tbuckley/cabot-search huggingface dataset:
Cost-effectiveness evaluation of abiraterone in the treatment of patients with castration-resistant prostate cancer who previously received docetaxel.
Authors: Akhil Chopra, Stefan Gluck, Alberto J. Montero, Kiran Kumar Venkata Raja Avancha, Gilberto Lopes
Journal: Journal of Clinical Oncology (2012)

e15107 Background: Treatment with abiraterone improves overall survival (OS), time to prostate-specific antigen progression and radiologic progression-free survival when added to prednisone and best supportive care in patients with advanced castrate-resistant prostate cancer (CRPC) who previously received docetaxel. Little is known about its cost-effectiveness in the United States. Methods: In order to raise awareness of pharmacoeconomics concepts and inform policy-makers in the US, this study aimed to assess the cost-effectiveness of abiraterone in the treatment of advanced CRPC patients, from a payer perspective. We created a decision-analytical model using clinical data from the pivotal phase III trial: COU-AA-301. Health utilities were derived from the available literature. Costs for drug acquisition, physician visits and laboratory tests were obtained from the Center for Medicare Services Drug Payment Table and Physician Fee Schedule and are represented in 2011 US dollars. Life-years saved (LY), Quality-adjusted life years (QALY) and Incremental Cost Effectiveness Ratio (ICER) were calculated using updated survival data presented at the 2011 ASCO meeting. Other main scenarios used the original median survival data published in the New England Journal of Medicine article and adjusted median OS to represent an overall survival hazard ratio of .66. Sensitivity analyses were performed using the confidence intervals for median OS in the pivotal study as well as by halving or doubling all other model inputs. No discounting was used due to the short time-horizon. Results: Abiraterone added 0.38 LY and 0.30 QALY with an incremental cost of $39,320 and therefore a cost of $102,600/LY and an ICER of $129,000/QALY. The main drivers of the model were drug acquisition cost, median OS, and health utility values. The results of the model were robust in different scenarios and sensitivity analyses. Conclusions: Using commonly accepted willingness-to-pay thresholds, such as those suggested by the World Health Organization, treatment of patients with advanced CRPC patients with abiraterone is likely to be cost-effective in the US.
Differences in mutation rates between right- and left-sided colorectal adenocarcinoma.
Authors: Christopher E. Jensen, Arturo Loaiza-Bonilla, Jonathan Yap Villanueva, Jennifer J. Morrissette
Journal: Journal of Clinical Oncology (2017)

622 Background: Recent reports have demonstrated inferior outcomes for patients with right-sided colorectal cancer (CRC) compared to patients with left-sided disease (Schrag et al 2016, JCO 34 (suppl; abstr 3505)) as well as differences in treatment response based on disease sidedness (Venook et al 2016, JCO 34 (suppl; abstr 3504)). However, the biological and genetic underpinnings of these clinical differences are incompletely understood. Methods: We compared mutation rates among 38 genes in a retrospective review of next-generation sequencing data of CRC samples obtained in routine clinical practice at a single academic medical center. Primary location was identified via chart review. Right = cecum to transverse colon; Left = descending colon to rectum. Results: Among 293 samples (167 left-sided, 103 right, 23 synchronous or without clear primary), BRAF and CTNNB1 mutations were more prevalent in right-sided CRC. BRAF was mutated in 15.5% of right-sided CRC (95% CI: 8.5-22.5%) compared to 4.8% (CI: 1.6-8.0%) (p=0.003). CTNNB1 was mutated in 3.9% of right-sided CRC (CI: 0.2-7.6%) compared to no instances of CTNNB1 mutations in left-sided disease (p=0.01). Among right-sided CRC, there was a trend toward more KRAS mutations at 57.3% (CI: 47.7-66.8%) versus 44.9% (CI: 37.4-52.5%) and more PIK3CA mutations at 26.2% (CI:17.7-34.7%) versus 17.4% (CI: 11.6-23.1%), though these differences did not rise to the level of statistical significance. The overall rate of BRAF mutations in our sample (8.9%, CI: 5.5-12.3%) was consistent with the rate of BRAF mutations among large intestine adenocarcinomas in the COSMIC database (10.6%, CI: 10.4-10.8%), lending support to the external validity of these data. Conclusions: These differing mutation rates may implicate these genetic pathways in the mechanisms underlying the discrepant outcomes and treatment responses between right and left-sided disease described in prior studies. Further work is needed to more clearly elucidate genetic difference between right and left-sided CRC, as well as the mechanistic relationship between these mutations and prognosis.
