tbuckley/cabot-search huggingface dataset:
MeDeCom: discovery and quantification of latent components of heterogeneous methylomes
Authors: Pavlo Lutsik, Martin Slawski, Gilles Gasparoni, Nikita Vedeneev, Matthias Hein, Jörn Walter
Journal: Genome biology (2017)

Abstract It is important for large-scale epigenomic studies to determine and explore the nature of hidden confounding variation, most importantly cell composition. We developed MeDeCom as a novel reference-free computational framework that allows the decomposition of complex DNA methylomes into latent methylation components and their proportions in each sample. MeDeCom is based on constrained non-negative matrix factorization with a new biologically motivated regularization function. It accurately recovers cell-type-specific latent methylation components and their proportions. MeDeCom is a new unsupervised tool for the exploratory study of the major sources of methylation variation, which should lead to a deeper understanding and better biological interpretation.
EPIC: A phase III trial of ponatinib (PON) versus imatinib (IM) in patients (pts) with newly diagnosed CP-CML.
Authors: Jeffrey Howard Lipton, Charles Chuah, Agnes Guerci-Bresler, Gianantonio Rosti, David Simpson, Stephanie Lustgarten, Nikolaus S. Trede, Victor M. Rivera, Tim Clackson, Frank G. Haluska, Michele Baccarani, Jorge E. Cortes, Francois Guilhot, Andreas Hochhaus, Timothy P. Hughes, Hagop M. Kantarjian, Neil P. Shah, Moshe Talpaz, Michael W.N. Deininger
Journal: Journal of Clinical Oncology (2014)

7023 Background: PON is a potent oral TKI active against native and mutated forms of BCR-ABL, including T315I. The ph 2 PACE study demonstrated that PON is highly active in heavily pretreated Ph+ leukemia pts. Methods: EPIC was an international, Ph 3 trial of PON (45 mg QD) vs IM (400 mg QD) in newly diagnosed CP-CML pts, with randomization stratified by Sokal risk score. The primary endpoint was major molecular response (MMR) rate at 1 yr. On 18 Oct 2013,EPIC was terminated due to accumulating vascular events in long-term follow-up of the PACE trial. Data as of 7 Oct 2013 are presented, median follow-up 3 (0.03-12) m. Results: At the time of analysis, 306 were randomized. Baseline characteristics were balanced for PON vs IM; median age 55 vs 52 yrs, 17% vs 16% high Sokal risk score, 62% vs 66% received prior hydroxyurea. Data on 267 treated pts were available (133 PON; 134 IM). 77% PON and 84% IM pts were ongoing; 14 PON and 6 IM pts D/C, (D/C due to AE; 9 PON pts [most common: thrombocytopenia and rash] and 1 IM pt). Response rates are in the table (evaluable pts). Most common (≥25%) all grade (G) AEs were PON: rash (36%), abdominal pain (32%), headache (31%), lipase increased (26%), myalgia (26%); IM: nausea (32%), muscle spasms (31%). 11% PON and 2% IM had G 3/4 thrombocytopenia; 3% PON and 8% IM had G 3/4 neutropenia. Serious AEs (SAEs) occurring in ≥3 PON pts were: pancreatitis (5 pts), atrial fibrillation (3), thrombocytopenia (3); no individual SAEs occurred in ≥3 IM pts. 9 (7%) PON and 5 (4%) IM pts experienced vascular occlusive events (SAEs: 6 PON, 1 IM). Updated data will be presented. Conclusions: While PON demonstrated early activity in frontline CP-CML, EPIC was terminated as its objectives could not be met with PON dose reductions implemented mid-trial due to safety observations in PACE. Further investigation of PON safety is warranted. PON remains an important treatment option for pretreated CML and Ph+ ALL pts in whom the need and benefit outweigh the risk. Clinical trial information: NCT01650805. At 3 m At 6 m At 9 m PON IM PON IM PON IM MMR 29% (28/95) 0% (0/98) 66% (27/41) 21% (9/42) 83% (10/12) 44% (7/16) MR4.5 4% (4/95) 0% (0/98) 10% (4/41) 0% (0/42) 25% (3/12) 0% (0/16) ≤10% BCR-ABL transcripts 94% (89/95) 68% (67/98) 100% (41/41) 83% (35/42)
Safety of ipilimumab in patients (pts) with untreated, advanced melanoma alive beyond 2 years: Results from a phase III study.
Authors: Luc Thomas, Jedd D. Wolchok, Claus Garbe, Celeste Lebbe, Igor Bondarenko, Kristen Rodrigues, Cyril Konto, Kevin M. Chin, Stephen Francis, Caroline Robert
Journal: Journal of Clinical Oncology (2012)

