Dissecting the Evolving Risk of Relapse over Time in Surveillance for Testicular Cancer

Testicular cancer is the most common malignancy in young men, and the incidence is increasing in most countries worldwide. The vast majority of patients present with clinical stage I disease, and surveillance is being increasingly adopted as the preferred management strategy. At the time of diagnosis, patients on surveillance are often counselled about their risk of relapse based on risk factors present at diagnosis, but this risk estimate becomes less informative in patients that have survived a period of time without experiencing relapse. Conditional survival estimates, on the other hand, provide information on a patient’s evolving risk of relapse over time. In this review, we describe the concept of conditional survival and its applications for surveillance of clinical stage I seminoma and nonseminoma germ cell tumours. These estimates can be used to tailor surveillance protocols based on future risk of relapse within risk subgroups of seminoma and nonseminoma, which may reduce the burden of follow-up for some patients, physicians, and the health care system. Furthermore, conditional survival estimates provide patients with a meaningful, evolving risk estimate and may be helpful to reassure patients and reduce potential anxiety of being on surveillance

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

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

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

Chemoprevention in Kidney Cancer

Background: This thesis is a composition of three studies that explore the role of statins in kidney cancer. Furthermore, I evaluate the potential for different interpretations from the same data depending on the method of classifying medication use. Methods: The first study was a population-based case-control study evaluating the association of statin use with risk of incident kidney cancer. The second study was a systematic review and meta-analysis reviewing the current evidence relating statins with kidney cancer survival outcomes. The final study was a population-based cohort study evaluating the association of statin use with survival. In the observational studies, I used fractional polynomials for the primary analysis to allow for a non-linear relationship between cumulative exposure and the risk of the outcome. I also compared risk estimates obtained by different methods of classifying medication exposure. Results: The population-based case-control study included 10,377 incident cases of kidney cancer and 35,939 matched controls. Increasing cumulative use of statins was not associated with kidney cancer risk. I identified 12 studies for inclusion in the systematic review and meta-analysis and found that statin use was significantly associated with markedly improved cancer-specific and overall survival. However, none of these studies evaluated cumulative use. In the population-based cohort study of 9124 patients with incident kidney cancer, increasing cumulative use of statins was associated with minimal improvement in cancer-specific and overall survival. The association of statin use with kidney cancer risk or survival varied depending on the method of classifying exposure. Conclusions: This thesis does not support the use of statins for the prevention or adjunctive treatment in kidney cancer. Furthermore, risk estimates in pharmacoepidemiology may be sensitive to the method of classifying exposure.Ph.D

The effect of metformin on cancer-specific survival outcomes in diabetic patients undergoing radical cystectomy for urothelial carcinoma of the bladder

PURPOSE Metformin, a first-line oral therapy for diabetes, has anticancer properties. Our objective was to evaluate the association between metformin use and oncologic outcomes in diabetic patients undergoing radical cystectomy (RC) for bladder cancer (BC). METHODS A single-institution retrospective cohort (January 1997-June 2013) of diabetic patients undergoing RC was assembled. Medication use was assessed at time of surgery. Outcome measures were recurrence-free survival (RFS), BC-specific survival (BCSS), and overall survival (OS). Multivariable Cox proportional hazards models were used. To create parsimonious models, the change of estimate approach (10% threshold) was used as a variable selection strategy for final model inclusion separately for each outcome measure. RESULTS Of 421 patients, 85 (20%) had diabetes. There were 39 (46%) patients on metformin therapy. Among diabetic patients, there were 21 patients with BC recurrence, 16 who died of BC, and 30 who died overall. In univariate analyses, metformin use among diabetic patients was associated with improved RFS (hazard ratio = 0.54, 95% CI: 0.33-0.88, P = 0.013) and trended toward improved BCSS (hazard ratio = 0.65, 95% CI: 0.40-1.07, P = 0.087), but not with OS (P = 0.87). In multivariable models, metformin use among diabetic patients was associated with significantly improved RFS (adjusted hazard ratio = 0.38, 95% CI: 0.20-0.72, P = 0.003) and BCSS (adjusted hazard ratio = 0.57, 95% CI: 0.35-0.91, P = 0.019), but not with OS (P = 0.89). Use of other oral hypoglycemic agents or insulin was not associated with oncologic outcomes. CONCLUSIONS Our study is among the first to report an association between metformin use and improved RFS and BCSS in diabetic patients undergoing RC. Given its low cost and demonstrated safety among nondiabetic patients, further studies are warranted to evaluate potential therapeutic and preventive roles of metformin in BC

The initiation of a multidisciplinary bladder cancer clinic and the uptake of neoadjuvant chemotherapy: A time-series analysis

INTRODUCTION: While level 1 evidence supports the use of neoadjuvant chemotherapy (NAC) for patients with muscle-invasive bladder cancer (MIBC), its uptake has been underwhelming, even in academic centres. Our aim was to determine if the initiation of a multidisciplinary bladder cancer clinic (MDBCC) in 2008 at our institution, where patients are assessed simultaneously by bladder cancer-focused urologists and radiation oncologists with easy access to a medical oncologist, was associated with an increased use of NAC. METHODS: Patients with MIBC initiating treatment between July 2000 and June 2013 were identified and classified by academic year (July 1 to June 30). Time-series analyses using interventional autoregressive integrated moving average (ARIMA) models with ramp intervention functions were then conducted. A sensitivity analysis was performed on clinical N0 patients. RESULTS: The cohort included 278 patients: 168 from 2000-2007 and 110 from 2008-2012 (academic years). Forty-two (15.1%) patients received NAC and 74 (26.6%) received adjuvant chemotherapy (AC). Overall the proportion of patients receiving NAC increased from 7.7% before the MDBCC to 47.6% in 2012 (Interventional ARIMA p=0.036). The results were similar when restricting to cN0 patients (p<0.001). NAC use gradually increased over time regardless of MDBCC attendance, although the proportion of patients receiving NAC appears to have risen more sharply among MDBCC attendees. CONCLUSIONS: At our institution, the initiation of the MDBCC was temporally associated with increased use of NAC. In addition to multidisciplinary collaboration, having a critical mass of NAC physician advocates and support from institutional leaders are essential to the uptake of NAC