Improving outcomes in patients with perihilar cholangiocarcinoma

The aim of this thesis was to investigate how to improve outcomes in patients with perihilar cholangiocarcinoma (pCCA). To achieve this, several topics including resection margin, lymph node status, additional resection, preoperative (chemo) therapy and follow-up methods were covered. In Chapter 1, we gave an introduction on how to improve outcome in patients with pCCA. After imaging and defining resectability, the first step towards optimal surgical treatment is optimizing biliary drainage and preventing cholangitis, followed by securing adequate future liver remnant volume and/or function. The main goal of resection for pCCA is achieving radical resection and ultimately long-term survival. In Chapter 2, we described the long-term outcomes of patients with initially resectable pCCA who were randomized between endoscopic (EBD) and percutaneous biliary drainage (PTBD) in the DRAINAGE trial. This study demonstrates the complexity of biliary drainage for patients with potentially resectable pCCA. To date, the decision whether a patient seems resectable is based on expert opinion and decided by consensus. Resectability is based on preoperative imaging and actual resectability is determined during surgical exploration. Unfortunately, 10 to 30 % turns out to have unresectable disease during exploration due to more extensive disease than expected on imaging. Preoperative chemotherapy may downstage and convert unresectable tumors to resectable. However, in order to allocate patients for the best possible treatment, (e.g. resection, preoperative (chemo) therapy, or palliative (chemo) therapy) universal, widely implemented, and reproducible resectability criteria are needed. Therefore a study using the modified Delphi method, including Thirteen HPB-surgeons, from six tertiary referral centers in the Netherlands, was presented in Chapter 3. In Chapter 4, a systematic literature review is described. In this study we aimed to investigate the efficacy and safety of systemic induction therapy in initially unresectable locally advanced pCCA and intrahepatic cholangiocarcinoma (iCCA) and summarized resectability criteria used across these studies. In Chapter 5, a retrospective cohort study towards the potential of gemcitabine and cisplatin chemotherapy as future preoperative therapy for patients with unresectable locally advanced or borderline resectable iCCA, pCCA, and mid-cholangiocarcinoma is discussed. Unresectable patients or patients with recurrent disease are treated with palliative chemotherapy consisting of gemcitabine and cisplatin. Unfortunately, a large variation in treatment response within these patients exists. In Chapter 6, we investigated the Human Equilibrative Nucleoside Transporter 1 (hENT1) biomarker. hENT1 is considered a potential predictive biomarker for chemotherapy efficacy, its prognostic value is however still under debate. Currently, the potential benefits of additional resection after positive proximal intraoperative frozen sections (IFS) in pCCA on residual disease and oncological outcome remain uncertain. Therefore, in Chapter 7 a retrospective, multicenter, matched case-control study was performed. Lymph node metastasis and positive resection margins have been reported to be major determinants of overall survival and poor recurrence-free survival for patients after resection for pCCA. Therefore the aim of the study described in Chapter 8 was to assess the prognostic value of positive lymph nodes and resection margin status on OS. Currently, There is no evidence to support the structured use of imaging or biomarkers in the follow-up of patients after curative resection of biliary tract cancer (BTC). structured follow-up could cause recurrence to be noticed in an earlier stage. Which could ensure a better performance status of these patients, leading to a quick start with palliative chemotherapy ultimately prolonging survival. In Chapter 9 two follow-up strategies for resected BTC are investigated

Automatic discovery of data-centric and artifact-centric processes

Process discovery is a technique that allows for automatically discovering a process model from recorded executions of a process as it happens in reality. This technique has successfully been applied for classical processes where one process execution is constituted by a single case with a unique case identifier. Data-centric and artifact-centric systems such as ERP systems violate this assumption. Here a process execution is driven by process data having various notions of interrelated identifiers that distinguish the various interrelated data objects of the process. Classical process mining techniques fail in this setting. This paper presents a fully automatic technique for discovering for each notion of data object in the process a separate process model that describes the evolution of this object, also known as artifact life-cycle model. Given a relational database that stores process execution information of a data-centric system, the technique extracts event information, case identifiers and their interrelations, discovers the central process data objects and their associated events, and decomposes the data source into multiple logs, each describing the cases of a separate data object. Then classical process discovery techniques can be applied to obtain a process model for each object. The technique is implemented and has been evaluated on the production ERP system of a large retailer