8512 Background: Ipilimumab (IPI), a fully human monoclonal antibody, blocks cytotoxic T-lymphocyte antigen-4 to potentiate an antitumor T-cell response. In a phase 3 study (CA184-024) of previously untreated pts with stage III or IV melanoma, IPI + dacarbazine (DTIC) significantly improved overall survival (OS) vs. DTIC alone (Robert et al. NEJM 2011). We now report safety data of IPI in pts from this study alive &gt; 2 yrs from study initiation. Methods: Pts with untreated advanced melanoma, were randomized to IPI (10 mg/kg) + DTIC (850 mg/m 2 ) or placebo + DTIC (850 mg/m 2 ) given at Wks 1, 4, 7, 10 followed by DTIC q 3 wks through Wk 22. Eligible pts (stable disease or better) received IPI or placebo q 12 wks as maintenance. In the population of subjects alive &gt;2 yrs, the appearance of immune-related adverse events (irAEs) occurring after 2 yrs was evaluated. Within this group was a subset of subjects still receiving IPI dosing after 2 yrs; safety for these pts was evaluated to assess the impact of prolonged IPI exposure. Results: In the IPI + DTIC group 68 (28%) pts survived &gt; 2 yrs compared to 44 (18%) in the DTIC alone group; 11 of the 68 continued IPI dosing for ≥ 2 yrs. Safety assessment beyond 2 yrs showed 3 of the 11 pts had any grade irAEs; 1 pt had grade 3/4 rash, pruritus while low grade events included rash, pruritus (n=2) and elevated ALT / AST (n=1). Overall among all 68 pts in the Ipi + DTIC group, there were 5 pts (7.4%) with any grade irAEs including grade 3/4 rash, pruritus (n=1) and low grade rash (n=3), pruritus (n=2), skin hypopigmentation, and elevated ALT / AST (n=1). No gastrointestinal or endocrine events (any grade) were observed. Conclusions: In Study 024, IPI + DTIC treatment improved OS pts with untreated, advanced melanoma with higher survival rates in the IPI + DTIC group at 1 yr (47.3% vs. 36.3%), 2 yrs (28.5% vs. 17.9%), and 3 yrs (20.8% vs. 12.2%) (HR 0.72, p&lt;0.001). The safety profile of pts alive after 2 yrs suggests that treatment with IPI + DTIC is associated with low rates of irAEs in these pts. Furthermore, in pts still receiving active IPI treatment beyond ≥ 2 yrs, the safety profile appears to be consistent and medically manageable using established safety guidelines (Weber, Oncologist 2007).
Progress in disease progression genetics: dissecting the genetic origins of lung function decline in COPD
Authors: Robert Busch, Michael H Cho, Edwin K Silverman
Journal: Thorax (2017)

Lung function is a heritable trait. Heritability estimates posit that approximately30%–50% of the phenotypic variation in FEV1 is explained by genetics,1–3 and genome-wide association studies (GWAS) of lung function4–11 have discovered multiple genetic variants that are associated with cross-sectional measurements in adults of FEV1, FVC and FEV1/FVC ratio at genome-wide significance levels. Many of these same loci have also been implicated in GWAS of COPD. Additional work is required to link these loci to pathophysiology. Functional studies on GWAS loci involving HHIP ,12 ,13 FAM13A ,14 HTR4 ,15 AGER 16 and IREB2 17 have already provided important insights into the biological mechanisms for genetic determinants of COPD and/or lung function.

