tbuckley/cabot-search huggingface dataset:
Proteinuria as a predictive factor in metastatic colorectal cancer patients treated with bevacizumab.
Authors: Mukremin Uysal, Hakan Sat Bozcuk, Sema Sezgin Goksu, Ali Murat Tatli, Deniz Arslan, Seyda Gunduz, Hasan Senol Coskun, Mustafa Ozdogan, Burhan Savas
Journal: Journal of Clinical Oncology (2012)

e14070 Background: Efficacy of bevacizumab -which is widely used at metastatic colorectal cancer (mCRC)- on clinical survival has been proved. But parameters predicting this clinical efficacy are unknown at present. With this study, we aimed to investigate the predictors of treatment benefit with bevacizumab based chemotherapy in patients with mCRC. Methods: Thirty-six successive patients with mCRC receiving bevacizumab based chemotherapy were enrolled into the study. Hypertension, 24-hour proteinuria and other routine parameters were recorded before and during the treatment with certain intervals. After a 1-year follow up, relationship of progression free survival (PFS) and response with various parameters and especially proteinuria, was evaluated. Results: Of 36 patients included, 20 (55.6%) were male and 16 (44.4%) were female, where mean age was 57. Overall median PFS was calculated as 275 days (9.8 months). Patients with basal proteinuria higher than 114 gr/day had a lower median PFS as 184 days (6.5 months) (p=0.046), where median PFS of patients with basal proteinuria equal to or lower than 114 gr/day was not reached. Therefore, higher level of renal proteinuria is a negative prognostic factor in these patients. Similarly, PFS was observed to be lower at patients with high LDH levels (p=0.0024, Exp(B)=23). Bevacizumab response was observed to be better at patients with favorable performance status (p=0.05), who have a single liver metastasis (p=0.034) and who tend to be hypertensive during the treatment (p=0.034). Conclusions: In conclusion, we demonstrated that basal proteinuria and LDH levels may be prognostic at patients with mCRC receiving bevacizumab-based treatment. In the literature, there has been no study up to now that questions basal proteinuria as a prognostic factor for patients receiving bevacizumab-based treatment. This observation is an important step for more focused use of bevacizumab. We believe that it is important to investigate whether basal proteinuria really has a predictive role in this group of patient with further studies, and this has practical and clinical implications.
Neonatal BCG vaccination has no effect on recurrent wheeze in the first year of life: A randomized clinical trial
Authors: Lisbeth Marianne Thøstesen, Lone Graff Stensballe, Gitte Thybo Pihl, Jesper Kjærgaard, Nina Marie Birk, Thomas Nørrelykke Nissen, Aksel Karl Georg Jensen, Peter Aaby, Annette Wind Olesen, Dorthe Lisbeth Jeppesen, Christine Stabell Benn, Poul-Erik Kofoed
Journal: Journal of Allergy and Clinical Immunology (2017)

BackgroundRecurrent wheeze (RW) is frequent in childhood. Studies have suggested that BCG vaccination can have nonspecific effects, reducing general nontuberculosis morbidity, including respiratory tract infections and atopic diseases. The mechanisms behind these nonspecific effects of BCG are not fully understood, but a shift from a TH2 to a TH1 response has been suggested as a possible explanation.ObjectiveWe hypothesized that BCG at birth would reduce the cumulative incidence of RW during the first year of life.MethodsThe Danish Calmette Study is a multicenter randomized trial conducted from 2012-2015 at 3 Danish hospitals. The 4262 newborns of 4184 included mothers were randomized 1:1 to BCG (SSI strain 1331) or to a no-intervention control group within 7 days of birth; siblings were randomized together as one randomization unit. Exclusion criteria were gestational age of less than 32 weeks, birth weight of less than 1000 g, known immunodeficiency, or no Danish-speaking parent. Information was collected through telephone interviews and clinical examinations at 3 and 13 months of age; data collectors were blind to randomization group. RW was defined in several ways, with the main definition being physician-diagnosed and medically treated RW up to 13 months of age.ResultsBy 13 months, 211 (10.0%) of 2100 children in the BCG group and 195 (9.4%) of 2071 children in the control group had received a diagnosis of RW from a medical doctor and received antiasthma treatment (relative risk, 1.07; 95% CI, 0.89-1.28). Supplementary analyses were made, including an analysis of baseline risk factors for development of RW.ConclusionNeonatal BCG had no effect on the development of RW before 13 months of age.
