Citations

Background— Targeted postmortem genetic testing of the 4 major channelopathy-susceptibility genes ( KCNQ1 , KCNH2 , SCN5A , and RYR2 ) have yielded putative pathogenic mutations in ≤30% of autopsy-negative sudden unexplained death in the young (SUDY) cases with highest yields derived from the subset of exertion-related SUDY. Here, we evaluate the role of whole-exome sequencing in exertion-related SUDY cases. Methods and Results— From 1998 to 2010, 32 cases of exertion-related SUDY were referred by Medical Examiners for a cardiac channel molecular autopsy. A mutational analysis of the major long-QT syndrome–susceptibility genes ( KCNQ1 , KCNH2 , and SCN5A ) and catecholaminergic polymorphic ventricular tachycardia–susceptibility gene ( RYR2 ) identified a putative pathogenic mutation in 11 cases. Whole-exome sequencing was performed on the remaining 21 targeted gene–negative SUDY cases. After whole-exome sequencing, a gene-specific surveillance of all genes (N=100) implicated in sudden death was performed to identify putative pathogenic mutation(s). Three of these 21 decedents had a clinically actionable, pathogenic mutation (CALM2-F90L, CALM2-N98S, and PKP2-N634fs). Of the 18 remaining cases, 7 hosted at least 1 variant of unknown significance with a minor allele frequency <1:20 000. The overall yield of pathogenic mutations was higher among decedents aged 1 to 10 years (10/11, 91%) than those aged 11 to 19 years (4/21, 19%, P =0.0001). Conclusions— Molecular screening in this clinical scenario is appropriate with a pathogenic mutation detection rate of 44% using direct DNA sequencing followed by whole-exome sequencing. Only 5 of the 100 interrogated sudden death genes hosted actionable pathogenic mutations for more than one third of these exertion-related, autopsy-negative SUDY cases.

AbstractAimThe Cleveland Clinic has proposed a prognostic model of preoperative risk factors for failure of restorative proctocolectomy (RPC) with ileal pouch–anal anastomosis. The model incorporates four predictive variables: completion proctectomy, handsewn anastomosis, diabetes mellitus and Crohn's disease. The aim of the present study was to perform an external validation of this model in a new cohort of patients who had RPC.MethodValidation was performed in a multicentre cohort of 747 consecutive patients who had an RPC between 1990 and 2015 in three tertiary‐care facilities, using a Kaplan–Meier survival analysis and Cox regression analysis. The performance of the model was expressed using the Harrell concordance error rate. The primary outcome measure was pouch survival with maintenance of anal function.ResultsDuring the study period, 45 (6.0%) patients experienced failure at a median interval of 31 months (interquartile range 9–82 months) from the original RPC. Multivariable analysis showed handsewn anastomosis to be the only significant independent predictor. The Harrell concordance error rate was 0.42, indicating poor performance. Anastomotic leakage and Crohn's disease of the pouch were strong postoperative predictors for pouch failure and showed a significant difference in pouch survival after 10 years (P < 0.001).ConclusionThe poor performance of the Cleveland Clinic prognostic model makes it unsuitable for daily clinical practice. Handsewn anastomosis was associated with pouch failure in our cohort with relatively few events. A prediction model for anastomotic leakage or Crohn's disease of the pouch may be a better solution since these variables are strongly associated with pouch failure.

SummaryObjectiveThe role of percutaneous adrenal biopsy in a high‐risk population for adrenal malignancy has not been fully investigated. Our aim was to describe the clinical presentation leading to the adrenal biopsy and evaluate the diagnostic performance, complications and non diagnostic rate of adrenal biopsy.DesignSingle‐centre, retrospective cohort study.Patients and MeasurementsMedical records of patients who underwent adrenal biopsy between 1994 and 2014 were reviewed. Adrenal biopsy outcome was compared to a predefined reference standard.ResultsBiopsy was performed in 418 patients [62% men, median age 69 years (range, 15–91)] on 419 adrenal lesions, median size 3·1 cm (range, 0·6–24). The main indication for adrenal mass biopsy was (349/419, 83%) suspected adrenal metastasis from a known or suspected extra‐adrenal primary source. Only 116 of 419, 28% of cases had prebiopsy biochemical testing for pheochromocytoma. Biopsy‐related complications occurred in 4% of the patients. Histology revealed a metastasis in 231 of 419 (55%), benign adrenal tissue in 137 of 419 (33%), adrenocortical carcinoma in eight of 419 (2%), other lesions in 23 of 419 (5%) including seven cases of pheochromocytoma and six cases of infectious process. Biopsy was nondiagnostic in 20 of 419 (5%). All adrenal masses with unenhanced radiodensity ≤10 HU (42/137, 31%) proved to be benign adrenal adenomas. Adrenal biopsy diagnosed malignancy with a sensitivity of 88·5%, specificity of 91·5%, positive predictive value of 93·4% and negative predictive value of 85·5%.ConclusionWhen used in the appropriate clinical setting, adrenal biopsy is a powerful tool in the diagnostic algorithm of the evaluation of adrenal masses with features suspicious for malignancy. Efforts to increase awareness to perform biochemical testing for pheochromocytoma prior to adrenal biopsy are needed.

