tbuckley/cabot-search huggingface dataset:
FOLFOXIRI plus bevacizumab (BV) versus FOLFIRI plus BV as first-line treatment of metastatic colorectal cancer (MCRC): Preliminary safety results of the phase III randomized TRIBE study by the Gruppo Oncologico Nord-Ovest (GONO).
Authors: A. Falcone, F. Loupakis, S. Cupini, E. Cortesi, A. Buonadonna, G. Tomasello, M. Banzi, M. Ronzoni, A. Zaniboni, G. Masi
Journal: Journal of Clinical Oncology (2010)

3543 Background: The combination of BV with cytotoxic drugs is an efficacious strategy in the treatment of mCRC. The triple drug combination FOLFOXIRI demonstrated increased activity and efficacy over FOLFIRI in a randomized trial (Falcone, JCO 2007). The combination of FOLFOXIRI plus BV demonstrated promising results in phase II. Methods: TRIBE is a multicenter, randomized, Italian trial. CRC patients (pts) with metastatic disease deemed unresectable were randomized to receive in first-line BV in combination with FOLFIRI (arm A) or with FOLFOXIRI (arm B) for a maximum of 6 months (induction treatment). In both arms a maintenance treatment with BV and fluoropyrimidines until progression or unacceptable toxicity were scheduled. Primary endpoint is progression-free survival and the planned accrual is 450 pts. Results: The trial is still ongoing. We present the safety analysis of the first 100 randomized pts. Patients characteristics are (arm A/arm B): number 51/49, gender M45%-F55%/M61%-F39%, median age 60 (29-74) years/ 62 (29-74) years, ECOG PS=0 88%/84%, primary rectal 37%/33%, primary on site 24%/27%, multiple site of metastasis 73%/63%, prior adjuvant therapy 16%/10%. Administered cycles were: arm A 503 (median 12), arm B 485 (median 11). Main grade 3-4 observed toxicities are reported in the Table. For arm A and arm B respectively serious adverse events occurred in 18% and 20% of pts, probably treatment-related deaths in 3 pts (2 pulmonary embolism and 1 stroke) and 1 pt (GI bleeding). Conclusions: These preliminary results demonstrate that both treatment arms are safe and feasible, side effects occur with the expected incidence and there were not unexpected toxicities. NCI-CTC 3.0 grade 3-4 Arm A (FOLFIRI + BV) Arm B (FOLFOXIRI + BV) N % N % Vomiting 0 0% 2 4% Diarrhea 6 12% 9 18% Stomatitis 3 6% 4 8% Neutropenia 7 14% 26 53% Febrile neutropenia 3 6% 3 6% Thrombocytopenia 0 0% 1 2% Anemia 0 0% 0 0% Neurotoxicity (grade 2-3) NA NA 9 18% Asthenia 5 10% 2 4% Hypertension 1 2% 1 2% Bleeding 0 0% 1 2% Venous thrombosis 4 8% 3 6% Arterial thrombosis 1 2% 1 2% GI perforation 0 0% 1 2% Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Merck, Roche Amgen, Merck, Roche, sanofi-aventis Amgen, Merck, Roche
Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions
Authors: Janne T. Backman, Anne M. Filppula, Mikko Niemi, Pertti J. Neuvonen
Journal: Pharmacological Reviews (2015)

