Citations

PurposeThe association of deficient DNA mismatch repair (dMMR) with prognosis in patients with colon cancer treated with adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy remains unknown.Patients and MethodsResected, stage III colon carcinomas from patients (N = 2,686) randomly assigned to FOLFOX ± cetuximab (North Central Cancer Treatment Group N0147 trial) were analyzed for mismatch repair (MMR) protein expression and mutations in BRAFV600E(exon 15) and KRAS (codons 12 and 13). Association of biomarkers with disease-free survival (DFS) was determined using Cox models. A validation cohort (Cancer and Leukemia Group B 88903 trial) was used.ResultsdMMR was detected in 314 (12%) of 2,580 tumors, of which 49.3% and 10.6% had BRAFV600Eor KRAS mutations, respectively. MMR status was not prognostic overall (adjusted hazard ratio [HR], 0.82; 95% CI, 0.64 to 1.07; P = .14), yet significant interactions were found between MMR and primary tumor site (Pinteraction= .009) and lymph node category (N1 v N2; Pinteraction= .014). Favorable DFS was observed for dMMR versus proficient MMR proximal tumors (HR, 0.71; 95% CI, 0.53 to 0.94; P = .018) but not dMMR distal tumors (HR, 1.71; 95% CI, 0.99 to 2.95; P = .056), adjusting for mutations and covariates. Any survival benefit of dMMR was lost in N2 tumors. Mutations in BRAFV600E(HR, 1.37; 95% CI, 1.08 to 1.70; P = .009) or KRAS (HR, 1.44; 95% CI, 1.21 to 1.70; P < .001) were independently associated with worse DFS. The observed MMR by tumor site interaction was validated in an independent cohort of stage III colon cancers (Pinteraction= .037).ConclusionThe prognostic impact of MMR depended on tumor site, and this interaction was validated in an independent cohort. Among dMMR cancers, proximal tumors had favorable outcome, whereas distal or N2 tumors had poor outcome. BRAF or KRAS mutations were independently associated with adverse outcome.

SummaryThere is a remarkable dearth of information about the various therapies used, often widely so, to control refractory or super‐refractory status epilepticus despite its high mortality and morbidity. As pointed out by recent literature reviews, there are no controlled studies, and information is based almost entirely on open, often small and retrospective, case series or case reports. Randomized or controlled studies that are sufficiently powered are not feasible in relation to the many therapies and treatment approaches available. For this reason, we proposed an international case registry of therapies used in refractory and super‐refractory cases and their outcome. Clinicians from different countries will be asked to complete an online questionnaire when they treat a patient with refractory or super‐refractory status epilepticus. Information gathered from this database will summarize the spectrum of etiologies, treatments, and outcomes of this challenging condition and may even form the bases for treatment guidelines or future targeted treatment trials.

Abstract Purpose: This study investigated the association between tumor MYC protein expression and disease-free survival (DFS) of patients randomized to receive chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the N9831 (Alliance) adjuvant HER2+ trastuzumab breast cancer trial. Experimental Design: This analysis included 1,736 patients randomized to Arms A, B, and C on N9831. Nuclear MYC protein expression was determined in tissue microarray sections containing three biopsies per patient or whole tissue sections using standard immunohistochemistry (clone 9E10). A tumor was considered positive for MYC protein overexpression (MYC+) if the nuclear 3+ staining percentage was more than 30%. Results: Five hundred and seventy-four (33%) tumors were MYC+. MYC+ was associated with hormone receptor positivity (χ2, P = 0.006), tumors 2 cm or more (χ2, P = 0.02), and a higher rate of nodal positivity (χ2, P &lt; 0.001). HRs for DFS (median follow-up: 6.1 years) for Arm C versus A were 0.52 (P = 0.006) and 0.65 (P = 0.006) for patients with MYC+ and MYC− tumors, respectively (Pinteraction = 0.40). For Arm B versus A, HRs for patients with MYC+ and MYC− tumors were 0.79 (P = 0.21) and 0.74 (P = 0.04), respectively (Pinteraction = 0.71). For Arm C versus B, HRs for patients with MYC+ and MYC− tumors were 0.56 (P = 0.02) and 0.89 (P = 0.49), respectively (Pinteraction = 0.17). Conclusions: Our data do not support an impact of tumor MYC protein expression on differential benefit from adjuvant trastuzumab. Clin Cancer Res; 19(20); 5798–807. ©2013 AACR.

Time is a ubiquitous but often omitted variable in career selection decisions. This study investigates the impact of temporal elements on career selection decisions, thus advancing our understanding of both career decision making and the impact of timing on decision making. We investigate the influence of timing and duration of experience with career options on career selection decisions in an archival study using medical residents’ rotation schedules. We also investigate factors that mitigate the influence of timing on career selection decisions by examining the interaction of timing with the duration of experience and the diversity of options that an individual experiences. Conditional logit results indicate that decisions often based on career and individual attributes are significantly influenced by the timing and duration of options even when controlling for option attributes. Additionally, significant interactions between timing and diversity of experience and timing and duration of experience revealed boundary conditions for timing. Individuals were more likely to select later-appearing career options when they appeared for a greater duration or when they experienced a greater diversity of options in their schedule. Results illustrate that schedules over which individuals have no control can influence consequential decisions.

