Validation of the Preoperative Platelet-to-Lymphocyte Ratio as a Prognostic Factor in a European Cohort of Patients with Upper Tract Urothelial Carcinoma.

INTRODUCTION: This study is aimed at investigating the potential prognostic impact of the preoperatively assessed platelet-to-lymphocyte ratio (PLR) in a European cohort of patients with non-metastatic upper tract urothelial carcinoma (UTUC). MATERIALS AND METHODS: Clinicopathological data from 180 consecutive non-metastatic UTUC patients, operated between 1990 and 2012 at a single tertiary academic center, were evaluated retrospectively. The preoperative PLR was assessed one day before surgery. Patients were categorized using a PLR cut-off value according to receiver-operating curve analysis. Cancer-specific survival (CSS) and overall survival (OS) were assessed using the Kaplan-Meier method. Additionally, multivariate proportional Cox regression models were applied. RESULTS: In multivariate analyses, age at the date of surgery (<65 vs. ≥65 years, hazard ratio (HR) 1.827, 95% CI 1.051-3.175, p = 0.033), pathologic T-stage (pT1 vs. pT2-4, HR 1.873, 95% CI 1.066-3.292, p = 0.029), and pretreatment PLR (<150.0 vs. ≥150.0, HR 1.782, 95% CI 1.041-3.050, p = 0.035) were independent predictors of OS. Regarding CSS, pathologic T-stage (pT1 vs. pT2-4, HR 2.176, 95% CI 1.062-4.460, p = 0.034) and pretreatment PLR (<150.0 vs. ≥150.0, HR 2.026, 95% CI 1.045-3.930, p = 0.037) were considered independent predictors. CONCLUSIONS: In the cohort studied, patients with an elevated (≥150.0) preoperative PLR had a higher cancer-specific mortality and overall mortality after radical surgery for UTUC, compared with those with a low pretreatment PLR.

Preoperative Leucocytosis, Thrombocytosis and Anemia as Potential Prognostic Factors in Non-metastatic Renal Cell Carcinoma.

BACKGROUND: To validate the potential prognostic significance of preoperatively assessed inflammatory parameters leucocytosis, thrombocytosis and anemia in patients with non-metastatic renal cell carcinoma (RCC). MATERIALS AND METHODS: We retrospectively evaluated a cohort comprising 736 consecutive patients with non-metastatic RCC, operated on between 2004 and 2012 with curative radical or partial nephrectomy at a single tertiary academic centre. Laboratory parameters were assessed within one week before surgical intervention. Patients were categorized using laboratory parameter cut-off values according to receiver operating characteristics (ROC) analyses. Cancer-specific survival (CSS) was assessed using the Kaplan-Meier method. To evaluate the potential prognostic significance of the preoperative laboratory parameters, multivariate Cox regression models were applied. RESULTS: Multivariable analysis identified preoperative thrombocytosis (≥285,000/µl) as an independent prognostic factor for CSS (Hazard ratio=2.28, 95% confidence interval=1.24-4.20, p=0.008). CONCLUSION: Regarding CSS, an elevated preoperative platelet count represented an independent prognostic factor of poor survival. Our findings strengthen the potential prognostic significance of preoperative thrombocytosis in patients with non-metastatic RCC.

Designing a fully automated multi-bioreactor plant for fast DoE optimization of pharmaceutical protein production.

The identification of optimal expression conditions for state-of-the-art production of pharmaceutical proteins is a very time-consuming and expensive process. In this report a method for rapid and reproducible optimization of protein expression in an in-house designed small-scale BIOSTAT® multi-bioreactor plant is described. A newly developed BioPAT® MFCS/win Design of Experiments (DoE) module (Sartorius Stedim Systems, Germany) connects the process control system MFCS/win and the DoE software MODDE® (Umetrics AB, Sweden) and enables therefore the implementation of fully automated optimization procedures. As a proof of concept, a commercial Pichia pastoris strain KM71H has been transformed for the expression of potential malaria vaccines. This approach has allowed a doubling of intact protein secretion productivity due to the DoE optimization procedure compared to initial cultivation results. In a next step, robustness regarding the sensitivity to process parameter variability has been proven around the determined optimum. Thereby, a pharmaceutical production process that is significantly improved within seven 24-hour cultivation cycles was established. Specifically, regarding the regulatory demands pointed out in the process analytical technology (PAT) initiative of the United States Food and Drug Administration (FDA), the combination of a highly instrumented, fully automated multi-bioreactor platform with proper cultivation strategies and extended DoE software solutions opens up promising benefits and opportunities for pharmaceutical protein production.

A multi-bioreactor system for optimal production of malaria vaccines with Pichia pastoris.

The successful development of optimal multistage production processes for recombinant products with Pichia pastoris needs to meet three pre-conditions. These pre-conditions are (i) strategies for performing fully automated and observable processes, (ii) characterization of the host cell-specific reaction parameters in order to make an adapted process layout for feeding and aeration strategies, and (iii) knowledge of optimal operation parameter conditions for maximizing the expression productivity of target protein amount and/or quality. In this report, an approach of a fully automated multi-bioreactor plant is described that meets all these requirements. The expression and secretion of a potential malaria vaccine with Pichia pastoris was chosen as an example to demonstrate the quality of the bioreactor system. Methods for the simultaneous identification of reaction kinetics were developed for strain characterization. Process optimization was carried out by applying a sequential/parallel Design of Experiments. In the view of Process Analytical Technology (PAT)-applications and in order to develop fully automated and globally observable production processes, methods for quasi on-line monitoring of recombinant protein secretion titers and the immunological quality of the products are also discussed in detail.