During the last 10-15 years, cytochrome P450 (CYP) 2C8 has emerged as an important drug-metabolizing enzyme. CYP2C8 is highly expressed in human liver and is known to metabolize more than 100 drugs. CYP2C8 substrate drugs include amodiaquine, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone, and the number is increasing. Similarly, many drugs have been identified as CYP2C8 inhibitors or inducers. In vivo, already a small dose of gemfibrozil, i.e., 10% of its therapeutic dose, is a strong, irreversible inhibitor of CYP2C8. Interestingly, recent findings indicate that the acyl-<i>β</i>-glucuronides of gemfibrozil and clopidogrel cause metabolism-dependent inactivation of CYP2C8, leading to a strong potential for drug interactions. Also several other glucuronide metabolites interact with CYP2C8 as substrates or inhibitors, suggesting that an interplay between CYP2C8 and glucuronides is common. Lack of fully selective and safe probe substrates, inhibitors, and inducers challenges execution and interpretation of drug-drug interaction studies in humans. Apart from drug-drug interactions, some <i>CYP2C8</i> genetic variants are associated with altered CYP2C8 activity and exhibit significant interethnic frequency differences. Herein, we review the current knowledge on substrates, inhibitors, inducers, and pharmacogenetics of CYP2C8, as well as its role in clinically relevant drug interactions. In addition, implications for selection of CYP2C8 marker and perpetrator drugs to investigate CYP2C8-mediated drug metabolism and interactions in preclinical and clinical studies are discussed.
Phase II Study of Nedaplatin / Irinotecan for Advanced Squamous Cell Carcinoma of the Lung(Torg0910)
Authors: Shunichiro Iwasawa, Yuichi Takiguchi, Haruhiro Saito, Yamada Kouzo, Noriyuki Masuda, Hiroaki Okamoto, Yukio Hosomi, Kazuma Kishi, Fumihiro Oshita, Koshiro Watanabe
Journal: Annals of Oncology (2014)
REGARD: A phase III, randomized, double-blinded trial of ramucirumab and best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing combination therapy.
Authors: Charles S. Fuchs, Jiri Tomasek, Jae Yong Cho, Filip Dumitru, Rodolfo Passalacqua, Chanchal Goswami, Howard Safran, Lucas Vieira dos Santos, Giuseppe Aprile, David R. Ferry, Bohuslav Melichar, Mustapha Tehfe, Eldar Topuzov, Josep Tabernero, John Raymond Zalcberg, Ian Chau, Minori Koshiji, Yanzhi Hsu, Jonathan D. Schwartz, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2013)

LBA5 Background: VEGF and VEGF receptor-2 mediated signaling and angiogenesis may contribute to gastric cancer pathogenesis. Ramucirumab (RAM; IMC-1121B) is a fully human IgG1 monoclonal antibody targeting VEGF-receptor 2. We conducted a placebo-controlled, double-blind, phase III international trial to evaluate the safety and efficacy of RAM in pts with metastatic gastric or GEJ adenocarcinoma progressing on first-line platinum- and/or fluoropyrimidine containing combination therapy. Methods: Pts were randomized 2:1 to receive RAM (8 mg/kg IV) plus BSC or placebo (PL) plus BSC every 2 weeks (wks) until disease progression, unacceptable toxicity, or death. Eligible patients had disease progression within 4 months (m) after 1 st -line therapy for metastatic disease or within 6 m after adjuvant therapy. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), 12-wk PFS rate, overall response rate (ORR) and safety. Results: From 10/09 to 01/12, 355 pts were randomized (RAM: 238; PL: 117). Baseline characteristics were well balanced between arms. The Hazard Ratio (HR) for OS was 0.776 (95% CI, 0.603-0.998; p = 0.0473). Median OS was 5.2 m for RAM and 3.8 m for PL. The HR for PFS was 0.483 (95% CI, 0.376-0.620; p &lt; 0.0001). Median PFS was 2.1 m for RAM and 1.3 m for PL. 12-wk PFS was 40% for RAM and 16% for PL. ORR was 3.4% for RAM and 2.6% for PL. Disease control rate was 49% for RAM and 23% for PL (p &lt; 0.0001). Use of anti-cancer therapy post-study: 32% RAM; 39% PL. The most frequent of grade ≥ 3 adverse events (AEs) were: hypertension (7.2% RAM; 2.6% PL), anemia (6.4% RAM; 7.8% PL), abdominal pain (5.1% RAM; 2.6% PL), ascites (4.2% RAM; 4.3% PL), fatigue (4.2% RAM; 3.5% PL), decreased appetite (3.4% RAM; 3.5% PL) and hyponatremia (3.4% RAM; 0.9% PL). Conclusions: Ramucirumab conferred a statistically significant benefit in OS and PFS compared to PL in metastatic gastric or GEJ adenocarcinoma following progression on 1st-line therapy with an acceptable safety profile. Clinical trial information: NCT00917384.
Optimizing Patient Care in Chronic Phase Chronic Myelogenous Leukemia: A Multidisciplinary Approach
Authors: Hema Sundar, Jerald Radich
Journal: Journal of the National Comprehensive Cancer Network (2016)

Chronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia chromosome arising from a reciprocal translocation between chromosomes 9 and 22 [t(9;22)]. This translocation results in the formation of the BCR-ABL fusion gene. The product of this fusion gene, p210, a protein with deregulated tyrosine kinase activity, plays a central role in the pathogenesis of CML. Tyrosine kinase inhibitor (TKI) therapy with small molecule inhibitors of BCR-ABL tyrosine kinase has significantly reduced the annual mortality rate among patients with CML. Although most of these patients respond to first-line TKI therapy, the use of TKIs is complicated by the development of resistance or intolerance in some patients, resulting in a loss of response or discontinuation of treatment. Inadequate response to TKI therapy is associated with poor long-term outcome, and the cases of patients with resistance or intolerance should be carefully evaluated for alternative treatment options. This report discusses the challenges associated with the management of newly diagnosed chronic phase CML in a patient with intolerance to multiple TKI therapies.
Effects Of Eltrombopag On Thrombocytopenia, Platelet Function and Bleeding In Patients With Wiskott-Aldrich Syndrome/X-Linked Thrombocytopenia
Authors: Anja J Gerrits, Emily Leven, Andrew L. Frelinger, Michelle A. Berny-Lang, Hannah Tamary, Shoshana Revel-Vilk, Sabrina L. Carmichael, W. Beau Mitchell, Alan D. Michelson, James B Bussel
Journal: Blood (2013)
The International Prognostic Index Predicts Outcome In Patients With Untreated Nodal Peripheral T-Cell Lymphomas Staged With PET/CT
Authors: Tarec Christoffer El-Galaly, Martin B Pedersen, Lars Christian Gormsen, Karen Juul Mylam, Anne Ortved Gang, Jakob Madsen, Victor Iyer, Helle Westergren Hendel, Annika Loft, Anne Lerberg Nielsen, Peter deNully Brown, Martin Hutchings, Francesco d'Amore
Journal: Blood (2013)
Coronary artery disease is the major determinant of excess mortality in patients with insulin-dependent diabetes mellitus and persistent proteinuria.
Authors: J H Warram, L M Laffel, O P Ganda, A R Christlieb
Journal: Journal of the American Society of Nephrology (1992)

The goal of this review was to assess the magnitude of coronary artery disease (CAD) mortality and its determinants in insulin-dependent diabetes mellitus (IDDM) patients with persistent proteinuria. By reanalyzing data from two previously published studies of patients with nephropathy, it was found that these patients had extremely high CAD mortality rates in comparison with IDDM patients without proteinuria, but only after the age of 35 yr. In addition, the risk of CAD death was associated with high serum cholesterol levels but was unrelated to systemic blood pressure, smoking habits, and obesity. Further studies of the determinants of CAD in patients with IDDM and proteinuria are urgently needed. Except for efforts to lower serum cholesterol, it is not known whether any other measure can be undertaken to reduce the extremely high mortality due to CAD that afflicts IDDM patients with persistent proteinuria, in particular those patients whose renal failure might have been "successfully" postponed by antihypertensive therapy.
Abstract 19083: Predicting Aortic Valve Stenosis Progression: Discordance Between Anatomical and Hemodynamic Assessment of Aortic Valve Severity
Authors: Glenn K Lee, Wern Miin Soo, Wen Ruan, Eric Chong, Edgar Tay, Kian Keong Poh
Journal: Circulation (2012)

