Anti-colorectal cancer immunity : control ‘the force’!

This dissertation reports on the relation between the immune system, colorectal cancer and immunotherapy. In the first part, expression of HLA class I and expression of CXCL5 in colocectal cancer was studied. Low expression of HLA class I in rectal tumors was associated with poor survival of rectal cancer patients. Low expression of CXCL5 in cancer cells was significantly associated with poor prognosis in a population of colorectal cancer patients and correlated with presence of intra-tumoral CD8+ T-cell infiltration. In the second part of this thesis we focused on induction of tumor specific T-cells. For immunotherapeutic purposes distinction should be made between microsatellite instable (MSI-H) and microsatellite stable (MSS) colorectal tumors, as MSI-H tumors express neo-antigens __foreign__ to the immune system while immunotherapy against MSS tumors depends on tumor associated __self__-antigens. We developed a methodology predicting immunogenic behavior of frameshift-mutated antigens present in MSI-H tumors that was based on accumulation and MHC class I presentation. This method can be used to develop cancer immunotherapy of patients at risk for MSI-H tumors. In the last two chapters we described safety and immunogenicity of a p53 synthetic long peptides vaccine combined with and without Interferon-alpha. Addition of IFN-_ to the p53-SLP_ vaccine significantly improved p53-specific after vaccination. Altogether this dissertation reports on the relation between the immune system, colorectal cancer and immunotherapy. This knowledge can be used to further optimize immunotherapeutic strategies to treat cancer patients.UBL - phd migration 201

A data-based reduced-order model for dynamic simulation and control of district-heating networks

This study concerns the development of a data-based compact model for the prediction of the fluid temperature evolution in district heating (DH) pipeline networks. This so-called “reduced-order model” (ROM) is obtained from reduction of the conservation law for energy for each pipe segment to a semi-analytical input–output relation between the pipe outlet temperature and the pipe inlet and ground temperatures that can be identified from training data. The ROM basically is valid for generic pipe configurations involving 3D unsteady heat transfer and 3D steady flow as long as heat-transfer mechanisms are linearly dependent on the temperature field. Moreover, the training data can be generated by physics-based computational “full-order” models (FOMs) yet also by (calibration) experiments or field measurements. Performance tests using computational training data for a single-pipe configuration demonstrate that the ROM (i) can be successfully identified and (ii) can accurately describe the response of the outlet temperature to arbitrary input profiles for inlet and ground temperatures. Application of the ROM to two case studies, i.e. fast simulation of a small DH network and design of a controller for user-defined temperature regulation of a DH system, demonstrate its predictive ability and efficiency also for realistic systems. Dedicated cost analyses further reveal that the ROM may significantly reduce the computational costs compared to FOMs by (up to) orders of magnitude for higher-dimensional pipe configurations. These findings advance the proposed ROM as a robust and efficient simulation tool for practical DH systems with a far greater predictive ability than existing compact models

Numerical model of the Tikitere geothermal system

The Tikitere geothermal field is one of the 21 high-enthalpy geothermal fields in the Taupo Volcanic Zone (TVZ) in New Zealand. The field is renowned for the tourist attraction Hell’s Gate, which consists of many natural geothermal surface features. Based on geoscientific data from the open-source literature, a conceptual model was set up in Leapfrog Geothermal. A corresponding natural state reservoir model was then set up and calibrated using temperature and heat flux data from fourteen thermal areas. The calibrated numerical model matches the higher temperatures at the locations of some of the surface thermal features but does not match the estimated heat flows

Numerical model of the Tikitere geothermal system

The Tikitere geothermal field is one of the 21 high-enthalpy geothermal fields in the Taupo Volcanic Zone (TVZ) in New Zealand. The field is renowned for the tourist attraction Hell’s Gate, which consists of many natural geothermal surface features. Based on geoscientific data from the open-source literature, a conceptual model was set up in Leapfrog Geothermal. A corresponding natural state reservoir model was then set up and calibrated using temperature and heat flux data from fourteen thermal areas. The calibrated numerical model matches the higher temperatures at the locations of some of the surface thermal features but does not match the estimated heat flows

Survival analysis of 3 different age groups and prognostic factors among 402 patients with skeletal high-grade osteosarcoma: real world data from a single tertiary sarcoma center

