tbuckley/cabot-search huggingface dataset:
Determination of mean population values of the prostate-specific antigen test after correcting for verification bias
Authors: R. S. Punglia, A. V. D’Amico, W. J. Catalona, K. A. Roehl, K. M. Kuntz
Journal: Journal of Clinical Oncology (2005)

6031 Background: A recent study has suggested that serum prostate-specific antigen (PSA) is associated with prostate gland volume but not prostate cancer. However, the distribution of PSA values for those with and without cancer cannot be determined accurately in the presence of verification bias. Accordingly, we propose an approach to estimate mean and standard deviation (SD) of PSA values for men with and without prostate cancer after correcting for verification bias, and dichotomize the groups by prostate gland volume in order to gain insights into the diagnostic characteristics of the PSA test. Methods: We estimated a logistic regression model using data from men who underwent prostate biopsy to derive the probability of cancer in a screening population at the Washington University School of Medicine in order to correct for verification bias. Adjusted receiver operating characteristic (ROC) curves were derived separately by age and digital rectal exam (DRE) result using a standard approach. We now report the mean PSA value and SD for each subgroup by finding those values that most closely approximated the distributions in the adjusted ROC curves, assuming normal distribution of the natural log of PSA (lnPSA) values. Results: The presence of prostate cancer results in a higher mean PSA level independent of prostate gland volume and age. The table below shows adjusted mean and SD of PSA values in each subgroup. Conclusions: Using adjusted curves to generate the mean and SD for PSA values in men with and without cancer allows for more accurate estimations. We found higher PSA values in the men with cancer independent of prostate size. Better population estimates may have important implications regarding the threshold PSA value used to recommend biopsy as a function of age and DRE result. Our results show that a substantial proportion of biopsy-detectable prostate cancers are missed in all the subgroups studied using the traditional 4.0 ng/ml cutoff. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Beckman Coulter Beckman Coulter
Structural optimization and biological evaluation of 1,5-disubstituted pyrazole-3-carboxamines as potent inhibitors of human 5-lipoxygenase
Authors: Yu Zhou, Jun Liu, Mingyue Zheng, Shuli Zheng, Chunyi Jiang, Xiaomei Zhou, Dong Zhang, Jihui Zhao, Deju Ye, Mingfang Zheng, Hualiang Jiang, Dongxiang Liu, Jian Cheng, Hong Liu
Journal: Acta Pharmaceutica Sinica B (2016)

Human 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds, 3a and 3b, exhibiting a potent inhibitory profile against 5-LOX with IC50 values less than 1 µmol/L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fused-ring system. Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX. In particular, compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity, but also significantly decreased infarct damage in a mouse model of cerebral ischemia. Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data. In conclusion, the excellent in vitro and in vivo inhibitory activities of these compounds against 5-LOX suggested that these novel chemical structures have a promising therapeutic potential to treat leukotriene-related disorders.
Phase I feasibility study of carboplatin plus capecitabine followed by maintenance capecitabine in patients (pts) with recurrent platinum-sensitive epithelial ovarian cancer (EOC)
Authors: A. Montes, S. K. Sandhu, C. Rothermundt, I. Coombes, R. A'Hern, C. Keyzor, A. Thomas, S. Kaye, M. Gore
Journal: Journal of Clinical Oncology (2009)