Long-chain omega-3 fatty acid and fish intake after colon cancer diagnosis and disease-free, recurrence-free, and overall survival in CALGB 89803 (Alliance).
Authors: Erin Van Blarigan, Charles S. Fuchs, Donna Niedzwiecki, Xing Ye, Sui Zhang, Mingyang Song, Leonard Saltz, Robert J. Mayer, Rex B. Mowat, Renaud Whittom, Alexander Hantel, Al Bowen Benson, Daniel M. Atienza, Michael J. Messino, Hedy L. Kindler, Alan P. Venook, Shuji Ogino, Walter C. Willett, Edward L. Giovannucci, Jeffrey A. Meyerhardt
Journal: Journal of Clinical Oncology (2017)

585 Background: Long-chain omega-3 fatty acids (LCN-3 FA) may prevent colon cancer (CC) progression, but data in humans are lacking. We hypothesized that LCN-3 FA and dark meat fish intake after CC diagnosis would be associated with longer disease-free survival (DFS), particularly among patients (pts) whose tumors expressed COX2. Methods: We conducted a prospective study among 1011 stage III CC pts enrolled in an adjuvant chemotherapy trial in 1999-2001. Intakes of dark meat fish; canned tuna; breaded fish; shrimp, lobster, scallops, clams; other fish; and fish oil supplements were assessed via food frequency questionnaire during and 6 months (mo) after therapy. Less than 5% of pts reported fish oil supplements. We estimated hazard ratios (HR) and 95% confidence intervals (CI) for disease-free, recurrence-free (RFS), and overall (OS) survival, adjusting for clinical, sociodemographic, and lifestyle factors. In a subset of 510 pts, we examined whether tumor COX2 expression modified the association between LCN-3 FA intake and DFS. Results: We observed 343 CC recurrences and 305 deaths (7 y median follow-up). Higher LCN-3 FA intake after CC diagnosis was associated with 28% improved DFS [HR highest (Q4) vs. lowest (Q1) quartile: 0.72 (0.54, 0.97); p: 0.03]. The association was driven by CC recurrence [RFS - HR Q4 vs. Q1: 0.68 (0.50, 0.94); p: 0.01; OS - HR Q4 vs. Q1: 0.79 (0.56, 1.13); p: 0.17]. Among pts with moderate/high COX2 expression tumors, LCN-3 FA intake was associated with 80% improved DFS [HR Q4 vs. Q1: 0.2 (0.06-0.76); p: 0.006]; there was no association among pts with absent/low COX2 expression ( p-interaction: 0.13). When we examined dietary sources of LCN-3 FA, pts who consumed dark meat fish ≥ 2 times/mo vs. none had longer DFS [HR: 0.64 (0.48, 0.86); p: 0.007), RFS [HR: 0.61 (0.44, 0.83); p: 0.005], and OS [HR: 0.68 (0.48, 0.97); p: 0.05]. No other fish or seafood after CC diagnosis was associated with DFS, RFS, or OS. Conclusions: LCN-3 FA and dark meat fish intake after CC diagnosis may be associated with improved DFS, especially among pts with high COX2 expression tumors. Support: K07CA197077, U10CA180821, U10CA180882. ClinicalTrials.gov: NCT00003835.
Efficacy/safety analysis of a phase 2 study of ruxolitinib (Rux) + regorafenib (Re) in patients (pts) with relapsed/refractory (r/r) metastatic colorectal cancer (mCRC).