Longitudinal change in lung function (ΔFEV1, ΔFEV1/FVC) is also heritable,18 albeit perhaps to a lesser degree than cross-sectional lung function levels. Although studies of longitudinal lung function have discovered a few loci associated with ΔFEV1 at genome-wide significance levels, none were robust to replication in the available populations. While at first glance the genetic determinants of FEV1 level and ΔFEV1 might be expected to show significant overlap, a recent study of COPD by Lange et al 19 and a complementary study in asthma by McGeachie et al 20 have suggested that low maximum attained lung function and accelerated lung function decline are distinct processes that can exert independent effects on the risk for chronic airflow obstruction. Therefore, it would not be surprising if different genetic determinants influenced cross-sectional and longitudinal lung function change. Longitudinal measurements of lung function are highly informative for identifying these separate processes. In contrast, one …
Quality of life (QoL) of patients with metastatic castration resistant prostate cancer (mCRPC) treated with cabazitaxel.
Authors: Eric Winquist, Srikala S. Sridhar, Stacey Hubay, Hazem Assi, Scott R. Berry, Karine Alloul, Eric Levesque, Nathalie Aucoin, Piotr Czaykowski, Fred Saad
Journal: Journal of Clinical Oncology (2013)

e16088 Background: The effects of cabazitaxel on QoL, pain response and preference/utility data have not been well studied in men with CRPC treated post-docetaxel. As part of a single-arm multicenter Sanofi-funded Early Access Program (EAP) for cabazitaxel, QoL data were collected on Canadian patients. Methods: Between May 2011 and February 2012, 61 patients (pts) were enrolled at 9 centers. QoL was assessed at the start of each cycle using the FACT-P and its subscales, and the EQ 5D-3L. EQ 5D-3L health state index (HIS) data were converted into utility values (Canadian tariff, Bansback 2011). Present pain intensity (PPI) and analgesic scores were assessed using the McGill-Melzack questionnaire. Results: QoL data were evaluable in 55 pts. Baseline pt characteristics were: median age 65 years (range, 42-79), 92.7% of pts were ECOG PS 0 or 1, 87% had bone metastases, and 56% (31/55) received at least 6 cycles of cabazitaxel. Statistically significant changes from baseline in mean QoL scores were observed on FACT-P total score at cycle 2, and prostate cancer specific subscale (PCS) at cycles 1 to 4. As a measure of QoL response, increases were observed and maintained for &gt; 2 consecutive cycles in 9% (&gt;16 points) and 25% (≥10) of pts for FACT-P total score. Improvements to the level of Minimal Important Differences (MID) (Cella 2009) maintained for &gt; 2 consecutive cycles were observed in 36% of pts for FACT-P total score (MID=6), 49% for PCS subscale (MID=2), and 26% for PCS-Pain subscale (MID=2), respectively. The percentage of pts reporting "no problem" in the EQ-5D pain/discomfort domain were above baseline levels at every cycle and improved from baseline to end of treatment from 19% to 29% (p &lt; 0.05). Other EQ-5D dimensions (anxiety/depression, mobility, self-care and usual activities) remained stable over the course of treatment. Improvement from baseline in utility value (HIS) was observed at cycle 4 with a utility value of 0.769 (vs 0.713 at baseline). PPI scores improved despite stable analgesic use and were significantly different from baseline at cycles 2, 4 and 9. Conclusions: Data from this EAP suggest improvements in QoL, pain and prostate cancer specific symptoms with second-line cabazitaxel treatment. Clinical trial information: NCT01254279.
Variance in physician attitudes toward androgen deprivation therapy initiation for biochemical cancer recurrence
Authors: J. A. Hemmerich, F. Ahmed, K. Bylow, W. Stadler, W. Dale
Journal: Journal of Clinical Oncology (2007)