5564 Background: In a previous study, we noted a response rate (RR) of 61% for the 3 drug combination of carboplatin, epirubicin and capecitabine in platinum-sensitive recurrent EOC. This combination however resulted in excessive grade (G) 3–4 haematological toxicity (55%) (BJC 2006; 94:74). The current trial therefore assessed the feasibility and efficacy of the 2 drugs, carboplatin and capecitabine as second- or third-line treatment. Methods: Pts were administered carboplatin (AUC5) day 1 and capecitabine at a starting dose of 750 mg/m2 bd, days 1–21, q21 (dose level 1). The capecitabine dose was deescalated to 625 mg/m2 (dose level -1) and 500 mg/m2 (dose level -2) according to toxicity. Pts with an objective response or stable disease received maintenance capecitabine (at the same dose level) for up to 12 months or until progression. Responses were assessed with RECIST criteria and CA-125. Results: 19 of the 20 pts enrolled were evaluable for toxicity and response. Dose-limiting toxicity was observed at dose level 1 (G3 fatigue, G3 diarrhoea, G3 neutropenia of &gt; 14 days; n = 3/5), dose level -1 (G3 angina (n = 2), G3 vomiting, G3 palmar plantar erythema; n = 4/7) and dose level-2 (diarrhoea / fatigue; n = 1/7). One patient had a G3 carboplatin hypersensivity reaction. 8 pts received maintenance capecitabine which was well tolerated. The overall RR was 53% with 10 partial responses and 5 stable diseases. The median progression free survival (PFS) was 6.5 months (m) and the 6mPFS was 63% with 2 pts currently ongoing treatment. The median PFS on maintenance was 3.2 m. Conclusions: The combination was well tolerated at the recommended phase II dose of carboplatin (AUC 5) and capecitabine (500 mg/m2 bd) with partial responses in over half of the cases. [Table: see text]
A short-term biomarker modulation prevention study of simvastatin in women at increased risk for breast cancer.
Authors: M. J. Higgins, T. M. Prowell, A. Blackford, S. Slater, P. Argani, H. Green, N. Khouri, R. Blumenthal, J. E. Garber, V. Stearns
Journal: Journal of Clinical Oncology (2010)

1505 Background: Observational studies have reported a decreased incidence of breast cancer in users of HMG Co-A reductase inhibitors. The primary objective of this phase II study was to screen potential surrogate biomarkers of statin chemopreventive activity including high sensitivity C-reactive protein (hsCRP), fasting lipid profile, circulating estrogens, and contralateral breast density, in women at high risk for a new breast cancer. An exploratory endpoint was to evaluate change in cumulative candidate gene methylation. Methods: Women at least 3 months (m) postcompletion of all local and systemic therapy for stage 0-III breast cancer received simvastatin 40 mg daily for 6 m. Contralateral breast mammography to assess breast density, blood collection, and the SF36 Health-Survey were performed at baseline and after 6 m of study treatment. We obtained optional contralateral breast core biopsies at baseline and 6 m for biomarker studies. Results: Accrual (N=50) is complete. Median age was 53, 76% of women were postmenopausal, 62% had hormone receptor-negative tumors. Treatment was well tolerated. Median total cholesterol, triglycerides (TG) and LDL cholesterol (LDL-C) values decreased significantly between baseline and end of study suggesting compliance with study drug (Table). We observed a nonsignificant reduction in hsCRP and no change in SF-36 scores. Baseline and end-of-study mammograms and samples for estrogen measurements are available for 45 (90%) patients; 26 (52%) agreed to the optional breast biopsy. Conclusions: 6 m of simvastatin did not impact well-being scores. Changes in potential chemopreventive biomarkers may be detected following 6 m of simvastatin therapy. Changes in biomarkers of inflammation and cardiovascular risk will be correlated with changes in biomarkers of breast cancer risk. Median change (95% confidence intervals) p value hsCRP mg/L 0.2 (0.95-0.05) 0.086 Total cholesterol mg/dL -52 (-58, -37) < 0.001 TG mg/dL -7 (-18.5, -2.5) 0.006 HDL-C mg/dL -1 (-2, 3.5) 0.56 LDL-C mg/dL -48 (-57, -35.5) < 0.001 Physical functioning 0 (-15, 2.5) 0.097 Energy 0 (-12.5, 2.5) 0.12 Pain 0 (-16.25, 15) 0.76 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Generation Health, Novartis, Source MDx AstraZeneca, Merck, Novartis
Neutropenia as a prognostic factor in metastatic colorectal cancer patients undergoing chemotherapy with first-line FOLFOX
Authors: K. Shitara, K. Matsuo, D. Takahari, T. Yokota, T. Ura, K. Muro
Journal: Journal of Clinical Oncology (2009)