Benefit of EGFR-inhibition therapy for metastatic colorectal cancer patients with KRAS-mutated tumors and high plasma TIMP-1 level: Results from the NORDIC VII study.
Authors: Nils Brunner, Line Schmidt Tarpgaard, Ib Jarle Christensen, Jose Moreira, Tormod Kyrre Guren, Bengt Glimelius, Halfdan Sorby, Tone Ikdahl, Elin Kure, Kjell Magne Tveit, Hans Jørgen Nielsen, Per Pfeiffer
Journal: Journal of Clinical Oncology (2014)

3590 Background: RAS status is the only biomarker to select patients with metastatic colorectal cancer (mCRC) for therapy with an epidermal growth factor receptor (EGFR) inhibitor. However, not all KRASwild-type tumors respond to EGFR-inhibition, and some patients with mutated tumors may still benefit from therapy. To improve selection of patients for treatment with EGFR inhibitors, new biomarkers are needed. Plasma Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) induces intracellular signalling activating the Akt-survival pathway, and we hypothesize that high TIMP-1 levels interact with the signalling of EGFR and thereby with the anti-tumor effects of EGFR inhibitors. The present study tests the above hypothesis in patients included in the NORDIC VII Study. Methods: mCRC patients were randomized to Nordic FLOX +/- cetuximab (Tveit et al., JCO, 2012). Pre-treatment plasma samples (n=426) were analysed for TIMP-1 using the MAC15 antibody kinetic ELISA. Results: Univariate Cox analyses including all patients showed that high pre-treatment plasma TIMP-1 was significantly associated with shorter PFS (P = .003), and OS (P < .0001). Multivariate analysis (not including treatment) demonstrated that high plasma TIMP-1 was an independent biomarker of OS (P = .016). A significant interaction between plasma TIMP-1, KRAS status and treatment (+/- cetuximab) was demonstrated for OS (P = .002). Patients with KRAS mutated tumors and high TIMP-1 level (> 3rdquartile) had a significantly longer OS if treated with cetuximab (HR, .48; 95% CI, .25 to .93) compared to patients not treated with cetuximab. Conclusions: Patients with KRAS mutated tumors and a high plasma TIMP-1 level seem to benefit from EGFR-inhibition therapy. Based on these results we propose a novel hypothesis on the interaction between EGFR-1 signalling and TIMP-1.
Pharmacogenetic predictors of adverse events in stage II-III colon cancer (CC) patients treated with oxaliplatin and fluoropyrimidines-based adjuvant chemotherapy (CT): A GEMCAD study.