15626 Background: The optimal timing for starting Androgen Deprivation Therapy (ADT) for patients with recurrent prostate cancer (PCa) remains uncertain. In 2004, the American Society of Clinical Oncology deemed the evidence insufficient to recommend early ADT initiation. Recent evidence shows a slight survival benefit to recurrent PCa patients with high risk features; however, early initiation can prematurely reduce patients’ quality of life without providing benefit. This pilot study surveys physician attitudes and practices regarding ADT initiation at a single institution. Methods: Physicians (n=20), including 7 attendings and 13 fellows, who treated biochemically- recurrent PCa patients enrolled in a companion study completed a survey about clinical experience, knowledge of recommendations, and attitudes regarding decisions to start ADT. They also rated the importance of sixteen factors potentially contributing to the decision. Results: Consistent with the ASTRO definition, forty-five percent answered, that three consecutive PSA-rising tests constitute recurrence. For patients with high risk features (Gleason &gt; 7, doubling time &lt; 10 months), 55% said ADT should be started immediately, while only 15% noted that the literature remains unresolved on this issue. For patients without high risk features, 100% would defer ADT. The two factors rated most important in determining ADT initiation timing were PSA doubling time (100%) and patient preferences (95%). Conclusions: Our preliminary data suggest that even within one institution, there is variance in physicians’ definitions of PCa recurrence and the correct treatment strategy. Despite the lack of definitive data on the benefit of early ADT initiation even for high risk patients, over 50% said such patients should start immediately. No significant financial relationships to disclose.
Propensity-score analysis of neoadjuvant chemotherapy vs. primary surgery in advanced ovarian cancer: Does surgical quality matter?
Authors: Hyo Sook Bae, Sokbom Kang, Seok Ju Seong, Jae Weon Kim, Sang Young Ryu, Byoung-Gie Kim, Joo-Hyun Nam
Journal: Journal of Clinical Oncology (2015)

5568 Background: Although there are many studies that compared the outcome of neoadjuvant chemotherapy (NAC) and primary surgery in advanced ovarian cancer, most of them showed some limitations such as selection bias and the quality control of surgical procedure. Methods: Data of 1124 patients with advanced epithelial ovarian cancer (stage III-IV) were reviewed retrospectively. To mitigate the possible biases from the retrospective nature of the study, we performed a propensity score analysis. Progression-free survival was assessed using a multivariate Cox-proportional hazards regression model with inverse probability weights to adjust for propensity score. Results: Among the 1124 patients, 198 patients (17.6%) underwent NAC. The factors associated with the use of NAC were old age, non-serous histology, poor histologic grade, stage IV and higher serum CA 125 levels (P-value 0.211, 0.050, < 0.001, < 0.001 and < 0.001, respectively). After a propensity score adjustment using those factors, the progression-free survival of the NAC group was not significantly different from that of the primary surgery group (HR 1.187, CI 0.932-1.512, P-value 0.164). Especially, no significant difference was observed between the two treatment strategies in the subgroup from the hospitals with higher surgical standards with the average rate of optimal cytoreduction was over 50% (HR 1.166, CI 0.885-1.536, P-value = 0.275). However, when we did not adjust the confounders, the outcome of primary surgery group was superior to that of NAC group (HR 1.24, CI 1.016-1.515, P-value 0.035). Conclusions: Progression-free survival of NAC group did not differ significantly from primary surgery in patients with advanced ovarian cancer. Even in the institutions providing a good standard of surgical care, we did not found any evidence suggesting that primary surgery is better than NAC in patients with advanced ovarian cancer. Treatment All (N = 1124) High-performance institutions (N = 928) HR 95% CI P-value HR 95% CI P-value Before adjustment NAC 1.24 1.04-1.50 0.020 1.24 1.016-1.515 0.035 After adjustment by the propensity score NAC 1.187 0.932-1.512 0.164 1.166 0.885-1.536 0.275
Phase II study of S-1 plus oxaliplatin (OX) at dose of 130 mg/m<sup>2</sup> (SOX130) in Japanese patients (pts) with advanced gastric cancer (AGC).
Authors: Yosuke Kito, Nozomu Machida, Satoshi Hamauchi, Takahiro Tsushima, Akiko Todaka, Tomoya Yokota, Kentaro Yamazaki, Akira Fukutomi, Yusuke Onozawa, Kunihiro Tsuji, Hisashi Doyama, Yutaka Haraguchi, Koji Nakashima, Kenji Kunieda, Keisei Taku, Keita Mori, Hirofumi Yasui
Journal: Journal of Clinical Oncology (2017)