4115 Background: FOLFOX combined with bevacizumab is established as standard first-line chemotherapy for metastatic colorectal cancer (MCRC), and neutropenia is one of the most common of its side effects. Neutropenia during chemotherapy has been reported to be a predictor of better survival in patients with several type of cancers, although there are no reports in MCRC. We aimed to assess whether neutropenia during chemotherapy could be a marker of improved survival of patients with MCRC. Methods: Patients with MCRC who received FOLFOX with or without bevacizumab as first-line chemotherapy were retrospectively analyzed to assess whether neutropenia during chemotherapy is associated with improved survival. Several background characteristics and chemotherapy features (grade of neutropenia, use of bevacizumab, use of irinotecan, reintroduction of oxaliplatin, and tumor progression) as time-varying covariates (TVCs) were analyzed as potential prognostic factors. Results: Of 153 patients, mild neutropenia (grade 1–2) occurred in 60 patients (39%) and severe neutropenia (grade 3–4) occurred in 46 patients (30%). The other 47 patients (31%) did not experience neutropenia. In 106 patients experiencing neutropenia, 66% of patients experienced their highest grade within 4 cycles. According to a multivariate Cox model with TVCs, hazard ratios of death were 0.55 (95% CI, 0.31–0.98; P = 0.044) for patients with mild neutropenia and 0.35 (95% CI, 0.18–0.66; P = 0.002) for those with severe neutropenia. If the analysis of neutropenia was limited to 4 cycles of FOLFOX, mild or severe neutropenia remained a significant prognostic factor according to survival analysis with TVCs. Conclusions: Both mild and severe neutropenia during chemotherapy are associated with improved survival in patients with MCRC. Prospective trials are required to assess whether dosing adjustments based on neutropenia may improve chemotherapy efficacy. No significant financial relationships to disclose.
Evaluation of weekly epirubicin-paclitaxel (EP) cardiotoxicity with serum troponin-t and myoglobin and echocardiography in advanced breast cancer (ABC)
Authors: C. Nisticò, E. Bria, A. Carpino, G. Vitelli, F. Cuppone, F. Izzo, F. Tropea, B. Vanni, P. Astorre, E. Terzoli
Journal: Journal of Clinical Oncology (2004)

775 Background: Troponin (TnT) and myoglobin (M) seem to be involved in myocardial damage; increasing serum level of TnT has been recently related to cumulative antracyclines exposure. Left ventricular ejection fraction (L-FEV) seems accurate in monitoring systolic function for cardiac damage measurement; its decreasing is recently entered as parameter of toxicity criteria of chemotherapeutics (CTC 3.0). E/A ratio is useful to assay diastolic function to predict systolic failure. Methods: From January 2002, 20 pts with untreated ABC underwent E: 25 mg/m2/week and P: 80 mg/m2/week with G-CSF support days 2,4, for 24 consecutive weeks. We had checked TnT, myoglobin, ALT, AST, LDH, CPK, CK-MB, PcR (protein-C-reactive) lab serum assay immediately before and 4 hours after E administration, every week. Pts underwent EKG and echocardiography (Eco) (L-FEV and E/A ratio measurement) at week n° 0, 8, 16 and 24. Results: Number of courses was 352 (median: 18, range: 4–24). E median achieved dose: 550 mg/m2, range 100–600; E median dose intensity (DI mg/m2/week): 22,95 (91,8%), range 15,6–25. P median achieved dose: 1760 mg/m2; P median dose intensity (DI mg/m2/week): 73,46 (91,8%), range 50–80. TnT never went over nrv (normal range values); 1 patient experienced increasing without any clinical/instrumental sign of cardiotoxicity. M never significantly increased except for a patient undergone several paracentesys. CK-MB and PcR never moved outside nrv. ALT, AST, LDH always within nrv except for pts with liver metastases. No symptomatic cardiac event were recorded; neither L-FEV and E/A significant decreasing occurred. In 55 Eco examinations at week 0, 8, 16, 24, median L-FEV (%) and median E/A were respectively: 66%, 67%, 64,5%, 65,5%, and 1.1, 1.11, 1,015, 1,1. Conclusions: No TnT/M and L-FEV/E/A alteration were seen in our subset of ABC non-symptomatic pts during weekly chemotherapy with E and P. No acute cardiac toxicity were record. We're waiting a longer follow-up to understand if the combination of these serum and instrumental parameters are useful in monitoring chronic cardiac damage. No significant financial relationships to disclose.
Association of oliguria with the development of acute kidney injury in the critically ill
Authors: Suvi T. Vaara, Ilkka Parviainen, Ville Pettilä, Sara Nisula, Outi Inkinen, Ari Uusaro, Raili Laru-Sompa, Anni Pulkkinen, Minna Saarelainen, Mikko Reilama, Sinikka Tolmunen, Ulla Rantalainen, Markku Suvela, Katrine Pesola, Pekka Saastamoinen, Ville Pettilä, Kirsi-Maija Kaukonen, Anna-Maija Korhonen, Sara Nisula, Suvi Vaara, Raili Suojaranta-Ylinen, Leena Mildh, Mikko Haapio, Laura Nurminen, Sari Sutinen, Leena Pettilä, Helinä Laitinen, Heidi Syrjä, Kirsi Henttonen, Elina Lappi, Tero Varpula, Päivi Porkka, Mirka Sivula, Mira Rahkonen, Anne Tsurkka, Taina Nieminen, Ari Alaspää, Ville Salanto, Hanna Juntunen, Ilkka Parviainen, Ari Uusaro, Esko Ruokonen, Stepani Bendel, Niina Rissanen, Maarit Lång, Sari Rahikainen, Saija Rissanen, Merja Ahonen, Elina Halonen, Meri Poukkanen, Esa Lintula, Jorma Heikkinen, Timo Lavander, Kirsi Heinonen, Tadeusz Kaminski, Fiia Gäddnäs, Tuija Kuusela, Sari Karlsson, Matti Reinikainen, Tero Surakka, Helena Jyrkönen, Tanja Eiserbeck, Tero Ala-Kokko, Jouko Laurila, Vesa Lund, Päivi Tuominen, Pauliina Perkola, Riikka Tuominen, Marika Hietaranta, Seppo Hovilehto, Anne Kirsi, Pekka Tiainen, Tuija Myllärinen, Pirjo Leino, Anne Kuitunen, Jyrki Tenhu-nen, Ilona Leppänen, Markus Levoranta, Sanna Hoppu, Jukka Sauranen, Atte Kukkurainen, Samuli Kortelainen, Outi Inkinen, Niina Koivuviita, Jutta Kotamäki, Simo-Pekka Koivisto, Raku Hautamäki, Maria Skinnar
Journal: Kidney International (2015)
Shifting Paradigms About Hormonal Risk Factors for Postmenopausal Depression
Authors: Hadine Joffe, Joyce T. Bromberger
Journal: JAMA Psychiatry (2016)

