Rectal cancer : developments in multidisciplinary treatment, quality control and European collaboration

In the last two decades, treatment of rectal cancer has considerably improved in Europe. Although this applies to most solid malignancies, improvements in the diagnosis and treatment of rectal cancer surpass virtually all others. In the early 1990s, outcome after rectal cancer treatment was poor, with survival and recurrence rates of approximately 45%.1 Nowadays, survival after rectal cancer is sometimes even better than after colon cancer.2 While radiotherapy and chemoradiotherapy play an important role in the current, multidisciplinary treatment of rectal cancer, surgery remains the inevitable cornerstone for cure. For each and every improvement in surgical techniques, (neo)adjuvant treatment schedules, imaging and pathology, clinical trials and population-based audit registrations have played a crucial role. The aim of this thesis is to contribute to further improvements in rectal cancer treatment by investigating the multidisciplinary treatment forms, quality control and European collaboration.UBL - phd migration 201

Curation and expansion of the Human Phenotype Ontology for systemic autoinflammatory diseases improves phenotype-driven disease-matching

INTRODUCTION: Accurate and standardized phenotypic descriptions are essential in diagnosing rare diseases and discovering new diseases, and the Human Phenotype Ontology (HPO) system was developed to provide a rich collection of hierarchical phenotypic descriptions. However, although the HPO terms for inborn errors of immunity have been improved and curated, it has not been investigated whether this curation improves the diagnosis of systemic autoinflammatory disease (SAID) patients. Here, we aimed to study if improved HPO annotation for SAIDs enhanced SAID identification and to demonstrate the potential of phenotype-driven genome diagnostics using curated HPO terms for SAIDs. METHODS: We collected HPO terms from 98 genetically confirmed SAID patients across eight different European SAID expertise centers and used the LIRICAL (Likelihood Ratio Interpretation of Clinical Abnormalities) computational algorithm to estimate the effect of HPO curation on the prioritization of the correct SAID for each patient. RESULTS: Our results show that the percentage of correct diagnoses increased from 66% to 86% and that the number of diagnoses with the highest ranking increased from 38 to 45. In a further pilot study, curation also improved HPO-based whole-exome sequencing (WES) analysis, diagnosing 10/12 patients before and 12/12 after curation. In addition, the average number of candidate diseases that needed to be interpreted decreased from 35 to 2. DISCUSSION: This study demonstrates that curation of HPO terms can increase identification of the correct diagnosis, emphasizing the high potential of HPO-based genome diagnostics for SAIDs

EURECCA colorectal: multidisciplinary mission statement on better care for patients with colon and rectal cancer in Europe

Background: Care for patients with colon and rectal cancer has improved in the last twenty years however still considerable variation exists in cancer management and outcome between European countries. Therefore, EURECCA, which is the acronym of European Registration of cancer care, is aiming at defining core treatment strategies and developing a European audit structure in order to improve the quality of care for all patients with colon and rectal cancer. In December 2012 the first multidisciplinary consensus conference about colon and rectum was held looking for multidisciplinary consensus. The expert panel consisted of representatives of European scientific organisations involved in cancer care of patients with colon and rectal cancer and representatives of national colorectal registries. Methods: The expert panel had delegates of the European Society of Surgical Oncology (ESSO), European Society for Radiotherapy & Oncology (ESTRO), European Society of Pathology (ESP), European Society for Medical Oncology (ESMO), European Society of Radiology (ESR), European Society of Coloproctology (ESCP), European CanCer Organisation (ECCO), European Oncology Nursing Society (EONS) and the European Colorectal Cancer Patient Organisation (EuropaColon), as well as delegates from national registries or audits. Experts commented and voted on the two web-based online voting rounds before the meeting (between 4th and 25th October and between the 20th November and 3rd December 2012) as well as one online round after the meeting (4th-20th March 2013) and were invited to lecture on the subjects during the meeting (13th-15th December 2012). The sentences in the consensus document were available during the meeting and a televoting round during the conference by all participants was performed. All sentences that were voted on are available on the EURECCA website www.canceraudit.eu. The consensus document was divided in sections describing evidence based algorithms of diagnostics, pathology, surgery, medical oncology, radiotherapy, and follow-up where applicable for treatment of colon cancer, rectal cancer and stage IV separately. Consensus was achieved using the Delphi method. Results: The total number of the voted sentences was 465. All chapters were voted on by at least 75% of the experts. Of the 465 sentences, 84% achieved large consensus, 6% achieved moderate consensus, and 7% resulted in minimum consensus. Only 3% was disagreed by more than 50% of the members. Conclusions: It is feasible to achieve European Consensus on key diagnostic and treatment issues using the Delphi method. This consensus embodies the expertise of professionals from all disciplines involved in the care for patients with colon and rectal cancer. Diagnostic and treatment algorithms were developed to implement the current evidence and to define core treatment guidance for multidisciplinary team management of colon and rectal cancer throughout Europe

Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Rectal cancer : developments in multidisciplinary treatment, quality control and European collaboration

In the last two decades, treatment of rectal cancer has considerably improved in Europe. Although this applies to most solid malignancies, improvements in the diagnosis and treatment of rectal cancer surpass virtually all others. In the early 1990s, outcome after rectal cancer treatment was poor, with survival and recurrence rates of approximately 45%.1 Nowadays, survival after rectal cancer is sometimes even better than after colon cancer.2 While radiotherapy and chemoradiotherapy play an important role in the current, multidisciplinary treatment of rectal cancer, surgery remains the inevitable cornerstone for cure. For each and every improvement in surgical techniques, (neo)adjuvant treatment schedules, imaging and pathology, clinical trials and population-based audit registrations have played a crucial role. The aim of this thesis is to contribute to further improvements in rectal cancer treatment by investigating the multidisciplinary treatment forms, quality control and European collaboration

Rectal cancer: developments in multidisciplinary treatment, quality control and European collaboration

In the last two decades, treatment of rectal cancer has considerably improved in Europe. Although this applies to most solid malignancies, improvements in the diagnosis and treatment of rectal cancer surpass virtually all others. In the early 1990s, outcome after rectal cancer treatment was poor, with survival and recurrence rates of approximately 45%.1 Nowadays, survival after rectal cancer is sometimes even better than after colon cancer.2 While radiotherapy and chemoradiotherapy play an important role in the current, multidisciplinary treatment of rectal cancer, surgery remains the inevitable cornerstone for cure. For each and every improvement in surgical techniques, (neo)adjuvant treatment schedules, imaging and pathology, clinical trials and population-based audit registrations have played a crucial role. The aim of this thesis is to contribute to further improvements in rectal cancer treatment by investigating the multidisciplinary treatment forms, quality control and European collaboration

A retrospective analysis of surgical site infections after chlorhexidine-alcohol versus iodine-alcohol for pre-operative antisepsis

Background: Surgical site infection (SSI) is the most common hospital-acquired infection in the Netherlands. There is little evidence in regard to differences in the efficacy of pre-operative topical antisepsis with iodine-alcohol as compared with chlorhexidine-alcohol for preventing SSI. Methods: We conducted a retrospective analysis at a single center, involving all patients who underwent breast, colon, or vascular surgery in 2010 and 2011, in which pre-operative disinfection of the skin was done with iodine-alcohol in 2010 and with chlorhexidine-alcohol in 2011. Demographic characteristics, surgical parameters, and rates of SSI were compared in the two groups of patients. Subgroup analyses were done for wound classification, wound type, and type of surgery performed. Associations of patient characteristics with SSI were also investigated. Data were analyzed with χ2 tests, Student t-tests, and logistic regression analysis. Results: No statistically significant difference was found in the rates of SSI in the two study groups, at 6.1% for the patients who underwent antisepsis with iodine-alcohol and 3.8% for those who underwent disinfection with chlorhexidine-alcohol (p=0.20). After multivariable analysis, an odds ratio (OR) of 0.68 (95% confidence interval [CI] 0.30-1.47) in favor of chlorhexidine-alcohol was found. Male gender, acute surgery, absence of antibiotic prophylaxis, and longer hospital length of stay (LOS) were all associated with SSI after pre-operative topical antisepsis. Conclusion: In this single-center study conducted over a course of one year with each of the preparations investigated, no difference in the rate of SSI was found after an instantaneous protocol change from iodine-alcohol to chlorhexidine-alcohol for pre-operative topical antisepsis. © Mary Ann Liebert, Inc

