Madhur Nayan

Angiopoietin-1-expressing adipose stem cells genetically modified with baculovirus nanocomplex: investigation in rat heart with acute infarction

The objective of this study was to develop angiopoietin-1 (Ang1)-expressing genetically modified human adipose tissue derived stem cells (hASCs) for myocardial therapy. For this, an efficient gene delivery system using recombinant baculovirus complexed with cell penetrating transactivating transcriptional activator TAT peptide/deoxyribonucleic acid nanoparticles (Bac-NP), through ionic interactions, was used. It was hypothesized that the hybrid Bac- NPAng1 system can efficiently transduce hASCs and induces favorable therapeutic effects when transplanted in vivo. To evaluate this hypothesis, a rat model with acute myocardial infarction and intramyocardially transplanted Ang1-expressing hASCs (hASC-Ang1), genetically modified by Bac-NPAng1, was used. Ang1 is a crucial pro-angiogenic factor for vascular maturation and neovasculogenesis. The released hAng1 from hASC-Ang1 demonstrated profound mitotic and anti-apoptotic activities on endothelial cells and cardiomyocytes. The transplanted hASC-Ang1 group showed higher cell retention compared to hASC and control groups. A significant increase in capillary density and reduction in infarct sizes were noted in the infarcted hearts with hASC-Ang1 treatment compared to infarcted hearts treated with hASC or the untreated group. Furthermore, the hASC-Ang1 group showed significantly higher cardiac performance in echocardiography (ejection fraction 46.28% ± 6.3%, P < 0.001 versus control, n = 8) than the hASC group (36.35% ± 5.7%, P < 0.01, n = 8), 28 days post-infarction. The study identified Bac-NP complex as an advanced gene delivery vehicle for stem cells and demonstrated its potential to treat ischemic heart disease with high therapeutic index for combined stem cell-gene therapy strategy.

Marrow stromal cells for cell-based therapy: the role of antiinflammatory cytokines in cellular cardiomyoplasty.

BACKGROUNDnThe mechanism by which marrow stromal cells (MSCs) improve cardiac function after myocardial infarction (MI) is still unclear. Because MI patients with lower circulating proinflammatory/antiinflammatory cytokine ratios have been reported to have a better prognosis and in vitro studies showed that MSCs express antiinflammatory cytokines, we hypothesized that changes in cytokine ratios in the infarct microenvironment after MSC therapy may play a role in improving early cardiac function after MI.nnnMETHODSnSixty-three rats that survived left coronary artery ligations were injected with culture media (group M) or MSCs (group C). Cardiac functional changes were assessed with echocardiography. Cytokine gene expressions of interleukin (IL)-1beta, IL-6, IL-8, (proinflammatory) and IL-10 (antiinflammatory) were quantified by real-time polymerase chain reaction. Extracellular matrix deposition, injury score, and the matrix metallopeptidase 2/tissue inhibitor of metallopeptidase 1 ratio were also analyzed.nnnRESULTSnThe ratio of proinflammatory/antiinflammatory cytokine gene expression was decreased in group C at various times, particularly in the early postoperative period. In group C, the matrix metallopeptidase 2/tissue inhibitor of metallopeptidase 1 gene expression ratio was significantly lower than group M at the early phase (12 hours), which in group C was translated into significantly lower extracellular matrix deposition at 24 hours, 1, and 2 weeks. Functional recovery was also significantly better in cell therapy group C.nnnCONCLUSIONSnOur data demonstrate that MSC therapy decreases the proinflammatory/antiinflammatory cytokine ratio in the microenvironment early after MI. This is associated with subsequent less scar formation and improved cardiac function.

Superior therapeutic potential of young bone marrow mesenchymal stem cells by direct intramyocardial delivery in aged recipients with acute myocardial infarction: in vitro and in vivo investigation.

