Citations

Abstract Introduction The MAPT H1 haplotype has been associated with several neurodegenerative diseases. We were interested in exploring the role of MAPT haplotypic variation in risk of dementia with Lewy bodies (DLB). Method We genotyped six MAPT haplotype tagging SNPs and screened 431 clinical DLB cases, 347 pathologically defined high‐likelihood DLB cases, and 1049 controls. Result We performed haplotypic association tests and detected an association with the protective H2 haplotype in our combined series (odds ratio [OR] = 0.75). We fine‐mapped the locus and identified a relatively rare haplotype, H1G, that is associated with an increased risk of DLB (OR = 3.30, P = .0017). This association was replicated in our pathologically defined series (OR = 2.26, P = .035). Discussion These results support a role for H1 and specifically H1G in susceptibility to DLB. However, the exact functional variant at the locus is still unknown, and additional studies are warranted to fully explain genetic risk of DLB at the MAPT locus.

Abstract Breast cancer diagnosis and death has risen in low to middle income countries (LMIC) in the past 20 years. Early detection, diagnosis and treatment in the LMIC setting are thought to impact morbidity and survivorship. The population of South Florida is composed of a significant portion of Afro-Caribbean immigrants from LMICs. We compared a cohort of recent Haitian immigrants with residents in Haiti who had a diagnosis of breast cancer to evaluate the effects of geographical location on presentation, treatment and outcomes. Methods: Retrospective cohort study. Participants were Haitian females with breast cancer that were living in Miami and presented to the University of Miami/Jackson Memorial Hospital (UM/JMH) between 2008 and 2014 and patients living in Haiti and presented to the Breast Cancer Treatment program at the Hospital Bernard Mevs Project Medishare (HBMPM) from 2013 to 2015 with a new diagnosis or who had been diagnosed as far back as 2008 and were presenting for continuation of care. The main outcome was the relationship between cohort location and breast cancer characteristics and cancer–specific survival by log-rank. Cox proportional hazards regression was used to compare breast cancer–specific survival overall and analyzed by stage and other significant explanatory factors. Results: 102 patients from UM/JMH and 94 patients from HBMPM were included in the analysis. The cohort in Haiti presented after longer median duration of symptoms (20 vs 3 months, p<0.001) and more advanced stage (31% Vs 20% with locally advance and 27% vs 19% with metastatic disease). The median age of diagnosis was 55 years in Miami compared to 50 years in Haiti (p=0.03). In Miami all patients had estrogen receptor (ER) and her-2 status ascertained at diagnosis, whereas only 52% and 27% of the Haitian cohort had them. Tumor characteristics in Miami vs Haiti in patients with reported status: ER + 74% (n=102) vs 55% (n=49), p=0.02, her-2+ 20% (n=102) vs 28% (n=25), p=0.36, triple negative 27% (n=102) vs 28% (n=25),p=0.49. Treatment modalities and censoring was available for all the patients in Miami and 72 patients in Haiti. In Haiti, radiation therapy was not widely available compared to Miami. Once patients had known ER and her-2 status, there was no difference in treatment with hormonal therapy (p=0.97) but none of the patients in Haiti received her-2 directed therapy (p<0.001). 50% of the patients with unknown ER status in Haiti received Tamoxifen. Twice as many Haitian women died after a median follow-up of 23 months (12% vs 24%), with median survival of 53 months for Haitians in Haiti (not reached for Miami cohort). Breast cancer specific survival was significantly different in the two cohorts (p<0.000). After exploratory analysis, the risk of death was higher for Haitians in Haiti than Haitians in Miami [HR 3.13 (CI 1.50-6.51)] and was higher for more advanced disease [HR 2.58 (CI 1.67-3.99)]. No other variable or interaction reached statistical significance in our model. Conclusion: Haitian women diagnosed with breast cancer in Haiti experience a significantly worse outcome than Haitians living in Miami that appears to be related to a more advanced stage, younger age, more ER negative tumors and lack of timely effective treatments including restricted access to trastuzumab and radiation. In addition there is a difference in the age of breast cancer onset (Caucasian 62, African American 58, Haitian American 55, Haitian 50) and ER positivity (Caucasian 70%, African American 48%, Haitian American 74%, Haitian 55%) depending on race and ethnic group that raises the question of whether there are disparities within subgroups of women of African origin who have breast cancer. Confounding epigenetic-related variables may impact survival and they need further exploration in these populations. Citation Format: Alexandra Gomez, Vincent DeGennaro, Jr., Sophia George, Estefania Santamaria, Gustavo Westin, Gabriel Dieudina, Judith Hurley. Presentation, treatment, and outcomes of Haitian women with breast cancer in Miami and Haiti: Disparities in breast cancer. A retrospective cohort study. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C55.