Authors: Ana Custodio, Juan Moreno, Jorge Aparicio, Javier Gallego Plazas, Carlos Fernandez-Martos, Ricardo Yaya, Ana M Calatrava, Juan Maurel, Emilio Burgos, Eva Tejerina, Jorge Barriuso, Victor Moreno, Virginia Martinez Marín, Javier De Castro, Angela Lamarca, Pablo Lapunzina, Rosario Madero, Paloma Cejas, Jaime Feliu
Journal: Journal of Clinical Oncology (2012)

10547 Background: Although the benefit of oxaliplatin-based adjuvant CT has been demonstrated in patients with resected stage II-III CC, the recommendation to administer postoperative treatment must consider its potential adverse events. Predicting individual patients’risk of severe toxicity could potentially improve the quality of care by allowing individualization of treatment. We investigate the utility of determining single nucleotide polymorphisms (SNPs) in genes involved in oxaliplatin and fluoropyrimidines metabolisms to predict the toxicity of adjuvant CT in stage II-III CC patients. Methods: DNA was extracted from formalin-fixed paraffin-embedded samples from 379 surgically treated high-risk stage II (27.71%) and stage III (72.29%) CC patients receiving adjuvant CT (54.35% FOLFOX, 45.65% XELOX) from January 2004 to December 2008. Genotyping was performed for 35 SNP in 18 genes using the MassARRAY (SEQUENOM) technology. Results: A total of 89 (23.4%) patients experienced at least one grade 3-4 adverse event. The most common grade 3-4 toxicities were neutropenia (15.3%), diarrhea (8.17%) and neurotoxicity (7.65%). The MTHFR rs1801133 C&gt;T C/C (30.1% C/C, 17.5% C/T, 21.7% T/T; p=0.043) and XRCC2 rs3218408 T&gt;G T/T (28.3% T/T, 16.2% G/T and 10% G/G; p=0.007) genotypes were associated with higher risk of any grade 3-4 toxicities, whereas the incidence of severe toxicity was lower in patients with the UMPS rs3772807 G&gt;C C/C (14% C/C, 21% C/G, 28.9% G/G; p=0.021) and DPYD rs970337 G&gt;A A/A (16.7% A/A, 21.1% A/G, 30.1% G/G; p=0.028) genotypes. In addition, the DPYD rs970337 G&gt;A A/A genotype was associated with a lower rate of grade 3-4 diarrhea (5% A/A, 9.4% A/G, 8.1% G/G; p=0.030), the ABCG2 rs3114018 A&gt;C C/C genotype with an increased rate of grade 3-4 neutropenia (15.2% C/C, 6.3% A/C, 4.5% A/A; p=0.034) and the ERCC1 rs11615 T&gt;C T/T genotype with a lower rate of grade 3-4 neurotoxicity (5.4% T/T, 9.1% C/T, 10.2% C/C; p=0.032). Conclusions: Our data suggest that SNPs in genes involved in oxaliplatin and fluoropyrimidines metabolisms can potentially predict severe toxicity in stage II-III CC patients treated with adjuvant CT.
The effect of BMI at time of surgery on long-term outcome after radical prostatectomy.
Authors: Rochelle Payne Ondracek, Matthew H. Hayn, Michael Adam Poch, Warren Davis, Alexandra Curtis, Hyung Lae Kim, Carl D Morrison, James Mohler, James Roger Marshall
Journal: Journal of Clinical Oncology (2012)

e15203 Background: Body mass index (BMI) at time of surgery was determined among 715 radical prostatectomy patients. The association of BMI with a range of treatment outcomes was considered. Methods: The associations of BMI at time of radical prostatectomy (RP) with disease stage and aggressiveness and long-term outcome were evaluated among 715 patients treated with RP at Roswell Park Cancer Institute between 1993 and 2005. Clinical and pathological aggressiveness indicators included clinical Gleason sum and tumor stage (2002 TNM), highest preoperative PSA, pathological Gleason sum and tumor stage (2002 TNM) and surgical margin status. Ten post-RP recurrence definitions were considered: 1) PSA ≥ 0.2 ng/ml; 2) PSA ≥ 0.4 ng/ml (with 1 confirming value); 3) 1 or more post RP treatments (ADT, radiation, chemotherapy); 4) PSA doubling time &lt; 12 months; 5) PSA doubling time &lt; 9 months; 6) PSA doubling time &lt; 6 months; 7) NCCN definition of PSA failure; 8) AUA definition of PSA failure; 9) diagnosis of metastatic CaP; and 10) death from CaP. Results: Of the 715 men, 33 developed metastatic prostate cancer, and 17 died of prostate cancer. 246 men had BMI ≥ 30. BMI was not significantly associated with clinical or pathological aggressiveness criteria. These analyses showed that there is a trend towards higher risk of the development of metastasis or death for men with BMI ≥ 30, although the association with high BMI and these failure types is not significant. With adjustment for the most significant tumor aggressiveness features (clinical Gleason sum, pathological tumor stage, pathological Gleason sum, and surgical margin status) in proportional hazards regression, men with BMI ≥ 30 had consistently lower risk for all definitions of recurrence except metastasis and death, although no hazard ratios were significant. In contrast, men with higher BMIs had higher risk for metastasis and death from prostate cancer, although neither association is statistically significant. Conclusions: Men with higher BMIs show similar to slightly reduced risk for PSA-based recurrence definitions. Men with higher BMIs had slightly higher risk, though not significant, for metastasis and death. These results seem to support theories that PSA is diluted in men with higher BMIs.
