tbuckley/cabot-search huggingface dataset:
An indirect treatment comparison (ITC) and cost-effectiveness analysis of abiraterone acetate and enzalutamide for the treatment of metastatic castration-resistant prostate cancer (mCRPC) post-chemotherapy.
Authors: Tracy Li, Melissa Thompson, Mary Beth Todd, Margaret K. Yu, Thian San Kheoh, Jianming He, Ryan Saadi
Journal: Journal of Clinical Oncology (2014)

270 Background: Abiraterone acetate (AA) and enzalutamide (ENZ) are two new agents indicated for the treatment of patients with mCRPC. Presently, there is a high level of interest in understanding the relative clinical and economic value of these therapies. The objective of this study was to determine the comparative effectiveness and cost-effectiveness of AA vs. ENZ. Methods: The PICO (population, intervention, comparison, and outcomes) construct was used to assess the comparability of Study COU-AA-301 for AA and the AFFIRM trial for ENZ, and an ITC was conducted using the Bucher method and Bayesian statistics. A survival-based Markov cohort model with three health states (progression-free, progressed, and death) was developed to project cost-effectiveness over a life time horizon. Since only the US price of ENZ was publicly available at the time of analysis, US drug acquisition costs were used. Average wholesale prices for 30-day supplies of AA and ENZ were $7,674 and $8,940, respectively. One-way sensitivity analyses were performed for all probability, utility, and cost values incorporated into the model. Results: The ITC result on overall survival (OS) was HR = 0.95 (95% CI: 0.71-1.26) for AA vs. ENZ on the risk of mortality, after accounting for important differences in comparators and background treatments. In the base case of the economic analysis, AA was found to provide a substantial cost savings of $13,322 per patient vs. ENZ, primarily due to higher acquisition costs. Quality adjusted life years gained were comparable for AA and ENZ. These results were supported by sensitivity analyses. Conclusions: While benefits are similar for OS, AA is cost-saving compared with ENZ for the treatment of patients with mCRPC following treatment with docetaxel.
Machine learning identifies a compact gene set for monitoring the circadian clock in human blood
Authors: Jacob J. Hughey
Journal: Genome Medicine (2017)

The circadian clock and the daily rhythms it produces are crucial for human health, but are often disrupted by the modern environment. At the same time, circadian rhythms may influence the efficacy and toxicity of therapeutics and the metabolic response to food intake. Developing treatments for circadian dysfunction, as well as optimizing the daily timing of treatments for other health conditions, will require a simple and accurate method to monitor the molecular state of the circadian clock.Here we used a recently developed method called ZeitZeiger to predict circadian time (CT, time of day according to the circadian clock) from genome-wide gene expression in human blood.In cross-validation on 498 samples from 60 individuals across three publicly available datasets, ZeitZeiger predicted CT in single samples with a median absolute error of 2.1 h. The predictor trained on all 498 samples used 15 genes, only two of which are part of the core circadian clock. By then applying ZeitZeiger to 475 additional samples from the same three datasets, we quantified how the circadian clock in the blood was affected by various perturbations to the sleep-wake and light-dark cycles. Finally, we extended ZeitZeiger (1) to handle intra-individual variation by making predictions based on multiple samples taken a known time apart, and (2) to handle inter-individual variation by personalizing predictions based on samples from the respective individual. Each of these strategies improved prediction of CT by ~20%.Our results are an important step towards precision circadian medicine. In addition, our generalizable extensions to ZeitZeiger may be applicable to the growing number of biological datasets that contain multiple observations per individual.
Phase II trial of topical heparin as treatment for patients (pts) with hand-foot syndrome (HFS) induced by capecitabine (CAP).
Authors: A. A. Rodriguez Garzotto A, L. C. Iglesias Docampo, C. Gravalos Castro, J. A. Lopez-Martin, T. Agullo Ortuno, V. Diaz Garcia, B. Homet, E. M. Ciruelos Gil, L. Manso, C. Mendiola, C. Gomez-Martin, R. Hitt, A. Gomez Camara, H. Cortes-Funes
Journal: Journal of Clinical Oncology (2011)

