Search

Karin ATGM Wasmann,1 Charlotte EL Klaver,1 Jarmila DW van der Bilt,1,2 Susan van Dieren,3 Iris D Nagtegaal,4 Cornelis JA Punt,5 Bert van Ramshorst,6 Albert M Wolthuis,2 Johannes HW de Wilt,7 André D’Hoore,2 Hjalmar C van Santvoort,6 Pieter J Tanis11Department of Surgery, Amsterdam University Medical Centre, University of Amsterdam, AZ 1105, Amsterdam, The Netherlands; 2Department of Abdominal Surgery, University Hospital Leuven, Leuven 3000, Belgium; 3Clinical Research Unit, Amsterdam University Medical Centre, University of Amsterdam, AZ 1105, Amsterdam, The Netherlands; 4Department of Pathology, Radboud University Medical Centre, GA 6525, Nijmegen, The Netherlands; 5Department of Medical Oncology, Amsterdam University Medical Centre, University of Amsterdam, AZ 1105, Amsterdam, The Netherlands; 6Department of Surgery, St. Antonius Hospital, CM 3435, Nieuwegein, The Netherlands; 7Department of Surgery, Radboud University Medical Centre, GA 6525, Nijmegen, The NetherlandsPurpose: The aim of this study was to evaluate the impact of a laparoscopic approach on long-term oncological outcomes in curative intent surgery for pT4 colon cancer, in both overall and stratified subgroups with distinct clinical entities.Patients and methods: Patients with a pT4N0-2M0 colon cancer from four centers between 2000 and 2014 were included. Laparoscopic and open approaches were compared according to the intention-to-treat principle. Propensity scores were used to adjust for baseline differences between the groups in three manners: i) as a linear predictor in a Cox regression model, ii) to create a 1:1 matched cohort, and iii) to stratify patients into four groups with an increasing chance of receiving laparoscopy.Results: In total, 424 patients were included. After 1:1 matching, a laparoscopic approach correlated with higher rates of radical resection, lower morbidity, and a higher percentage of patients receiving adjuvant chemotherapy. This translated into better 5-year disease-free survival (52% vs 40%, HR 0.70; 95% CI 0.50–0.96) and 5-year overall survival (68% vs 57%, HR 0.66; 95% CI 0.43–0.99). These results were confirmed in the other two propensity score analyses. In the multivariable models, adjuvant chemotherapy remained independently associated with better survival, whereas surgical approach lost significance.Conclusions: In locally advanced colon cancer, an intentional laparoscopic approach in experienced hands seems to decrease morbidity and to increase the proportion of patients receiving adjuvant chemotherapy. Receiving adjuvant chemotherapy was independently associated with improved survival.Keywords: T4 colon cancer, laparoscopy, lower GI

Methods to work-up sentinel nodes (SN) vary considerably between institutes. This single institution study evaluated the positive SN-identification rate of the EORTC Melanoma Group (MG) protocol and investigated the prognostic value of the SN status regarding disease-free survival (DFS) and overall survival (OS) and evaluated the locoregional control after the SN procedure. Multivariate and univariate analyses using Cox's proportional hazard regression model was employed to assess the prognostic value of covariates regarding DFS and OS. The positive SN-identification rate was 29% at a median Breslow thickness of 2.00 mm and the false-negative rate was 9.4%. Breslow thickness and ulceration of the primary correlated with SN status. SN status, ulceration and site of the primary tumour correlated with DFS. SN status and ulceration of the primary correlated with OS. The in-transit metastasis rate correlated with SN-positivity, Breslow thickness and ulceration. Projected 3-year OS was 95% in SN-negative and 74% in SN-positive patients. Transhilar bivalving of the SN with step sections from the central planes is simple and had a high SN-positive detection rate of about 30%. The SN status is the most important predictive value for DFS and OS. In-transit metastasis rates correlated with SN-positivity, Breslow thickness and ulceration of the primary. [ABSTRACT FROM AUTHOR]

