tbuckley/cabot-search huggingface dataset:
Pharmacokinetic (PK) modeling of serum platinum to reveal extent of long-term exposure and associated comorbidities after cisplatin treatment.
Authors: Omar El Charif, Zepeng Mu, Eric R Gamazon, Paul C Dinh, Shirin Ardeshirrouhanifard, Patrick O. Monahan, Darren R. Feldman, Lawrence H. Einhorn, Robert James Hamilton, David J. Vaughn, Neil E. Martin, Chunkit Fung, Sophie D. Fossa, Lois B. Travis, M. Eileen Dolan
Journal: Journal of Clinical Oncology (2018)

10058 Background: Platinum (Pt) is detectable for years after cisplatin treatment completion, but few studies have examined the extent of long-term exposure to Pt and associated co-morbidities. Methods: Eligible testicular cancer survivors (TCS, n = 633) given 300 or 400 ± 15 mg/m2 cisplatin underwent lab tests and extensive audiometry, and completed questionnaires at follow-up (median 5 y, range 1-35). Since subject-level PK parameters cannot be estimated in cross-sectional designs, we regressed log(Pt) on dose and follow-up time in the entire cohort. Each subject’s PK trait was defined as the deviation from the average concentration-time curve (the residual). High values indicate Pt levels exceeding the expected value, i.e. slower elimination. The Pt reference interval (RI) used (central 95% of 147 non-Pt exposed patients) was 8-47 ng/L (JALM 2016; 1:2, 143). Linear regression at α = 0.05 was used for associations with co-morbidities. Hearing loss was quantified as the geometric mean of thresholds: 4-12 kHz (JCO 2016; 34, 2712). Sensory neuropathy was self-reported using EORTC-CIPN20. Cardiovascular (CV) burden was defined as angina, angioplasty, stroke, DVT, PE, CAD, and/or MI > 1 month after therapy. Serum Pt, LDL, HDL, and creatinine (used to estimate creatinine clearance [CrCl] with the Cockroft-Gault formula) were measured. Results: Only 35 TCS (5.6%) were within the RI (median follow-up for this group: 20 y, range: 10-35). The estimated time to reach RI upper limit was 18 and 21 y after 300 and 400 mg/m2 cisplatin respectively (time to RI median: 46 and 57 y). The Pt PK phenotype was strongly negatively associated with CrCl (p < 10-9), and positively associated with age (p < 10-8), neuropathy (p = 0.002; age-adjusted p = 0.04), and HDL (age-adjusted p < 0.001). When adjusted for age, no associations were apparent with LDL, CV burden, or hearing loss. Conclusions: Circulating Pt persists for decades and may contribute to adverse outcomes. We previously showed that hearing loss, but not neuropathy, is associated with cumulative cisplatin dose. In conjunction with our findings here, this suggests differential kinetics of ototoxicity and neurotoxicity.
Comparing the cost-effectiveness of immunotherapy strategies in BRAF wild-type advanced melanoma.