Abstract Background: Workplace concerns are particularly salient for young women with breast cancer (BC), and a cancer diagnosis (dx) and treatment may affect their careers. We sought to evaluate the perceived impact of dx on employment, describe job changes, and identify factors associated with transition out of the workforce after dx of BC at a young age. Methods: As part of an ongoing, multi-center cohort of young women diagnosed with BC at age ≤ 40, we surveyed women with early-stage BC about their pre- and post-dx employment status. Additional items assessed socio-demographic and treatment information; tumor characteristics were ascertained via pathology and medical record review. We used logistic regression to identify predictors of transitioning from pre-dx employment to unemployment at 1 year after dx. Among women employed 1 year after dx, we evaluated job satisfaction, perceived impact of dx on job performance, accommodations made by employers, and perceived likelihood of employment in the future. Results: 76% of women (555/730) were employed both before dx and at 1 year; 13% were not employed at either time point; 7% were employed pre-dx but unemployed at 1 year; 4% were not employed prior to dx but reported employment at 1 year. Among women employed 1 year after dx, 74% (427/581) were somewhat or completely satisfied with their job. Only 6% said cancer or treatment limited their ability to perform their job quite a bit or very much; 38% said their ability was affected a little bit. Most (63%) said their employers had made accommodations for them, and almost all women (93%) said it was very likely they would be working in 1 year. In multivariable analyses (Table 1), women with stage 3 disease (vs. stage 1), were more likely to transition out of the workforce following dx, while women with a college or graduate degree (vs. no college degree) were less likely to transition out. Conclusion: Most young women with early stage BC remain employed and report a willingness by their employer to make accommodations following a breast cancer dx. While few women reported that their dx or treatment limited their job performance, the finding that women with more advanced disease were more likely to transition out of the workforce suggests an impact of dx/treatment burden on employment. Women without a college degree were also at risk for unemployment post-dx, suggesting that job type, socioeconomic status, and environment affect employment outcomes. Attention to these subgroups of women is warranted to ensure that they are sufficiently supported given the potential adverse psychosocial and financial impacts of unemployment on patients, families, communities, and society. Table 1. Multivariable analysis of factors associated with transition out of workforce 1year post-dx (N=634) OR (95% CI)Stage (ref=1) 04.52 (0.60-33.85)21.11 (0.48-2.58)34.05 (1.53-10.72)*White non-Hispanic (ref=non-WNH)1.47 (0.56-3.81)College graduate (ref=no college degree)0.44 (0.22-0.90)*Married/Living as married (ref=unmarried)0.95 (0.43-2.08)Parous (ref=nulliparous)1.75 (0.83-3.69)Age at diagnosis (years)0.98 (0.90-1.06)Mastectomy (ref=lumpectomy)1.74 (0.75-4.05)Endocrine therapy (ref=none)0.75 (0.41-1.39)Chemotherapy (ref=none)5.20 (0.93-29.22)Radiation (ref=none)1.38 (0.64-2.96)*p&lt;0.05 Citation Format: Partridge AH, Rosenberg SM, Rajagopal PS, Ruddy KJ, Tamimi RM, Schapira L, Come S, Borges V, Gelber S. Employment trends in young women following a breast cancer diagnosis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-10-04.

