Citations

AbstractAlthough coding variants in THAP1 have been causally associated with primary dystonia, the contribution of noncoding variants remains uncertain. Herein, we examine a previously identified Intron 1 variant (c.71+9C>A, rs200209986). Among 1672 subjects with mainly adult‐onset primary dystonia, 12 harbored the variant in contrast to 1/1574 controls (P < 0.01). Dystonia classification included cervical dystonia (N = 3), laryngeal dystonia (adductor subtype, N = 3), jaw‐opening oromandibular dystonia (N = 1), blepharospasm (N = 2), and unclassified (N = 3). Age of dystonia onset ranged from 25 to 69 years (mean = 54 years). In comparison to controls with no identified THAP1 sequence variants, the c.71+9C>A variant was associated with an elevated ratio of Isoform 1 (NM_018105) to Isoform 2 (NM_199003) in leukocytes. In silico and minigene analyses indicated that c.71+9C>A alters THAP1 splicing. Lymphoblastoid cells harboring the c.71+9C>A variant showed extensive apoptosis with relatively fewer cells in the G2 phase of the cell cycle. Differentially expressed genes from lymphoblastoid cells revealed that the c.71+9C>A variant exerts effects on DNA synthesis, cell growth and proliferation, cell survival, and cytotoxicity. In aggregate, these data indicate that THAP1 c.71+9C>A is a risk factor for adult‐onset primary dystonia.

Purpose We sought to test and validate the predictive utility of trichotomous tumor response (TriTR; complete response [CR] or partial response [PR] v stable disease [SD] v progressive disease [PD]), disease control rate (DCR; CR/PR/SD v PD), and dichotomous tumor response (DiTR; CR/PR v others) metrics using alternate cut points for PR and PD. The data warehouse assembled to guide the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was used. Methods Data from 13 trials (5,480 patients with metastatic breast cancer, non–small-cell lung cancer, or colorectal cancer) were randomly split (60:40) into training and validation data sets. In all, 27 pairs of cut points for PR and PD were considered: PR (10% to 50% decrease by 5% increments) and PD (10% to 20% increase by 5% increments), for which 30% and 20% correspond to the RECIST categorization. Cox proportional hazards models with landmark analyses at 12 and 24 weeks stratified by study and number of lesions (fewer than three v three or more) and adjusted for average baseline tumor size were used to assess the impact of each metric on overall survival (OS). Model discrimination was assessed by using the concordance index (c-index). Results Standard RECIST cut points demonstrated predictive ability similar to the alternate PR and PD cut points. Regardless of tumor type, the TriTR, DiTR, and DCR metrics had similar predictive performance. The 24-week metrics (albeit with higher c-index point estimate) were not meaningfully better than the 12-week metrics. None of the metrics did particularly well for breast cancer. Conclusion Alternative cut points to RECIST standards provided no meaningful improvement in OS prediction. Metrics assessed at 12 weeks have good predictive performance.

Background— The impact of changing demographics on causes of long-term death after percutaneous coronary intervention (PCI) remains incompletely defined. Methods and Results— We evaluated trends in cause-specific long-term mortality after index PCI performed at a single center from 1991 to 2008. Deaths were ascertained by scheduled prospective surveillance. Cause was determined via telephone interviews, medical records, autopsy reports, and death certificates. Competing-risks analysis of cause-specific mortality was performed using 3 time periods of PCI (1991–1996, 1997–2002, and 2003–2008). Final follow-up was December 31, 2012. A total of 19 077 patients survived index PCI hospitalization, of whom 6988 subsequently died (37%, 4.48 per 100 person-years). Cause was determined in 6857 (98.1%). Across 3 time periods, there was a 33% decline in cardiac deaths at 5 years after PCI (incidence: 9.8%, 7.4%, and 6.6%) but a 57% increase in noncardiac deaths (7.1%, 8.5%, and 11.2%). Only 36.8% of deaths in the recent era were cardiac. Similar trends were observed regardless of age, extent of coronary disease, or PCI indication. After adjustment for baseline variables, there was a 50% temporal decline in cardiac mortality but no change in noncardiac mortality. The decline in cardiac mortality was driven by fewer deaths from myocardial infarction/sudden death ( P <0.001) but not heart failure ( P =0.85). The increase in noncardiac mortality was primarily attributable to cancer and chronic diseases ( P <0.001). Conclusions— This study found a marked temporal switch from predominantly cardiac to predominantly noncardiac causes of death after PCI over 2 decades. The decline in cardiac mortality was independent of changes in baseline clinical characteristics. These findings have implications for patient care and clinical trial design.

Easy M Our immune systems can produce a vastly diverse repertoire of antibody molecules that each recognize and bind to a specific foreign antigen via a hypervariable region. However, there are a few bacterial antigens—such as Protein A, Protein G, and Protein L—that instead bind to the antibody's conserved regions and can bind to a large number of different antibodies. These high-affinity broad-spectrum antibody-binding properties have been widely exploited both in the laboratory and in industry for purifying, immobilizing, and detecting antibodies. Grover et al. (p. 656 ) have now identified Protein M found on the surface of human mycoplasma, which displays even broader antibody-binding specificity. The crystal structure of Protein M revealed how Protein-M binding blocks the antibody's antigen binding site. This mechanism may be exploited by mycoplasma to escape the humoral immune response.

