tbuckley/cabot-search huggingface dataset:
The role of intensity modulated radiation therapy for locally advanced hypopharyngeal cancer after resection and ileocolic free flap reconstruction
Authors: C. H. Hsieh, Y. S. Leu, Y. F. Chang, H. C. Tai, M. Z. Huang, H. T. Hsiao, Y. C. Chang, Y. J. Chen
Journal: Journal of Clinical Oncology (2007)

16521 Background: To estimate the toxicity/efficacy of concurrent chemoradiation therapy (CCRT) and with different modalities for locally advanced hypopharyngeal carcinoma post ileocolic free flap reconstruction (ICFR). Methods: Between April 2003 and December 2006, 15 patients had enrolled and a total of 13 patients were treated for locally advanced hypopharyeal cancer after resection and ICFR. The majority in group was stage IVa and all were squamous cell histology. Five were treated with intensity modulated radiation therapy (IMRT)/chemotherapy (CT) and 8 were treated with the conventional radiotherapy (CRT)/CT, both to a median dose of 64.8 Gy. Two to three cycles of CT given concurrent with RT every 3 or 4 weeks of cisplatin, 15 mg/m2 i.v., D1–5, plus 5-FU, 750 mg/m2 continue infusion, D1–5. Two same regiment of CT had applied monthly after CCRT one month latter for all. Results: The mean survival was 33 months (range, 6–42 months). Two-year actuarial overall survival (OS), disease-free (DFS), locoregional progression-free (LRPF) and distant- metastases-free (DMF) rates of all were 74%, 67%, 83%, 83%, respectively. Comparing the IMRT and CRT group, two-year OS, DFS, LRP and DM rates were 67% vs. 62%, 75% vs. 63%, 75% vs. 87%, 100% vs. 75%, respectively. Except OS rate (p = 0.04), others were not statistically significant. In IMRT group, one left side lower neck failure was noted. In CRT group, one over flap and the other over level III of neck recurrent was noted. Speech ability above 70% in IMRT vs. CRT group were 4/5 (80%) vs. 4/8 (50%). Swallowing with solid diet in IMRT vs. CRT group were 3/5 (60%) vs.3/8 (37.5%). Grade III of dermatitis and mucositis for IMRT vs. CRT group were 40% vs. 100% and 20% vs. 87.5%. The median duration of post surgery to start CCRT and of CCRT were 33 days and 54 days. The interval from post-operation to start CCRT and of CCRT longer than median time would influence LRPF rate (p = 0.05). Conclusions: For locally advanced hypopharyngeal carcinoma post ICFR, IMRT results in lower toxicity, better speech, swallowing ability and superior treatment outcomes when compared with the CRT group. Prolong starting CCRT and extend CCRT time influence LRPF rate. No significant financial relationships to disclose.
The British Society of Gastroenterology
Authors: W P Small, C W Falconer, A N Smith, J P McManus, W Sircus
Journal: Gut (1971)

the Presidency of Professor A. A. Harper.The programme included the abstracts that follow and in addition symposia on 'Aetiology and epidemiology of carcinoma of the colon and rectum' and 'Ischaemic colitis', and a progress report by Professor E. L. Blair on 'Measurement of gastrointestinal hormones'.
P60 * WHY ANIMAL MODELS OF GENE THERAPY HAVE LET GLIOMA PATIENTS DOWN
Authors: T. C. Hirst, H. M. Vesterinen, S. Conlin, K. J. Egan, A. Antonic, A. L. McLean, M. R. Macleod, I. R. Whittle, R. Grant, P. M. Brennan, E. S. Sena
Journal: Neuro-Oncology (2014)

