Citations

Cholangiocarcinoma (CCA) has poor prognosis due to late‐stage, symptomatic presentation. Altered DNA methylation markers may improve diagnosis of CCA. Reduced‐representation bisulfite sequencing was performed on DNA extracted from frozen CCA tissues and matched to adjacent benign biliary epithelia or liver parenchyma. Methylated DNA markers (MDMs) identified from sequenced differentially methylated regions were selected for biological validation on DNA from independent formalin‐fixed, paraffin‐embedded CCA tumors and adjacent hepatobiliary control tissues using methylation‐specific polymerase chain reaction. Selected MDMs were then blindly assayed on DNA extracted from independent archival biliary brushing specimens, including 12 perihilar cholangiocarcinoma, 4 distal cholangiocarcinoma cases, and 18 controls. Next, MDMs were blindly assayed on plasma DNA from patients with extrahepatic CCA (eCCA), including 54 perihilar CCA and 5 distal CCA cases and 95 healthy and 22 primary sclerosing cholangitis controls, balanced for age and sex. From more than 3,600 MDMs discovered in frozen tissues, 39 were tested in independent samples. In the clinical pilot of 16 MDMs on cytology brushings, methylated EMX1 (empty spiracles homeobox 1) had an area under the curve (AUC) of 0.98 (95% confidence interval [CI], 0.95‐1.0). In the clinical pilot on plasma, a cross‐validated recursive partitioning tree prediction model from nine MDMs was accurate for de novo eCCA (AUC, 0.88 [0.81‐0.95]) but not for primary sclerosing cholangitis–associated eCCA (AUC, 0.54 [0.35‐0.73]). Conclusion : Next‐generation DNA sequencing yielded highly discriminant methylation markers for CCA. Confirmation of these findings in independent tissues, cytology brushings, and plasma supports further development of DNA methylation to augment diagnosis of CCA.

AbstractBackgroundParotid gland mucoepidermoid carcinoma (MEC) has published five‐year cancer‐specific survival (CSS) rates of 77%–97%, with variance related to grade.MethodsPatients receiving primary surgery for parotid gland MEC from 1995 to 2014 at a tertiary medical center underwent clinical review, histopathologic review, and cytogenetic analysis. Survival outcomes were evaluated.ResultsAmong 58 patients, T/N/M classification was as follows: T1 in 35 patients, T2 in 14, T4a in 9, N0 in 53, N1 in 2, N2b in 3. Histologic grade was low in 27, intermediate in 17, and high in 12 patients with 98% MAML2 positivity. All patients underwent parotidectomy, and seven patients received adjuvant radiation therapy. CSS was 100% at 5 years and 94.1% at 10 and 15 years. Two patients experienced locoregional recurrence.ConclusionsTreatment with adequate surgical resection and adjuvant radiation therapy for high‐grade or advanced‐stage tumors yields excellent survival, independent of clinical stage or pathologic grade.

Abstract Considerable efforts have been made to characterize active enhancer elements, which can be annotated by accessible chromatin and H3 lysine 27 acetylation (H3K27ac). However, apart from poised enhancers that are observed in early stages of development and putative silencers, the functional significance of cis-regulatory elements lacking H3K27ac is poorly understood. Here we show that macroH2A histone variants mark a subset of enhancers in normal and cancer cells, which we coined ‘macroH2A-Bound Enhancers’, that negatively modulate enhancer activity. We find macroH2A variants enriched at enhancer elements that are devoid of H3K27ac in a cell type-specific manner, indicating a role for macroH2A at inactive enhancers to maintain cell identity. In following, reactivation of macro-bound enhancers is associated with oncogenic programs in breast cancer and its repressive role is correlated with the activity of macroH2A2 as a negative regulator of BRD4 chromatin occupancy. Finally, through single cell epigenomic profiling, we show that the loss of macroH2A2 leads to increased cellular heterogeneity that may help to explain the role of macroH2A variants in defining oncogenic transcriptional dependencies.