Authors: Simon B. Zeichner, Christine Kohn, Qiushi Chen, Daniel A. Goldstein, Alberto J. Montero, Christopher Flowers
Journal: Journal of Clinical Oncology (2016)

6607 Background: Patients (pts) diagnosed with unresectable stage III or IV melanoma have 5-year survival rates of 15-20%. Recent FDA approved treatment options include pembrolizumab (PEM), nivolumab (NIVO), and ipilimumab (IPI), and these are associated with improved survival, particularly for pts with BRAF wild-type tumors. To inform policy makers regarding the value of treatments, we compared the cost-effectiveness of immunotherapy strategies. Methods: We developed Markov models, utilizing a US Medicare perspective and lifetime horizon, to estimate costs (2015 US$) and quality-adjusted life years (QALYs) for various combinations and sequences of PEM, NIVO, IPI, and chemotherapy. Each sequence was compared to the baseline sequence with dacarbazine (chemo) as a 1st line treatment strategy followed by immunotherapy. Health states were defined for each treatment line and transition probabilities between health states were derived from progression-free and overall survival data. Survival data, frequency of adverse effects, and rates of discontinuation were obtained from randomized phase III trials. We evaluated model uncertainty through univariate and probabilistic sensitivity analyses. Results: The table reports incremental costs, effectiveness, and incremental cost-effectiveness ratio (ICER) of immunotherapy-based strategies compared with dacarbazine followed by immunotherapy. Results were most sensitive to changes in drug acquisition costs and rates of discontinuation for immunotherapeutic agents. Conclusions: Our results find that single agent NIVO or PEM followed by IPI are the most cost-effective immunotherapy-based treatment strategies in pts with newly diagnosed BRAF wild-type unrespectable stage III or IV melanoma. When the cost of IPI is decreased by 50%, the cost of NIVO must be lowered to ≤ $765 for the treatment strategy of 1st line NIVO + IPI to fall below the willingness-to-pay threshold of $150,000. Treatment sequence Incremental Costs ($) Incremental QALY ICER ($) 1st line 2nd line PEM every 3 weeks IPI -- -- Dominated PEM every 2 weeks IPI 25,195 0.16 157,469 NIVO IPI 35,772 0.27 132,488 IPI NIVO 12,943 0.04 323,550 NIVO + IPI Chemo 113,088 0.27 418,844
A genetic risk-stratified, randomized phase 2 intergroup study of fludarabine/antibody combinations in symptomatic, untreated chronic lymphocytic leukemia (CLL): Results from Cancer and Leukemia Group B (CALGB) 10404 (Alliance).
Authors: Amy S. Ruppert, John C. Byrd, Nyla A. Heerema, Mitchell Reed Smith, John E. Godwin, Stephen Couban, Todd A. Fehniger, Michael Thirman, Alese E. Halvorson, Martin S. Tallman, Frederick R. Appelbaum, Richard M. Stone, Sue Robinson, Julie E. Chang, Sumithra J. Mandrekar, Richard A. Larson
Journal: Journal of Clinical Oncology (2017)

7503 Background: Prior to use of novel targeted agents for CLL, debate existed regarding the best chemoimmunotherapy regimen to build upon in patients (pts) with non-del(11q) disease. The role of lenalidomide (L) was also not defined. CALGB 10404 was a randomized phase 2 study addressing these questions. Methods: Pts with untreated CLL requiring therapy were randomized to treatment with fludarabine + rituximab (FR), FR + 6 monthly consolidative treatments of L (5 mg days 1-21/28 x 1 then 10 mg days 1-21/28 x 5) (FR+L), or FR + cyclophosphamide (FCR). Based on pretreatment central interphase cytogenetic screening, pts with del(11q22.3) in at least 20% of cells were excluded from the primary analysis, testing whether 2-year progression-free survival (PFS) rate was improved in non-del(11q) pts within each arm. A target accrual of 103 non-del(11q) pts per arm provided at least 84% power to detect an increase in 2-year PFS rate from 60% to 73%; the critical value was 69% using a single stage design and type I error rate of 4%. Results: A total of 342 non-del(11q) CLL pts were randomized to treatment with FR (n = 123), FR+L (n = 109), or FCR (n = 110). Baseline characteristics were similar across arms. Two-year PFS rates with exact 90% CIs were 64% (57-71%) (FR), 71% (63-78%) (FR+L), and 74% (66-80%) (FCR). Median PFS was significantly shorter with FR compared to FR+L (p = 0.03) and FCR (p &lt; 0.01): 43 (95% CI: 33-50), 66 (95% CI: 45-not reached), and 78 (95% CI: 58-not reached) months respectively. Median overall survival (OS) has not been reached for any arm. OS at 1, 2, and 3 years was similar across arms, although there was a plateau in OS with no events beyond 41 months in the FR+L arm, different from FR/FCR where events continued to occur. The most common adverse events were cytopenias and infections. Conclusions: FR+L and FCR met the protocol defined primary endpoint. FR+L extended PFS relative to FR and a plateau in survival differentiated this arm from the FR/FCR arms. Future studies comparing FR+L to FCR or incorporating L into other novel treatment regimens are justified. Support: U10CA180821, U10CA180882, Celgene. Clinical trial information: NCT00602459.