INTRODUCTION: The development of new therapeutics is often characterised by promising animal research that fails to translate into clinical efficacy; this holds for the development of gene therapy in glioma. We set out to test the hypothesis that this is because of limitations in the internal and external validity of studies reporting the use of gene therapy in rodent models of glioma. METHOD: We systematically identified studies testing gene therapy in rodent glioma models by searching three online databases. The number of animals treated and median survival were extracted and studies graded using a 9-point quality checklist. We calculated median survival ratios and used random effects meta-analysis to provide estimates of efficacy. We explored the effects of study design and quality and searched for evidence of publication bias. RESULTS: We found 194 publications using gene therapy in experimental glioma, describing 427 experiments involving 6366 animals. Overall, genetherapy improved median survival by 1.60 fold (95%CI 1.53-1.67). Study quality was low and the type of gene therapy did not account for observed differences in outcome. Study design characteristics accounted for a significant proportion of between-study heterogeneity and we observedsimilar findings in a subset of data limited to the most common genetherapy. CONCLUSION: As the dysregulation of key molecular pathways is characteristic of gliomas, gene therapy remains a promising treatment forglioma. Nevertheless, we have identified areas for improvement in conduct and reporting of such studies. Further work should focus on genes of interest in paradigms that recapitulate human disease. This may improve the translation of such therapies into the clinic.
ACCORD COPD I: Safety and tolerability of twice daily aclidinium bromide in COPD patients
Authors: Anthony D'Urzo, Barry Make, Edward Kerwin, Ludmyla Rekeda, Esther Garcia Gil, Cynthia Caracta, Brian Maurer
Journal: European Respiratory Journal (2011)

Introduction:  Aclidinium bromide is a long-acting muscarinic antagonist in development for COPD. Safety and tolerability of aclidinium 200 μg and 400 μg BID in moderate to severe COPD patients were assessed in this Phase III study.   Methods:  In this 12-week, double-blind study, COPD patients were randomised to aclidinium 200 μg, 400 μg, or placebo BID (1:1:1). Safety was assessed via adverse events (AEs), clinical laboratory measures, vital signs, and electrocardiograms (ECGs).   Results:  Baseline demographics were similar across treatment groups (N=561). The number (%) of patients with a treatment-emergent AE (TEAE) was comparable between aclidinium 400 μg, 200 μg, and placebo [85 (44.7), 93 (50.5), 97 (52.2), respectively]. COPD exacerbation was the most frequently reported TEAE in all groups (12.4%, placebo; 9.2%, 200 μg; 7.4%, 400 μg). Incidence of serious AEs was low (2.2%-4.3% for all groups). Incidence of potential anticholinergic AEs (eg, constipation and dry mouth) was low (n≤3) in both aclidinium groups and comparable to placebo. The most frequently reported AEs resulting in discontinuation were COPD exacerbation (n=7, placebo; n=4, 200 μg; n=1, 400 μg) and dyspnea (n=2 each, placebo and 400 μg). One patient in the aclidinium 400 μg group died due to metastatic lung cancer but this was not considered to be related to treatment. Changes from baseline in laboratory tests, vital signs, and ECGs, were similar across all groups.   Conclusions:  Aclidinium 200 μg and 400 μg BID were safe and well tolerated throughout this 12-week study with a low incidence of systemic anticholinergic adverse events, similar to placebo. There were no differences in safety profiles between the two aclidinium doses.
Comparison of radical surgery followed by adjuvant chemotherapy with radical surgery following neoadjuvant chemotherapy as initial treatment for patients with locally advanced thoracic esophageal squamous cell carcinoma.
Authors: Yasuhiro Tsubosa, Masahiro Niihara, Satoru Matsuda, Katsuhisa Ogi, Katsushi Takebayashi, Keisuke Kawamorita, Yusuke Onozawa, Tomoya Yokota, Takahiro Tsushima, Hirofumi Yasui, Keita Mori, Hiroshi Sato
Journal: Journal of Clinical Oncology (2015)