Introduction. Bone-marrow-derived mesenchymal stem cells (MSCs) have been studied for treatment of myocardial infarction (MI). Since MSCs from older donors show quantitative and qualitative senescent changes, we hypothesized that a better outcome may be achieved if aged recipients are given MSCs obtained from young donors, rather than using their own autologous MSCs. Methods. In vitro studies compared properties of young and old MSCs. Aged rats randomized into 3 groups underwent coronary artery ligations and were then injected with either old (O) or young (Y) MSCs, or ligation alone. Echocardiography evaluated ejection fractions (EF). At 16 weeks, scar deposition was analyzed. Results. Old MSCs exhibited decreased cell viability, proliferation, and differentiation potentials. EF significantly improved early in both cell therapy groups (P < .05). However, at later stages of the study, group Y showed significantly better function which correlated with decreased scar deposition. Conclusions. The significant difference between young and old cells indicates the possible advantage for allotransplanting MSCs from young donors to elderly patients with MI.

Surgical Outcomes in the Management of Isolated Nodal Recurrences: A Multicenter, International Retrospective Cohort

PURPOSEnWe report a multicenter international cohort representing what is toxa0our knowledge the largest surgical experience with managing isolated retroperitoneal nodal recurrence of renal cell carcinoma, a unique subset of locoregional disease, yet to be described in detail.nnnMATERIALS AND METHODSnPatients with isolated nodal recurrence of pTanyN+M0 disease after nephrectomy were identified by retrospective chart review at 3 independent institutions. Progression-free survival was estimated by the Kaplan-Meier method and used to compare survival outcomes between primary T(1-2)N(any)M0 and T3N(any)M0 tumors as well as clear cell and nonclear cell histology renal cell carcinoma.nnnRESULTSnA total of 22 patients met study inclusion criteria. Median time to localxa0postoperative recurrence was 31.5 months (IQR 12.9-43.3). After resection of isolated nodal recurrence 10 patients (46%) had a secondary recurrence at axa0median of 11.2 months (IQR 8.1-18.4), of whom 2 (9%) died of the disease. Overall median progression-free survival was 12.7 months, including 24.8 months for T(1-2)N(any)M0 tumors, 9.9 months for T3N(any)M0 tumors, andxa013.4 and 17.6 months for clear and nonclear cell renal cell carcinoma, respectively.nnnCONCLUSIONSnSurgical resection represents the best curative option for patients who present with isolated retroperitoneal lymph node recurrence of renal cell carcinoma. Durable postoperative progression-free survival is attainable in many patients regardless of histology or clinical TNM stage. In addition, our cohort showed a lower renal cell carcinoma related mortality rate than in previous series of local metastasis. As such, all patients free of precluding comorbidities should be considered candidates for complete surgical resection performed by an experienced genitourinary surgeon.

PD53-07 CONDITIONAL RISK OF RELAPSE IN 3,601 PATIENTS MANAGED WITH SURVEILLANCE FOR STAGE I TESTICULAR CANCER

evaluated. Kaplan-Meier curves estimated 5, 10, and 15-year overall (OS) and cancer-specific survival (CSS). Men receiving frontline radiation therapy were identified, and Cox proportional hazards models estimated impact on OS and CSS. Log-binomial regression estimated risk of secondary malignancy after radiation therapy. Causes of death were quantified, and excess deaths from secondary malignancies associated with radiation therapy were identified. RESULTS: A total of 17830 men (median age 37, 76% Caucasian, 15% Hispanic) with testicular seminomas were included for survival analysis of whom 16969 (95%) had data on radiation therapy and no prior history of malignancy. Over 50% of men with stage 1A, 1B, and 2A seminoma underwent radiation therapy. Survival rates were generally excellent (10-year CSS 1A (99.5%), 1B (99.5%), 2A (98.2%), 2B (97.3%), 2C (96.8%), 1S (99.1%)); improvement in OS was observed with radiation therapy for stage 1 (HR 0.59 (95%CI 0.50-0.70), p<0.001)) and stage 2A (HR 0.29 (95%CI 0.13-0.67), p<0.004) disease. No benefit was observed for stage 2B (p1⁄40.70) and 2C (p1⁄40.91) disease. The most common causes of death were cardiovascular/peripheral vascular disease (N1⁄4131), testicular cancer (N1⁄4116), other cancer (N1⁄4115), and accident/suicide/homicide (N1⁄4107). Radiation increased risk of secondary malignancy (RR 1.78 (1.56-2.04), p<0.001) and relative proportion of deaths from other cancers (0.90% vs. 0.41% for no radiation) with most notable differences for respiratory (prevalence ratio (PR) 2.5), gastrointestinal (PR 1.7), lymphoma/leukemia (PR 1.5), and other visceral cancers. For stage 1A (radiation vs. no radiation), the increase in absolute proportion of deaths from other cancers (0.98% vs. 0.28%, p<0.001) was not offset by any reduction in cancer deaths (0.55% vs. 0.46%, p1⁄40.502). CONCLUSIONS: In a national sample of men, survival rates for testicular seminoma were excellent with increased incidence of secondary malignancies associated with radiation therapy. While deaths due to other cancers was increased, the relative survival benefit of radiation therapy for stage 1B, 1S, and 2A testicular seminoma appeared to outweigh the risks but not for stage 1A.