112 Background: The phase III G-SOX trial had adopted SOX100 due to high incidence of thrombocytopenia in the previous phase I/II study, and failed to demonstrate the non-inferiority of SOX100 to S-1 plus cisplatin in chemotherapy-naïve Japanese pts with AGC. However, OX 130 mg/m 2 has been approved for AGC in Japan since Sep 2014 on the evidence of the REAL-2 trial. Therefore, we conducted a study to evaluate the feasibility of SOX130 in Japanese AGC pts. Methods: This is a single-arm, open-label, multicenter, phase II study. Pts with unresectable or recurrent adenocarcinoma of stomach, no prior chemotherapy and ECOG PS 0 or 1 were treated with SOX130 (S-1 80-120 mg/day according to BSA for 2 weeks, OX 130 mg/m 2 on day 1, every 3 weeks). The primary endpoint was the 3-cycle completion rate, defined as the proportion of pts who receive at least 80% of the planned OX dose for the first 3-cycle. We set the threshold 3-cycle completion rate at 50% and the expected rate at 75%. A sample size of 23 pts was needed with 80% power at a 5% α-level (one-sided). Results: From April 2015 to June 2016, 25 pts were enrolled. Pts’ characteristics were as follows: median age 64.5 years (range, 32-76), male/female 21/4, PS 0/1 15/10, unresectable/recurrent 21/4, and intestinal/diffuse 7/18. The 3-cycle completion rate was 72.0% (90% CI 53.8-86.1%). Among the 12 pts with measurable lesions, objective response rate and disease control rate were 58.3% and 83.3%, respectively. With a median follow-up period of 5.2 months, median progression-free survival was 7.5 months. Grade 3 adverse events were anorexia (n = 5), anemia (n = 3), thrombocytopenia (n = 2), neutropenia (n = 1) and nausea (n = 1). No treatment-related death was observed. Conclusions: SOX130 could be a first-line treatment option even in Japanese AGC pts. Clinical trial information: UMIN000016973.
Clinical features of cobimetinib (COBI)–associated serous retinopathy (SR) in <i>BRAF</i>-mutated melanoma patients (pts) treated in the coBRIM study.
Authors: Luis De La Cruz-Merino, Lorenza Di Guardo, Jean-Jacques Grob, Alfredo Venosa, James M. G. Larkin, Grant A. McArthur, Antoni Ribas, Susan Eng, Jessie J. Hsu, Giulio Barteselli, Nicholas W. Choong, Brigitte Dréno
Journal: Journal of Clinical Oncology (2015)