187 Background: Although radical surgery with neoadjuvant chemotherapy (NAC) is a standard therapy for locally advanced thoracic esophageal squamous cell carcinoma (ESCC) in response to the result of JCOG 9907 study in Japan, there was no significant difference in survival rate at adjuvant chemotherapy and neoadjuvant chemotherapy in cStage III at subanalysis. Methods: Consecutive patients histologically diagnosed with ESCC and planned to undergo radical surgery followed by adjuvant chemotherapy (ADJ) from September 2002 to April 2007 and radical surgery following NAC from May 2007 to December 2011 as initial treatment were eligible for this retrospective study. To select patients who could tolerate transthoracic esophagectomy, respiratory function, Eastern Cooperative Oncology Group performance status, and preoperative complications were considered. As adjuvant and neoadjuvant chemotherapy, cisplatin and 5-fluorouracil were administered every 3 weeks for 2 cycles (FP). Patient characteristics, 3-year overall survival (3yOS) and non complete resection rate were investigated. We analyzed in intent-to-treat analysis. Results: Ninety patients were included in ADJ group, 98 included in NAC group. No significant differences were observed in clinicopathological factors between ADJ group (cStage IB/II/III/IV=6/22/57/5) and NAC group (cStage IB/II/III/IV=10/28/52/8). In intention-to-treat analysis, there was no significant difference in 3yOS rate by ADJ group and NAC group (ADJ group, 67.2%; NAC group, 66.0%; p = 0.301). However, non complete resection rate was significantly higher for NAC group than for ADJ group {ADJ group, 16.7% (3/90); NAC group, 3.4% (14/98); p = 0.009}. In cStage III, non complete resection rate of ADJ group was 3.5% (2/57) and NAC group was 25% (13/52). In the patients with cStage III, NAC group had a tendency for 3yOS rate to be low rather than ADJ group (ADJ group, 66.3%; NAC group, 51.1%; p = 0.09). Conclusions: In cStage III advanced ESCC, FP as NAC may be insufficient and development of the more powerful NAC is desired.
Testicular lymphoma: improved outcome with early brief chemotherapy.
Authors: J M Connors, P Klimo, N Voss, R N Fairey, S Jackson
Journal: Journal of Clinical Oncology (1988)

We investigated the impact of early brief chemotherapy on the natural history of primary testicular lymphoma. We compared the outcome for patients seen before 1980--a group primarily managed with orchiectomy and regional radiation--with those seen from 1980 to 1986--a prospectively and consecutively gathered group who were offered brief chemotherapy in addition to standard orchiectomy and irradiation. The historical and study groups were similar in clinical characteristics. However, the chemotherapy group had a better relapse-free survival, 93% v 50% (P less than .02), and overall survival, 93% v 50% (P less than .02). With a median follow-up of 44 months in the chemotherapy group, it is clear that the use of early, brief chemotherapy strongly alters the natural history of testicular lymphoma by preventing relapses, the large majority of which occur early after regional therapy. We conclude that a program incorporating orchiectomy, early brief chemotherapy, and involved-field radiation therapy confers the following benefits on patients with primary testicular lymphoma: (1) laparotomy is not needed for staging; (2) relapses, including those in the opposite testicle and CNS, are largely prevented; and (3) toxicity can be kept to a modest level acceptable in elderly patients.
A retrospective analysis of tumor size (TS) as a continuous rather than discrete variable in advanced pancreatic cancer
Authors: N. C. Dhani, D. Tu, W. Parulekar, L. Seymour, M. J. Moore
Journal: Journal of Clinical Oncology (2009)