The genetic landscape of severe combined immunodeficiency in the United States and Canada in the current era (2010-2018)
Authors: Christopher C. Dvorak, Elie Haddad, Rebecca H. Buckley, Morton J. Cowan, Brent Logan, Linda M. Griffith, Donald B. Kohn, Sung-Yun Pai, Luigi Notarangelo, William Shearer, Susan Prockop, Neena Kapoor, Jennifer Heimall, Sonali Chaudhury, David Shyr, Sharat Chandra, Geoff Cuvelier, Theodore Moore, Shalini Shenoy, Fred Goldman, Angela R. Smith, Gauri Sunkersett, Mark Vander Lugt, Emi Caywood, Troy Quigg, Troy Torgerson, Shanmuganathan Chandrakasan, John Craddock, Blachy J. Dávila Saldaña, Alfred Gillio, Evan Shereck, Victor Aquino, Kenneth DeSantes, Alan Knutsen, Monica Thakar, Lolie Yu, Jennifer M. Puck
Journal: Journal of Allergy and Clinical Immunology (2018)
Phosphopeptide mapping of DLC1 in ER+ breast cancer reveals AMOTL2, a key hippo pathway component, as an important target.
Authors: Yesim Gokmen-Polar, Jason D True, Edyta Vieth, Guihong D Qi, Amber L Mosley, Sunil S. Badve
Journal: Journal of Clinical Oncology (2017)

11592 Background: Metastases suppressor genes are believed to control tumor progression and metastases. Deleted in Liver Cancer 1 (DLC1) acts as a gatekeeper for tumor and metastasis suppression. Low expression of DLC1 correlates with poor prognosis in patients with ER+ breast cancer. It is essential to understand the impact of DLC1 and its functional network in preventing tumor and metastasis suppression. Methods: T47D cells with stable DLC1-Full-Length (DLC1-FL) were generated using mammalian expression cloning vector, pcDNA3.1+/C-(K)-DYK, and CloneEZ™ technology. Growth rate of control and DLC1-FL knock-in cells was assessed for 2 weeks using clonogenic assay. Proteomic and phosphopeptide enrichment assays (Pierce TiO2 enrichment kit) were performed in triplicates to examine the basis of altered growth phenotype. The PeakJuggler node in Proteome Discoverer was utilized for label-free quantitation of both protein and peptide MS peak areas. In addition, GO term enrichment analysis was performed in DAVID for the significantly changed phosphopeptides. Results: Stable knock-in of T47D-DLC1-FL inhibits cell growth significantly in vitro compared to T47D-control in clonogenic assay. The phosphopeptide enrichment proteomic analyses showed 199 phosphopeptides were identified only in T47D-DLC1-FL and 182 peptides were identified only in T47D-control cells. Pathway analysis using DAVID showed 3 main clusters of significantly differently identified phosphopeptides (p-values ≤ 0.01) involving cadherin binding (p = 4.9e-12), cell-cell adherens junction (p = 3.9e-10), and cell-cell adhesion (p = 9.4e-7). Analysis of specific phosphopeptides showed canonical pathways such as CTNNB1 (Thr552), and BCL2L13 (370-385). More importantly, phosphorylation of HIPPO-pathway component AMOTL2 at S766, critical for promoting YAP signaling and invasion was only identified in T47D-control but not T47D-DLC1-FL (p = 5.78e-5). Conclusions: This data suggest that the absence of DLC1 promotes phosphorylation of AMOTL2, and thereby activating YAP-TAZ signaling leading to invasiveness. This data provides mechanistic basis for targeting this pathway to prevent recurrence in ER+ breast cancer.
Pattern of care and outcome of ederly patients with glioblastoma: Preliminary analysis of the Timone Cohort.