9033 Background: Various ocular adverse events (AE) have been described with targeted agents. MEK inhibitors (MEKi) are associated with SR. We describe the clinical features of SR observed with COBI in the coBRIM study. Methods: coBRIM is a multicenter phase 3 study that evaluated the efficacy and safety of COBI + vemurafenib (VEM) in advanced BRAFV600-mutated melanoma pts (Larkin et al. N Engl J Med 2014;371:1867-76). Ophthalmic examinations, including optical coherence tomography, were performed at baseline, day 28 and every 3 cycles thereafter (84 days). SR cases were identified in the study database using a group of relevant and synonymous AE terms. Corresponding clinical data were abstracted. Results: 495 advanced BRAFV600-mutated melanoma pts were randomly assigned to receive COBI + VEM or placebo (PB) + VEM. No pt had retinal abnormalities at baseline. A total of 83 SR events were reported in 63 pts (26%) in the COBI + VEM arm (median age: 59 yr, male: 59%) and 7 SR events in 7 pts (3%) in the PB + VEM arm (median age: 62 yr, male: 29%). Highest severity grade of SR observed in the COBI + VEM arm were NCI-CTCAE grade 1 (asymptomatic/mild symptoms) – 33 pts (52%), 2 – 23 (37%), 3 – 6 (10%) and 4 – 1 (2%). All pts in the PB + VEM arm had grade 1 SR, except 1 pt with grade 2 SR. Median time to first onset of SR was 1 month in both arms. In the COBI + VEM arm, the majority of grade ≥ 2 SR (52%) occurred before study day 12 and most grade 1 SRs were identified during surveillance ophthalmic examination. No other concurrent ocular abnormalities (cornea, conjunctiva, anterior chamber or vitreous) were reported. Most (74%) grade 1 SR events were followed clinically without modification of COBI doses, while grade 2 and 3 SR events were commonly managed with interruption or reduction of COBI. After dose interruption, reduction, or permanent discontinuation of COBI, 75% of SR events resolved or were resolving. Conclusions: COBI-related SR occurred in 26% of COBI + VEM treated pts. The majority of SR observed with COBI was of low severity grade and was managed with dose modification of COBI. Surveillance ophthalmic examination identified mostly asymptomatic low severity grade SR, for which clinical significance is uncertain. Clinical trial information: NCT01689519.
North Japan multicenter phase II study of oxaliplatin-containing regimen as adjuvant chemotherapy for stage III colon cancer (NORTH/HGCSG1003).
Authors: Toshiaki Shichinohe, Satoshi Yuki, Norihiko Takahashi, Hiroshi Nakatsumi, Yasuyuki Kawamoto, Takaya Kusumi, Atsushi Ishiguro, Susumu Sogabe, Ichiro Iwanaga, Kazuteru Hatanaka, Kazuyoshi Oomori, Michio Nakamura, Naoto Senmaru, Kazuhiro Iwai, Masahiko Koike, Naoya Sakamoto, Akinobu Taketomi, Satoshi Hirano, Yoichi M Ito, Yoshito Komatsu
Journal: Journal of Clinical Oncology (2017)

807 Background: FOLFOX and XELOX are standard adjuvant chemotherapy for resected stage III colon cancer. MOSAIC and XELOXA trials were performed outside of Japan, thus, we conducted a phase II study (NORTH/HGCSG1003) to assess the efficacy and safety of FOLFOX as adjuvant chemotherapy for Japanese patients(pts) with resected stage III colon cancer (UMIN ID: 000004590). Methods: This phase II study enrolled patients with resected stage III colon cancer. Patients received 12 cycles of FOLFOX4 or mFOLFOX6. Sample size was determined to be 243 pts. Primary endpoint was disease-free survival (DFS). We assumed an expected 3-year DFS rate of 81.2% in this study. Secondary endpoints included overall survival (OS) and safety. In this meeting, we present for the 3-year DFS rate. Results: From Sep 2010 to Mar 2013, 273 pts were enrolled at 28 institutions. Full analysis included 265 patients who received FOLFOX. Patients characteristics were as follows: median age ; 65(33-84), Male/female ; 131/134, PS 0/1 ; 258/7, stage IIIA/IIIB/IIIC ; 37/197/31, colon/rectosigmoid: 214/51. The most common grade 3-4 adverse events were neutrophil count decreased (48.1%), peripheral sensory neuropathy (6.4%), platelet count decreased (2.3%), and allergic reaction (1.5%). The median number of cycles of FOLFOX was 12, and the completion treatment rate was 80.4%. There was no treatment-related death. The 3-year DFS rate was 75.2 percent (95% confidence interval, 69.6 to 80.0). Conclusions: In Japanese patients with stage III colon cancer, FOLFOX is a well-tolerable regimen as adjuvant chemotherapy. In this trial, the 3-year DFS rate of primary endpoint was not meet the expectation (81.2%). However, the 3-year DFS rate in this trial was similar to several pivotal trials. We plan to do subset analysis. Clinical trial information: UMIN000004590.