Allogeneic hematopoietic stem cell transplantation in a cohort of 314 advanced lymphoma patients.
Authors: Sylvain Garciaz, Luca Castagna, Jean El Cheikh, Stefania Bramanti, Sabine Furst, Roberto Crocchiolo, Diane Coso, Benjamin Esterni, Florence Broussais, Barbara Sarina, Claure Lemarie, Angela Granata, Raynier Devillier, Samia Harbi, Reda Bouabdallah, Armando Santoro, Didier Blaise
Journal: Journal of Clinical Oncology (2014)

8568 Background: Patients with refractory/relapsed Hodgkin Lymphoma and Non Hodgkin Lymphoma (R/R HL-NHL) have poor prognosis. Allogeneic stem cell transplantation (allo-HSCT) represents a potentially curative strategy. The increased use of Reduced Intensity conditioning (RIC) regimens has decreased the non-relapse mortality (NRM) previously reported with myeloablative conditioning. However, Chronic Graft versus Host disease (cGVHD) is still matter of concern. The aim of this study is to evaluate the long-term survival of a cohort of R/R HL-NHL. Methods: From 9/1999 to 10/2013, 314 patients from 2 associated institutions received allo-HSCT. Diagnoses were aggressive-NHL in 157 patients, indolent-NHL in 59 and HL in 98. 148 patients relapsed after autologous transplant (auto-HSCT). Out of the 166 remaining patients, 109 received a tandem auto-allo-HSCT and 57 benefit of allo-HSCT without prior auto-HSCT. At transplant, 172 were on complete remission, 86 were on partial remission and 56 were not in response. Donors were HLA identical sibling in 54%, unrelated in 21% and haploidentical in 21%. Conditioning regimen consisted in RIC in 68% of cases. Results: With a median follow-up of 29 months [2-160] the 5-year overall survival (OS), the 5-years progression free survival (PFS) and the five years incidence of relapse were 53.9% [47-61], 47.2% [41-54] and 26%[21-32]. The 1-years NRM was 18% [14-23]. Incidence of acute and chronic GVHD was 28% (9% grade 3-4) and 35% (severe NIH cGVHD: 14%). The median duration of immunosuppressive therapy was 7 months [2-117] and it was interrupted in 72% at 1 year for patients who did not relapse. In multivariate analysis, disease status at transplant only influences OS. Age, comorbidities, prior auto-ASCT, donor and conditioning regimen do not have any significant prognostic impact. Conclusions: Allo-ASCT is an option for patients with R/RHL-NHL with a 5-years OS of 54% and PFS of 47%. Taking into account population characteristics and period of treatment, toxicity is acceptable with only 14% of severe NIH cGVHD. Most of patient (72%) could stop immunosuppressive therapy demonstrating the absence of GVHD affecting their quality of life.
A phase II study of tivantinib monotherapy in patients with previously treated advanced or recurrent gastric cancer.