Simple SummaryAge is one of many prognostic factors for overall survival in patients with skeletal osteosarcoma. This retrospective study provides an overview of survival in patients with high-grade osteosarcoma in different age groups. It shows prognostic variables for survival and local control among the overall cohort. In this study, in which 402 patients with skeletal high-grade osteosarcoma were included, poor survival was associated with increasing age. Age groups, tumor size, poor histopathological response, distant metastasis at presentation, and local recurrence were independent prognostic factors associated to overall survival and event-free survival. Differences in outcome among different age groups can be partially explained by patient characteristics and treatment characteristics.Age is a known prognostic factor for many sarcoma subtypes, however in the literature there are limited data on the different risk profiles of different age groups for osteosarcoma survival. This study aims to provide an overview of survival in patients with high-grade osteosarcoma in different age groups and prognostic variables for survival and local control among the entire cohort. In this single center retrospective cohort study, 402 patients with skeletal high-grade osteosarcoma were diagnosed and treated with curative intent between 1978 and 2017 at the Leiden University Medical Center (LUMC). Prognostic factors for survival were analyzed using a Cox proportional hazard model. In this study poor overall survival (OS) and event-free survival (EFS) were associated with increasing age. Age groups, tumor size, poor histopathological response, distant metastasis (DM) at presentation and local recurrence (LR) were important independent prognostic factors influencing OS and EFS. Differences in outcome among different age groups can be partially explained by patient and treatment characteristics.Experimentele farmacotherapi

Combining melphalan percutaneous hepatic perfusion with ipilimumab plus nivolumab in advanced uveal melanoma: first safety and efficacy data from the phase Ib part of the Chopin trial

Purpose To define a safe treatment dose of ipilimumab (IPI) and nivolumab (NIVO) when applied in combination with percutaneous hepatic perfusion with melphalan (M-PHP) in metastatic uveal melanoma (mUM) patients (NCT04283890), primary objective was defining a safe treatment dose of IPI/NIVO plus M-PHP. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.03 (CTCAEv4.03). Secondary objective was response rate, PFS and OS.Materials and Methods Patients between 18-75 years with confirmed measurable hepatic mUM according to RECIST 1.1 and WHO performance score 0-1 were included. Intravenous IPI was applied at 1 mg/kg while NIVO dose was increased from 1 mg/kg in cohort 1 to 3 mg/kg in cohort 2. Transarterial melphalan dose for M-PHP was 3 mg/kg (maximum of 220 mg) in both cohorts. Treatment duration was 12 weeks, consisting of four 3-weekly courses IPI/NIVO and two 6-weekly M-PHPs.Results Seven patients were included with a median age of 63.6 years (range 50-74). Both dose levels were well tolerated without dose-limiting toxicities or deaths. Grade III/IV adverse events (AE) were observed in 2/3 patients in cohort 1 and in 3/4 patients in cohort 2, including Systemic Inflammatory Response Syndrome (SIRS), febrile neutropenia and cholecystitis. Grade I/II immune-related AEs occurred in all patients, including myositis, hypothyroidism, hepatitis and dermatitis. There were no dose-limiting toxicities. The safe IPI/NIVO dose was defined as IPI 1 mg/kg and NIVO 3 mg/kg. There was 1 complete response, 5 partial responses and 1 stable disease (3 ongoing responses with a median FU of 29.1 months).Conclusion Combining M-PHP with IPI/NIVO was safe in this small cohort of patients with mUM at a dose of IPI 1 mg/kg and NIVO 3 mg/kg.Radiolog

Linear vs nonlinear transport during chaotic advection in fluid flows

Goal is explicit demarcation of the region of validity of a linear canonical representation for chaotic advection of Lagrangian fluid parcels in "chaotic seas" in two-dimensional (2D) and three-dimensional (3D) time-periodic fluid flows governed by Hamiltonian mechanics. The concept of lobe dynamics admits exact and unique geometric demarcation of this region and, inherently, distinction of the portions of chaotic seas with essentially linear versus nonlinear Lagrangian transport. This furthermore admits explicit establishment of a topological equivalence between the (embedded) Hamiltonian structure of the Lagrangian dynamics in 2D (3D) flows and their canonical form. The linear transport region in physical space encompasses four adjacent subregions that each correspond with one of the four quadrants in canonical space and may exchange material with their environment in two essentially nonlinear ways. First, exchange between quadrants within the linear transport region and, second, exchange with the exterior of this region. Both forms of exchange can be linked to specific subsets of material elements defined by interacting lobes and combined give rise to a circulation through the quadrants of the linear transport region that systematically exchanges material with the exterior

Comment re: Intratumoral Immune Reaction in Human Colorectal Cancer

Surgical oncolog

Rapid thermalization by adaptive flow reorientation

Aim of this paper is the enhancement of scalar transport (heat, chemical species) in flow systems with reorientations of a laminar base flow. Conventional heating/mixing protocols comprise of temporal or spatial periodic reorientations of these base flows to promote fluid mixing. However, thermal homogenisation rates of scalar fields are not necessarily accelerated with these approaches due to the substantial effect of diffusion and/or chemical reactions on heat/chemical transport. In the present study we numerically study heat transport with an adaptive approach for an entire parameter space of fluid and flow properties. Key to the approach is real-time control of the fluid flow based on the scalar field due to an efficient numerical model. Results show that the adaptive approach can significantly enhance heat transport over the conventional periodic heating/mixing approach designed for efficient mixing