Citations

Three-dimensional (3D) printing is an additive manufacturing method that holds great potential in a variety of future patient-specific medical technologies. This project validated a novel crosslinked polyvinyl alcohol (XL-PVA) 3D printed stent infused with collagen, human placental mesenchymal stem cells (PMSCs), and cholangiocytes. The biofabrication method in the present study examined 3D printing and collagen injection molding for rapid prototyping of customized living biliary stents with clinical applications in the setting of malignant and benign bile duct obstructions. XL-PVA stents showed hydrophilic swelling and addition of radiocontrast to the stent matrix improved radiographic opacity. Collagen loaded with PMSCs contracted tightly around hydrophilic stents and dense choloangiocyte coatings were verified through histology and fluorescence microscopy. It is anticipated that design elements used in these stents may enable appropriate stent placement, provide protection of the stent-stem cell matrix against bile constituents, and potentially limit biofilm development. Overall, this approach may allow physicians to create personalized bio-integrating stents for use in biliary procedures and lays a foundation for new patient-specific stent fabrication techniques.

This study aimed to understand prescribing practices during acute psychiatric hospitalization in a large cohort of patients (N = 569) with borderline personality disorder (BPD) at a tertiary care psychiatry unit from January 1, 2013, through January 1, 2015. The mean number of hospitalizations per patient was 1.5 (range, 1–7). The odds of being prescribed antidepressants, antipsychotics, mood stabilizers, hypnotics, or anxiolytics were higher at discharge than at admission. The rate of psychotropic prescriptions was also higher at discharge than at admission (incidence rate ratio, 1.9). This pattern was true for the combined psychotropic and nonpsychotropic (“medical”) prescriptions. Further guidelines are needed regarding optimal psychosocial, medical, and psychopharmacological care of patients with BPD during acute psychiatric hospitalizations.

Abstract Background In 2017, the International Parkinson and Movement Disorder Society put forward new clinical criteria for the diagnosis of PSP, recognizing diverse PSP phenotypes. In this study, we compared the sensitivity and specificity of the new criteria with the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria at different times. Methods Patients with clinical parkinsonism, clinical and/or neuropathological diagnosis of PSP, were identified from the Society for Progressive Supranuclear Palsy brain bank. All patients had neuropathologic diagnoses and detailed clinical examination performed by a neurologist at 1 of the 3 Mayo Clinic sites, in Florida, Arizona, and Minnesota. Clinical symptoms and signs were abstracted retrospectively in a blinded fashion and used to determine whether patients met either diagnostic criterion. Patients were divided into early and late disease stage groups using a 3‐year cutoff. Results A total of 129 patients were included, of whom 66 had PSP pathology (51%). The remainder had other neurodegenerative diseases. The overall sensitivity of the International Parkinson and Movement Disorder Society criteria was 87.9%, compared with 45.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria, whereas the specificity of the International Parkinson and Movement Disorder Society probable PSP criteria was 85.7%, compared with 90.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy. Individual patients were noted to have features of multiple PSP phenotypes. Conclusion The International Parkinson and Movement Disorder Society criteria recognize several phenotypes of progressive supranuclear palsy and hence have higher sensitivity than the previous criteria. © 2019 International Parkinson and Movement Disorder Society

Acute‐on‐chronic liver failure (ACLF) characterized with ≥2 extrahepatic organ failures in cirrhosis carries a high mortality. Outcomes of patients listed for liver transplantation (LT) after ACLF and after LT are largely unknown. The North American Consortium for the Study of End‐Stage Liver Disease prospectively enrolled 2793 nonelectively hospitalized patients with cirrhosis; 768 were listed for LT. Within 3 months, 265 (35%) received a LT, 395 remained alive without LT, and 108 died/delisted. Compared with nonlisted patients, those listed were younger and more often had ACLF, acute kidney injury, and a higher admission Model for End‐Stage Liver Disease (MELD) score. ACLF was most common in patients who died/delisted, followed by those alive with and without LT respectively, (30%, 22%, and 7%, respectively; P < 0.001). At LT, median MELD was 27.9% and 70% were inpatients; median time from hospitalization to LT was 26 days. Post‐LT survival at 6 months was unchanged between those with and without ACLF (93% each at 6 months). There was no difference in 3‐ and 6‐month mean post‐LT creatinine in those with and without ACLF, despite those with ACLF having a higher mean pre‐LT creatinine and a higher rate of perioperative dialysis (61%). In conclusion, patients with and without ACLF had similar survival after transplant with excellent renal recovery in both groups.

