Citations

SummaryReliable clinical or molecular predictors of benefit from azacitidine therapy in patients with myelodysplastic syndromes (MDS) are not defined. Doubling of platelet count at start of second cycle of azacitidine therapy compared to baseline was associated with achieving response and survival advantage in a Dutch cohort. To validate this observation, we analysed a larger cohort of North American patients, whose data was collected in a prospective clinical trial with a longer median follow‐up. We found a significant association between platelet count doubling after first cycle of azacitidine therapy and probability of achieving objective response. Among patients with MDS or oligoblastic acute myeloid leukaemia (<30% bone marrow blasts, n = 102), there was a statistically significant reduction in risk of death for patients who achieved platelet count doubling (n = 23, median OS, 21·0 months) compared to those who did not (n = 79, median OS, 16·7 months, adjusted hazard ratio (no/yes)=1·88, 95% confidence interval, 1·03–3·40, P = 0·04). Nonetheless, the addition of this platelet count doubling variable did not improve the survival prediction provided by the revised International Prognostic Scoring System or the French Prognostic Scoring System. Identification of reliable and consistent predictors for clinical benefit for azacitidine therapy remains an unmet medical need and a top research priority.

Introduction Hepatocellular carcinoma (HCC) is an important but infrequent outcome in primary biliary cirrhosis (PBC). Improved risk evaluation is an important goal for stratified surveillance. Methods Risk-factor analysis of the ‘Global PBC Study Group’ comprising 15 centres across North America and Europe spanning >40-years follow-up was performed using Cox proportional hazards model, logistic regression and Kaplan-Meier estimates (SPSSv21). Results Of 3546 patients with PBC (med. follow-up 8.6 yrs; IQR 4.4–14.1), 131 developed HCC. Excluding those who developed HCC within 12 months of PBC diagnosis (n = 23), median time to HCC was 12.7 yrs (6.9–16.8) and subsequent survival 1.1 yrs. (0.2–2.7). At diagnosis, factors associated with HCC development were male gender (adj. HR: 4.4;1.4–12.2, p = 0.014) and thrombocytopenia (adj. HR: 4.5;1.4–14.8, p = 0.012). Use of ursodeoxycholic acid per-se was not associated with future risk of HCC, but stratification of risk by biochemical response at 12 months was effective by Rotterdam (adj. HR: 8.9;2.1–37.3, P = 0.003), Paris-I (adj. HR: 7.6;2.0–29.0, p = 0.003) or Toronto criteria (HR: 5.6;1.6–18.8, P = 0.006). Five (4.6 vs. 0.2%) and 10-year (13%vs.1.9%) HCC incidence was significantly increased for biochemical non-responders (p = 2.2 × 10 –9 ), and by multivariate analysis non-response remained the only significant risk factor. Conclusion Our uniquely powered cohort allows robust demonstration that 12-month biochemical non-response is associated with an increased risk of developing HCC in PBC. Routine surveillance in those achieving biochemical response is unlikely cost-effective. Disclosure of Interest None Declared.

Background Expansion of the endovascular and surgical workforce in the USA might lead to carotid revascularization procedures being carried out at low volume centers. Objective To evaluate trends in the treatment of carotid stenosis at high volume centers in the USA and compare outcomes by hospital volume. Methods Using the Nationwide Inpatient Sample, we evaluated trends in the proportion of carotid revascularization procedures performed at high volume centers in the USA from 2005 to 2011. High volume was defined as combined endarterectomy/stenting volume ≥130 patients/year, carotid endarterectomy volume ≥117 cases/year and carotid stenting volume ≥38 cases/year. In-hospital mortality, discharge to a long-term facility, intracranial hemorrhage, and postoperative stroke rates were compared between high and low volume centers. Results A total of 181 972 patients were included in this study. Overall, 63 442 patients (34.9%) were treated at high volume centers. The proportion of patients treated at high volume carotid revascularization centers decreased from 38.3% in 2005–2006 to 30.2% in 2010–2011. The proportion of patients treated at high volume centers decreased from 35.7% to 30.0% for carotid endarterectomy (p<0.0001) and 45.2% to 35.1% for carotid stenting. Patients treated at low volume centers had significantly higher rates of discharge to a long-term facility than high volume center patients (6.3% vs 5.0%, p<0.0001). The same was true for endarterectomy patients (6.0% vs 4.7%, p<0.0001) and stenting patients (8.3% vs 6.5%, p<0.0001). Conclusions A trend toward a lower proportion of patients with carotid stenosis being treated in high volume centers from 2005 to 2011 is concerning as these high volume centers had lower complication rates.

