tbuckley/cabot-search huggingface dataset:
Perifosine (P) can be combined with docetaxel (T) without dose reduction of either drug
Authors: A. Cervera, B. Bernhardt, J. J. Nemunaitis, B. Ebrahimi, R. Birch, D. A. Richards, G. B. Smith, J. P. Allerton, I. C. Henderson
Journal: Journal of Clinical Oncology (2006)

13066 Background: Perifosine is an alkylphospholipid that modulates several signal transduction pathways, including Akt, which is often activated in taxane resistant tumors and is thought to be one mediator of such resistance. The combination of T, 75 mg/m 2 every 3 weeks, and prednisone (Pr), 5 mg bid has become standard therapy for patients (pts) with metastatic prostate cancer. The addition of P might decrease resistance to T in these patients who often have activated Akt because of PTEN mutations. This phase I trial is the first attempt to combine these agents. Methods: Between 12/04 and 9/05, 39 pts were enrolled. P was given either daily as a 50 mg tablet 1, 2 or 3 times per day on days 1–14 or weekly in doses of 300 mg every 4 - 6 hours 3, 4 or 5 times on days 1–2, 8–9 and 15–16 of each 21 day cycle. T, 75 mg/m 2 , was given on day 8 of a 21 day cycle with or without Pr. Results: Disease sites: prostate 11, NSCLC 9, ovary 4, head/neck 3, pancreas 3, breast 2 &amp; other 7. Median age was 63 (range 37–80); 24 patients were male and median ECOG performance status was 1 (range 0–2). 34 pts had received prior chemotherapy including 24 previously given a taxane. Three patients were entered at each dose level for each schedule and the cohort expanded to 6 patients if 2 or more patients experienced a grade 3/4 non-hematologic toxicity (DLT) during the first cycle of therapy. A dose level was toxic if 4 or more patients experienced a DLT during cycle 1. The grade 3/4 toxicities for each perifosine dosing schedule are given in the table . Glucose values for the grade 3 toxicities were between 253 and 306. This was seen only in the Pr pts &amp; has not been observed in other P trials. P dose reductions were required in 4% of cycles for daily P, 5% for daily P+Pr and 37% for weekly P. Conclusions: Daily doses up to 150 mg could be administered either with or without Pr but the maximum tolerated dose for the weekly regimen was 1200 mg It is concluded that daily P ± Pr is well tolerated with T 75 mg/m 2 q 3 weeks and that daily doses are preferred for phase II studies to further define activity of the combination. [Table: see text] [Table: see text]
IRFinder: assessing the impact of intron retention on mammalian gene expression
Authors: Robert Middleton, Dadi Gao, Aubin Thomas, Babita Singh, Amy Au, Justin J-L Wong, Alexandra Bomane, Bertrand Cosson, Eduardo Eyras, John E. J. Rasko, William Ritchie
Journal: Genome biology (2017)

Intron retention (IR) occurs when an intron is transcribed into pre-mRNA and remains in the final mRNA. We have developed a program and database called IRFinder to accurately detect IR from mRNA sequencing data. Analysis of 2573 samples showed that IR occurs in all tissues analyzed, affects over 80% of all coding genes and is associated with cell differentiation and the cell cycle. Frequently retained introns are enriched for specific RNA binding protein sites and are often retained in clusters in the same gene. IR is associated with lower protein levels and intron-retaining transcripts that escape nonsense-mediated decay are not actively translated.
Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1
Authors: Niki M. Moutsopoulos, Christa S. Zerbe, Teresa Wild, Nicolas Dutzan, Laurie Brenchley, Giovanni DiPasquale, Gulbu Uzel, Karen C. Axelrod, Andrea Lisco, Lucia D. Notarangelo, George Hajishengallis, Luigi D. Notarangelo, Steven M. Holland
Journal: New England Journal of Medicine (2017)