ObjectivesTo review the natural history of occult head and neck malignancy presenting with facial pain and evaluate the risk factors, diagnostic workup, and management of facial pain in the setting of occult malignancy.Study DesignRetrospective chart review.SettingTertiary care center.Subjects and MethodsAll patients presenting from 1980 to 2010 with facial pain and a delayed diagnosis of a head and neck cancer were reviewed.ResultsThirty‐eight patients were included. Onset of pain was rapid or sudden in 94.7%, intermittent in 84.2%, and sharp in 86.8%. Facial nerve weakness was present in 15.8%. Five patients had a history of locoregional skin cancer, and 14% had a history of malignancy. Average delay to diagnosis was 18.4 months. On average, the suspicious lesion was identified on the second scan (mean, 2.1; range, 1‐4 scans). Diagnosis was suggested by magnetic resonance imaging in 54.8% and computed tomography in 38.7% of patients. The most common pathology was squamous cell carcinoma (39.5%), and the predominant location was the parotid gland (28.9%). Surgical resection (66%) was the most common intervention. In patients who received treatment and had clinical follow‐up available for review, 97.0% (32/33) reported symptomatic improvement.ConclusionsIn our series, sudden‐onset, intermittent, sharp facial pain without resolution or improvement was associated with occult malignancy and should be considered in the differential diagnosis for facial pain. Based on the high incidence of early negative imaging, consideration should be given to repeat imaging when there is concern for malignancy. Therapeutic interventions often result in improvement of facial pain.

Abstract Atypical hyperplasia is a high-risk premalignant lesion of the breast, but its biology is poorly understood. Many believe that atypical ductal hyperplasia (ADH) is a direct precursor for low-grade ductal breast cancer, whereas atypical lobular hyperplasia (ALH) serves as a risk indicator. These assumptions underlie current clinical recommendations. We tested these assumptions by studying the characteristics of the breast cancers that develop in women with ADH or ALH. Using the Mayo Benign Breast Disease Cohort, we identified all women with ADH or ALH from 1967 to 2001 and followed them for later breast cancers, characterizing side of breast cancer versus side of atypia; time to breast cancer; type, histology, and grade of breast cancer, looking for patterns consistent with precursors versus risk indicators. A total of 698 women with atypical hyperplasia were followed a mean of 12.5 years; 143 developed breast cancer. For both ADH and ALH, there is a 2:1 ratio of ipsilateral to contralateral breast cancer. The ipsilateral predominance is marked in the first 5 years, consistent with a precursor phenotype for both ADH and ALH. For both, there is a predominance of invasive ductal cancers with 69% of moderate or high grade. Twenty-five percent are node positive. Both ADH and ALH portend risk for ductal carcinoma in situ and invasive breast cancers, predominantly ductal, with two thirds moderate or high grade. The ipsilateral breast is at especially high risk for breast cancer in the first 5 years after atypia, with risk remaining elevated in both breasts long term. ADH and ALH behave similarly in terms of later breast cancer endpoints. Cancer Prev Res; 7(2); 211–7. ©2014 AACR.

Purpose To evaluate the personal and professional characteristics associated with career satisfaction and burnout among US oncologists. Methods Between October 2012 and March 2013, the American Society of Clinical Oncology conducted a survey of US oncologists evaluating burnout and career satisfaction. The survey sample included equal numbers of men and women and represented all career stages. Results Of 2,998 oncologists contacted, 1,490 (49.7%) returned surveys (median age of respondents, 52 years; 49.6% women). Among the 1,117 oncologists (37.3% of overall sample) who completed full-length surveys, 377 (33.8%) were in academic practice (AP) and 482 (43.2%) in private practice (PP), with the remainder in other settings. Oncologists worked an average of 57.6 hours per week (AP, 58.6 hours per week; PP, 62.9 hours per week) and saw a mean of 52 outpatients per week. Overall, 484 oncologists (44.7%) were burned out on the emotional exhaustion and/or depersonalization domain of Maslach Burnout Inventory (AP, 45.9%; PP, 50.5%; P = .18). Hours per week devoted to direct patient care was the dominant professional predictor of burnout for both PP and AP oncologists on univariable and multivariable analyses. Although a majority of oncologists were satisfied with their career (82.5%) and specialty (80.4%) choices, both measures of career satisfaction were lower for those in PP relative to AP (all P < .006). Conclusion Overall career satisfaction is high among US oncologists, albeit lower for those in PP relative to AP. Burnout rates among oncologists seem similar to those described in recent studies of US physicians in general. Those oncologists who devote the greatest amount of their professional time to patient care seem to be at greatest risk for burnout.

Abstract The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22–1.64; P = 5.7 × 10−6], rs791587 (HR, 1.36; 95% CI, 1.17–1.57; P = 6.2 × 10−5), rs2476491 (HR, = 1.40; 95% CI, 1.19–1.64; P = 5.6 × 10−5), and rs10795763 (HR, 1.35; 95% CI, 1.17–1.57; P = 7.9 × 10−5), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54–0.82; P = 9.3 × 10−5) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332–40. ©2014 AACR.

Abstract Transient neonatal zinc deficiency ( TNZD ) has a clinical presentation similar to that of acrodermatitis enteropathica but is caused by a low zinc concentration in maternal breast milk. TNZD becomes clinically evident during breastfeeding and is resolved by weaning and the introduction of complementary nutrition. We present a 4‐month‐old girl with TNZD due to a new autosomal dominant mutation (663delC) in the maternal SLC 30A2 gene not previously described in the literature.