PURPOSE Predictive biomarkers to identify patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer who may benefit from targeted therapy alone are required. We hypothesized that early measurements of tumor maximum standardized uptake values corrected for lean body mass (SULmax) on [ 18 F]fluorodeoxyglucose positron emission tomography/computed tomography would predict pathologic complete response (pCR) to neoadjuvant pertuzumab and trastuzumab (PT). PATIENTS AND METHODS Patients with stage II/III, estrogen receptor–negative, HER2-positive breast cancer received four cycles of neoadjuvant PT. [ 18 F]Fluorodeoxyglucose positron emission tomography/computed tomography was performed at baseline and 15 days after PT initiation (C1D15). Eighty evaluable patients were required to test the null hypothesis that the area under the curve of percentage of change in SULmax by C1D15 predicting pCR is less than or equal to 0.65, with a one-sided type I error rate of 10%. RESULTS Eighty-eight women were enrolled (83 evaluable), and 85% (75 of 88) completed all four cycles of PT. pCR after PT alone was 34%. Receiver operating characteristic analysis yielded an area under the curve of 0.76 (90% CI, 0.67 to 0.85), which rejected the null hypothesis. Between patients who obtained pCR versus not, a significant difference in median percent reduction in SULmax by C1D15 was observed (63.8% v 33.5%; P < .001), an SULmax reduction greater than or equal to 40% was more prevalent (86% v 46%; P < .001; negative predictive value, 88%; positive predictive value, 49%), and a significant difference in median C1D15 SULmax (1.6 v 3.9; P < .001) and higher proportion of C1D15 SULmax less than or equal to 3 (93% v 38%; P < .001; negative predictive value, 94%; positive predictive value, 55%) were observed. CONCLUSION Early changes in SULmax predict response to four cycles of PT in estrogen receptor–negative, HER2-positive breast cancer. Once optimized, this quantitative imaging strategy may facilitate a more tailored approach to therapy in this setting.

Abstract Introduction: Epidemiologic data support an inverse association between statin use and risk of lethal prostate cancer, but contributing mechanisms have not been elucidated. Herein, using data from the Health Professionals Follow-up Study (HPFS), we updated our previous analysis of statins and lethal prostate cancer with a decade of additional follow-up, and incorporated immunohistochemistry (IHC)-based biomarkers and gene expression profiling to identify putative molecular mechanisms contributing to the association. Methods: We included data from 44,076 HPFS participants who were cancer free in 1990, with follow-up through 2012. Participants reported prediagnostic statin use on biennial questionnaires. Statin use was categorized as current vs. never/past use, with current users further categorized as long-term vs. short-term users (≥6 vs. &lt;6 years). To classify prostate cancer molecular subtypes, genetically validated IHC assays for TMPRSS2:ERG fusion and PTEN loss were conducted on tissue microarrays for 891 and 660 cases, respectively. Whole-genome mRNA profiling of tumor and adjacent normal tissue was completed for 237 and 114 cases, respectively, using Affymetrix GeneChip Human Gene 1.0 ST arrays. We used Cox proportional hazards analysis to generate hazard ratios (HR) and 95% confidence intervals (CI) for associations between statin use and risk of overall, advanced (stage T3b or higher at diagnosis, metastatic or fatal), and lethal (metastatic or fatal) prostate cancer, as well as molecular subtypes, adjusted for PSA testing behavior and potential confounders including obesity and smoking. Moreover, we explored gene expression pathways in tumor and adjacent normal prostate tissue of statin users vs. nonusers using gene set enrichment analysis (GSEA). Results: During 22 years of follow-up, 6,144 men were diagnosed with prostate cancer; 1,051 (17%) had advanced disease and 827 (13%) developed lethal prostate cancer. Of cases with molecular subtype available, 48% were ERG-positive and 14% PTEN-null. In multivariable analysis, relative to never/past use, current statin use was inversely associated with risk of advanced (HR 0.84; 95% CI 0.68-1.04) and lethal (HR 0.78; 95% CI 0.68-1.01) prostate cancer. These associations were more pronounced in long-term users, where ≥6 years of prediagnosis statin use was significantly associated with a lower risk of advanced (HR 0.72; 95% CI 0.53-0.97) and lethal prostate cancer (HR 0.64; 95% CI 0.45-0.92), relative to nonuse. Long-term statin use was not associated with overall prostate cancer risk, whether ERG-positive (HR 0.89; 95% CI 0.59-1.35) or ERG-negative (HR 1.06; 95% CI 0.74-1.50). However, relative to nonuse, a longer duration of prediagnosis statin use was associated with reduced risk of PTEN-null cancers (HR 0.42; 95% CI 0.20-0.90), but not PTEN-intact disease (HR 1.18; 95% CI 0.95-1.46; p-heterogeneity=0.01). In GSEA, we identified T cell, B cell, and phosphatidylinositol (PI3K) signaling among the top pathways enriched in tumor-adjacent normal prostate tissue of current statin users, relative to never users. Intriguingly, no gene sets were differentially expressed by statin use in the tumor. Discussion: Our updated findings from the HPFS are consistent with our prior findings and other epidemiologic data supporting a role for statins in lethal prostate cancer prevention. Molecular classification of tumors identified PTEN/PI3K signaling and inflammation/immune activation as two potential mechanisms contributing to this association. Elucidating molecular mechanisms mediating the association between statin use and lower risk of lethal prostate cancer will provide support for a causal effect of statins on lethal prostate cancer risk and could inform statin clinical trials with appropriate intermediate endpoints. Citation Format: Emma H. Allott, Ericka M. Ebot, Amparo G. Gonzalez-Feliciano, Sarah C. Markt, Kathryn M. Wilson, Thomas U. Ahearn, Travis A. Gerke, Mary K. Downer, Konrad H. Stopsack, Jennifer R. Rider, Stephen J. Freedland, Elizabeth A. Platz, Meir J. Stampfer, Edward L. Giovannucci, Christopher J. Sweeney, Stephen P. Finn, Lorelei A. Mucci. Molecular tumor profiling to identify mechanisms linking statin use with lower risk of lethal prostate cancer: Results from the Health Professionals Follow-up Study [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A015.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) affects 30% to 40% of patients with cancer with long-lasting disability. Scrambler therapy (ST) appeared to benefit patients in uncontrolled trials, so we performed a randomized sham-controlled Phase II trial of ST. Methods: The primary end point was “average pain” after 28 days on the Numeric Rating Scale. Each received ten 30-minute sessions of ST on the dermatomes above the painful areas, or sham treatment on the back, typically at L3-5 where the nerve roots would enter the spinal cord. Outcomes included the Brief Pain Inventory (BPI)-CIPN and the EORTC CIPN-20 scale. Patients were evaluated before treatment (day 0), day 10, and days 28, 60, and 90. Results: Data regarding pain as a primary outcome were collected for 33 of the 35 patients. There were no significant differences between the sham and the “real” ST group at day 10, 28, 60, or 90, for average pain, the BPI, or EORTC CIPN-20. Individual responses were noted during the ST treatment on the real arm, but most dissipated by day 30. There was improvement in the sensory subscale of the CIPN-20 at 2 months in the “real” group ( P = .14). All “real” patients wanted to continue treatment if available. Discussion: We observed no difference between sham and real ST CIPN treatment. Potential reasons include at least the following: ST does not work; the sham treatment had some effect; small sample size with heterogeneous patients; misplaced electrodes on an area of nonpainful but damaged nerves; or a combination of these factors.