A patient with leukocyte adhesion deficiency type 1 (LAD1) had severe periodontitis and an intractable, deep, nonhealing sacral wound. We had previously found a dominant interleukin-23-interleukin-17 signature at inflamed sites in humans with LAD1 and in mouse models of the disorder. Blockade of this pathway in mouse models has resulted in resolution of the immunopathologic condition. We treated our patient with ustekinumab, an antibody that binds the p40 subunit of interleukin-23 and interleukin-12 and thereby blocks the activity of these cytokines, inhibiting interleukin-23-dependent production of interleukin-17. After 1 year of therapy, our patient had resolution of his inflammatory lesions without serious infections or adverse reactions. Inhibition of interleukin-23 and interleukin-17 may have a role in the management of LAD1. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
Ixazomib, Thalidomide and Dexamethasone (IxaThalDex) in Relapsed/Refractory Multiple Myeloma (RRMM): An Interim Analysis of a Phase II Trial
Authors: Heinz Ludwig, Eberhard Gunsilius, Michael Fridrik, Richard Greil, Andreas Petzer, Thomas Kühr, Stefan Knop, Martin Schreder, Elisabeth Rauch, Wolfram Poenisch, Niklas Zojer
Journal: Blood (2016)
A Multicenter, Double-Blind, Randomized Safety and Efficacy Study of Two Dose Levels of Taliglucerase Alfa in Pediatric Patients with Gaucher Disease.
Authors: Ari Zimran, Derlis Emilio Gonzalez-Rodriguez, Aya Abrahamov, Deborah Elstein, Rene Heitner, Alona Paz, Einat Brill-Almon, Raul Chertkoff
Journal: Blood (2012)
Cigarette Smoking and Pancreatic Cancer Survival
Authors: Chen Yuan, Vicente Morales-Oyarvide, Ana Babic, Clary B. Clish, Peter Kraft, Ying Bao, Zhi Rong Qian, Douglas A. Rubinson, Kimmie Ng, Edward L. Giovannucci, Shuji Ogino, Meir J. Stampfer, John Michael Gaziano, Howard D. Sesso, Barbara B. Cochrane, JoAnn E. Manson, Charles S. Fuchs, Brian M. Wolpin
Journal: Journal of Clinical Oncology (2017)

Purpose Cigarette smoking is associated with increased incidence of pancreatic cancer. However, few studies have prospectively evaluated the association of smoking with patient survival. Patients and Methods We analyzed survival by smoking status among 1,037 patients from two large US prospective cohort studies diagnosed from 1986 to 2013. Among 485 patients from four prospective US cohorts, we also evaluated survival by prediagnostic circulating levels of cotinine, a metabolite of nicotine that is proportional to tobacco smoke exposure. On the basis of prediagnosis cotinine levels, we classified patients as nonsmokers (&lt; 3.1 ng/mL), light smokers (3.1-20.9 ng/mL), or heavy smokers (≥ 21.0 ng/mL). We estimated hazard ratios (HRs) for death by using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, body mass index, diabetes status, diagnosis year, and cancer stage. Results The multivariable-adjusted HR for death was 1.37 (95% CI, 1.11 to 1.69) comparing current smokers with never smokers ( P = .003). A statistically significant negative trend in survival was observed for increasing pack-years of smoking ( P trend = .008), with HR for death of 1.49 (95% CI, 1.05 to 2.10) for &gt; 60 pack-years of smoking versus never smoking. Survival among former smokers was similar to that for never smokers, regardless of time since quitting. Heavy smokers defined by prediagnostic circulating cotinine levels had a multivariable-adjusted HR for death of 1.76 (95% CI, 1.23 to 2.51) compared with nonsmokers. Among patients with circulating cotinine levels measured within 5 years before diagnosis, heavy smokers had a multivariable-adjusted HR for death of 2.47 (95% CI, 1.24 to 4.92) compared with nonsmokers. Conclusion Cigarette smoking was associated with a reduction in survival among patients with pancreatic cancer.
Long-term survival in primary glioblastoma revisited: The contribution of isocitrate dehydrogenase mutations.
Authors: Michael Weller, Bettina Hentschel, Matthias Simon, Manfred Westphal, Gabriele Schackert, Joerg Christian Tonn, Markus Loeffler, Guido Reifenberger, Torsten Pietsch, Andreas von Deimling, Christian Hartmann
Journal: Journal of Clinical Oncology (2013)

2027 Background: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in WHO grade 2/3 gliomas, but rare in primary glioblastomas, and associated with longer survival. Methods: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival &gt; 36 months (LTS-36), including 33 patients surviving &gt; 60 months (LTS-60), with 259 patients surviving &lt; 36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations and IDH1/2mutations were determined by standard techniques. Results: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23/67 patients) as opposed to 4.3% in controls (11/257 patients). Long-term survivors with IDH1/2 -mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Among LTS-36 patients, wild-type TP53 status, MGMT promoter methylation, and absence of EGFR amplification, but not IDH1/2 mutation, were associated with prolonged survival. Among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had been treated initially with radiotherapy alone and had TP53 mutations less frequently. Conclusions: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade 2/3 gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.
Effect of multidisciplinary tumor conference on clinical management of rectal cancer.
Authors: Georgios Karagkounis, Luca Stocchi, Ian C. Lavery, David Liska, Emre Gorgun, Sudha Amarnath, Alok A. Khorana, Matthew Kalady
Journal: Journal of Clinical Oncology (2017)