Abstract Background: Young women with breast cancer need highly effective contraception given the potential implications of unplanned pregnancy for optimal treatment, and the teratogenic risks. We sought to determine the contraceptive methods used by young women after diagnosis (dx) of breast cancer and factors associated with use of less effective methods or no contraceptive method, which confers a 6-90% annual risk of pregnancy in sexually active women in contrast to highly effective methods (risk &lt;1%). Methods: As part of a randomized trial conducted in 54 sites to test an education and support intervention for young women with breast cancer and their oncologists, we surveyed women about their pre-dx, current, and planned contraceptive use, and about communication with their providers regarding contraception. Women enrolled within 3 months of dx; contraception items were included on 3- and 12-month post-enrollment surveys. Intrauterine device (IUD) use, tubal sterilization, hysterectomy or bilateral salpingo-oophorectomy (hyst/BSO) after dx, or male partner vasectomy were classified as highly effective methods; all other methods and non-use were categorized as less effective. We excluded women not at risk of pregnancy: hyst/BSO prior to dx, or no indication for contraception. We used logistic regression to explore factors associated with use of less effective methods. Results: Of 424 women who completed the 3-month post-enrollment survey, median age at dx was 39 (range 22-45). 312 women at risk of pregnancy were included in this analysis, including 291 reporting sexual activity with a male partner within the last 6 months, and 21 reporting no recent sexual activity but reporting use of birth control. 123 women (39%) used highly effective contraceptive methods prior to dx; after dx, 161 (52%) reported current use of or a plan to use a highly effective method. 19 women (6%) reported use of a hormonal birth control method since dx; 7 (2%) reported withdrawal as their only contraceptive method; 25 (8%) reported no contraception. 30% of women did not recall a discussion of avoiding pregnancy or need for contraception during treatment with their providers. In multivariable analyses (N=310), desire for additional biologic children (OR 7.54, 95% CI 3.88-14.66) and provider discussion of contraception and pregnancy (OR 2.13 95% CI 1.20-3.78) were associated with use of less effective contraception. Age, race/ethnicity, disease stage, and partner status were not significantly associated with use of less effective methods. Conclusion: About half of women who are at risk of pregnancy reported use or planned use of less effective contraceptive methods or no method of contraception following dx of breast cancer. Women with breast cancer and their providers may benefit from targeted education on contraceptive options and method effectiveness. Citation Format: Rosenberg SM, Dutton CR, Ligibel J, Barry W, Ruddy KJ, Sprunck-Harrild K, Emmons KM, Partridge AH. Contraception use in young women with breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-18.

Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age and histories of cancer from their 1,903 first‐ and 3,255 second‐degree relatives were analyzed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer 19 (3.7–97) and ovarian cancer 17 (2.4–115). The HRs (95% CI) for monoallelic MUTYH mutation carriers were: gastric cancer 9.3 (6.7–13); hepatobiliary cancer 4.5 (2.7–7.5); endometrial cancer 2.1 (1.1–3.9) and breast cancer 1.4 (1.0–2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95% CI) to age 70 years for biallelic mutation carriers were: bladder cancer 25% (5–77%) for males and 8% (2–33%) for females and ovarian cancer 14% (2–65%). The cumulative risks (95% CI) for monoallelic mutation carriers were: gastric cancer 5% (4–7%) for males and 2.3% (1.7–3.3%) for females; hepatobiliary cancer 3% (2–5%) for males and 1.4% (0.8–2.3%) for females; endometrial cancer 3% (2%–6%) and breast cancer 11% (8–16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.

Purpose: To describe a bailout technique for use during branched/fenestrated thoracoabdominal aortic aneurysm (TAAA) repair to address celiac artery (CA) dissection. Technique: The technique is demonstrated in a 69-year-old man who underwent fenestrated stent-graft repair of a 6-cm type III TAAA. The main fenestrated stent-graft was positioned without difficulty, and the renal and superior mesenteric arteries were stented. A stent-graft was placed in the CA, but angiography showed the vessel to be occluded by dissection beyond the stent-graft. Wire manipulations to regain access to the true lumen culminated in perforation. At this point, the gastroduodenal artery was catheterized with a 0.035-inch guidewire, which was advanced in retrograde fashion into the CA true lumen and then snared back to the left brachial artery forming a loop. After exchange for a 0.014-inch system, self-expanding stents were deployed into the hepatic artery. Postoperative recovery was uneventful, and the patient was discharged on day 6. At 1-year follow-up, the patient was doing very well. Imaging demonstrated no endoleak, no graft migration, and sac shrinkage to a diameter of 5.1 cm. Conclusion: The “loop technique” can be a very useful and effective bailout maneuver in regaining access to the true lumen of a dissected CA in patients undergoing branched/fenestrated thoracoabdominal aortic aneurysm repair.

Significance Ubiquitin-specific protease 6 (USP6) is a deubiquitylase that is overexpressed by chromosome translocation in two human neoplasms, aneurysmal bone cyst and nodular fasciitis. The relevant substrates of this ubiquitin-specific protease are not clear. Here, we identify the Wnt receptor Frizzled (Fzd) as a key target of the USP6 oncogene. Increased expression of USP6 increases the membrane abundance of Fzd, and hence increases cellular sensitivity to Wnts. USP6 opposes the activity of the ubiquitin ligase and tumor suppressor ring finger protein 43 (RNF43). This study identifies a new mechanism for pathological Wnt pathway activation in human disease and suggests a new approach to regulate Wnt activity therapeutically.