Authors: David R. Fogelman, Johanna C. Bendell, Antonio Cubillo, Pilar Garcia Alfonso, María Luisa Limón Mirón, John J. Nemunaitis, Daniel Blake Flora, Christophe Borg, Laurent Mineur, Jose M Vieitez, Allen Lee Cohn, Gene Brian Saylors, Albert Assad, Julie C. Switzky, Peter O'Neill, Li Zhou, Mark D. Kochenderfer
Journal: Journal of Clinical Oncology (2017)

663 Background: The JAK-STAT pathway plays a role in the systemic inflammatory response in CRC. Rux, a potent JAK1/2 inhibitor, was evaluated in r/r mCRC pts. Methods: After a safety run-in (Rux 20 mg BID + Re 160 mg QD), pts were randomized to Rux 15 mg BID or placebo (Pb) + Re 160 mg QD. Rux could be titrated to 20 mg BID. The randomized phase included Substudy 1 (S1, pts with C-reactive protein [CRP] &gt; 10 mg/L) and Substudy 2 (S2, pts with CRP ≤ 10 mg/L). Primary endpoint: OS. Results: Rux 20 mg BID was well tolerated in the safety run-in (n = 11). 396 pts were randomized (S1: n = 175; S2: n = 221). Median age in Rux vs (v) Pb groups: 62 v 60 yr (S1), 59 v 61 yr (S2). Most pts had ≥ 3 prior chemotherapy regimens: 85% v 84% (S1); 81% v 78% (S2). Median treatment durations: 57 d with Rux v 56 d with Pb (S1), 106 d with Rux v 56 d with Pb (S2). Discontinuations were mainly due to disease progression (S1: 61% v 63%, S2: 62% v 66%) or AEs (S1: 10% v 19%, S2: 9% v 9%). Rux + Re did not improve OS/PFS over Re + Pb in S1/S2 (see Table). S1 was terminated for futility at interim analysis; S2 was terminated per sponsor decision. The number of events required for final efficacy analysis was reached in S1, not in S2. Most common non-hematologic AEs (Rux v Pb): palmar-plantar erythrodysesthesia syndrome (PPES; S1: 42% v 44%; S2: 58% v 47%), diarrhea (S1: 38% v 31%; S2: 39% v 27%), decreased appetite (S1: 37% v 36%; S2: 26% v 33%), fatigue (S1: 34% v 36%; S2: 41% v 44%), hypertension (S1: 21% v 26%; S2: 42% v 40%). Most common grade (G) 3/4 non-hematologic AEs: PPES (S1: 13% v 15%; S2: 17% v 13%) and hypertension (S1: 9% v 7%; S2: 22% v 16%). Most common G 3/4 hematologic AEs (new/worsening lab abnormalities): lymphopenia (S1: 13% v 8%; S2: 14% v 7%) and anemia (S1: 4% v 5%; S2: 9% v 4%). Conclusions: Rux + Re did not improve OS/PFS in mCRC pts over Re alone. There was a nonsignificant trend towards improved OS/PFS in S2. Rux 15-20 mg BID safety profile was consistent with previous studies in other tumors. Clinical trial information: NCT02119676. [Table: see text]
Phase I clinical trials attrition related to central molecular prescreening.