e15565 Background: Objective “response rate” (RR) dichotomizes patients into categories of “response” (complete or partial) and “non-response”. This ignores a lot of data captured within the trial on tumor size changes, and may miss clinically important effects on tumor growth may occur in the absence of a response. Analyzing TS as a continuous variable (TS-CV) has been suggested as a more robust indicator of efficacy. Methods: Tumor size data from 2 randomized controlled trials in advanced pancreatic cancer conducted by NCIC.CTG were analyzed; NCIC.PA1 randomized patients to BAY12–9566 (MMPI) or Gemcitabine (Gem) and demonstrated a large and significant survival (OS) benefit for Gem (6.7 vs 3.4 months), NCIC.PA.3 randomized patients to Gem ± Erlotinib and showed a modest OS benefit for the combination (HR =0.81). In PA1, an early interim analysis (IA) using absence of progression as the primary measure did not halt accrual. Measures of TS at baseline and 8 wks were transformed and represented as a logarithm of the sum of the longest diameters. The difference in logarithms (d-LTS) from baseline to 8 weeks was calculated to indicate change in tumor size. Groups were compared using Wilcoxon rank-sum test. Results: In PA1, TS was significantly decreased in the Gem arm (mean d-LTS 0.087 on MMPI vs. -0.066 on Gem; p&lt;0.0001), in keeping with the OS benefit (p&lt;0.001). The decrease was also significant in the interim analysis cohort (p=0.007) and this result would, if used, have halted accrual earlier. In PA3, for all patients, decrease in TS was significantly larger for the combination arm (mean d- LTS -0.148 on combination vs. -0.114 on Gem; p=0.04), consistent with the OS benefit (p=0.038). Analysis on the 1 st 130 patients yielded similar results (p=0.02) Conclusions: Tumor size changes may be a reasonable endpoint for screening efficacy trials in advanced pancreatic cancer. These results support further assessment of this alternate efficacy endpoint. No significant financial relationships to disclose.
Abstract P121: Comparative Effectiveness Study of the Diabetes Prevention Program in Families: Preliminary Results
Authors: Jennifer Wessel, Erin O'Kelly-Phillips, Kelly Palmer, Chandan Saha, Tamara Hannon, Aaron Carroll, David G Marrero
Journal: Circulation (2015)

The prevalence of gestational diabetes (GDM) is increasing substantially and currently affects up to 14% of pregnancies. As many as 70% of women with GDM will develop type 2 diabetes (T2D) in the next 10 years. Moreover as many as 40% of children exposed to in-utero diabetes will develop obesity and T2D. The Diabetes Prevention Program (DPP) is an evidence-based lifestyle intervention that has been shown to lower T2D risk by 58% in high-risk adults. Family based lifestyle interventions that target either children, parents or both have reported mixed results. We modified the DPP curriculum to use with families (DPPF) and recruited mothers with a history of GDM and their children 8-15 years old. We randomized n=130 families to test which method of delivering the DPPF (mothers only (M) or mothers and their children (M+C)) is more effective at lowering families T2D risk. Baseline characteristics of women were similar among each intervention group (n=65 M and n=65 M+C, respectively): age (38±8 vs 39±11, P=0.5), ethnicity (Black 55% vs 55%, White 20% vs 17%, Latino 20% vs 27%, other 5% vs 2%, P=0.6), body mass index (BMI, 37±8 vs 38±7, P=0.24), systolic blood pressure (SBP, 121±11 vs 122±13, P=0.8), diastolic blood pressure (DBP, 103±26 vs 105±21, P=0.6), HbA1c (5.6±0.4 vs 5.7±0.3, p=0.2). The majority of women self-reported low levels of physical activity (PA): moderate PA (2 days or less per week, 42% vs 26%, P=0.06) or vigorous PA (2 days or less per week, 38% vs 25%, P=0.1), and high levels of sedentary activities (3 or more hours per day, 49% vs 58%, P=0.2). For diet related obesogenic behaviors women self-reported high levels of eating meals while watching TV (3 days or more per week, 58% vs 74%, P=.06) and eating at restaurants (3 days or more per week, 28% vs 41%, P=0.1). Follow-up is ongoing and currently n=32 families have completed the 3-month follow-up. Preliminary analyses of mothers show decreases in HbA1c (-.01±.3 vs -.1±.2), SBP (-9.7±30 vs -3.1±8), DBP (-8±19 vs -1±9) but not BMI (0.07±1.6 vs 0.04±1.2); however results were not significantly different by intervention group.
Treatment-related deaths (TRD) in investigator-initiated cancer cooperative group trials: From the datasets of 44 studies (4,964 patients) by the Japan Clinical Oncology Group (JCOG)
Authors: K. Kanato, K. Nakamura, I. Saito, A. Takashima, Y. Tomii, H. Kaba, T. Shibata, H. Fukuda, A. Sato, Y. Shimada
Journal: Journal of Clinical Oncology (2009)