749 Background: Presentation of rectal cancer cases at a multidisciplinary tumor conference (MTC) is a required standard for the newly formed National Accreditation Program for Rectal Cancer. However, its impact on clinical decision-making remains incompletely defined. Our aim was to determine the frequency and manner in which MTC changed the management of patients with rectal cancer at a tertiary academic center. Methods: All rectal cancer cases presented at the weekly Colorectal Cancer MTC between July 2015 and June 2016 at a single institution were prospectively included. Patient demographics and clinical information were recorded. The presenting physician completed a uniform written questionnaire outlining their plan before and after the MTC discussion, and any changes in management as a result of the discussion. Imaging and pathology were reviewed for each case at MTC and consistency with prior interpretation was recorded. Results: 234 unique initial rectal cancer cases were included. Survey responses were obtained for 212 cases (90.6%). The mean patient age was 58.3 years. 37 patients (15.8%) presented with Stage IV disease and 20 (9.4%) had locally recurrent cancer. There was a documented change in plan as a result of the MTC discussion in 70 of 212 (33%) cases surveyed, including 22 cases (10.4%) in which the presenting physician had a “definitive plan” prior to the MTC. Changes in management included a change in therapy or change in therapy sequence in 45 cases (64%), and recommendation of further evaluation in 26 cases (37%). Change in management following MTC did not vary by surgeon experience: it occurred in 31.4%, 37.2% and 29.8% of cases presented by surgeons with &lt; 10, 10-20, and ≥ 20 years of experience respectively (Chi-square p= 0.71). The imaging or pathology review at MTC resulted in a different interpretation than previously reported in 23% and 12% of cases, respectively. Conclusions: MTC changes clinical management for a significant portion of rectal cancer patients at a tertiary care center, independent of the presenting surgeons’ years of clinical experience. Our results highlight the utility of multidisciplinary rectal cancer care and support the MTC standard for the National Accreditation Program for Rectal Cancer.
GP numbers drop despite government pledge to boost workforce
Authors: Gareth Iacobucci
Journal: BMJ (2017)

General practice leaders have expressed alarm at new figures showing that the number of full time equivalent GPs in England fell by more than 400 in the last three months of 2016.

The new figures, from NHS Digital,1 also show a decrease in the overall GP head count in England between September and December 2016, despite pledges from government and NHS England to increase the workforce by 5000 GPs by 2020.2

GP leaders said that policymakers must start turning promises into action if the chronic decline in GP numbers is to be reversed.

The figures show that there were 34 050 full time equivalent (FTE) GPs, including registrars, locums, and retainers, as at …
Panobinostat, a novel histone deacetylase inhibitor, in advanced medullary and iodine-refractory differentiated thyroid cancer: A Wisconsin Oncology Network trial.
Authors: Anne M. Traynor, Glen E. Leverson, Diane F Elson, Hilary R Hernan, Martha M. Larson, Jules Harris Blank, Gilbert G Fareau, Kari Braun Wisinski, Ryan J. Mattison, Herbert Chen, Rebecca S Sippel
Journal: Journal of Clinical Oncology (2013)