The value of complementing administrative data with abstracted information on smoking and obesity: A study in kidney cancer

INTRODUCTIONnVariables, such as smoking and obesity, are rarely available in administrative databases. We explored the added value of including these data in an administrative database study evaluating the association of statin use with survival in kidney cancer.nnnMETHODSnWe linked administrative data with chart-abstracted data on smoking and obesity for 808 patients undergoing nephrectomy for kidney cancer. Base models consisted of variables from administrative databases (age, sex, year of surgery, and different measures of comorbidity [to compare their sensitivity to smoking and obesity data]); extended models added chart-abstracted data. We compared coefficients for statin use with overall (OS) and cancer-specific survival (CSS), and used the c-statistic and net reclassification improvement (NRI) to compare predications of five-year survival obtained from Cox proportional hazard models.nnnRESULTSnThe coefficient for statin use changed minimally following addition of abstracted data (<6% for OS, <2% for CSS). Base models performed similarly for OS, with c-statistics of 0.75 (95% confidence interval [CI] 0.72-0.79) for Charlson score and 0.73 (95% CI 0.69-0.78) for John Hopkins Aggregated Diagnosis Groups score. After including abstracted data, c-statistics modestly improved (change <0.02); CSS demonstrated similar findings. NRIs were 0.210 (95% CI 0.062-0.297) and 0.186 (-0.031-0.387) when using the Charlson score, and 0.207 (0.068-0.287) and 0.197 (0.007-0.399) when using the Aggregated Diagnosis Groups score, for OS and CSS, respectively.nnnCONCLUSIONSnThe inclusion of data on smoking and obesity marginally influences survival models in kidney cancer studies using administrative data.

MP19-11 THE EFFECT OF ETHNICITY AND RACE ON SEMEN ANALYSIS AND HORMONES IN THE INFERTILE PATIENT

METHODS Study Design and Setting: • Population based, prospectively collected retrospective study using patient survey and laboratory data (2008-2017) • All men who presented a single tertiary institution for male infertility work-up Questionnaire: • Self-reported questionnaire to collect data on: •Demographics & clinical history Ethnicities: • Caucasian • Native-Canadian • African-Canadian • Hispanic • Asian • Middle Eastern • Indo-Canadian Semen Parameters: • Assessed using 2010 World Health Organization Criteria • Recorded parameters included •Volume •Count •Morphology •Motility •Vitality Hormone Levels • Total Testosterone (nmol/L) • FSH levels (mIU/ml) Statistical Analysis: • Reported medians (IQR) and frequencies (count) for demographics • Linear regression for ethnicity and hormonal profiles • Multivariate logistic regression for ethnicity and semen parameters OBJECTIVE • To determine if race and ethnicity have any impact on semen analysis or baseline hormonal profiles for men with infertility

PD52-07 MEDICATION USE AND KIDNEY CANCER RISK: A POPULATION-BASED STUDY

CONCLUSIONS: Based on the proposed model, it is possible to accurately estimate the risk of positive BS at kidney cancer staging using pre-operative characteristics. If BS is performed only when the risk of positive result is >5%, a negative BS is spared in 80% of the population and a positive BS is missed in 2% of the population only. When compared to decision-making based on symptoms only, which represents the strategy recommended by available guidelines, the proposed model resulted more objective, statistically more accurate and clinically associated with higher net benefit. These figures support an update of the available guidelines.