Abstract Certain autoimmune bullous diseases ( AIBD ), including pemphigoid and pemphigus, confer increased infection risk. Infections have not been systematically studied in these conditions, however. Little is known about infection risk in these conditions, particularly dermatitis herpetiformis (DH). We aimed to characterize and compare infection patterns and risk factors in patients with pemphigoid, pemphigus, and DH. We retrospectively studied the medical records of Olmsted County, Minnesota, residents who had a diagnosis of AIBD between 1 January 1998 and 1 January 2011. Of 81 patients studied, 54 (67%) had pemphigoid, 11 (14%) had pemphigus and 16 (20%) had DH . Most patients studied developed at least one localized infection (72%) or one systemic infection (83%). Almost one‐third of patients (31%) developed infections requiring hospitalization or contributing to death. All patients taking systemic corticosteroids experienced a localized or systemic infection during the follow‐up period. Systemic infections were significantly less frequent in patients with DH than those with pemphigoid or pemphigus ( P = 0.03), as were systemic infections requiring hospitalization or contributing to death ( P = 0.002). Patients with DH were significantly less likely to require systemic corticosteroids ( P < 0.001) and significantly more likely to receive dapsone ( P = 0.002). The study design was retrospective and a limited number of patients met the inclusion criteria. Patients with AIBD frequently developed localized and systemic infections, a substantial portion of which contributed to hospitalization or death. Patients with DH experienced infections of lesser severity than patients with pemphigoid or pemphigus.

AbstractFrontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLD‐TDP). Recently, a genome‐wide association study identified the first FTLD‐TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD‐TDP risk. Intriguingly, the most significant association was in FTLD‐TDP patients carrying progranulin (GRN) mutations. Here, we investigated to what extent the coding variant, rs3173615 (p.T185S) in linkage disequilibrium with rs1990622, affects progranulin protein (PGRN) biology and transmembrane protein 106 B (TMEM106B) regulation. First, we confirmed the association of TMEM106B variants with FTLD‐TDP in a new cohort of GRN mutation carriers. We next generated and characterized a TMEM106B‐specific antibody for investigation of this protein. Enzyme‐linked immunoassay analysis of progranulin protein levels showed similar effects upon T185 and S185 TMEM106B over‐expression. However, over‐expression of T185 consistently led to higher TMEM106B protein levels than S185. Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N‐glycosylation at residue N183. Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD‐TDP risk. image We studied the p.T185S TMEM106B genetic variant previously implicated in frontotemporal dementia with TAR DNA binding protein 43 pathology caused by progranulin mutations. Our cell culture studies provide evidence that the protective S185 isoform is degraded more rapidly than T185 TMEM106B, potentially due to differences in glycosylation. These findings suggest that low TMEM106B levels might protect against FTLD‐TDP in these patients.

BACKGROUNDIncreased soluble human epidermal growth factor receptor 2 (sHER2) is an indicator of a poor prognosis in HER2‐positive metastatic breast cancer. In this study, the authors evaluated levels of sHER2 during treatment and at the time of disease recurrence in the adjuvant North Central Cancer Treatment Group N9831 clinical trial.METHODSThe objectives were to describe sHER2 levels during treatment and at the time of recurrence in patients who were randomized to treatment arms A (standard chemotherapy), B (standard chemotherapy with sequential trastuzumab), and C (standard chemotherapy with concurrent trastuzumab). Baseline samples were available from 2318 patients, serial samples were available from 105 patients, and recurrence samples were available from 124 patients. The cutoff sHER2 value for the assay was 15 ng/mL. Statistical methods included repeated measures linear models, Wilcoxon rank‐sum tests, and Cox regression models.RESULTSThere were differences between groups in terms of age, menopausal status, and hormone receptor status. Within treatment arms A, B, and C, patients who had baseline sHER2 levels ≥15 ng/mL had worse disease‐free survival than patients who had baseline sHER2 levels <15 ng/mL (arm A: hazard ratio, 1.81; P = .0014; arm B: hazard ratio, 2.08; P = .0015; arm C: hazard ratio, 1.96; P = .01). Among the 124 patients who experienced disease recurrence, sHER2 levels increased from baseline to the time of recurrence in arms A and B but remained unchanged in arm C. Patients who had recurrence sHER2 levels ≥15 ng/mL had a shorter survival after recurrence with a 3‐year overall survival rate of 51% compared with 77% for those who had recurrence sHER2 levels <15 ng/mL (hazard ratio, 2.36; 95% confidence interval, 1.19‐4.70; P = .01).CONCLUSIONSIn patients with early stage, HER2‐positive breast cancer, a high baseline sHER2 level was identified as a prognostic marker associated with shorter disease‐free survival, and a high sHER2 level at recurrence was predictive of shorter survival. Cancer 2013;119:2675–2682. © 2013 American Cancer Society.

Purpose It has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) –positive trial—North Central Cancer Treatment Group (NCCTG) N9831. Patients and Methods The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with ≥ 1+ staining. Median follow-up was 6.0 years. Results Of 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74%) had PTEN-positive tumors. PTEN positivity was associated with hormone receptor negativity (χ2 P < .001) and nodal positivity (χ2 P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47). Conclusion In contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status.