e17025 Background: Histone deacetylase (HDAC) inhibitors suppress tumor cell proliferation in medullary thyroid cancer (MTC) and differentiated thyroid cancer (DTC) in vivo. We conducted a multicenter single arm phase II trial of panobinostat, a potent inhibitor of Class I, II, and IV HDAC enzymes, in MTC and radioactive iodine (RAI)-refractory DTC. Methods: We enrolled 13 patients (pts) with progressive metastatic MTC or RAI-refractory DTC. Panobinostat was given at 20 mg orally TIW until disease progression or intolerable toxicities. The primary objective was anti-tumor response rate; secondary objectives included overall survival (OS), progression-free survival (PFS), tolerability, and changes in serum thyroglobulin (Tg) concentration. Results: Mean age was 61±13 yrs; 7 pts were female. 11 pts had DTC; 2 had MTC. Median study follow-up was 11.8 months (mos). 9 pts required dose holds/reductions due to thrombocytopenia (n=7), hypocalcemia (n=3), neutropenia (n=2), diarrhea (n=1), bone pain (n=1), or asthenia (n=1). Due to protocol specified rules, 2 pts were withdrawn from therapy with thrombocytopenia or neutropenia, both asymptomatic. Of the 3 pts with ≥ grade 3 thrombocytopenia, 2 had no bleeding. The third pt continued to bleed from her chronically erosive tumor without exacerbation. Median duration of treatment was 2.1 mos (range, 0.8-11.8). Stable disease (SD) was seen in 7 pts, with a median duration of 5.8 mos (range,1.8-13.8). All 7 SD pts are currently alive, including 2 with SD 4.9 mo and 11.8 mo on treatment. Progressive disease (PD) occurred, and was the cause of death, in 6 pts.No anti-tumor responses were observed. Median PFS for the 13 pts was 3.6 mos (95% CI, 1.8-5.8), with 2 pts having a PFS longer than 6 mos.Median OS for the 13 pts was 18.4 mos (95% CI, 5.8-not estimable). 5 of 11 pts had reductions of their serum Tg on study; however, changes in serial Tg values did not distinguish PD from SD pts. Conclusions: 20 mg TIW was not tolerated by most pts. However, dose modified treatment yielded SD in half of our previously progressing pts. This promising disease stabilization warrants further evaluation, possibly in combination with a VEGFR TKI. Clinical trial information: NCT01013597.
Racial disparities in prostate cancer outcome among prostate-specific antigen screening eligible populations in the United States.
Authors: Brandon Arvin Virgil Mahal, Yu-Wei Chen, Vinayak Muralidhar, Amandeep R. Mahal, Toni K. Choueiri, Karen E. Hoffman, Jim C. Hu, Christopher Sweeney, Clair Beard, Neil E. Martin, Felix Yi-Chung Feng, Simon P. Kim, James B. Yu, Quoc-Dien Trinh, Paul L. Nguyen
Journal: Journal of Clinical Oncology (2017)

18 Background: In 2012, the United States Preventive Services Task Force (USPSTF) recommended against Prostate-Specific Antigen (PSA) screening, despite evidence that Black men are at a higher risk of prostate cancer-specific mortality (PCSM). We evaluated whether Black men of potentially screening-eligible age (55-69) are at a disproportionally high risk of poor outcomes. Methods: The SEER database was used to study 390,259 men diagnosed with prostate cancer in the United States between 2004-2011. Multivariable logistic regression modeled the association between Black race and stage of presentation, while Fine-Gray competing risks regression modeled the association between Black race and PCSM, both as a function of screening eligibility (age 55-69 vs not). Results: Black men were more likely to present with metastatic disease (adjusted odds ratio [AOR] 1.65; 1.58-1.72; P&lt; 0.001) and were at a higher risk of PCSM (adjusted hazard ratio [AHR] 1.36; 1.27-1.46; P&lt; 0.001) compared to Non-Black men. There were significant interactions between race and PSA-screening eligibility such that Black patients experienced more disproportionate rates of metastatic disease (AOR 1.76; 1.65-1.87 vs. 1.55; 1.47-1.65; P interaction &lt; 0.001) and PCSM (AHR 1.53; 1.37-1.70 vs. 1.25; 1.14-1.37; P interaction = 0.01) in the potentially PSA-screening eligible group than in the group not eligible for screening. Conclusions: Racial disparities in prostate cancer outcome among Black men in are significantly worse in PSA-screening eligible populations. These results raise the possibility that Black men could be disproportionately impacted by recommendations to end PSA screening in the United States and suggest that Black race should inform clinical decisions on PSA screening.
Relationship of microRNA expression profiles and recurrence in advanced serous ovarian carcinoma.
Authors: Eun Ji Nam, Ga Won Yim, Jae Hoon Kim, Sunghoon Kim, Sang Wun Kim, Jae-Wook Kim, Young-Tae Kim
Journal: Journal of Clinical Oncology (2013)