6632 Background: The proportion of Serious Adverse Events (SAE) including TRDs has a critical impact on choosing a new standard therapy as well as the efficacy of treatment in clinical trials. The proportion of TRD (%TRD) has been reported in a single clinical trial, but an overall % TRD in plural clinical trials has merely been evaluated so far. Methods: The JCOG trials which met both of the following criteria were included in this analysis: i) started after 1995 by 2008, ii) primary analysis was completed. In JCOG, attribution of all reported SAE are classified by Data and Safety Monitoring Committee into 5 categories (definite, probable, possible, unlikely, not related) according to causality to protocol treatment, and the death with causality judged as definite, probable, or possible is defined as TRD. The total number of any deaths and TRD were counted in all included trials and the incidences (%) of TRD were calculated. The association between %TRD and the following trial profiles was evaluated: arm (standard vs. testing), phase, modality and median survival time of each arm. Results: In total, 44 JCOG trials (67 arms) with 4,964 patients were included in the analysis. The number of all deaths and TRD were 2,974 and 60. Thus, the overall %TRD for all enrolled patients was 1.2% (95%CI, 0.9–1.6%), and %TRD among all deaths was 2.0% (95%CI, 1.5–2.6%). Major results of the association between %TRD and trial profiles are shown in the table. The later phase trials showed the lower %TRD, and the trials with shorter MST tended to have higher %TRD. Conclusions: When the trial is in earlier phase and includes more advanced disease, the trial should be planned and performed more carefully about minimization of patient risk. [Table: see text] No significant financial relationships to disclose.
Lesinurad in combination with allopurinol: results of a phase 2, randomised, double-blind study in patients with gout with an inadequate response to allopurinol
Authors: Fernando Perez-Ruiz, John S Sundy, Jeffrey N Miner, Matthew Cravets, Chris Storgard
Journal: Annals of the Rheumatic Diseases (2016)

Objectives To assess the efficacy and tolerability of lesinurad, an oral selective uric acid reabsorption inhibitor, in combination with allopurinol versus allopurinol alone in patients with gout and an inadequate response to allopurinol. Methods Patients (N=227) with an inadequate response to allopurinol, defined as serum urate (sUA) ≥6 mg/dL on ≥2 occasions ≥2 weeks apart despite ≥6 weeks of allopurinol, were randomised 2:1 to 4 weeks of double-blind treatment with lesinurad (200, 400 or 600 mg/day) or matching placebo in combination with their prestudy allopurinol dose (200–600 mg/day). Colchicine prophylaxis for gout flares was required. The primary end point was percent reduction from baseline sUA levels at 4 weeks. A pharmacokinetic substudy was also conducted. Safety was assessed throughout. Results Patients (n=208) received ≥1 dose of blinded medication. Lesinurad 200, 400 and 600 mg in combination with allopurinol produced significant mean percent reductions from baseline sUA of 16%, 22% and 30%, respectively, versus a mean 3% increase with placebo (p&lt;0.0001, all doses vs placebo). Similar results were observed in patients with mild or moderate renal insufficiency (estimated creatinine clearance 30 to &lt;90 mL/min). The incidence of ≥1 treatment-emergent adverse event was 46%, 48% and 54% with lesinurad 200, 400 and 600 mg, respectively, and 46% with placebo (most frequent, gout flares, arthralgia, headache and nasopharyngitis), with no deaths or serious adverse events. Conclusions Lesinurad achieves clinically relevant and statistically significant reductions in sUA in combination with allopurinol in patients who warrant additional therapy on allopurinol alone. Trial registration number NCT01001338.
Peeping at TOMs—Diverse Entry Gates to Mitochondria Provide Insights into the Evolution of Eukaryotes
Authors: Jan Mani, Chris Meisinger, André Schneider
Journal: Molecular Biology and Evolution (2015)