e19671 Background: Molecular physiopathology of HFS induced by CAP is unclear. Interruption or dose reduction of CAP is the only effective strategy. Aims: to evaluate efficacy and safety of a topical heparin Menaven gel® and to analyse expression levels of four biomarkers. Methods: This is a Simon 2-stage phase 2 trial: if >3 responses were achieved in the first 12 pts, the study proceeded to its second stage. Key entry criteria: Age >18 years, diagnosis of cancer in treatment with CAP, as single-agent or in combination, and presence of HFS grade (G) 1 or 2 (NCI-CTCAE version 3.0). Topical heparin was administered in palms and soles four times/day for three weeks (w). No other concurrent treatment for HFS was allowed. Physical examination and Visual Analogic Pain Scale (VAS) were assessed at baseline, and weekly. Changes were photographically documented by investigator. Skin biopsies of palms and blood samples were obtained at baseline and after 3w. Expression of thymidine phosphorylase (TP), dihydropyrimidine-dehydrogenase (DPD), Fibroblast Growth Factor (FGF) and Keratinocyte Growth Factor (KGFR) were analyzed by immunohistochemistry (IHC) and immunoperoxydase revelation in skin. TP and DPD mRNA expression was determined by quantitative real-time PCR in blood samples. Results: Between Oct/2010 and Jan/2011, 21 pts were included. So far, 16 pts are evaluable: 6 males, median age 61 y. Breast cancer (n=8), colorectal cancer (n=5) and others (n=3). Baseline HFS was G1 18% and G2 82%. CAP was administered as single-agent (n=4) and combination (n=12). Improvement of HFS was observed in 68% and 75% pts in w3 and 6, respectively. Median VAS decreased from 5,6 at baseline to 1,1 in w3, p<0,001. No changes were observed in the skin biopsies. However, high expression of TP was found in conjunction of decreased DPD in blood samples in 12pts with clear response. Definitive results from 21 subjects will be presented at the meeting. Conclusions: Our preliminary results suggest that topical heparin may be effective to relief CAP-induced HFS. A study evaluating topic heparin as a preventive therapy of HFS is planned.
A questionnaire study to document surgical and oncologic management of axillary micrometastases and isolated tumor cells in early-stage breast cancer across the United Kingdom.
Authors: Nikhil Tanna, Susan Jane Cleator, Dmitri Hadjaminas, Carlo Palmieri
Journal: Journal of Clinical Oncology (2013)

68 Background: A questionnaire study to document Surgical and Oncological management of Axillary Micrometastases and Isolated Tumour Cells in early-stage breast cancer across the U.K. Methods: A web-based 10-question survey examining management of axillary micrometastases (Mi) and Isolated Tumour Cells (ITCs) in early stage breast cancer was distributed to the membership of the UK Intergroup, a group of 130 breast cancer surgeons and 223 oncologists engaged in clinical breast research. Results: Responses were obtained from 58 breast cancer teams (‘multidisciplinary teams, MDTs’ or ‘tumour boards’), including academic and community-based. Of the 79 responses, 23 (29%) were from surgeons and 56 (71%) from oncologists. 15 centres provided responses from more than one member. For a given question, MDTs for which members gave inconsistent answers were excluded from the analysis. 17 centres (29.3%) reported performing intra-operative assessment of sentinel node biopsies (SNB); 23% Imprint Cytology; 31% PCR and 46% reported using frozen section. Regarding management of Mi, 8 centres (16%) reported performing axillary node clearance (ANC) to level 2 always; 8 centres (16%) clearance to level 3 always, 10 centres (20%) never ANC for Mi and 24 (48%) centres reported sometimes performing ANC. On asking whether centres would consider performing neither ANC nor delivering axillary Radiotherapy (RT) for macrometastases discovered at SNB, 1 centre (2%) reported always, 22 centres (42%) reported never and 29 centres (56%) reported sometimes. Regarding management of ITC’s, 2 centres (3.5%) reported performing ANC, 3 centres (5.3%) delivering RT only and 52 centres (91%) performed neither. The question associated with most inconsistency within an MDT was that which explored giving chemotherapy for patients with Mi or ITCs (80%). Conclusions: In a survey of U.K. breast cancer MDTs, significant variation in management of low volume disease in the axilla was seen. Given the challenge of performing phase 3 trials in this setting, clinicians should be supported to audit treatment and outcomes so the impact of differing protocols on outcomes may be established.
Surgical management trends of penile cancer in the United States between 2000 and 2010.
Authors: Elizabeth Kate Ferry, Hui Zhu
Journal: Journal of Clinical Oncology (2014)