IntroductionHyperthermic isolated limb perfusion (HILP) has an established role in the management of melanoma, but its role for Merkel cell carcinoma (MCC) is less well defined.MethodsRetrospective review of our institutional experience with HILP for MCC was conducted (2009–2015). Literature search was performed through 04/2015 and 10 studies met inclusion criteria.ResultsFour patients underwent HILP for MCC at our institution. There were no major complications and complete response was achieved in all patients. Early metastatic recurrence developed in two patients. The remaining two had no evidence of disease at last follow‐up (36 months) or death (39 months). Systematic review identified an additional 12 pts that underwent HILP for MCC, for a total of 16 cases. Median age was 73 [IQR 69–78] years and 56% were men. Of the patients with reported follow‐up, 12 (86%) had complete response, 1 had stable disease, and 1 partial response. Four patients developed local–regional recurrence and six distant metastases, all within 6 months. Overall median follow‐up time was 15 [7–36] months.ConclusionAmong a highly selective group of patients, regional perfusion for MCC is safe and has a high complete response rate. HILP is an acceptable therapeutic modality for obtaining durable loco‐regional control but early distant metastatic disease remains a significant cause of mortality. J. Surg. Oncol. 2016;114:187–192. © 2016 Wiley Periodicals, Inc.

Engineered protein therapeutics offer advantages, including strong target affinity, selectivity and low toxicity, but like natural proteins can be susceptible to proteolytic degradation, thereby limiting their effectiveness. A compelling therapeutic target is mesotrypsin, a protease up-regulated with tumour progression, associated with poor prognosis, and implicated in tumour growth and progression of many cancers. However, with its unique capability for cleavage and inactivation of proteinaceous inhibitors, mesotrypsin presents a formidable challenge to the development of biological inhibitors. We used a powerful yeast display platform for directed evolution, employing a novel multi-modal library screening strategy, to engineer the human amyloid precursor protein Kunitz protease inhibitor domain (APPI) simultaneously for increased proteolytic stability, stronger binding affinity and improved selectivity for mesotrypsin inhibition. We identified a triple mutant APPIM17G/I18F/F34V, with a mesotrypsin inhibition constant (Ki) of 89 pM, as the strongest mesotrypsin inhibitor yet reported; this variant displays 1459-fold improved affinity, up to 350 000-fold greater specificity and 83-fold improved proteolytic stability compared with wild-type APPI. We demonstrated that APPIM17G/I18F/F34V acts as a functional inhibitor in cell-based models of mesotrypsin-dependent prostate cancer cellular invasiveness. Additionally, by solving the crystal structure of the APPIM17G/I18F/F34V–mesotrypsin complex, we obtained new insights into the structural and mechanistic basis for improved binding and proteolytic resistance. Our study identifies a promising mesotrypsin inhibitor as a starting point for development of anticancer protein therapeutics and establishes proof-of-principle for a novel library screening approach that will be widely applicable for simultaneously evolving proteolytic stability in tandem with desired functionality for diverse protein scaffolds.

OBJECTIVE Primary spinal osteosarcomas are rare and aggressive neoplasms. Poor outcomes can occur, as obtaining marginal margins is technically demanding; further Enneking-appropriate en bloc resection can have significant morbidity. The goal of this study is to identify prognostic variables for local recurrence and mortality in surgically treated patients diagnosed with a primary osteosarcoma of the spine. METHODS A multicenter ambispective database of surgically treated patients with primary spine osteosarcomas was developed by AOSpine Knowledge Forum Tumor. Patient demographic, diagnosis, treatment, perioperative morbidity, local recurrence, and cross-sectional survival data were collected. Tumors were classified in 2 cohorts: Enneking appropriate (EA) and Enneking inappropriate (EI), as defined by pathology margin matching Enneking-recommended surgical margins. Prognostic variables were analyzed in reference to local recurrence and survival. RESULTS Between 1987 and 2012, 58 patients (32 female patients) underwent surgical treatment for primary spinal osteosarcoma. Patients were followed for a mean period of 3.5 ± 3.5 years (range 0.5 days to 14.3 years). The median survival for the entire cohort was 6.7 years postoperative. Twenty-four (41%) patients died, and 17 (30%) patients suffered a local recurrence, 10 (59%) of whom died. Twenty-nine (53%) patients underwent EA resection while 26 (47%) patients underwent EI resection with a postoperative median survival of 6.8 and 3.7 years, respectively (p = 0.048). EI patients had a higher rate of local recurrence than EA patients (p = 0.001). Patient age, previous surgery, biopsy type, tumor size, spine level, and chemotherapy timing did not significantly influence recurrence and survival. CONCLUSIONS Osteosarcoma of the spine presents a significant challenge, and most patients die in spite of aggressive surgery. There is a significant decrease in recurrence and an increase in survival with en bloc resection (EA) when compared with intralesional resection (EI). The effect of adjuvant and neoadjuvant chemotherapeutics, as well as method of biopsy, requires further exploration.