AbstractRecommended colorectal cancer screening modalities vary with respect to safety, efficacy, and cost. Better understanding of the factors that influence patient preference is, therefore, critical for improving population adherence to colorectal cancer screening. To address this knowledge gap, we conducted a panel survey focused on three commonly utilized colorectal cancer screening options [fecal immunochemical test or guaiac-based fecal occult blood test (FIT/gFOBT), multi-target stool DNA (mt-sDNA) test, and colonoscopy] with a national sample of U.S. adults, ages 40–75 years and at average risk of colorectal cancer, in November 2019. Of 5,097 panelists invited to participate, 1,595 completed the survey (completion rate, 31.3%). Our results showed that when presented a choice between two colorectal cancer screening modalities, more respondents preferred mt-sDNA (65.4%) over colonoscopy, FIT/gFOBT (61%) over colonoscopy, and mt-sDNA (66.9%) over FIT/gFOBT. Certain demographic characteristics and awareness of and/or experience with various screening modalities influenced preferences. For example, uninsured people were more likely to prefer stool-based tests over colonoscopy [OR, 2.53; 95% confidence interval (CI), 1.22–5.65 and OR, 2.73; 95% CI, 1.13–7.47]. People who had heard of stool-based screening were more likely to prefer mt-sDNA over FIT/gFOBT (OR, 2.07; 95% CI, 1.26–3.40). People who previously had a stool-based test were more likely to prefer FIT/gFOBT over colonoscopy (OR, 2.75; 95% CI, 1.74–4.41), while people who previously had a colonoscopy were less likely to prefer mt-sDNA or FIT/gFOBT over colonoscopy (OR, 0.39; 95% CI, 0.24–0.63 and OR, 0.40; 95% CI, 0.26–0.62). Our survey demonstrated broad patient preference for stool-based tests over colonoscopy, contrasting the heavy reliance on colonoscopy for colorectal cancer screening in clinical practice and highlighting the importance of considering patient preference in colorectal cancer screening recommendations.Prevention Relevance:Our national survey demonstrated broad patient preference for stool-based tests over colonoscopy, contrasting the heavy reliance on colonoscopy for colorectal cancer screening in clinical practice and highlighting the importance of considering patient preference in colorectal screening recommendations.

PURPOSE New technology might pose problems for older patients with cancer. This study sought to understand how a trial in older patients with cancer (Alliance A171603) was successful in capturing electronic patient-reported data. METHODS Study personnel were invited via e-mail to participate in semistructured phone interviews, which were audio-recorded and qualitatively analyzed. RESULTS Twenty-four study personnel from the 10 sites were interviewed; three themes emerged. The first was that successful patient-reported electronic data capture shifted work toward patients and toward study personnel at the beginning of the study. One interviewee explained, “I mean it kind of lost all advantages…by being extremely laborious.” Study personnel described how they ensured electronic devices were charged, wireless internet access was up and running, and login codes were available. The second theme was related to the first and dealt with data filtering. Study personnel described high involvement in data gathering; for example, one interviewee described, “I answered on the iPad, whatever they said. They didn't even want to use it at all.” A third theme dealt with advantages of electronic data entry, such as prompt data availability at study completion. Surprisingly, some remarks described how electronic devices brought people together, “Some of the patients, you know, it just gave them a chance to kinda talk about, you know, what was going on.” CONCLUSION High rates of capture of patient-reported electronic data were viewed favorably but occurred in exchange for increased effort from patients and study personnel and in exchange for data that were not always patient-reported in the strictest sense.

Computational fluid dynamics (CFD) has grown as a tool to help understand the hemodynamic properties related to the rupture of cerebral aneurysms. Few of these studies deal specifically with aneurysm growth and most only use a single time instance within the aneurysm growth history. The present retrospective study investigated four patient-specific aneurysms, once at initial diagnosis and then at follow-up, to analyze hemodynamic and morphological changes. Aneurysm geometries were segmented via the medical image processing software Mimics. The geometries were meshed and a computational fluid dynamics (CFD) analysis was performed using ANSYS. Results showed that major geometry bulk growth occurred in areas of low wall shear stress (WSS). Wall shape remodeling near neck impingement regions occurred in areas with large gradients of WSS and oscillatory shear index. This study found that growth occurred in areas where low WSS was accompanied by high velocity gradients between the aneurysm wall and large swirling flow structures. A new finding was that all cases showed an increase in kinetic energy from the first time point to the second, and this change in kinetic energy seems correlated to the change in aneurysm volume.

PURPOSE This study determined whether an electronic version of the geriatric assessment is feasible in a multi-institutional, diverse setting. METHODs Ten sites within the Alliance for Clinical Trials in Oncology participated. Patients who had active cancer or a history of cancer and were 65 years of age or older were eligible. The geriatric assessment was completed with an electronic data capture system that had been loaded onto iPads. Feasibility was defined a priori as completion in at least 70% of patients either with or without help. To enhance racial diversity, the original sample size was later changed and augmented by 50% with the intention of increasing enrollment of older minority patients. RESULTS A total of one hundred fifty-four patients were registered with a median age of 72 years (range, 65-91 years). Forty-three (28%) identified themselves as African American or Black. One hundred forty-one patients (92%) completed the electronic geriatric assessment. Feasibility was observed across all subgroups, regardless of race, education, performance status, comorbidities, and cognition; 124 patients (81%) completed the geriatric assessment without help. Reasons for not completing the geriatric assessment are as follows: clinic visit did not occur (n = 6), no iPad connection to the Internet (n = 3), patient declined (n = 2), prolonged hospitalization (n = 1), and patient died (n = 1). Reasons for needing help, as reported by study personnel, were as follows: the patient preferred that research personnel ask the questions (n = 9), vision problem (n = 3), lack of comfort with the iPad (n = 2), questions were not clear (n = 1), less proficient in English (n = 1), and challenge in pressing the green button to go to the next question (n = 1). CONCLUSION The electronic geriatric assessment is feasible in a multi-institutional setting that includes a notable proportion of African American or Black patients.