379 Background: Penile cancer may cause significant morbidities to those who are treated with aggressive surgery. Conversely, there has been no improvement in penile cancer survival rates since 1990. While the causes for this stagnation may be multifactorial, one potential cause is undertreatment of high-risk disease. This study aimed to examine both the trend in the stage-dependent surgical treatment for penile cancer from 2000 to 2010 and the patterns of possible over and/or undertreatment during this period. Methods: The National Cancer Database (NCDB) Datalinks Portal was queried. Diagnosis by year, first course surgery by stage, in all hospitals from 2000-2010 was first obtained. Data was grouped into no surgery, penile sparing, and radical surgery. Data was also obtained for first course surgery by stage in community hospitals (C), comprehensive centers (CC), and teaching research hospitals (TR), individually. Groups were similar as above, with the exclusion of the no surgery group. Results: There were 1,405 patients with recorded first course surgical treatments in community hospitals, 3,930 in comprehensive hospitals, and 3,667 in teaching research hospitals from 2000 to 2010. Graphically, there has been no change in the trend in the pattern of surgical management of penile cancer from 2000 to 2010 in high or low stage penile cancers. Consistent overtreatment of stage I penile cancer with radical surgery was observed in all hospitals during this period. A variable, but high, percentage of penile-sparing surgery was observed for advanced stages among all hospital types. Conclusions: Corresponding to the stagnation in the survival rates of penile cancer, the surgical management trends ded not change between 2000 and 2010. Contrary to the 2013 National Comprehensive Cancer Network (NCCN) Guidelines, penile-sparing surgery continues to be performed in all types of treating hospitals for higher stage penile cancers, which may represent an undertreatment of potentially fatal penile cancers. Conversely, there was a persistent pattern of overtreatment of stage I penile cancer. [Table: see text]
Phase I dose escalation and pharmacokinetics study of intravenous aflibercept plus irinotecan, 5-fluorouracil, and folinic acid (FOLFIRI) in patients with metastatic colorectal cancer.
Authors: K. Yamazaki, T. Yoshino, K. Yamaguchi, N. Boku, N. Machida, Y. Onozawa, M. Asayama, T. Doi, A. Ohtsu, T. Aoyama
Journal: Journal of Clinical Oncology (2011)

538 Background: Aflibercept (AF), a recombinant fusion protein, is a potent inhibitor of vascular endothelial growth factor. This study assessed the safety, dose limiting toxicities (DLTs), recommended dose (RD), and the pharmacokinetics (PK) of AF in combination with FOLFIRI. Methods: This was an open-label, sequential-cohort, dose-escalation study of intravenous AF administered every 2 weeks, in combination with FOLFIRI (fixed doses) in patients (pts) with metastatic colorectal cancer (MCRC). Two dose levels (DL) of AF (2 and 4 mg/kg) were set, and 3-6 pts were to be recruited in each DL. DLTs were to be evaluated in the first 2 cycles. RD was defined as the highest AF dose at which &lt;33% of all evaluable pts experienced DLTs. After establishment of RD, 10 additional pts were treated at RD. PK of AF, irinotecan, SN38, and 5-FU were studied in cycle 1. Results: 16 pts (3 at 2 mg/kg and 13 at 4 mg/kg) with MCRC were treated (M/F, 10/6; median age, 57.0 [47-69]; and ECOG PS 0/1, 9/7), and all had received prior chemotherapies. A total of 131 cycles of AF + FOLFIRI were administered at the two DLs of AF (2 and 4 mg/kg). No DLT was observed. The most common all-causality grade 3/4 adverse events were neutropenia (75.0 %) including one febrile neutropenia after DLT evaluation period and hypertension (25.0%). There was no major safety issue at the RD. Response rate and progression free survival at RD (N=13 pts) was 7.8% and 7.6 month, respectively. Conclusions: RD was determined as 4 mg/kg in this first clinical study of AF in Japanese pts with MCRC. The combination of AF (4 mg/kg) and FOLFIRI was well tolerated in line with results of prior overseas studies. The PK results in Japanese patients showed similar tendency to those reported in patients from other regions of the world. [Table: see text]
Systemic chemotherapy in the setting of unresectable appendiceal epithelial neoplasms (AEN).
Authors: Cathy Eng, Aaron Udell Blackham, Michael J. Overman, Keith F. Fournier, Richard E. Royal, Prianka Gajula, Edward Allen Levine, Robert A. Wolff, Paul F. Mansfield
Journal: Journal of Clinical Oncology (2012)