Background The authors conducted a cluster randomized study to determine the effect of an exportable educational intervention for young women with breast cancer (YWI) on improving care. Methods Sites were randomized 1:1 to the YWI or a contact time control physical activity intervention (PAI) stratified by academic or community site. Up to 15 women aged ≤45 years with newly diagnosed breast cancer were enrolled at each of 14 academic sites and 10 were enrolled at each of 40 community sites. The primary endpoint, attention to fertility, was ascertained by medical record review. Statistical inferences concerning the effect of the intervention used general estimating equations for clustered data. Results A total of 467 patients across 54 sites were enrolled between July 2012 and December 2013. The median age of the patients at the time of diagnosis was 40 years (range, 22‐45 years). Attention to fertility by 3 months was observed in 55% of patients in the YWI and 58% of patients in the PAI ( P = .88). Rates were found to be strongly correlated with age ( P < .0001), and were highest in patients aged <30 years. Attention to genetics was similar (80% in the YWI and 81% in the PAI), whereas attention to emotional health was higher in patients in the YWI (87% vs 76%; estimated odds ratio, 2.63 [95% confidence interval, 1.20‐5.76; P = .016]). Patients rated both interventions as valuable in providing education (64% in the YWI and 63% in the PAI). Conclusions The current study failed to demonstrate differences in attention to fertility with an intervention to improve care for women with breast cancer, although attention to fertility was found to be higher than expected in both groups and emotional health was improved in the YWI group. Greater attention to young women with breast cancer in general may promote more comprehensive care for this population.

Background: High blood pressure (BP), particularly in mid-life, increases the risk for late-life cognitive impairment and dementia (CID). The extent to which Blacks’ and Hispanics’ worse BP control starting in young adulthood contributes to their greater risk of CID compared to Whites is uncertain. Objective: To describe a pooled, multi-ethnic cohort created to determine the associations between BP levels over the life course and CID risk in Blacks, Hispanics, and Whites. Methods: We pooled individual-level data from 35,473 adults (22.6% Blacks, 8.1% Hispanics, 67.3% Whites, 2% Other) with baseline age ≥18 and cognitive assessments across 6 longitudinal cohorts in the United States from 1971 to 2016: Atherosclerosis Risk in Communities Study (ARIC), Coronary Artery Risk Development in Young Adults Study (CARDIA), Cardiovascular Health Study (CHS), Framingham Offspring Study (FOS), Multi-Ethnic Study of Atherosclerosis (MESA), and Northern Manhattan Study (NOMAS). We harmonized cognitive tests across studies into 3 factors representing global cognitive performance, executive function, and memory using statistically appropriate confirmatory factor analysis. Mean (SD) follow up was 17.1 (10.9) years. Results: The mean (SD) baseline age was 54.3 (16.4) years and 19554 (55.1%) participants were female (Table). There were 3193 (9.0%) first incident strokes (2651 ischemic, 348 hemorrhagic, and 117 other or undetermined type) and 15147 (42.7%) deaths. The Table presents mean BPs at the first and last visits by cohort and the pooled sample. From the initial to the last assessment, mean global cognition decreased over time (p<0.001), as did mean executive function (p<0.001) and mean memory scores (p<0.001) in the pooled sample. Conclusion: This will be the first comprehensive, large investigation of the association of BP levels from young adulthood to late-life and CID risk in Blacks, Hispanics, and Whites.