5557 Background: Most patients with epithelial ovarian cancer eventually succumb to chemo-resistant disease. Although microRNAs have been recognized as important regulators of gene expression, little is known about microRNA expression profiles in recurrent serous ovarian carcinoma. We assessed the microRNA expression profiles which contribute to recurrence in advanced serous ovarian carcinoma. Methods: Eight pairs of primary and recurrent tumor samples from 8 patients with advanced serous ovarian carcinoma and 4 normal ovarian samples from patients treated for benign uterine disease between May 2006 and Dec 2012 were examined using miRNA microarray. microRNA profiling were validated using real-time reverse transcription-polymerase chain reaction (RT-PCR). Results: Alterations of microRNA expression profiles in primary and recurrent tumor samples have similar patterns when compared with normal ovarian tissues. Among 31 up-regulated microRNAs more than 4-fold in primary tumors, 27 microRNAs were also significantly up-regulated in recurrent tumor samples. Likewise, Among 35 down-regulated microRNAs more than 4-fold in primary tumors, 34 microRNAs were also significantly down-regulated in recurrent tumor samples. Comparing to primary tumor, we found 60 microRNAs which were significantly up-regulated, including miR-630, 370, and 575, and 52 microRNAs which were significantly down-regulated, including miR-509-3p, 514a-3p, and 506-3p in recurrent serous ovarian carcinoma. Conclusions: Our results indicate that dysregulation of microRNAs may play a role in recurrence of serous ovarian carcinoma.
Multivariate prospective pharmacogenetic analysis in patients with resectable metastatic colorectal cancer (mCRC) receiving FOLFOX chemotherapy.
Authors: Marie-Christine Etienne-Grimaldi, Mohamed Hebbar, Aimery De Gramont, Benoist Chibaudel, Thierry André, Patricia Formento, Laurence Llorca, Alexandra Hadengue, Laurent Mineur, Ahmed Khalil, Jean Luc Dutel, Marc Ychou, May Mabro, Denis Michel Smith, Roger Faroux, David Brusquant, Stephanie Truant, Francois Paye, Dominique Auby, Gerard Milano
Journal: Journal of Clinical Oncology (2014)

3569 Background: To prospectively test the predictive value of gene polymorphisms related to fluorouracil (FU) and oxaliplatin (Oxa) pharmacodynamics in mCRC patients receiving FOLFOX regimens. Methods: 205 mCRC patients out of 284 included in the MIROX trial (GERCOR group) were enrolled (67 women, 138 men; mean age 60). All received a FOLFOX regimen (FOLFOX4 for 104 patients, FOLFOX7 for 101 patients). Maximum toxicity (NCI-CTCAE) for each toxic pattern along with best response (RECIST criteria) were recorded. Polymorphisms of genes relevant for FU, thymidylate synthase (TYMS, 5’UTR repeats and 3’UTR deletion), dihydropyrimidine dehydrogenase (DPYD, IVS14+1 G>A), 5-10methylenetetrahydrofolate reductase (MTHFR, 677C>T and 1298A>C), and for Oxa, glutathione S-transferase pi (GSTP1, 105Ile>Val), xeroderma pigmentosum (ERCC2, 751Lys>Gln), were determined (blood). Results: 62% of patients presented at least a grade 3-4 (G3-4) toxicity (29.8% neutropenia, 22% digestive toxicity (nausea/vomiting/diarrhea/mucositis)). Global toxicity, hematotoxicity and vomiting were significantly more frequent in women. Patients homozygous for the deficient MTHFR 1298C allele (favouring elevated methylenetetrahydrofolate concentrations) had a significantly higher risk of developing G3-4 neutropenia as compared to others (OR 3.1, 95%CI 1.1-8.6, adjusted on gender), and tended to present a greater risk of digestive toxicity (OR 2.4, 95%CI 0.9-7.0). Patients with ERCC2 751Lys/Gln or Gln/Gln genotype had a greater global toxicity as compared to others (OR 2.30, 95%CI 1.25-4.24, adjusted on gender), and a greater digestive toxicity (OR 2.35, 95%CI 1.1-5.1, adjusted on gender). Among the 3 patients with DPYD mutation (heterozygous) only 2 developed G3-4 toxicity. Response (51.8% CR+PR) was significantly lower in MTHFR 677TT patients relative to others (OR 0.16, 95%CI 0.05-0.52). ERCC2 751Lys/Gln+Gln/Gln genotype tended to be associated with longer DFS relative to Lys/Lys (RR 0.74, 95%CI 0.51-1.07). Conclusions: Present data confirm previous findings showing that toxicity and response to FOLFOX therapy may be driven by MTHFR germinal polymorphisms. Clinical trial information: NCT00268398.