568 Background: AEN is a malignancy including both indolent well-differentiated and highly aggressive signet ring carcinoma. Optimal therapy is believed to be cytoreductive surgery (CRS) followed by heated intraperitoneal chemotherapy (HIPEC). Yet, some patients (pts) will recur, are suboptimal for surgery, and are considered for systemic chemotherapy (SC). The purpose of this study is to compare SC regimens in treatment-naïve surgically unresectable AEN pts. Currently, no standard exists. Methods: A retrospective review of AEN pts who were registered in our tumor registries between Jan. 2005 to Dec. 2009 was completed. Electronic medical records were reviewed for CRS, HIPEC, histology, stage, SC received, CEA, CA-125, and/or CA 19-9, response (R), and progression-free survival (PFS). All patients were required to be restaged at their respective institution with R defined as clinical or radiographic benefit. K-M method, Log-Rank, and Cox proportional hazard regression models were used for statistical analysis. Results: Of 659 pts with AEN diagnosis, 134 pts were evaluable for PFS and R. Forty-eight (36%) pts were poorly-differentiated; 29 (22%) signet ring; and 22 (16%) had both features. Thirty-four (25%) were well-differentiated. After a median follow-up of 35M, adjusting PFS for prior CRS, HIPEC, histology, ascites, and biologic therapy, pts who received 5-FU alone fared worse vs. FOLFOX [HR: 2.39; 95% CI: 1.2-4.6; p-value = 0.01]. FOLFIRI trended in favor of improved PFS, but was underpowered. No statistical difference in R was noted (Table). Conclusions: In the treatment of surgically unresectable AEN, combination chemotherapy resulted in improved PFS vs. single agent 5-FU. Quality of life analysis will be reported at a later date. Randomized prospective analysis should be considered. [Table: see text]
Consolidative radiotherapy in the treatment of aggressive and localized non-Hodgkin's lymphoma (NHL): A systematic review with meta-analysis.
Authors: L. V. Santos, J. S. Lima, C. S. Lima, E. C. Sasse, A. D. Sasse
Journal: Journal of Clinical Oncology (2010)

e18507 Background: The current mainstay of NHL treatment is chemotherapy (CT). We sought to evaluate the addition of consolidative radiotherapy (RT) for aggressive and localized disease. Methods: We searched for randomized controlled trials that evaluated CT alone versus CT plus RT in electronic databases. The outcomes were overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and toxicity. Two reviewers independently assessed eligibility, quality, and time-to-event (TTE) outcomes. Hazard ratios (HR) were derived from reported TTE outcomes or extracted using Parmar methods with 95% confidence intervals (CI). Odds Ratio (OR) was used to compare dichotomous data. Results: Four trials (1,976 patients) met the inclusion criteria. All trials tested the use of RT after systemic therapy comprising anthracycline-based CT. CHOP regimen (cyclophosphamide, vincristine, doxorubicin and prednisone) was the preferred treatment in these trials. ORR were not different between groups (RR 0.98; 95%CI 0.95-1.02; p=0.33), with no heterogeneity between trials (p=0.53; I2=0%). Data for PFS could not be pooled due to heterogeneity among trials (p=0.0001; I2=86%). Sensitivity analysis showed that one trial has considerable difference in intensity and duration of systemic therapy in both arms, and after its exclusion, PFS showed to be longer for combined-modality treatment (HR 0.81; 95% CI 0.67-0.98; p=0.03), with an acceptable heterogeneity among trials (p=0.03; I2=35%). Data for OS were also heterogeneous and could not be combined (p=0.0009; I2=82%). When we chose to pool the OS data from the studies with same CT regimen in both arms, the addition of RT to CT showed no improvement in OS (HR 1.00; 95%CI 0.79- 1.26; p=0.99), with considerable heterogeneity among trials (p=0.15; I2=51%). There were great differences in the reporting of adverse events. Conclusions: This systematic review with meta-analysis shows no improvement in survival adding RT to systemic therapy for aggressive and localized NHL, although conclusions are limited due to heterogeneity among trials. Further evaluations of new RT technologies in the era of biologic agents are needed. No significant financial relationships to disclose.
Observational study of the first-line chemotherapy including cetuximab in patients with metastatic colorectal cancer: CORAL trial.
Authors: Kei Muro, Michio Itabashi, Hiroki Hashida, Toshiki Masuishi, Masanori Kotake, Tadamichi Denda, Yasuo Ohashi, Kenichi Sugihara
Journal: Journal of Clinical Oncology (2014)

