Citations

Background and objective Survival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma. Methods We analysed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (p≤10 −5 ) were advanced to a joint analysis with 363 additional patients from China (ChinaPC). Results In the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21 and 1p36.13, tagged by rs12362504 (p=1.63×10 −7 ), rs981621 (p=1.65×10 −7 ) and rs16861827 (p=3.75×10 −7 ), respectively. 131 SNPs with p≤10 −5 were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; p=1.72×10 −7 ) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The HR (95% CI) for death was 0.74 (0.66 to 0.84) in PanScan I, 0.79 (0.65 to 0.97) in ChinaPC and 0.76 (0.68 to 0.84) in the joint analysis. Conclusions Germline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.

Object The goal of vestibular schwannoma surgery is tumor removal and preservation of neural function. Intraoperative facial nerve (FN) monitoring has emerged as the standard of care, but its role in predicting long-term facial function remains a matter of debate. The present report seeks to describe and critically assess the value of applying current at supramaximal levels in an effort to identify patients destined for permanent facial paralysis. Methods Over more than a decade, the protocol for stimulating and assessing the FN during vestibular schwannoma surgery at the authors' institution has consisted of applying pulsed constant-current stimulation at supramaximal levels proximally and distally following tumor resection to generate an amplitude ratio, which subtracted from 100% yields the degree to which the functional integrity of the FN “dropped off” intraoperatively. These data were prospectively collected and additional variables that might impact postoperative FN function were retrospectively reviewed from the medical record. Only patients with anatomically intact FNs and > 12 months of follow-up data were analyzed. Results There were 267 patients available for review. The average posterior fossa tumor diameter was 24 mm and the rate of long-term good (House-Brackmann Grade I–II) FN function was 84%. Univariate logistic regression analysis revealed that prior treatment, neurofibromatosis Type 2 status, tumor size, cerebellopontine angle extension, subjectively thinned FN at the time of operation, minimal stimulation threshold, percent dropoff by supramaximal stimulation (SMS), and postoperative FN function all correlated statistically (p < 0.05) with long-term FN function. When evaluating patients with significant FN weakness at the time of hospital discharge, only the percent dropoff by SMS remained a significant predictor of long-term FN function. However, the positive predictive value of SMS for long-term weakness is low, at 46%. Conclusions In a large cohort of patients, the authors found that interrogating intraoperative FN function with SMS is safe and technically simple. It is useful for predicting which patients will ultimately have good facial function, but is very limited in identifying patients destined for long-term facial weakness. This test may prove helpful in the future in tailoring less than gross-total tumor removal to limit postoperative facial weakness.

Background— Type 2 long QT syndrome involves mutations in the human ether a-go-go–related gene ( hERG or KCNH2 ). T421M, an S1 domain mutation in the Kv11.1 channel protein, was identified in a resuscitated patient. We assessed its biophysical, protein trafficking, and pharmacological mechanisms in adult rat ventricular myocytes. Methods and Results— Isolated adult rat ventricular myocytes were infected with wild-type (WT)–Kv11.1– and T421M-Kv11.1–expressing adenovirus and analyzed with the use of patch clamp, Western blot, and confocal imaging techniques. Expression of WT-Kv11.1 or T421M-Kv11.1 produced peak tail current ( I Kv11.1 ) of 8.78±1.18 and 1.91±0.22 pA/pF, respectively. Loss of mutant I Kv11.1 resulted from (1) a partially trafficking-deficient channel protein with reduced cell surface expression and (2) altered channel gating with a positive shift in the voltage dependence of activation and altered kinetics of activation and deactivation. Coexpression of WT+T421M-Kv11.1 resulted in heterotetrameric channels that remained partially trafficking deficient with only a minimal increase in peak I Kv11.1 density, whereas the voltage dependence of channel gating became WT-like. In the adult rat ventricular myocyte model, both WT-Kv11.1 and T421M-Kv11.1 channels responded to β-adrenergic stimulation by increasing I Kv11.1 . Conclusions— The T421M-Kv11.1 mutation caused a loss of I Kv11.1 through interactions of abnormal protein trafficking and channel gating. Furthermore, for coexpressed WT+T421M-Kv11.1 channels, different dominant-negative interactions govern protein trafficking and ion channel gating, and these are likely to be reflected in the clinical phenotype. Our results also show that WT and mutant Kv11.1 channels responded to β-adrenergic stimulation.

Object The goals of this retrospective cohort study were as follows: 1) to describe the long-term prevalence and timing of hearing deterioration following low-dose (12- to 13-Gy marginal dose) stereotactic radiosurgery (SRS) for vestibular schwannoma (VS); and 2) to identify clinical variables associated with long-term preservation of useful hearing following treatment. Methods Patients with serviceable hearing who underwent SRS for VS between 1997 and 2002 were studied. Data including radiosurgery treatment plans, tumor characteristics, pre- and posttreatment pure tone average, speech discrimination scores, and American Academy of Otolaryngology–Head and Neck Surgery hearing class were collected. Time to nonserviceable hearing was estimated using the Kaplan-Meier method. Univariate and multivariate associations with time to nonserviceable hearing were evaluated using Cox proportional hazards regression models. Results Forty-four patients met the study criteria and were included. The median duration of audiometric follow-up was 9.3 years. Thirty-six patients developed nonserviceable hearing at a mean of 4.2 years following SRS. The Kaplan-Meier estimated rates of serviceable hearing at 1, 3, 5, 7, and 10 years following SRS were 80%, 55%, 48%, 38%, and 23%, respectively. Multivariate analysis revealed that pretreatment ipsilateral pure tone average (p < 0.001) and tumor size (p = 0.009) were statistically significantly associated with time to nonserviceable hearing. Conclusions Durable hearing preservation a decade after low-dose SRS for VS occurs in less than one-fourth of patients. Variables including preoperative hearing capacity and tumor size may be used to predict hearing outcomes following treatment. These findings may assist in pretreatment risk disclosure. Furthermore, these data demonstrate the importance of long-term follow-up when reporting audiometric outcomes following SRS for VS.