Authors: Laetiita Padovani, Emmeline Tabouret, Celine Boucard, Gregorio Petrirena, Chantal Campello, Maryline Barrie, Severine Queant, Mohamed Boucekine, Sebastien Boissonneau, Xavier Muracciole, Thomas Graillon, Dominique Figarella, Pascal Auquier, Olivier L. Chinot
Journal: Journal of Clinical Oncology (2018)

e14065 Background: To describe pattern of care and identify predictors of outcome in a glioblastoma (GB) population including ederly patients. Methods: In January 2014 a prospective cohort of patients (pts) with high grade glioma was initiated in Timone University Hospital, Marseille. We report an interim analysis of pts diagnosed with GB up to March 2017 (n = 261pts). All patients signed an informed consent. Methods: In January 2014 a prospective cohort of patients (pts) with high grade glioma was initiated in Timone University Hospital, Marseille. We report an interim analysis of pts diagnosed with GB up to March 2017 (n = 261pts). All patients signed an informed consent. Results: 111 females, 150 males; median age: 64y (24-88); median KPS : 70 with KPS < 70 in 24,9% of pts. Total/subtotal resection: 44 %, partial resection: 28%, biopsy: 28%. IDH status mutated 3.1%, missing 1.9%; MGMT status methylated 27.2%, unmethylated 33.3%, missing 39.5%. After initial surgery, 59.2% of pts received concomitant radiochemotherapy (RT-TMZ) 22.2% temozolomide (TMZ) alone, and 18,8% other regimens. As 12/2017, Median OS was 16.48 months (95%CI: 14.7-18.2) with survival rate of 66%, 29,6% and 17,6% at 12, 24 and 36 months respectively. In mutivariate analysis, sex (p = 0.033), type of resection (p = 0.023), KPS (p = 0.0001) MGMT status (p = 0.002) were significantly associated with OS. In pts > 70y (n = 78), median KPS was 70 with 37% < 70, median age: 74,4 years. 41% (n = 32) underwent MGMT methylation. 24 pts had biopsy, 24 partial resection and 28 total resection. Median OS was 11,5 months (95%CI: 7,13-15,86). Pts with KPS > 70 (n = .49) were treated with RT-TMZ (n = 21), TMZ (n = 18), other (n = .9) with a median OS of 26 (19-33,1) and 9.2 (5,9-12,6) mths respectively. Conclusions: In this cohort, selected elderly patients treated with RT-TMZ exhibit prolonged survival similar to younger patients. RT-TMZ should be considered as the primary option in patients in elderly patient with a KPS > 70.
Patterns of futile care for comorbidities in colorectal cancer patients near the end of life.
Authors: Davis Sam, Richard M. Lee-Ying, Sally C Lau, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2017)

e18242 Background: Futile care includes interventions that no longer provide benefit, may cause significant harm, and/or lack sufficient utility to justify the required resources. Cancer care such as chemotherapy use has been shown to be overly aggressive near the end of life. We hypothesized that futile care for non-cancer comorbidities in terminal colorectal cancer (CRC) patients may also be prevalent and associated with specific clinical factors. Methods: We constructed a large retrospective cohort of decedents aged ≥18 years who were diagnosed with CRC during 2008-2012 and who died by the end of 2013. We analyzed population-based data through linked provincial files with information on cancer management, pharmacy records, hospital discharges, and vital statistics. We defined endpoints for futile care as ≥1 hospitalization and/or ≥1 prescription for statins, dihydropyridine calcium channel blockers (CCBs), or acid suppressants within 2 months preceding death. Different time points were used in sensitivity analyses. Results: We included 2,530 patients. Median age at CRC diagnosis and death was 70 (IQR 61-79) and 72 (IQR 62-80) years, respectively. Among them, 59% were men, 66% had colon cancer, and 87% were diagnosed with advance disease. Median time from diagnosis to death was 452 (IQR 201-800) days. In terms of futile care, 4.7% had hospitalizations, 8.7% received statins, 6.8% received CCBs, and 38.2% received acid suppressants within 2 months prior to death. In multivariate analyses, there were no clear associations between demographics and hospitalizations. With respect to medication use, advanced age was correlated with increased use of statins (OR 2.235, 95%CI 1.469-3.401, p &lt; 0.001) and CCBs (OR 2.039, 95%CI 1.304-3.190, p = 0.002), but inversely associated with use of acid suppressants (OR 0.750, 95%CI 0.598-0.941, p = 0.013). Men were also more likely to receive statins (OR 1.653, 1.099-2.488, p = 0.016), but less likely to receive acid suppressants (OR 0.764, 0.608-0.960, p = 0.021). Conclusions: Even near death, a fair number of decedents with CRC continued to receive medications for comorbidities that were unlikely to provide clinically meaningful benefits. Futile care was more prevalent in men and in the elderly.
Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis
Authors: Xian Shen, Bin Zhao
Journal: BMJ (2018)

Abstract Objective To evaluate the relative efficacy of programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors versus conventional drugs in patients with cancer that were PD-L1 positive and PD-L1 negative. Design Meta-analysis of randomised controlled trials. Data sources PubMed, Embase, Cochrane database, and conference abstracts presented at the American Society of Clinical Oncology and European Society of Medical Oncology up to March 2018. Review methods Studies of PD-1 or PD-L1 inhibitors (avelumab, atezolizumab, durvalumab, nivolumab, and pembrolizumab) that had available hazard ratios for death based on PD-L1 positivity or negativity were included. The threshold for PD-L1 positivity or negativity was that PD-L1 stained cell accounted for 1% of tumour cells, or tumour and immune cells, assayed by immunohistochemistry staining methods. Results 4174 patients with advanced or metastatic cancers from eight randomised controlled trials were included in this study. Compared with conventional agents, PD-1 or PD-L1 inhibitors were associated with significantly prolonged overall survival in both patients that were PD-L1 positive (n=2254, hazard ratio 0.66, 95% confidence interval 0.59 to 0.74) and PD-L1 negative (1920, 0.80, 0.71 to 0.90). However, the efficacies of PD-1 or PD-L1 blockade treatment in patients that were PD-L1 positive and PD-L1 negative were significantly different (P=0.02 for interaction). Additionally, in both patients that were PD-L1 positive and PD-L1 negative, the long term clinical benefits from PD-1 or PD-L1 blockade were observed consistently across interventional agent, cancer histotype, method of randomisation stratification, type of immunohistochemical scoring system, drug target, type of control group, and median follow-up time. Conclusions PD-1 or PD-L1 blockade therapy is a preferable treatment option over conventional therapy for both patients that are PD-L1 positive and PD-L1 negative. This finding suggests that PD-L1 expression status alone is insufficient in determining which patients should be offered PD-1 or PD-L1 blockade therapy.
Natural history following recurrence after definitive locoregional treatment in 1000+ cases of locally advanced head and neck squamous cell carcinoma.
Authors: Jonathan Eric Leeman, Jin-Gao Li, Praveen Venigalla, Zachary Stephan Zumsteg, Sean Matthew McBride, Jay Boyle, Benjamin R Roman, Eric Jeffrey Sherman, Nancy Y. Lee, Nadeem Riaz
Journal: Journal of Clinical Oncology (2016)

6062 Background: Squamous cell carcinomas of the head and neck (HNSCC) arising from different subsites have unique biologic features and differing clinical outcomes. Herein, we report on the natural history following recurrence in a large cohort of locally advanced HNSCC patients treated with definitive loco-regional treatment with modern radiation techniques (IMRT). Methods: We reviewed outcomes from 1062 consecutive locally advanced HNSCC patients treated with definite chemo-RT or surgery with post-operative RT +/- chemotherapy from 2001-2013 at a large cancer center, including 734 cases of oropharyngeal carcinoma (OPC), 155 oral cavity carcinoma (OCC), 126 laryngeal carcinoma (LRX) and 47 hypopharyngeal carcinoma (HPX). We analyzed outcomes across sub-sites with a focus on survival following locoregional failure (LRF) or distant metastasis (DM). Median follow-up was 57.7 months in surviving patients. Results: Crude rates of LRF and DM, respectively, by sub-site were: OPC 9.4% and 12%, OCC 25.8% and 12.9%, LRX 19.8% and 18.2%, HPX 31.9%, 29.8%. Time from LRF to death was not significantly different between sub-sites. Across all sub-sites, patients who underwent salvage surgery or salvage re-irradiation following LRF experienced longer survival (surgery vs no surgery, 21.7 vs 6.0 mo, p < 0.01, re-RT vs no re-RT, 21.9 vs. 10.3 mo, p = 0.04). Time from DM to death was significantly shorter in OCC compared to other sub-sites (OCC median 3.9 months, OPC 13.4 mo, LRX 17.5 mo, HPX 7.5 mo, p < 0.01). Metastatic patients treated after 2006 experienced longer survival across all sub-sites (13.2 vs 6 mo, interquartile ranges [6.2-28.7] vs [3.2-13.4], p < 0.01). Conclusions: Salvage surgery and re-RT following LRF are associated with improved survival. DM from OCC portends inferior outcomes compared to other sub-sites. Metastatic patients treated after 2006, when cetuximab was FDA approved for HNSCC, experienced longer survival. Understanding the natural history of recurrent/metastatic HNSCC after definitive loco-regional treatment suggests several unique features which influence outcomes and may affect interpretation of clinical trials in these patients.
