Citations

OBJECTIVE The impact of treatment method—surgical clipping or endovascular coiling—on the cost of care for patients with aneurysmal subarachnoid hemorrhage (SAH) is debated. Here, the authors investigated the association between treatment method and long-term Medicare expenditures in elderly patients with aneurysmal SAH. METHODS The authors performed a cohort study of 100% of the Medicare fee-for-service claims data for elderly patients who had undergone treatment for ruptured cerebral aneurysms in the period from 2007 to 2012. To control for measured confounding, the authors used propensity score–adjusted multivariable regression analysis with mixed effects to account for clustering at the hospital referral region (HRR) level. An instrumental variable (regional rates of coiling) analysis was used to control for unmeasured confounding by creating pseudo-randomization on the treatment method. RESULTS During the study period, 3210 patients underwent treatment for ruptured cerebral aneurysms and met the inclusion criteria. Of these patients, 1206 (37.6%) had surgical clipping and 2004 (62.4%) had endovascular coiling. The median total Medicare expenditures in the 1st year after admission for SAH were $113,000 (IQR $77,500–$182,000) for surgical clipping and $103,000 (IQR $72,900–$159,000) for endovascular coiling. When the authors adjusted for unmeasured confounders by using an instrumental variable analysis, clipping was associated with increased 1-year Medicare expenditures by $19,577 (95% CI $4492–$34,663). CONCLUSIONS In a cohort of Medicare patients with aneurysmal SAH, after controlling for unmeasured confounding, surgical clipping was associated with increased 1-year expenditures in comparison with endovascular coiling.

Abstract Background: Mucinous ovarian carcinomas (MC) and mucinous borderline ovarian tumours (MBOT) are associated with ERBB2 amplification and KRAS activating mutations. These events occur in a near-mutually exclusive pattern, and KRAS mutations are more prevalent in MBOTs than MC's whereas ERBB2 amplification is more frequently seen in MCs. Frequencies of mutations in other oncogenes and tumour suppressor genes in MC are not well established though TP53, BRAF, NRAS, and CDKN2A mutations have all been reported. As these carcinomas are commonly chemo-resistant a definitive molecular categorization of this subtype is needed as treatment options are explored. Methods: We undertook review of pathology reports and after exclusion of potential gastric, appendiceal or pancreatic involvement over 100 mucinous ovarian tumours were identified. HPV testing was undertaken to exclude rare metastasis from endocervical primary site. All specimens were assayed for p53 expression via TMA and subject to sequencing of common cancer gene hotspots using Ion-Torrent or Illumina MiSeq. Previously derived data on ERBB2 status was combined in our analysis and, where available, samples showing heterogeneity of ERBB2 amplification and any other Ras-pathway activating mutation were microdissected with components evaluated independently for concurrent hotspot mutations. Results: All samples were consistent with mucinous tumours of ovarian origin and none were HPV positive. We detected mutations in KRAS, BRAF, CDKN2A, TP53, PTEN, PIK3CA as well as presumed somatic/detrimental, variants in APC that have not previously been reported in mucinous tumours. Despite some samples having enriched tumour content, lower than expected allelic frequencies of KRAS activating mutations suggested intra-tumoural heterogeneity. This was consistent with results observed previously with rare ERBB2 amplification coinciding KRAS mutations. Conclusions: The prevalence of Ras-pathway mutations, especially amongst borderline lesions, suggests these mutations are critical for tumour onset. However varying allelic frequencies of KRAS mutations suggest progression to carcinoma is strongly influenced by other molecular features. Citation Format: Michael S. Anglesio, Robertson Mackenzie, Stefan Kommoss, Boris J. Winterhoff, Benjamin Kipp, Jaoquin Garcia, Jesse S. Voss, Kevin Halling, Sarah Kerr, Janine Senz, Winnie Yang, Magnus von Knebel Doeberitz, Elena-Sophie Prigge, Miriam Reuschenbach, Anna V. Tinker, Blake Gilks, Jamie N. Bakkum-Gamez, David G. Huntsman, Jessica N. McAlpine. Defining ovarian mucinous tumors: Cancer genes and heterogeneity. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A18.

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.