Background: The aortic valve area (AVA) is a marker of severity in aortic stenosis (AS) patients and has prognostic and treatment implications. However, there is limited data on predictors of severity progression. Methods: We analyzed 509 consecutive patients with AS who underwent paired echocardiographic studies &gt;180 days apart. Anatomic and haemodynamic assessments of aortic valve stenosis severity were performed. Two hundred and sixty-seven patients (52%) had significant decrease (&gt;20%) in AVA. We compare their baseline echocardiographic parameters to the group without progression. Results: The mean time interval between the paired studies (1252±910 days) and the mean LV ejection fraction (60±12%) were not significantly different between the two groups. One hundred and forty patients (28.8%) had mild AS (defined as AVA &gt;1.5cm2), 217 (44.7%) had moderate AS (AVA 1 - 1.5 cm2) and 129 (26.5%) had severe AS (AVA &lt;1.0 cm2); the decrease in AVA was greatest in those with mild AS (24.7% vs. 10.0% vs. 4.2%, p&lt;0.001). Initial anatomic valve area but not pressure gradients predict progression (Table). Conclusions: The progression of AS appears fastest in those with mild AS. Determination of aortic valve area predicts progression. More frequent echocardiographic assessments may perhaps be performed in this group of patients for timely identification of patients who may benefit from subsequent intervention.
Exploring the Association Between Rosacea and Parkinson Disease
Authors: Alexander Egeberg, Peter Riis Hansen, Gunnar H. Gislason, Jacob P. Thyssen
Journal: JAMA Neurology (2016)

The pathogenesis of rosacea is unclear, but increased matrix metalloproteinase target tissue activity appears to play an important role. Parkinson disease and other neurodegenerative disorders also display increased matrix metalloproteinase activity that contribute to neuronal loss.To investigate the risk of incident (new-onset) Parkinson disease in patients with rosacea.A nationwide cohort study of the Danish population was conducted using individual-level linkage of administrative registers. All Danish citizens 18 years or older from January 1, 1997, to December 31, 2011 (N = 5 472 745), were included. Data analysis was conducted from June 26 to July 27, 2015.The main outcome was a diagnosis of Parkinson disease. Incidence rates (IRs) per 10 000 person-years were calculated, and incidence rate ratios (IRRs) adjusted for age, sex, socioeconomic status, smoking, alcohol abuse, medication, and comorbidity were estimated by Poisson regression models.A total of 5 404 692 individuals were included in the reference population; of these, 22 387 individuals (9812 [43.8%] women; mean [SD] age at diagnosis, 75.9 [10.2] years) received a diagnosis of Parkinson disease during the study period and 68 053 individuals (45 712 [67.2%] women; mean age, 42.2 [16.5] years) were registered as having rosacea. The IRs of Parkinson disease per 10 000 person-years were 3.54 (95% CI, 3.49-3.59) in the reference population and 7.62 (95% CI, 6.78-8.57) in patients with rosacea. The adjusted IRR of Parkinson disease was 1.71 (95%, CI 1.52-1.92) in patients with rosacea compared with the reference population. There was a 2-fold increased risk of Parkinson disease in patients classified as having ocular rosacea (adjusted IRR, 2.03 [95% CI, 1.67-2.48]), and tetracycline therapy appeared to reduce the risk of Parkinson disease (adjusted IRR, 0.98 [95% CI, 0.97-0.99]).Rosacea constitutes an independent risk factor for Parkinson disease. This association could be due to shared pathogenic mechanisms involving elevated matrix metalloproteinase activity. The clinical consequences of this association require further study.
New Appliances
Authors: P MARTIN
Journal: BMJ (1961)