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NCCTG trial of gemcitabine for relapsed B-cell chronic lymphocytic leukemia
Authors: T. G. Call, C. L. Constantinou, S. P. Kahanic, K. M. Rowland, S. R. Dakil, A. Hoering, C. Y. Li, G. W. Dewald, N. E. Kay, T. E. Witzig
Journal: Journal of Clinical Oncology (2004)

6726 Background: Gemcitabine demonstrates in vitro activity against lymphoid cell lines, and has shown clinical responses in patients with non-Hodgkin's lymphoma. This study was performed to determine the efficacy and toxicity of gemcitabine in B-CLL patients with relapsed disease. Methods: Patients with relapsed B-CLL and prior treatment with both a purine nucleoside (fludarabine or cladribine) and an alkylating agent were enrolled. Treatment was with gemcitabine (1,000mg/m2) on days 1 and 8 of a 28-day cycle. A two-stage phase II trial design was used to assess the proportion of confirmed responses and toxicities. Results: 22 patients were enrolled. One patient withdrew prior to treatment and two were deemed ineligible, leaving 19 eligible patients. The median age was 63 years and median prior treatments were 3. The study was terminated at the interim analysis due to lack of efficacy, with only one patient having a partial response. Only 6 patients completed the protocol due to: disease progression (8), adverse reaction (3), alternative treatment (2), refusal (1), and death on study (1). Thirteen patients (68%) had stable disease as their best response. The median time to progression was 72 days. The most common hematologic toxicity was thrombocytopenia. The most common non-hematologic toxicity was infection. The death on study occurred in a patient with known heart disease who died of a myocardial infarction. Correlative laboratory studies indicated a high risk group of CLL patients entered this protocol. Fluorescent in situ hybridization detected the following chromosome abnormalities: 17p-(3), 11q-(5), +12(4), 13q-(5), polyploid (1), and normal (1). IgVH mutation status was able to be obtained in 9 patients, it was non-mutated in 7 and mutated in 2. Nine of the nineteen patients were CD38 positive. Conclusions: As a single agent gemcitabine did not show sufficient efficacy in a fludarabine or cladribine pretreated patient cohort of relapsed B cell CLL patients, who also expressed both adverse FISH anomalies and IgVH status. Whether it has a role in more chemotherapy naïve CLL patients, or in combination with other agents, remains to be determined. No significant financial relationships to disclose.
Immediate Improvemement of Subepicardial Left Ventricular Twist Predicts Clinical and Echocardiographic Response to Cardiac Resynchronization Therapy
Authors: Matteo Bertini, Nina Ajmone Marsan, Gaetano Nucifora, Victoria Delgado Delgado, Rutger J van Bommel, C Jan Willem Borleffs, Arnold C Ng, Giuseppe Boriani, Mauro Biffi, Martin J Schalij, Jeroen J Bax
Journal: Circulation (2009)
Phase II study of irinotecan (I) and cetuximab (C) on an every 2 week schedule, as second line therapy in patients (pts) with advanced colo-rectal cancer (CRC)
Authors: R. K. Ramanathan, M. Fakih, S. S. Krishnamurthi, S. Lancaster, R. A. Pinkerton, T. L. Crandall, A. Schmotzer, N. Bahary, A. A. Khorana, B. C. Lembersky
Journal: Journal of Clinical Oncology (2008)