Mitochondria are essential for eukaryotic life and more than 95% of their proteins are imported as precursors from the cytosol. The targeting signals for this posttranslational import are conserved in all eukaryotes. However, this conservation does not hold true for the protein translocase of the mitochondrial outer membrane that serves as entry gate for essentially all precursor proteins. Only two of its subunits, Tom40 and Tom22, are conserved and thus likely were present in the last eukaryotic common ancestor. Tom7 is found in representatives of all supergroups except the Excavates. This suggests that it was added to the core of the translocase after the Excavates segregated from all other eukaryotes. A comparative analysis of the biochemically and functionally characterized outer membrane translocases of yeast, plants, and trypanosomes, which represent three eukaryotic supergroups, shows that the receptors that recognize the conserved import signals differ strongly between the different systems. They present a remarkable example of convergent evolution at the molecular level. The structural diversity of the functionally conserved import receptors therefore provides insight into the early evolutionary history of mitochondria.
Phase Ib study of mapatumumab in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC) and chronic viral hepatitis.
Authors: W. Sun, D. Nelson, S. R. Alberts, F. Poordad, S. Leong, U. R. Teitelbaum, L. Woods, N. Fox, B. H. O'Neil
Journal: Journal of Clinical Oncology (2011)

261 Background: Mapatumumab is a fully human agonist monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1). Sorafenib targets Mcl-1, a key TRAIL resistance protein, and accordingly could enhance mapatumumab's pro-apoptotic activity. Based on this and on preclinical data on mapatumumab in HCC cell lines, the current dose-escalation study is evaluating mapatumumab in combination with sorafenib in patients with advanced HCC. Methods: Eligible patients had advanced HCC, Child-Pugh A or Model for End-Stage Liver Disease score &lt; 15, and were positive for hepatitis B surface antigen or hepatitis C antibody. Intravenous mapatumumab was administered at 3, 10 or 30 mg/kg every 21 days with sorafenib (400 mg twice daily) until disease progression or unacceptable toxicity. Dose-limiting toxicities (DLTs) included events considered at least possibly related to mapatumumab and/or its interaction with sorafenib. Tumor measurements were performed every 2 cycles. Dose escalation required at least 3 patients in a cohort to receive &gt;= 50% of full-dose sorafenib in the first 2 cycles. Results: To date, 19 patients have been enrolled in the 3 mg/kg (n=6), 10 mg/kg (n=9) and 30 mg/kg (n=4) cohorts and have received a median of 4 cycles (range 1 to 24 cycles); 4 patients have received &gt;= 11 cycles. The maximum tolerated dose has not been reached. DLTs that prompted expansion of the 3 mg/kg and 10 mg/kg cohorts were elevations of amylase and/or lipase (1 at 3 mg/kg, 1 at 10 mg/kg). Other Grade 3-4 events considered at least possibly related to mapatumumab and/or its interaction with sorafenib included hepatic pain (1/17), thrombocytopenia (1/17), increased aspartate aminotransferase (1/17), increased lipase (1/17), and increased gamma-glutamyltransferase (1/17). Two patients have had a partial response and 4 patients have had stable disease lasting &gt; 12 weeks, based on investigator assessment. Conclusions: Mapatumumab was well-tolerated at doses up to 30 mg/kg in combination with sorafenib in patients with HCC and viral hepatitis. A randomized phase II study of this combination in patients with advanced HCC is planned. [Table: see text]