Of deep interest is the essay on " Dickensian Diagnoses," which shows how profound were Boz's observation and knowledge of disease, " so that he often gives us accounts which would do credit to a trained physician."An impression of Grock, the clown, follows, and then comes an account of Sir Russell sitting to Epstein for his portrait bust and the sculptor's reflections on men and things.As the book Tea with Walter de la Mare revealed, Sir Russell is a faithful recorder of interesting conversations.
Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans
Authors: Brian E. Cade, Han Chen, Adrienne M. Stilp, Kevin J. Gleason, Tamar Sofer, Sonia Ancoli-Israel, Raanan Arens, Graeme I. Bell, Jennifer E. Below, Andrew C. Bjonnes, Sung Chun, Matthew P. Conomos, Daniel S. Evans, W. Craig Johnson, Alexis C. Frazier-Wood, Jacqueline M. Lane, Emma K. Larkin, Jose S. Loredo, Wendy S. Post, Alberto R. Ramos, Ken Rice, Jerome I. Rotter, Neomi A. Shah, Katie L. Stone, Kent D. Taylor, Timothy A. Thornton, Gregory J. Tranah, Chaolong Wang, Phyllis C. Zee, Craig L. Hanis, Shamil R. Sunyaev, Sanjay R. Patel, Cathy C. Laurie, Xiaofeng Zhu, Richa Saxena, Xihong Lin, Susan Redline
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Obstructive sleep apnea is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. Although there is strong clinical and epidemiologic evidence supporting the importance of genetic factors in influencing obstructive sleep apnea, its genetic basis is still largely unknown. Prior genetic studies focused on traits defined using the apnea-hypopnea index, which contains limited information on potentially important genetically determined physiologic factors, such as propensity for hypoxemia and respiratory arousability.
Conservation and dynamics of microsatellite loci over 300 million years of marine turtle evolution.
Authors: N N FitzSimmons, C Moritz, S S Moore
Journal: Molecular Biology and Evolution (1995)

Microsatellite loci consisting of (CA)n repetitive arrays were obtained from three species of marine turtle, and primers were designed to test for polymorphism within species and the persistence of microsatellites across species. Homologous loci were found in each test of six marine species within two families (Cheloniidae and Dermochelyidae), as well as in a freshwater species (Emydidae, Trachemys scripta), which indicates a conservation of flanking sequences spanning approximately 300 million years of divergent evolution. The persistence of homologous microsatellites across marine turtles was confirmed by direct sequencing of loci across species and by the discovery of polymorphism in 24 of 30 cross species tests. The conservation of flanking sequences could be due to a slow rate of base substitution in turtle nuclear DNA, as previously reported for mtDNA. In contrast, the presence of up to 25 alleles per locus per species indicates that the replication slippage events responsible for changes in allele length operate as in mammals. Comparisons of alleles among species revealed that alleles of the same length may not be homologous due to mutations within the flanking sequences. Levels of heterozygosity were consistently higher in species from which the primers were designed, which suggests problems with cross-species comparisons of variability. Within species, microsatellite variation between divergent populations was consistent with results from previous mtDNA studies indicating the usefulness of microsatellites for comparing male- versus female-mediated gene flow.
Epidermal Cell Proliferation and Promoting Ability of Phorbol Esters2
Authors: Thomas J. Slaga, John D. Scribner, Sara Thompson, Aurora Viaje
Journal: JNCI Journal of the National Cancer Institute (1976)

Journal Article Epidermal Cell Proliferation and Promoting Ability of Phorbol Esters Get access Thomas J. Slaga, Thomas J. Slaga Search for other works by this author on: Oxford Academic PubMed Google Scholar John D. Scribner, John D. Scribner Search for other works by this author on: Oxford Academic PubMed Google Scholar Sara Thompson, Sara Thompson Search for other works by this author on: Oxford Academic PubMed Google Scholar Aurora Viaje Aurora Viaje Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 57, Issue 5, November 1976, Pages 1145–1149, https://doi.org/10.1093/jnci/57.5.1145 Published: 01 November 1976 Article history Received: 15 January 1976 Accepted: 16 April 1976 Published: 01 November 1976
Effect of Perilesional Injection of α-interferon on Cervical Intraepithelial Neoplasia and Associated Human Papillomavirus Infection
Authors: A M Dunham, J C McCartney, D J McCance, R W Taylor
Journal: Journal of the Royal Society of Medicine (1990)