Abstract Context: Type 2 diabetes is characterized by a β-cell deficit and a progressive defect in β-cell function. It has been proposed that the deficit in β-cells may be due to β-cell degranulation and transdifferentiation to other endocrine cell types. Objective: The objective of the study was to establish the potential impact of β-cell dedifferentiation and transdifferentiation on β-cell deficit in type 2 diabetes and to consider the alternative that cells with an incomplete identity may be newly forming rather than dedifferentiated. Design, Setting, and Participants: Pancreata obtained at autopsy were evaluated from 14 nondiabetic and 13 type 2 diabetic individuals, from four fetal cases, and from 10 neonatal cases. Results: Whereas there was a slight increase in islet endocrine cells expressing no hormone in type 2 diabetes (0.11 ± 0.03 cells/islet vs 0.03 ± 0.01 cells/islet, P < .01), the impact on the β-cell deficit would be minimal. Furthermore, we established that the deficit in β-cells per islet cannot be accounted for by an increase in other endocrine cell types. The distribution of hormone negative endocrine cells in type 2 diabetes (most abundant in cells scattered in the exocrine pancreas) mirrors that in developing (embryo and neonatal) pancreas, implying that these may represent newly forming cells. Conclusions: Therefore, although we concur that in type 2 diabetes there are endocrine cells with altered cell identity, this process does not account for the deficit in β-cells in type 2 diabetes but may reflect, in part, attempted β-cell regeneration.

OBJECT A chordoma is an indolent primary spinal tumor that has devastating effects on the patient's life. These lesions are chemoresistant, resistant to conventional radiotherapy, and moderately sensitive to proton therapy; however, en bloc resection remains the preferred treatment for optimizing patient outcomes. While multiple small and largely retrospective studies have investigated the outcomes following en bloc resection of chordomas in the sacrum, there have been few large-scale studies on patients with chordomas of the mobile spine. The goal of this study was to review the outcomes of surgically treated patients with mobile spine chordomas at multiple international centers with respect to local recurrence and survival. This multiinstitutional retrospective study collected data between 1988 and 2012 about prognosis-predicting factors, including various clinical characteristics and surgical techniques for mobile spine chordoma. Tumors were classified according to the Enneking principles and analyzed in 2 treatment cohorts: Enneking-appropriate (EA) and Enneking-inappropriate (EI) cohorts. Patients were categorized as EA when the final pathological assessment of the margin matched the Enneking recommendation; otherwise, they were categorized as EI. METHODS Descriptive statistics were used to summarize the data (Student t-test, chi-square, and Fisher exact tests). Recurrence and survival data were analyzed using Kaplan-Meier survival curves, log-rank tests, and multivariate Cox proportional hazard modeling. RESULTS A total of 166 patients (55 female and 111 male patients) with mobile spine chordoma were included. The median patient follow-up was 2.6 years (range 1 day to 22.5 years). Fifty-eight (41%) patients were EA and 84 (59%) patients were EI. The type of biopsy (p < 0.001), spinal location (p = 0.018), and if the patient received adjuvant therapy (p < 0.001) were significantly different between the 2 cohorts. Overall, 58 (35%) patients developed local recurrence and 57 (34%) patients died. Median survival was 7.0 years postoperative: 8.4 years postoperative for EA patients and 6.4 years postoperative for EI patients (p = 0.023). The multivariate analysis showed that the EI cohort was significantly associated with an increased risk of local recurrence in comparison with the EA cohort (HR 7.02; 95% CI 2.96–16.6; p < 0.001), although no significant difference in survival was observed. CONCLUSIONS EA resection plays a major role in decreasing the risk for local recurrence in patients with chordoma of the mobile spine.