Trickle-down strategies:integrating simulations with control loops of autonomous vessels on lab scale

This study integrates strategic decisions and operational control systems in autonomous shipping. By providing ships with situational information and adding a virtual operator, we show that vessels can make informed choices regarding their route and engine settings. To demonstrate this integration, we developed new components and put these to the test in three lab experiments. The green routing capability experiment showed the bridge between the control system of the autonomous vessel, operated via Robot Operating System (ROS), to the simulation environment of OpenCLSim. We developed a real-time variant of OpenCLSim and a communication component that could expose the state of the OpenCLSim simulation with the ROS system. This experiment showed that an autonomous vessel could follow a path provided by the simulation. The green steaming capability experiment showed that the ship could also adapt its speed based on information from the simulations. We developed an additional communication component capable of advising the vessel about its velocity. Together with the green-routing capability, this forms the basis for more complex experiments. The port layout experiment showed a potential use case of the green-routing and green-steaming capabilities. We created a waypoint layout similar to the port. While a ship is sailing, twelve simulations are computed every five seconds. The scenarios vary in engine order, route choices, resulting in varying emissions, fuel, and cost. We evaluated the impact of different tactics such as green-routing, green-steaming, and full-speed sailing on operational behavior like steering and engine order. Our approach, using a real-time version of a Vessel in the OpenCLSim simulation software, enabled predictive simulations to facilitate the chosen tactic based on a given strategy. Integrating simulations to evaluate the options with the control systems can develop into a valuable tool for optimizing vessel performance and reducing environmental impact in autonomous shipping operations.</p

Trickle-down strategies:integrating simulations with control loops of autonomous vessels on lab scale

This study integrates strategic decisions and operational control systems in autonomous shipping. By providing ships with situational information and adding a virtual operator, we show that vessels can make informed choices regarding their route and engine settings. To demonstrate this integration, we developed new components and put these to the test in three lab experiments. The green routing capability experiment showed the bridge between the control system of the autonomous vessel, operated via Robot Operating System (ROS), to the simulation environment of OpenCLSim. We developed a real-time variant of OpenCLSim and a communication component that could expose the state of the OpenCLSim simulation with the ROS system. This experiment showed that an autonomous vessel could follow a path provided by the simulation. The green steaming capability experiment showed that the ship could also adapt its speed based on information from the simulations. We developed an additional communication component capable of advising the vessel about its velocity. Together with the green-routing capability, this forms the basis for more complex experiments. The port layout experiment showed a potential use case of the green-routing and green-steaming capabilities. We created a waypoint layout similar to the port. While a ship is sailing, twelve simulations are computed every five seconds. The scenarios vary in engine order, route choices, resulting in varying emissions, fuel, and cost. We evaluated the impact of different tactics such as green-routing, green-steaming, and full-speed sailing on operational behavior like steering and engine order. Our approach, using a real-time version of a Vessel in the OpenCLSim simulation software, enabled predictive simulations to facilitate the chosen tactic based on a given strategy. Integrating simulations to evaluate the options with the control systems can develop into a valuable tool for optimizing vessel performance and reducing environmental impact in autonomous shipping operations.</p