Abstract Purpose: We examined the prognostic impact of specific KRAS mutations in patients with stage III colon adenocarcinoma receiving adjuvant FOLFOX alone or combined with cetuximab in a phase III trial (N0147). Analysis was restricted to BRAF–wild-type tumors, because BRAF mutation was associated with poor prognosis, and BRAF and KRAS mutations are mutually exclusive. Experimental Design: The seven most common KRAS mutations in codon 12 and codon 13 were examined in 2,478 BRAF–wild-type tumors. Because KRAS mutations in codon 12 (n = 779) or 13 (n = 220) were not predictive of adjuvant cetuximab benefit, study arms were pooled for analysis. Disease-free survival (DFS) was evaluated by HRs using Cox models. Results: KRAS mutations in codon 12 (multivariate HR, 1.52; 95% confidence interval, CI, 1.28–1.80; P &lt; 0.0001) or codon 13 (multivariate HR, 1.36; 95% CI, 1.04–1.77; P = 0.0248) were significantly associated with shorter DFS compared with patients with wild-type KRAS/BRAF tumors, independent of covariates. KRAS codon 12 mutations were independently associated with proficient mismatch repair (P &lt; 0.0001), proximal tumor site (P &lt; 0.0001), low grade, age, and sex, whereas codon 13 mutations were associated with proximal site (P &lt; 0.0001). Conclusion: KRAS mutations in either codon 12 or 13 are associated with inferior survival in patients with resected stage III colon cancer. These data highlight the importance of accurate molecular characterization and the significant role of KRAS mutations in both codons in the progression of this malignancy in the adjuvant setting. Clin Cancer Res; 20(11); 3033–43. ©2014 AACR.

Object Historically, surgery to the petrous apex has been addressed via craniotomy and open microscopic anterior petrosectomy (OAP). However, with the popularization of endoscopic approaches, the petrous apex can further be approached endonasally by way of an endoscopic endonasal anterior petrosectomy (EAP). Endonasal anterior petrosectomy is a relatively new procedure and has not been compared anatomically with OAP. The authors hypothesized that the EAP and OAP techniques approach different portions of the petrous apex and therefore may have different applications. Methods Four cadaveric heads were used. An OAP was performed on one side and an EAP was performed on the contralateral side; the limits of bony resection were defined. The extent of bony resection was then evaluated using predissection and postdissection thin-slice CT scans. The comparative resection was then reconstructed using 3D modeling on Brainlab workstations. Results The average resection volumes for EAP and OAP were 0.297 cm 3 and 0.649 cm 3 , respectively, representing a comparative percentage of 46% (EAP/OAP). An EAP and OAP achieved resection of 29% and 64% of the total petrous apex volume, respectively. Indeed, EAP addressed the inferior portion of the petrous apex located adjacent to the petroclival suture more completely than OAP, where 45% of the bone overlying the petroclival suture (petroclival angle to the jugular foramen) was resected with the EAP, while 0% was resected with the OAP. Conclusions In anatomically normal cadavers, OAP achieved nearly a 50% larger volumetric resection than EAP. Furthermore, while OAP appears to completely address the superior portion of the petrous apex, EAP appears to have a niche in approaches to lesions in the inferior petrous apex. Given these results, the authors propose that OAP be redefined as the “superior anterior petrosectomy,” while EAP be referred to as the “inferior anterior petrosectomy,” which more clearly defines the role of each approach in anterior petrosectomy.

Follicular thyroid carcinoma (FTC) exhibits frequent loss of heterozygosity (LOH) on chromosomes 10q and 3p, suggesting involvement of tumor suppressor genes. We screened 14 FTC (10 Hurthle cell carcinomas and 4 nonoxyphilic FTC), 14 papillary thyroid carcinomas, and 7 follicular adenomas for LOH on chromosome arms 1p, 3p, 3q, 10p, 10q, 11p, 11q, 13q, 17p, and 17q. LOH was more frequent in FTC than in follicular adenoma or papillary thyroid carcinoma. In FTC, rates of LOH on 3p (86%), 17p (72%), and 10q (57%) were higher than the average rate of LOH (33%; P &lt; 0.05). Most frequently involved were 3p21–25 and 17p13.1–13.3, the sites for the VHL (3p25–26) and p53 (17p13.1) tumor suppressors. We, therefore, characterized these genes by dideoxy fingerprinting and DNA sequencing. Two FTC had mutations in p53, but only 1 of these exhibited LOH at 17p. No VHL gene mutations were found. Thus, neither p53 nor VHL genes play a significant role in the pathogenesis of differentiated thyroid cancer. LOH on 17p, but not on 3p or 10q, was correlated with mortality. Accordingly, 3p and 10q LOH may represent early, and 17p LOH late, events in FTC development. The data suggest the presence of novel tumor suppressor genes on chromosomes 3p and 17p that may be important in the pathogenesis of FTC.

The acute ischemic strokes amenable to intraarterial therapy probably number no more than 20,000 per year in the United States. The future demand for intraarterial reperfusion techniques may change, but the fraction of patients who require intraarterial thrombolysis is currently rather low, and the number of neurointerventionists is adequate. Each hospital caring for patients with acute stroke will need to determine its own demand for intraarterial therapy and employ an adequate supply of qualified neurointerventionists available to meet demand. Comprehensive stroke centers are now being designated and hopefully will foster a rational, regionalized approach to the delivery of endovascular therapies for stroke.