Authors: Valentina Boni, Elena Garralda, Antonio Cubillo, Ivan Diaz-Padilla, Antonio Calles, Carlos Gomez-Martin, Sara Cerdá, Sonia Puerta, Esther Ordonez, Fernando López-Ríos, David Olmos, Manuel Hidalgo, Emiliano Calvo
Journal: Journal of Clinical Oncology (2013)

2600 Background: The increasing trend to incorporate molecular assays as part of selection assessment in Ph1 trials is based on the potential to observe early antitumor activity. Nonetheless, its impact has been almost negligible to date and might affect time to achieve a recommended dose. We assessed the impact on recruitment of pursuing central mandatory molecular assessment of tumor samples on a state-of-the-art Ph1 unit. Methods: Two first-in-human Ph1 studies, requiring central laboratory biomarker assessment as inclusion criterion (DS6 IHC and FGFR mut/ampl, respectively), and a consecutive series of pts in our program for central tumor mutation screening (OncoCarta Panel v1.0) to participate in molecularly-driven Ph1 studies, were reviewed. Results: 13 (4.8%) out of 267 pre-screened pts were able to receive treatment within a targeted Ph1 trial. Conclusions: A vast majority of pts trying to participate in molecularly-driven trial central biomarker screening are not included due to negative results. Still 71.1% pts who were initially eligible and were positive in the central review fail to participate due to clinical and/or analytical deterioration during the time of central molecular assessment. New strategies including local sample pre-screening allowance, as well as anticipated massive molecular profiling in the conventional setting, are needed to reduce this time and improve feasibility of these trials. The derived current “impoverishment” of studies with non-targeted drugs (that lack patients with tumors with “hot” mutations) and of those with targeted drugs (that miss patients with nonmutated tumors) within the same Ph1 Programs, and the need of a joint approach to co-finance for wide-spectrum molecular profiling for different studies, would be discussed as well. [Table: see text]
Uncertainty about the future for patients with advanced cancer and their informal caregivers: A qualitative view.
Authors: Valerie M Shilling, Rachel Starkings, Valerie A. Jenkins, Lesley Fallowfield
Journal: Journal of Clinical Oncology (2017)

218 Background: In the PROACT study, we developed two scales measuring wide-ranging life impacts of cancer and treatment for patients (pts) and caregivers (cgs). Qualitative work in the development phase produced rich data on the concerns of both groups. Here we explore one specific topic, uncertainty, and contrast pts' and cgs' experience. Methods: In-depth qualitative interviews with pts with advanced cancer and their informal cgs about the impact of extended cancer survival on broader aspects of life and well-being. Interviews were transcribed verbatim. A thematic framework was developed from an initial process of open coding and tested iteratively as new data were collected. Results: We interviewed 24 pt-cg dyads with advanced ovarian (9) melanoma (9) or lung cancer (6). Pts were aged 39-84 (median 62 years), cgs 19-85 (median 54 years). Cgs were pts’ partners/spouses (15), children (5), siblings (2), and friends (2). 20 major themes and 33 sub-themes were identified. One concerned the uncertainty when planning for the future and encompassed issues such as providing for one’s family, employment and finances. For both groups uncertainties were related to the timescale and trajectory of the disease and lack of control or ability to make plans, resulting in a life lived day-by-day. Some felt it would be easier to have a definite timeframe (about death) and struggled with accepting that no one could predict what was going to happen and when. There were marked age effects. Differences existed between the groups: pts were concerned with their family’s emotional and financial wellbeing while cgs expressed a lack of control over their own futures and a sense of life "being on hold." These thoughts were often accompanied by guilt. Accounts from within the same dyad often differed and pts and cgs rarely discussed concerns with each other. Conclusions: Both pts and their informal cgs are challenged about coping with death but equally about coping with life and the lack of a defined trajectory. This impacted many areas including employment and general planning for the future. Dyads seldom discussed these concerns so might benefit from professional help aimed at facilitating open discussion together.
Germline polymorphisms in genes involved in the Hippo pathway to predict recurrence in locally advanced colon cancer.