Racial, age, and sex disparities in chronic lymphocytic leukemia (CLL) patients treated with novel therapies.
Authors: Meghan Thompson, Chadi Nabhan, Bruce D. Cheson, John Nathan Allan, Paul M. Barr, Alan P. Skarbnik, Ryan Jacobs, Chaitra Shankar Ujjani, Richard R. Furman, Stephen J. Schuster, Nirav Niranjan Shah, John M. Pagel, Brian Thomas Hill, Danielle M. Brander, Mazyar Shadman, Clive Zent, Nicole Lamanna, Hande H. Tuncer, Frederick Lansigan, Anthony R. Mato
Journal: Journal of Clinical Oncology (2018)

6577 Background: Differences in outcomes have been reported in CLL pts receiving chemo±immunotherapy with non-Caucasians and males having inferior outcomes. Less is known if such disparities exist for pts receiving targeted therapies. We investigated how demographics impact outcomes of CLL pts treated with targeted agents. Methods: We analyzed 3 multicenter, retrospective cohort studies of CLL pts treated with ibrutinib (ibr) (front-line (F/L) or relapsed/refractory (R/R) disease) or venetoclax (ven) (R/R disease). Baseline demographics, responses (ORR), discontinuations (DC), progression-free survival (PFS), and overall survival (OS) were stratified by age ( < 65 vs ≥65 yr), sex (male (M) vs female (F)) and race (Caucasian vs other). Cox regression was used for comparisons. Results: 1068 pts were included: F/L ibr (n = 391), R/R ibr (n = 536), R/R ven (n = 141). F/L ibr pts were 38% F, 59% age ≥65 and 8% non-Caucasian. R/R ibr pts were 37% age ≥65 (sex / race data unavailable). R/R ven pts were 34% F, 63% age ≥65 and 13% non-Caucasian. Del17p was similar within all cohorts. AEs were the most common discontinuation (DC) reason in all ibr groups, while CLL progression was most common in ven pts. A higher proportion of M discontinued ven vs F (34% vs 17%). Table 1 includes ORR, PFS, OS and DC stratified by age, sex and race. Conclusions: In the largest series of pts treated with novel agents, we did not find differences in outcomes when stratified by age, sex and race. These data suggest ibr and ven may in part overcome traditional disparities. AGE: < 65 vs ≥ 65 years Sex: M vs F Race: Caucasian vs other Ibr (F/L) Ibr (R/R) Ven (R/R) Ibr (F/L) Ibr (R/R) Ven (R/R) Ibr (F/L) Ibr (R/R) Ven (R/R) ORR 85% vs 79% 67% vs 69% 68% vs 74% 80% vs 84% NA 68% vs 81% 83% vs 79% NA 71% vs 81% PFS (HR for ≥ 65 years, F and other race as events) HR 1.1 (0.6-2.0), p = 0.7 HR 0.9 (0.6-1.2), p = 0.3 HR 0.6 (0.3-1.3), p = 0.2 HR 0.9 (0.5-1.6), p = 0.7 NA HR 0.7 (0.3-1.7), p = 0.4 HR 1.9 (0.7-4.8), p = 0.2 NA HR 0.3 (0.03-1.9), p = 0.2 OS HR 2.2 (0.9-5.5), p = 0.1 HR 1.4 (0.9-2.1), p = 0.1 HR 0.9 (0.3-2.5), p = 0.8 HR 0.5 (0.2-1.3), p = 0.1 NA HR 0.8 (0.3-2.6), p = 0.7 HR 1.4 (0.3-5.9), p = 0.7 NA No deaths in Non-Caucasians DC 22% vs 25% 44% vs 47% 28% vs 28% 24% vs 24% NA 34% vs 17% NA NA NA