A perturbative approach to multireference equation-of-motion coupled cluster

We introduce a variant of the multireference equation-of-motion coupled-cluster (MR-EOMCC) method where the amplitudes used for the similarity transformations are estimated from perturbation theory. Consequently, the new variant retains the many-body formalism, a reliance on at most two-body densities, and the state-universal character. As a non-iterative variant, computational costs are reduced, and no convergence difficulties with near-singular amplitudes can arise. Its performance was evaluated on several test sets covering transition metal atoms, small diatomics, and organic molecules against (near-)full CI quality reference data. We further highlight its efficacy on the weakly avoided crossing of LiF and place MR-EOMCC and the new variant into context with linear response theory. The accuracy of the variant was found to be at least on par with expectations for multireference perturbation theories, judging by the NEVPT2 method. The variant can be especially useful in multistate situations where the high accuracy of the iterative MR-EOMCC method is not required

Reference Dependence of the Two-determinant Coupled-cluster Method for Triplet and Open-shell Singlet States of Biradical Molecules

We study the performance of the two-determinant (TD) coupled-cluster (CC) method which, unlike conventional ground-state single-reference (SR) CC methods, can, in principle, provide a naturally spin-adapted treatment of the lowest-lying open-shell singlet (OSS) and triplet electronic states. Various choices for the TD-CC reference orbitals are considered, including those generated by the multi-configurational self-consistent field method. Comparisons are made with the results of high-level SR-CC, equation-of-motion (EOM) CC, and multi-reference EOM calculations performed on a large test set of over 100 molecules with low-lying OSS states. It is shown that in cases where the EOMCC reference function is poorly described, TD-CC can provide a significantly better quantitative description of OSS total energies and OSS-triplet splittings

Gait quality is improved by locomotor training in individuals with SCI regardless of training approach

<p>Abstract</p> <p>Background</p> <p>While various body weight supported locomotor training (BWSLT) approaches are reported in the literature for individuals with spinal cord injury (SCI), none have evaluated outcomes in terms of gait quality. The purpose of this study was to compare changes in measures of gait quality associated with four different BWSLT approaches in individuals with chronic motor-incomplete SCI, and to identify how gait parameters differed from those of non-disabled (ND) individuals.</p> <p>Methods</p> <p>Data were analyzed from 51 subjects with SCI who had been randomized into one of four BWSLT groups: treadmill with manual assistance (TM), treadmill with electrical stimulation (TS), overground with electrical stimulation (OG), treadmill with locomotor robot (LR). Subjects with SCI performed a 10-meter kinematic walk test before and after 12 weeks of training. Ten ND subjects performed the test under three conditions: walking at preferred speed, at speed comparable to subjects with SCI, and with a walker at comparable speed. Six kinematic gait quality parameters were calculated including: cadence, step length, stride length, symmetry index, intralimb coordination, and timing of knee extension.</p> <p>Results</p> <p>In subjects with SCI, all training approaches were associated with improvements in gait quality. After training, subjects with SCI walked at higher cadence and had longer step and stride lengths. No significant differences were found among training groups, however there was an interaction effect indicating that step and stride length improved least in the LR group. Compared to when walking at preferred speed, gait quality of ND subjects was significantly different when walking at speeds comparable to those of the subjects with SCI (both with and without a walker). Post training, gait quality measures of subjects with SCI were more similar to those of ND subjects.</p> <p>Conclusion</p> <p>BWSLT leads to improvements in gait quality (values closer to ND subjects) regardless of training approach. We hypothesize that the smaller changes in the LR group were due to the passive settings used for the robotic device. Compared to walking at preferred speed, gait quality values of ND individuals walking at a slower speed and while using a walker were more similar to those of individuals with SCI.</p

Promoting physical activity in persons with subacute spinal cord injury

Abstract Introduction: After discharge from inpatient rehabilitation, physical activity levels in persons with spinal cord injury (SCI) are known to decline. Primary objective: To evaluate the added value of a behavioral intervention promoting an active lifestyle after discharge from inpatient rehabilitation. Design: Randomized controlled trial, multi-center, longitudinal Patients: Thirty-nine persons with subacute SCI (33% tetraplegia, 62% motor-complete, 150±74 days post injury), dependent on a manual wheelchair. Methods: The intervention and control group both received regular rehabilitation and a handcycle training program. Only the intervention group received a behavioral intervention, involving 13 individual sessions beginning two months before and ending six months after discharge, delivered by a coach trained in motivational interviewing. Outcome measures were objectively measured physical activity, health-related outcomes, participation and quality of life. Measurements were performed at baseline, discha