Authors: Ana Sebio Garcia, Wu Zhang, Dongyun Yang, Stefan Stremitzer, Sebastian Stintzing, Yan Ning, Yu Sunakawa, Shinichi Yamauchi, Satoshi Matsusaka, Rita Elie El-Khoueiry, Afsaneh Barzi, Syma Iqbal, Anthony B. El-Khoueiry, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2014)

e14505 Background: The Salvador-Warts-Hippo pathway regulates tissue growth and cell fate. The Hippo pathway deregulation has been described in several cancer types and promotes stem cell maintenance, migration, and metastasis. In colon cancer, the Hippo pathway plays a relevant role by interacting with the Wnt-β-catenin pathway and by promoting cellular quiescence and resistance to 5-Fluorouracil (5-Fu). The aim of this study was to evaluate the role of single nucleotide polymorphisms (SNPs) in the Hippo pathway as predictors of recurrence in colon cancer. Methods: We evaluated 204 patients with high-risk stage II and stage III colon cancer treated with 5-Fu based adjuvant chemotherapy.Genomic DNA was extracted from peripheral blood and genotypes were obtained by polymerase chain reaction-based direct sequencing. Fourteen SNPs in eight genes in the Hippo pathway (MST1, MST2, LATS1, LATS2, YAP, TAZ, FAT4, and RASSF1A) were selected. The endpoint was three-year recurrence probability. Results: In the overall populationtwo SNPs in the RASSF1A and TAZ genes correlated with the recurrence. For RASSF1A rs2236947, patients with an AA genotype had higher probability of recurrence compared to patients with CA/CC genotypes (53% vs 31%, hazard ratio (HR): 1.88; log-rank p=0.021; Cox model p=0.053). For TAZ rs3811715, patients with at least a T variant allele had lower probability of recurrence compared to patients with a CC genotype (26% vs 38%; HR: 0.61; log-rank p=0.047; Cox model p=0.098). In left-sided tumors, the association of TAZ rs3811715 with the three-year recurrence was stronger (HR: 0.27; Cox model p=0.016). Additionally, in left-sided tumors TAZ rs6783790 also correlated with the recurrence (33% for CT/TT genotypes compared to 44% for CC genotype; HR: 0.40; Cox model p=0.015). In right-sided tumors, RASSF1A rs2236947 was the most relevant polymorphism for predicting recurrence (HR: 2.19; log-rank p= 0.03; Cox model p=0.21). Recursive partitioning analysis confirmed the different relevance of these SNPs depending on the tumor location. Conclusions: Polymorphisms in the Hippo pathway are promising biomarkers for stage II and III colon cancer treated with adjuvant chemotherapy. The role of these SNPs is influenced by tumor location.
A phase IB study of CX-4945 in combination with gemcitabine plus cisplatin in the frontline systemic treatment of patients with advanced cholangiocarcinoma.
Authors: Mitesh J. Borad, Joleen Marie Hubbard, Do-Youn Oh, Sun Young Rha, Kabir Mody, John K.C. Lim, Donald A. Richards
Journal: Journal of Clinical Oncology (2017)

294 Background: CX-4945 is a first-in-class casein kinase-2 (CK2) threonine kinase small molecule inhibitor. CK2 is pleiotropic and regulates key cellular processes such as proliferation and DNA damage repair, and has been shown to enhance efficacy of gemcitabine (G) and cisplatin (C) in cell line and xenograft CCA model systems. A Phase IB study of G+C with CX-4945 was conducted in advanced cholangiocarcinoma (CCA) patients. Methods: A multi-center “3+3” dose escalation study was conducted in advanced CCA patients. Eligible patients had ECOG PS 0-1 and adequate hematologic, hepatic, and renal function. Primary endpoints were maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Secondary endpoints included pharmacokinetic (PK) analyses, overall toxicity evaluation and preliminary assessment of efficacy. Routine clinical dosing for G (1000 mg/m2) and C (25 mg/m2), both on days 1 and 8 every 21 days, was used. Dose escalation cohort were CX-4945 given twice daily on days 0,1,2 and 7,8,9 at 200 mg (DL1), 400mg (DL2), 600 mg (DL3), 800 mg (DL4) and 1000 (DL5) mg. NCI CTCAE v4.03 was used for toxicity assessment and RECIST v1.1 for efficacy evaluation. Results: Nineteen patients were enrolled (DL1:n = 3; DL2:n = 4 DL3:n = 3; DL4:n = 4; DL5:n = 5). No dose limiting toxicities were encountered. MTD and RP2D were ascertained to be DL5. No grade 3 or 4 toxicities at prevalence &gt; 10% were encountered and the overall toxicity profile of the combination was reflective of standard G+C toxicity profile. At data cut-off, preliminary efficacy evaluation demonstrated disease control rate (CR+PR+SD) of 64% (PR:32%, SD:32% and CR:0%), along with median progression-free survival (PFS) of 5 months (range 0-14 months). PK analyses showed no evidence of drug-drug interactions between G, C and CX-4945. Conclusions: RP2D for G+C with CX-4945 is DL5 (CX-4945 dosed on days 0,1,2 and 7,8,9 at 1000 mg PO bid with standard G and C dosing). Preliminary clinical efficacy and tolerability of the regimen support planned controlled, randomized Phase 2 evaluation. Clinical trial information: NCT02128282.
