Citations

It is widely accepted that traditional models of clinical investigation are becoming unsustainable in oncology and that trials must become more efficient in matching effective treatments to the patients most likely to benefit. In 2008, gastrointestinal oncologists from many countries began a collaboration to improve the design and conduct of clinical trials in their field, through the auspices of a French/U.S. charitable foundation, ARCAD. Whether this model of academic collaboration will be judged a success will depend on the quality of its scientific output during the next few years and whether this output, alongside that of other scientists, groups, and institutions, ultimately leads to more efficient trials and improved treatment options for patients.

Secondary, radiation-induced neoplasms represent a significant long-term risk after radiation treatment, and radiation-induced sarcomas (RAS) have an especially poor prognosis. These have rarely been reported after irradiation for pituitary adenomas.

Assistive equipment has helped lower task demands and back stress for patient-handlers; however, limited research exists on the psychological benefits (i.e., safety and comfort) of self-transfer devices for patients in postoperative care. A study was conducted to determine the efficacy of a bed assistive device in a patient population; the objectives were to compare self-perceived recovery measures and usage of pain medication between patients in the Control ( n = 8; age, 34 ± 6.3years) and Device ( n = 7; 41 ± 12) groups. Fifteen female participants undergoing either abdominal hysterectomy ( n = 6) or Cesareansection ( n = 9) procedures were recruited for the study. Both groups completed a total of twelve questionnaires over a five-week recovery period. The Device Group reported higher levels of energy, less pain interference, lower perceived pain, less reliance on pain medication and returned to activities of daily living faster than the Control Group.

Abstract Ischemic stroke (IS) is among the leading causes of death in Western countries. There is a significant genetic component to IS susceptibility, especially among young adults. To date, research to identify genetic loci predisposing to stroke has met only with limited success. We performed a genome-wide association (GWA) analysis of early-onset IS to identify potential stroke susceptibility loci. The GWA analysis was conducted by genotyping 1 million SNPs in a biracial population of 889 IS cases and 927 controls, ages 15–49 years. Genotypes were imputed using the HapMap3 reference panel to provide 1.4 million SNPs for analysis. Logistic regression models adjusting for age, recruitment stages, and population structure were used to determine the association of IS with individual SNPs. Although no single SNP reached genome-wide significance (P < 5 × 10−8), we identified two SNPs in chromosome 2q23.3, rs2304556 (in FMNL2; P = 1.2 × 10−7) and rs1986743 (in ARL6IP6; P = 2.7 × 10−7), strongly associated with early-onset stroke. These data suggest that a novel locus on human chromosome 2q23.3 may be associated with IS susceptibility among young adults.

Purpose Symptoms and complications of metastatic colorectal cancer (mCRC) differ by metastatic sites. There is a paucity of prospective survival data for patients with peritoneal carcinomatosis colorectal cancer (pcCRC). We characterized outcomes of patients with pcCRC enrolled onto two prospective randomized trials of chemotherapy and contrasted that with other manifestations of mCRC (non-pcCRC). Methods A total of 2,095 patients enrolled onto two prospective randomized trials were evaluated for overall survival (OS) and progression-free survival (PFS). A Cox proportional hazard model was used to assess the adjusted associations. Results The characteristics of the pcCRC group (n = 364) were similar to those of the non-pcCRC patients in median age (63 v 61 years, P = .23), sex (57% males v 61%, P = .23), and performance status (Eastern Cooperative Oncology Group performance status 0 or 1 94% v 96%, P = .06), but differed in frequency of liver (63% v 82%, P < .001) and lung metastases (27% v 34%, P = .01). Median OS (12.7 v 17.6 months, hazard ratio [HR] = 1.3; 95% CI, 1.2 to 1.5; P < .001) and PFS (5.8 v 7.2 months, HR = 1.2; 95% CI, 1.1 to 1.3; P = .001) were shorter for pcCRC versus non-pcCRC. The unfavorable prognostic influence of pcCRC remained after adjusting for age, PS, liver metastases, and other factors (OS: HR = 1.3, P < .001; PFS: HR = 1.1, P = .02). Infusional fluorouracil, leucovorin, and oxaliplatin was superior to irinotecan, leucovorin, and fluorouracil as a first-line treatment among pcCRC (HR for OS = 0.62, P = .005) and non-pcCRC patients (HR = 0.66, P < .001). Conclusion pcCRC is associated with a significantly shorter OS and PFS as compared with other manifestations of mCRC. Future trials for mCRC should consider stratifying on the basis of pcCRC status.

Abstract Background and Aims: Cancer and Leukemia Group B 80303 was a randomized, phase III study in patients with advanced pancreatic cancer treated with gemcitabine plus either bevacizumab or placebo. We prospectively collected germline DNA and conducted a genome-wide association study (GWAS) using overall survival (OS) as the endpoint. Experimental Design: DNA from 351 patients was genotyped for more than 550,000 single-nucleotide polymorphisms (SNP). Associations between OS and SNPs were investigated using the log-linear 2-way multiplicative Cox proportional hazards model. The subset of 294 genetically European patients was used for the primary analysis. Results: A nonsynonymous SNP in interleukin (IL)17F (rs763780, H161R) and an intronic SNP in strong linkage disequilibrium (rs7771466) were associated with OS using genome-wide criteria (P ≤ 10−7). Median OS was significantly shorter (P = 2.61 × 10−8) for the rs763780 heterozygotes [3.1 months; 95% confidence interval (CI), 2.3–4.3] than for the patients without this variant (6.8 months; 95% CI, 5.8–7.3). After adjustment by stratification factors, the P value for the association was 9.51 × 10−7. Conclusions: The variant 161R form of IL-17F is a natural antagonist of the antiangiogenic effects of wild-type 161H IL-17F, and angiogenesis may play an important role in the metastatic spread of pancreatic cancer. In this preliminary study, we hypothesize that the angiogenetic potential of pancreatic cancers in patients with variant IL-17F is higher than that of tumors in patients with wild-type IL-17F, conferring worse prognosis. This exploratory GWAS may provide the foundation for testing the biology and clinical effects of novel genes and their heritable variants through mechanistic and confirmatory studies in pancreatic cancer. Clin Cancer Res; 18(2); 577–84. ©2011 AACR.