Authors: Kei Muro, Min-Hee Ryu, Hirofumi Yasui, Tomohiro Nishina, Baek-Yeol Ryoo, Narikazu Boku, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2012)

4082 Background: Tivantinib is a selective, non-ATP competitive, small-molecule inhibitor of c-MET and is under development in several cancers such as NSCLC and HCC. Elevated expressions of c-MET and its ligand, hepatocyte growth factor, have been frequently found in gastric cancer, and are associated with a more aggressive phenotype. In this single-arm phase II study, we evaluated the efficacy of tivantinib monotherapy in Asian patients (pts) with previously treated metastatic gastric cancer (MGC). This is the first clinical trial evaluating the efficacy of a selective c-MET inhibitor for MGC. Methods: Eligibility criteria included MGC with at least 1 measurable lesion per RECIST; 1 or 2 prior chemotherapy regimens; ECOG PS 0 or 1; and normal CYP2C19 metabolism. Tivantinib was daily administered 360 mg bid orally. The primary endpoint was disease control rate (DCR) defined as CR, PR or SD after 8 weeks administration. Pretreatment tumor tissue collection was required to evaluate the relationship between biomarkers and efficacy. Pharmacokinetic (PK) evaluation was also conducted. Results: Thirty patients received tivantinib and were eligible for analysis: median age 62.5 (41-70) years; ECOG PS 0/1 (8/22); 1/2 prior regimen (16/14); 12 pts (40%) with prior gastrectomy. No objective response was observed, and DCR was 36.7% (11/30 pts). Median progression-free survival was 43 (95% CI: 29.0-92.0) days. Grade 3 or 4 adverse events (AEs) occurred in 13 pts (43.3%), in which neutropenia (n = 4) and anemia (n = 4) were recognized as drug-related. Only 2 pts discontinued due to AEs. There is no treatment-related death and novel safety concern. c-MET gene amplification (≥ 5 copies/cell) was observed in 4 pts (13.3%). No obvious relationship of treatment outcome with biomarkers including c-MET gene amplification, c-MET, p-c-MET and HGF expression in tumor and serum HGF was identified. Gastrectomy and/or ethnicity (Korean or Japanese) did not affect PK parameters. Conclusions: Tivantinib as a monotherapy showed only a modest efficacy in previously treated MGC, and further trial testing in combination would be warranted in MGC. It would be an important finding that gastrectomy do not affect PK profile of tivantinib.
Rates and Characteristics of Paid Malpractice Claims Among US Physicians by Specialty, 1992-2014
Authors: Adam C. Schaffer, Anupam B. Jena, Seth A. Seabury, Harnam Singh, Venkat Chalasani, Allen Kachalia
Journal: JAMA Internal Medicine (2017)

Although physician concerns about medical malpractice are substantial, national data are lacking on the rate of claims paid on behalf of US physicians by specialty.To characterize paid malpractice claims by specialty.A comprehensive analysis was conducted of all paid malpractice claims, with linkage to physician specialty, from the National Practitioner Data Bank from January 1, 1992, to December 31, 2014, a period including an estimated 19.9 million physician-years. All dollar amounts were inflation adjusted to 2014 dollars using the Consumer Price Index. The dates on which this analysis was performed were from May 1, 2015, to February 20, 2016, and from October 25 to December 16, 2016.For malpractice claims (n = 280 368) paid on behalf of physicians (in aggregate and by specialty): rates per physician-year, mean compensation amounts, the concentration of paid claims among a limited number of physicians, the proportion of paid claims that were greater than $1 million, severity of injury, and type of malpractice alleged.From 1992-1996 to 2009-2014, the rate of paid claims decreased by 55.7% (from 20.1 to 8.9 per 1000 physician-years; P < .001), ranging from a 13.5% decrease in cardiology (from 15.6 to 13.5 per 1000 physician-years; P = .15) to a 75.8% decrease in pediatrics (from 9.9 to 2.4 per 1000 physician-years; P < .001). The mean compensation payment was $329 565. The mean payment increased by 23.3%, from $286 751 in 1992-1996 to $353 473 in 2009-2014 (P < .001). The increases ranged from $17 431 in general practice (from $218 350 in 1992-1996 to $235 781 in 2009-2014; P = .36) to $114 410 in gastroenterology (from $276 128 in 1992-1996 to $390 538 in 2009-2014; P < .001) and $138 708 in pathology (from $335 249 in 1992-1996 to $473 957 in 2009-2014; P = .005). Of 280 368 paid claims, 21 271 (7.6%) exceeded $1 million (4304 of 69 617 [6.2%] in 1992-1996 and 4322 of 54 081 [8.0%] in 2009-2014), and 32.1% (35 293 of 109 865) involved a patient death. Diagnostic error was the most common type of allegation, present in 31.8% (35 349 of 111 066) of paid claims, ranging from 3.5% in anesthesiology (153 of 4317) to 87.0% in pathology (915 of 1052).Between 1992 and 2014, the rate of malpractice claims paid on behalf of physicians in the United States declined substantially. Mean compensation amounts and the percentage of paid claims exceeding $1 million increased, with wide differences in rates and characteristics across specialties. A better understanding of the causes of variation among specialties in paid malpractice claims may help reduce both patient injury and physicians' risk of liability.
Role of surveillance imaging in the management of peripheral T-cell lymphomas.
Authors: Tiffany Pool Ling Tang, Zhengming Chen, Pannee Praditsuktavorn, Lay Poh Khoo, Jia Ruan, Soon Thye Lim, Daryl C.L. Tan, Colin Diong, Yuh Shan Lee, Goh Yeow Tee, William Hwang, Miriam Tao, Richard Hong Hui Quek, Kevin Tay, Mohamad Farid, Richard R. Furman, John Leonard, Peter Martin
Journal: Journal of Clinical Oncology (2014)

8543 Background: The role of routine surveillance imaging (RSI) in patients with peripheral T-cell lymphoma (PTCL) in first complete remission (CR1) is unclear. RSI offers the theoretical advantage of detecting asymptomatic relapses so that second line therapy may be initiated earlier. We investigated the proportion of PTCL relapses detected by RSI and those by clinical findings (C) such as abnormal symptoms, signs or raised LDH, and compared outcomes of these two groups. Methods: PTCL patients were identified through prospectively maintained T-cell lymphoma databases from the National Cancer Centre Singapore/Singapore General Hospital and Weill-Cornell Medical College. PTCL subtypes included were PTCL-NOS, AITL, ALCL (ALK positive and negative), EATL, GDT, HSTL and ATLL. Patients with leukemias, indolent, composite and cutaneous lymphomas were excluded. Patients who achieved CR1 and then relapsed were retrospectively reviewed and stratified according to whether the relapse was detected by RSI or by C. Fisher exact and Mann Whitney U test was used to compare the baseline characteristics such as age, stage, PTCL subtype, IPI and treatments between the 2 groups. Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test. Results: There were 427 patients in the combined database and 341 were included in the study. Of these, 145 patients achieved CR1 and 64 relapsed. Relapses were detected by C in 51, RSI in 9 and unknown in 4 patients. Regardless of method of detection, 93% had symptoms, 87% had signs and 76% had raised LDH at relapse. Three patients had no clinical evidence of relapse: 2 had AITL and 1 had NKTL. A median of 2 scans were performed in the first 12 months of CR1. Baseline characteristics and median RSI numbers were similar in both groups. After a median follow-up of 37 months (range 5-402), the median PFS was 19.6 months (range 5-381) in the C group and 14.5 months (range 8-38) in the RSI group (p=0.740). The median OS was 65 months (95% CI 36-88) in the C group and NR (95% CI 16-NR) in the RSI group (p=0.652). Conclusions: Our data suggests that most patients with PTCL in CR1 have abnormal symptoms, signs or raised LDH at relapse and RSI does not impact the detection. RSI does not appear to affect survival outcomes.