포스터전시 : 간경변 환자에서 경색성 재생 결절(infracted regenerative nodule)의 임상 양상
Authors: 이주엽, 이경인, 서혜진, 김현아, 김경훈, 이정은, 장병국, 박경식, 조광범, 황재석, 안성훈, 권중혁
Journal: Clinical and Molecular Hepatology (2008)
Regular statin users and colorectal cancer (CRC) prognosis.
Authors: Wei-li Ma, Yu Yun Shao, Chih-Hung Hsu, Kun-Huei Yeh, Ho-Min Chen, Yi-Chun Yeh, Chiu-Lin Lai, Zhong-Zhe Lin, Ann-Lii Cheng, Mei-Shu Lai
Journal: Journal of Clinical Oncology (2013)

3554 Background: Statins are frequently used for the control of hyperlipidemia. Statins have multiple anti-cancer properties and may be associated with lower CRC risks among their users. This study tries to go a step further and explores whether statin use affects the prognosis of curatively resected CRC. Methods: We established a population cohort with patients (age ≥ 40 y) who were diagnosed as having stage I or II CRC from 2004 to 2008 and received curative surgery from the database of Taiwan Cancer Registry. Data of medication prescription and co-morbidities were retrieved from the database of National Health Insurance, Taiwan. Regular statin use was defined as taking statins for &gt; 180 days within the observation period from one year before the cancer diagnosis to one year afterward. The database of National Death Registry was used for survival outcomes. Another similar cohort consisting of patients with hepatocellular carcinoma (HCC) was used for comparison. Results: In total, 10762 patients with CRC were enrolled; 891 (8%) patients were regular stain users, 812 (8%) patients took statins but were not regular users, and 9059 (84%) patients never used statins. Regular statin users, compared to never users, were more likely to be female (p &lt; 0.001), older (p &lt; 0.001), have stage I disease (p &lt; 0.001) and co-morbidities such as diabetes, coronary artery disease, and renal disease. Adjuvant therapy was less frequently administered in regular statin users. In univariate analysis, cancer-specific survival (CSS) of regular stating users was significantly longer than that of never users (5-y CSS, 87% vs. 84%, p = 0.022), but overall survival (OS) was not significantly different (5-y OS, 80% vs. 77%, p = 0.156). In multivariate analysis adjusting for age, gender, stage, adjuvant therapy, co-morbidities, and the use of aspirin, regular stating use was an independent predictor both for better CSS (hazard ratio [HR] 0.72, p &lt; 0.001) and for better OS (HR 0.71, p&lt; 0.001). In contrast, no associations were found between statin use and CSS or OS in the HCC comparison cohort. Conclusions: Regular statin use was associated with better prognosis in CRC patients who received curative therapy. (This study was supported by grants DOH-101-TD-B-111-001 and DOH-102-TD-B-111-001).