Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial

Background: The peritoneum is the second most common site of recurrence in colorectal cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult. Patients eventually presenting with clinically apparent PC have a poor prognosis. Median survival is only about five months if untreated and the benefit of palliative systemic chemotherapy is limited. Only a quarter of patients are eligible for curative treatment, consisting of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC). However, the effectiveness depends highly on the extent of disease and the treatment is associated with a considerable complication rate. Methods/Design: The aim of this study is to determine the effectiveness of adjuvant HIPEC in preventing the development of PC in patients with colon cancer at high risk of peritoneal recurrence. This study will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible for inclusion are patients who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. After resection of the primary tumour, 176 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously or shortly after the primary resection. Oxaliplatin will be used as chemotherapeutic agent, for 30 min at 42-43 °C. Just before HIPEC, 5-fluorouracil and leucovorin will be administered intravenously. Primary endpoint is peritoneal disease-free survival at 18 months. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA. Discussion: Adjuvant HIPEC is assumed to reduce the expected 25 % absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10 %. This reduction is likely to translate into a prolonged overall survival. Trial registration number: NCT02231086 (Clinicaltrials.gov)

Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program ‘iTHER’

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival

Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program ‘iTHER’

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival

Reply letter to: Signet ring cell carcinoma as a potential confounding factor in the analysis of outcomes with colorectal mucinous adenocarcinoma

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Model uncertainty in the ecosystem approach to fisheries

Fisheries scientists habitually consider uncertainty in parameter values, but often neglect uncertainty about model structure. The importance of this latter source of uncertainty is likely to increase with the greater emphasis on ecosystem models in the move to an ecosystem approach to fisheries (EAF). It is therefore necessary to increase awareness about pragmatic approaches with which fisheries modellers and managers can account for model uncertainty and so we review current ways of dealing with model uncertainty in fisheries and other disciplines. These all involve considering a set of alternative models representing different structural assumptions, but differ in how those models are used. The models can be used to identify bounds on possible outcomes, find management actions that will perform adequately irrespective of the true model, find management actions that best achieve one or more objectives given weights assigned to each model, or formalise hypotheses for evaluation through experimentation. Data availability is likely to limit the use of approaches that involve weighting alternative models in an ecosystem setting, and the cost of experimentation is likely to limit its use. Practical implementation of the EAF should therefore be based on management approaches that acknowledge the uncertainty inherent in model predictions and are robust to it. Model results must be presented in a way that represents the risks and trade-offs associated with alternative actions and the degree of uncertainty in predictions. This presentation should not disguise the fact that, in many cases, estimates of model uncertainty may be based on subjective criteria. The problem of model uncertainty is far from unique to fisheries, and coordination among fisheries modellers and modellers from other communities will therefore be useful

Spawning and nursery habitat partitioning and movement patterns of Pagrus auratus (Sparidae) on the lower west coast of Australia

The ages and lengths of Pagrus auratus caught by line fishing in three marine embayments (Owen Anchorage, Cockburn Sound and Warnrbo Sound) and inshore (80. m depth) on the lower west coast of Australia (31°45'-32°45' S) were used to infer the movement patterns and habitats occupied by this species at different stages in its life cycle on this coast. These data were supplemented by results obtained by tagging individuals in spawning aggregations in the embayments. 0+ P. auratus <200. mm FL were caught exclusively in the three adjacent embayments. The ages and lengths of immature P. auratus, ranging from 1+ (ca. 200. mm FL) to 5+ years (ca. 400. mm FL), increased progressively with distance from these embayments. During the spawning period (from September to January), the relative abundances of P. auratus with either developing, developed or recently spent gonads were far greater in the three embayments (91%) than in either inshore (12%) or offshore waters (30%). Some tagged P. auratus were recaptured among spawning aggregations in the same embayment during subsequent spawning seasons, while others were recaptured in these embayments outside the spawning period. However, some other tagged individuals were recaptured up to 92. km north, 33. km west and 134. km south outside the spawning period and up to five years after tagging. The results of this study emphasise that the above three adjacent marine embayments constitute important spawning and nursery areas for P. auratus and are thus potentially critical for sustaining the stocks of this recreationally and commercially important species on the lower west coast of Australia

Reduced respiratory motion artifacts using structural similarity in fast 2D dynamic contrast enhanced MRI of liver lesions

The purpose of this work was to improve dynamic contrast enhanced MRI (DCE-MRI) of liver lesions by removing motion corrupted images as identified by a structural similarity (SSIM) algorithm, and to assess the effect of this correction on the pharmacokinetic parameter Ktrans using automatically determined arterial input functions (AIFs). Fifteen patients with colorectal liver metastases were measured twice with a T1 weighted multislice 2D FLASH sequence for DCE-MRI (time resolution 1.2 s). AIFs were automatically derived from contrast inflow in the aorta of each patient. Thereafter, SSIM identified motion corrupted images of the liver were removed from the DCE dataset. From this corrected data set Ktrans and its reproducibility were determined. Using the SSIM algorithm a median fraction of 46% (range 37-50%) of the liver images in DCE time series was labeled as motion distorted. Rejection of these images resulted in a significantly lower median Ktrans (p < 0.05) and lower coefficient of repeatability of Ktrans in liver metastases compared with an analysis without correction. SSIM correction improves the reproducibility of the DCE-MRI parameter Ktrans in liver metastasis and reduces contamination of Ktrans values of lesions by that of surrounding normal liver tissue