7% NA NA Gastric - Females 7% NA 11% 5%
Loss of the CD28 costimulatory molecules on the immune subsets of TCD4+ cells in prostate cancer elderly patients.
Authors: Leuridan Torres, Jurema Telles O Lima, Luiz Claudio Santos Thuler, Maria Julia Gonçalves Mello, Kleber Jatay
Journal: Journal of Clinical Oncology (2016)

e16612 Background: Cancers are increasing with aging and thus the number of elderly cancer patient is expected to increase significantly in years to come. The aims were to evaluate the cellular immune profiling associated with prostate cancer in elderly patients. Methods: We prospectively enrolled patients, who were treated and followed-up in the department geriatric clinicaloncology. Between 2015 and 2016, a prospective cohort study in 346 elderly incident cancer patients ( ≥ 60 years) , at the time of enrollment, assessed and collected socio-demographic and clinical variables and collected peripheral blood analysis in Experimental translational exploratory study. using PBMC were stained with following antibodies: anti-CD4, anti-CD8, anti-CD28, anti-CD20, anti-CD16, anti-CD56 and analyzed by four-color flow cytometry on a FACS Verse BD Bioscience. We analyzed the immune profiling of elderly patients with prostate cancer and non-cancer ( > 65). Results: We enrolled 38 patients with prostate cancer and the median age was 71,2 yo (SD 7.41). Then, we compared the population of TCD4+, TCD8+, NK and B cells based on the prostate cancer groups. Low median percentage of TCD4+ and TCD4+CD28+ cells when compared to non cancer elderly (41.2% vs. 50.3%, P= 0.04; 43.5 vs. 52.7%, P= 0.02; respectively). By contrast, the median percentage of TCD8+ and TCD8+CD28+ cells were similar between groups. There were no significant differences in B and NK cells. Conclusions: This study elucidated the profiling for cellular immune response in elderly patients with prostate cancer. We observed decreased percentage of TCD4+ cells and loss of the CD28 costimulatory molecules on the immune subsets of T CD4+ cells in prostate cancer elderly patients, suggesting decline of the immune function TCD4+ cells these patients.
Chemical space of <i>Escherichia coli</i> dihydrofolate reductase inhibitors: New approaches for discovering novel drugs for old bugs
Authors: Bharath Srinivasan*, Sam Tonddast‐Navaei, Ambrish Roy, Hongyi Zhou, Jeffrey Skolnick
Journal: Medicinal Research Reviews (2018)

Abstract Escherichia coli Dihydrofolate reductase is an important enzyme that is essential for the survival of the Gram‐negative microorganism. Inhibitors designed against this enzyme have demonstrated application as antibiotics. However, either because of poor bioavailability of the small‐molecules resulting from their inability to cross the double membrane in Gram‐negative bacteria or because the microorganism develops resistance to the antibiotics by mutating the DHFR target, discovery of new antibiotics against the enzyme is mandatory to overcome drug‐resistance. This review summarizes the field of DHFR inhibition with special focus on recent efforts to effectively interface computational and experimental efforts to discover novel classes of inhibitors that target allosteric and active‐sites in drug‐resistant variants of EcDHFR.