15050 Background: I + C is a standard second line regimen for pts treated with 5-flurouracil, oxaliplatin and bevacizumab in the US. Second line therapy with I + C results in a response rate (RR) of 16%, progression free survival (PFS) of 3.9 months, and overall survival 10.7 months (Sobrero AF et al, AACR 2007). C is administered on a weekly schedule (dose 250 mg/m2). C has a long terminal half-life (mean 112 hrs) and demonstrates near linear pharmacokinetics. Therefore doubling the standard dose of cetuximab to 500 mg/m2 over 2 weeks should result in a similar AUC to that of the weekly dose. Methods: Trial is designed to evaluate the I + C regimen in US patients with CRC as second line therapy. The primary endpoint is RR, requiring 31 pts to achieve a 25% RR with 80% power: Eligibility requirements include: Progression after a first-line oxaliplatin/fluoropyrimidine regimen, no prior I or C exposure and acceptable organ function. I given at a dose of 150 or 180 mg/m2 IV over 60 min and C at a dose of 500 mg/m2 IV over 60–120 min. Cycles are repeated every 2 weeks. Results: Twenty seven of 31 pts have been enrolled, with all evaluable for toxicity and 23 for response. Patient characteristics: Male (n=13); ECOG performance status 0 (n=16), 1 (n=10); median age 57 years (range 44–84). Starting dose of irinotecan was 150 mg/m2 every 2 weeks in 12 pts and 180 mg/m2 in 15 pts. Median cycles administered so far is 4. A confirmed partial was response seen in 1 pt and stable disease in 7 pts. Gr 3/4 toxicity included diarrhea (n=3), rash (n=4), neutropenic fever and neuropathy (n=2 each). Bowel perforation, fatigue, nausea, vomiting (n=1 each). Bowel obstruction was seen in 2 pts and was attributed to progressive disease. No Gr > 3 hypersensitivity reactions were observed. The PFS analysis is premature at this point. Conclusions: The I+ C, q 2 weekly regimen as second line therapy is well tolerated. C at the dose of 500 mg/m2, can be safely administered every 2 weeks. Sponsored by Bristol Myers Squibb Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration ImClone
SAMIT: A phase III randomized clinical trial of adjuvant paclitaxel followed by oral fluorinated pyrimidines for locally advanced gastric cancer.
Authors: Kazuhiro Yoshida, Akira Tsuburaya, Michiya Kobayashi, Shigefumi Yoshino, Masazumi Takahashi, Nobuhiro Takiguchi, Kazuaki Tanabe, Naoto Takahashi, Hiroshi Imamura, Naokuni Tatsumoto, Akinori Hara, Kazuhiro Nishikawa, Ryoji Fukushima, Akira Kurita, Hiroshi Kojima, Yumi Miyashita, Koji Oba, Marc E. Buyse, Satoshi Morita, Junichi Sakamoto
Journal: Journal of Clinical Oncology (2013)

LBA4002 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.