539 Background: The combination therapy of Cetuximab (Cmab) + chemotherapy is one option as the first-line chemotherapy for KRAS wild-type metastatic colorectal cancer (mCRC). The efficacy of Cmab+FOLFIRI has been shown by CRYSTAL trail. There has been little experience of Cmab as the first-line chemotherapy in Japan, the data on Cmab combined with other drugs are insufficient, and efficacy according to the ESMO guideline groups (groups 1, 2, 3) has not yet been reported. Methods: The subjects were mCRC patients with PS 0-2 who received the first-line chemotherapy including Cmab, either in combination with chemotherapy or as monotherapy. Treatment duration, reason of discontinuation of the first-line chemotherapy (PD, conversion to surgery, adverse events), the second-line treatment, time to treatment failure, progression-free survival, response rate (RR), changes in paraneoplastic symptoms, skin symptoms (incidence, degree, prevention), and incidence and degree of other adverse events were investigated. Results: The 578 patients from the 158 institutes between January 2012 and June 2013 were enrolled. There were PS0/1/2 at 409/144/25, male/female at 368/210, median age of 65 (31-88) and groups 1/2/3 at 172/231/175. KRAS was wild type/mutant type/undetermined in 95.5%/2.4%/2.1%. Chemotherapies combined with Cmab were oxaliplatin-based/irinotecan-based/others (377/176/25). In evaluable cases, RR in groups 1/2/3 were 68.3%/50.8%/41.7%. In the frequency of skin symptoms reported up to 8 weeks/16 weeks, acneform rash was observed in 70.1%/62.1% (all grades) and in 1.2%/5.7% (grade 3 or higher), while paronychia was in 32.1%/40.6% (all grades) and in 2.6%/9.4% (grade 3 or higher). Liver resection rate and survivals are to be examined in the future. Conclusions: This is the first report on the first-line chemotherapy using Cmab, with RR as efficacy and skin symptoms as safety. Efficacy of the patients with the first-line chemotherapy using Cmab is different among 3 groups. This study is sponsored by the Public Health Research Center Foundation CSPOR in Japan. Clinical trial information: UMIN000007275.
Venous thromboembolism (VTE) in patients with advanced gastric cancer: An Asian experience.
Authors: M. J. Kang, B. Ryoo, M. Ryu, D. Koo, H. Chang, J. Lee, T. W. Kim, Y. Kang
Journal: Journal of Clinical Oncology (2011)

e14652 Background: Advanced gastric cancer (AGC) is known to be associated with a high incidence of venous thromboembolism (VTE). But, the prognostic impact or even the incidence of VTE in AGC patients is still not completely understood. The aim of current study was to investigate the incidence of VTE and to evaluate clinical characteristics associated with VTE in AGC patients treated with systemic chemotherapy. Methods: Between January 2000 and December 2008, 3,095 patients with histologically diagnosed inoperable AGC were registered in department of oncology, Asan medical center. Incidence of radiologically confirmed VTE was assessed by review of medical records of all registered patients. Survival was analyzed according to the presence of VTE. Univariate and multivariate analyses were performed to identify independent predictors of VTE. Results: The incidence of VTE in patients with AGC was 3.3% (103/3,095 patients, 95% CI, 2.7-4%). The incidence rate of VTE was 1.88 events/100 person-years (95% CI, 1.54-2.28 events/100 person-years). The median time from cancer diagnosis to develop VTE was 4.6 months (range, 0-41 months). Overall survival was worse for VTE patients who concurrently diagnosed with AGC compared with the patients with VTE detected after AGC diagnosis (median OS, 4.5 months vs. 10.7 months; HR 2.171; 95% CI, 1.2-3.93; P=0.009). Multivariate analysis identified female, primary tumor site on cardia and fundus, number of metastatic sites, lung metastasis and baseline elevated CA19-9 as independent risk factors of VTE. Among the all registered patients with AGC, overall survival (OS) was significantly reduced in patients with VTE vs. no-VTE patients (1-year OS; 40% vs. 45.3%, 2-year OS; 10.5% vs. 19.3%; HR, 1.23; 95% CI, 1.0-1.52; P=0.048). However, VTE was not a statistically significant factor affecting survival in multivariate analysis (P=0.82). Conclusions: The incidence rate of VTE in patients with AGC was 1.88 events/100 person-years, which was lower than that observed in Caucasian groups. It was not clear that the development of VTE was associated with poor survival. However, the patients with VTE detected at the time of AGC diagnosis had markedly worse prognosis.