AbstractBackgroundCholangiocarcinomas (CCAs) are highly desmoplastic neoplasms with a tumour microenvironment plentiful in myofibroblasts (MFBs).MFB‐derivedPDGF‐BBsurvival signalling is a mediator ofCCAcell resistance to apoptotic stimuli. This raises the concept that targetingPDGFR‐β, a cognate receptor ofPDGF‐BB, represents a potential strategy for the treatment of humanCCA.AimsHerein, we examine a role for inhibitingPDGFR‐β in restoringCCAcell sensitivity to apoptotic stimuliin vitroandin vivo.MethodsWe employed humanCCAsamples from 41 patients (19 intrahepatic and 22 extrahepaticCCAsamples), the humanCCAcell linesKMCH‐1 andHUCCT‐1 as well as shPDGFR‐β‐KMCH‐1 and human myofibroblasticLX‐2 cells for these studies.In vivo‐experiments were conducted using a syngeneic rat orthotopicCCAmodel.ResultsOf severalMFB‐derived growth factors profiled,PDGF‐BBandCTGFwere most abundantly expressed; however, onlyPDGF‐BBattenuated tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) cytotoxicity. Co‐culturingCCAcells withPDGF‐BB‐secretingMFBs significantly decreasedTRAIL‐inducedCCAcell apoptosis when compared with monoculture conditions; this cytoprotective effect was abrogated in the presence of the tyrosine kinase inhibitors imatinib mesylate or linifanib, which inhibitPDGFR‐β. Consistent with these findings,MFB‐imparted cytoprotection also was abolished whenPDGFR‐β was knocked down as demonstrated in shPDGFR‐β‐KMCH‐1 cells. Finally, administration of imatinib mesylate increasedCCAcell apoptosis and reduced tumour growth in a rodentin vivo‐CCAmodel that mimics the human disease.ConclusionsTargetingPDGFR‐β sensitizesCCAcells to apoptotic stimuli and appears to be therapeuticin vivo.

Background Based on changes in core physical therapy documents and problems with the earlier version, the Physical Therapist Clinical Performance Instrument (PT CPI): Version 1997 was revised to create the PT CPI: Version 2006. Objective The purpose of this study was to validate the PT CPI: Version 2006 for use with physical therapist students as a measure of clinical performance. Design This was a combined cross-sectional and prospective study. Methods A convenience sample of physical therapist students from the United States and Canada participated in this study. The PT CPI: Version 2006 was used to collect CPI item–level data from the clinical instructor about student performance at midterm and final evaluation periods in the clinical internship. Midterm evaluation data were collected from 196 students, and final evaluation data were collected from 171 students. The students who participated in the study had a mean age of 24.8 years (SD=2.3, range=21–41). Sixty-seven percent of the participants were from programs in the United States, and 33% were from Canada. Results The PT CPI: Version 2006 demonstrated good internal consistency, and factor analysis with varimax rotation produced a 3-factor solution explaining 94% of the variance. Construct validity was supported by differences in CPI item scores between students on early compared with final clinical experiences. Validity also was supported by significant score changes from midterm to final evaluations for students on both early and final internships and by fair to moderate correlations between prior clinical experience and remaining course work. Limitations This study did not examine rater reliability. Conclusion The results support the PT CPI: Version 2006 as a valid measure of physical therapist student clinical performance.

Object The management of incidental small unruptured intracranial aneurysms (UIAs) is controversial and many factors need to be considered in the decision-making process. The authors describe a large consecutive series of patients harboring small incidental intracranial aneurysms. Treatment strategy, natural history, complications, and short-term outcomes are presented. Methods Between January 2008 and May 2011, the authors prospectively evaluated 212 patients with 272 small (< 10-mm) incidental aneurysms. Treatment recommendations (observation, endovascular treatment, or surgery), complications of treatment, and short-term outcomes were assessed. Results Recommended treatment consisted of observation in 125 patients, endovascular embolization in 64, and surgery in 18. Six patients were excluded from further analysis because they underwent treatment elsewhere. In the observation group, at a mean follow-up of 16.7 months, only 1 patient was moved to the embolization group. Seven (6%) of the 125 patients in the observation group died of causes unrelated to aneurysm. Sixty-five patients underwent 69 embolization procedures. The periprocedural permanent morbidity and mortality rates in patients undergoing endovascular treatment were 1.5% and 1.5%, respectively (overall morbidity and mortality rate 3.0%). In the surgery group no periprocedural complications were observed, although 1 patient did not return to her previous occupation. No aneurysmal rupture was documented in any of the 3 treatment groups during the follow-up period. Conclusions A cautious and individualized approach to incidental UIAs is of utmost importance for formulation of a safe and effective treatment algorithm. Invasive treatment (either endovascular or surgery) can be considered in selected younger patients, certain “higher-risk” locations, expanding aneurysms, patients with a family history of aneurysmal hemorrhage, and in those who cannot live their lives knowing that they harbor the UIA. Although the complication rate of invasive treatment is very low, it is not negligible. The study confirms that small incidental UIAs deemed to be not in need of treatment have a very benign short-term natural history, which makes observation a reasonable approach in selected patients.