In this controlled prospective study, 14 patients with cervical intraepithelial neoplasia (CIN) were observed for one month to exclude spontaneous regression, and then seven patients were treated twice-weekly with perilesional injections of α-interferon. Both groups were monitored colposcopically, and advised to use the contraceptive sheath. Cervical smears and biopsies for histology and viral studies were taken before and after the study. There was an improvement of six out of seven of the study group, with two complete cures. Koilocytosis disappeared if it had been present initially, as did human papillomavirus (HPV) 16. By contrast, three control cases showed improvement, but there were no cures, and one case deteriorated; Koilocytosis (2 cases) did not change; HPV 16 disappeared in two controls and appeared in one. A new focus of dysplasia appeared in a part of the transformation zone not being treated with α-interferon in one of the study cases, illustrating the advisability of treating the whole transformation zone in CIN.
Genomic and Immune Characterization of Metastatic Breast Cancer (Mbc): and Ancillary Study of the Safir01 &amp; Moscato Trials
Authors: M. Arnedos, T. Filleron, M.V. Dieci, J. Adam, P.B. Robbins, S. Loi, M. Campone, H. Bonnefoi, V. Diéras, F. Dalenc, M. Jimenez, J. Soria, C. Lefebvre, F. André, T. Bachelot, M. Lacroix-Triki
Journal: Annals of Oncology (2014)
Neoadjuvant FOLFOX-bev, without radiation, for locally advanced rectal cancer.
Authors: D. Schrag, M. R. Weiser, K. A. Goodman, M. Gonen, A. Cercek, D. L. Reidy, L. K. Temple, W. D. Wong, P. Paty, L. Saltz
Journal: Journal of Clinical Oncology (2010)

3511 Background: Preoperative 5FU-based chemo plus radiation therapy (RT) is standard for U.S. patients (pts) with locally advanced rectal cancer (RC). We conducted a pilot feasibility trial of pre-op FOLFOX-bevacizumab (bev) without RT for good-risk RC. Methods: Pts with clinical stage II-III RC (but not T4 tumors) who were candidates for sphincter-sparing surgery, were treated with 6 cycles of FOLFOX. Bev was included for cycles 1-4. Pts then were re-imaged and had repeat sigmoidoscopy with endorectal ultrasound (ERUS) performed by their surgeon to assess the primary tumor response. Those with stable/progressive disease were to be referred for pre-op 5FU plus RT, followed by surgery, and those with clinical regression were to have surgery without pre-op RT. Post-op 5FU plus RT was planned for any pts who did not have an R0 resection. Post-op chemo was left to investigator discretion, however 6 cycles of FOLFOX were recommended. The primary outcome was the R0 resection rate. Secondary outcomes were the pathologic CR rate, the 3-year disease free survival and local recurrence (LR) rate. Results: Of 31 pts accrued since March 2007, two were withdrawn from the study for cardiovascular toxicity (1 angina, 1 arrhythmia) after 1-2 cycles of FOLFOX-bev. Both had R0 resections. Of 29 who have completed pre-op chemo, all 29 had clinical regression and proceeded to surgery without pre-op RT. All 29 had R0 resections. Eight of 29 (27%) had a path CR. One pt with 14+ nodes and a close deep margin received post-op RT, and has since developed pulmonary mets. One pt with pathologic yT1N0 disease had high output ileostomy post-op but was discharged home in stable condition on day 10. He died suddenly 3 days later. Autopsy did not identify a cause. Local and distant recurrence rate data are immature; however thus far, there have been no LRs and 3 distant recurrences, all pulmonary. 26 patients remain alive and disease-free. Conclusions: Preliminary results of this pilot trial indicate that preoperative FOLFOX-bev chemo without RT achieves a high rate of R0 resections and path CRs in good risk RC. Further trials of non-RT-containing approaches are warranted. Supported by Genentech. No significant financial relationships to disclose.