Background: Capecitabine is an oral chemotherapeutic drug showing antitumor activity through inhibition of thymidylate synthase, an enzyme involved in folate metabolism. There are concerns about the high intake of certain vitamins, and specifically folate, during chemotherapy with capecitabine. Whether folate or folic acid, the synthetic variant of the vitamin, impact treatment toxicity remains unclear., Objective: We studied associations between intake and biomarkers of folate as well as folic acid and toxicities in patients with colorectal cancer (CRC) receiving capecitabine., Methods: Within the prospective COLON (Colorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that influence recurrence, survival, and quality of life) cohort, 290 patients with stage II to III CRC receiving capecitabine were identified. Dietary and supplemental intake of folate and folic acid were assessed at diagnosis and during chemotherapy using questionnaires (available for 280 patients). Plasma folate and folic acid levels were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) and were available for 212 patients. Toxicities were defined as toxicity-related modifications of treatment, including dose reductions, regimen switches, and early discontinuation. Associations of intake and biomarkers of folate and folic acid with toxicities were determined using Cox proportional hazards regression adjusted for age and sex., Results: In total, 153 (53%) patients experienced toxicities leading to modification of capecitabine treatment. Folate intake and plasma folate levels were not associated with risk of toxicities. However, use of folic acid-containing supplements during treatment (hazard ratio (HR) 1.81 and 95% confidence interval (CI) 1.15-2.85) and presence of folic acid in plasma at diagnosis (HR 2.09, 95% CI: 1.24, 3.52) and during treatment (HR 2.31, 95% CI: 1.29, 4.13) were associated with an increased risk of toxicities., Conclusions: This study suggests a potential association between folic acid and capecitabine-induced toxicities, providing a rationale to study diet-drug interactions and raise further awareness of the use of dietary supplements during oncological treatment., Clinical Trial Details: This trial was registered at clinicaltrials.gov as NCT03191110., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Both lymph node metastases (LNMs) and tumour deposits (TDs) are included in colorectal cancer (CRC) staging, although knowledge regarding their biological background is lacking. This study aimed to compare the biology of these prognostic features, which is essential for a better understanding of their role in CRC spread. Spatially resolved transcriptomic analysis using digital spatial profiling was performed on TDs and LNMs from 10 CRC patients using 1,388 RNA targets, for the tumour cells and tumour microenvironment. Shotgun proteomics identified 5,578 proteins in 12 different patients. Differences in RNA and protein expression were analysed, and spatial deconvolution was performed. Image-based consensus molecular subtype (imCMS) analysis was performed on all TDs and LNMs included in the study. Transcriptome and proteome profiles identified distinct clusters for TDs and LNMs in both the tumour and tumour microenvironment segment, with upregulation of matrix remodelling, cell adhesion/motility, and epithelial-mesenchymal transition (EMT) in TDs (all p < 0.05). Spatial deconvolution showed a significantly increased abundance of fibroblasts, macrophages, and regulatory T-cells (p < 0.05) in TDs. Consistent with a higher fibroblast and EMT component, imCMS classified 62% of TDs as poor prognosis subtype CMS4 compared to 36% of LNMs (p < 0.05). Compared to LNMs, TDs have a more invasive state involving a distinct tumour microenvironment and upregulation of EMT, which are reflected in a more frequent histological classification of TDs as CMS4. These results emphasise the heterogeneity of locoregional spread and the fact that TDs should merit more attention both in future research and during staging. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Background: The inflammatory potential of the diet has been associated with colorectal cancer (CRC) risk, but its association with CRC prognosis is unclear., Objective: To investigate the inflammatory potential of the diet in relation to recurrence and all-cause mortality among persons diagnosed with stage I to III CRC., Methods: Data of the COLON study, a prospective cohort among CRC survivors were used. Dietary intake, 6 mo after diagnosis, was assessed by using a food frequency questionnaire and was available for 1631 individuals. The empirical dietary inflammatory pattern (EDIP) score was used as a proxy for the inflammatory potential of the diet. The EDIP score was created by using reduced rank regression and stepwise linear regression to identify food groups that explained most of the variations in plasma inflammatory markers (IL6, IL8, C-reactive protein, and tumor necrosis factor-α) measured in a subgroup of survivors (n = 421). Multivariable Cox proportional hazard models with restricted cubic splines were used to investigate the relation between the EDIP score and CRC recurrence and all-cause mortality. Models were adjusted for age, sex, BMI, PAL, smoking status, stage of disease, and tumor location., Results: The median follow-up time was 2.6 y (IQR: 2.1) for recurrence and 5.6 y (IQR: 3.0) for all-cause mortality, during which 154 and 239 events occurred, respectively. A nonlinear positive association between the EDIP score and recurrence and all-cause mortality was observed. For example, a more proinflammatory diet (EDIP score +0.75) compared with the median (EDIP score 0) was associated with a higher risk of CRC recurrence (HR: 1.15; 95% CI: 1.03, 1.29) and all-cause mortality (HR: 1.23; 95% CI: 1.12, 1.35)., Conclusions: A more proinflammatory diet was associated with a higher risk of recurrence and all-cause mortality in CRC survivors. Further intervention studies should investigate whether a switch to a more anti-inflammatory diet improves CRC prognosis., (Copyright © 2022 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: Although surgical resection has been considered the only curative option for colorectal liver metastases, thermal ablation has recently been suggested as an alternative curative treatment. There have been no adequately powered trials comparing surgery with thermal ablation., Objectives: Main objective - to compare the clinical effectiveness and cost-effectiveness of thermal ablation versus liver resection surgery in high surgical risk patients who would be eligible for liver resection. Pilot study objectives - to assess the feasibility of recruitment (through qualitative study), to assess the quality of ablations and liver resection surgery to determine acceptable standards for the main trial and to centrally review the reporting of computed tomography scan findings relating to ablation and outcomes and recurrence rate in both arms., Design: A prospective, international (UK and the Netherlands), multicentre, open, pragmatic, parallel-group, randomised controlled non-inferiority trial with a 1-year internal pilot study., Setting: Tertiary liver, pancreatic and gallbladder (hepatopancreatobiliary) centres in the UK and the Netherlands., Participants: Adults with a specialist multidisciplinary team diagnosis of colorectal liver metastases who are at high surgical risk because of their age, comorbidities or tumour burden and who would be suitable for liver resection or thermal ablation., Interventions: Thermal ablation conducted as per local policy (but centres were encouraged to recruit within Cardiovascular and Interventional Radiological Society of Europe guidelines) versus surgical liver resection performed as per centre protocol., Main Outcome Measures: Pilot study - patients' and clinicians' acceptability of the trial to assist in optimisation of recruitment. Primary outcome - disease-free survival at 2 years post randomisation. Secondary outcomes - overall survival, timing and site of recurrence, additional therapy after treatment failure, quality of life, complications, length of hospital stay, costs, trial acceptability, and disease-free survival measured from end of intervention. It was planned that 5-year survival data would be documented through record linkage. Randomisation was performed by minimisation incorporating a random element, and this was a non-blinded study., Results: In the pilot study over 1 year, a total of 366 patients with colorectal liver metastases were screened and 59 were considered eligible. Only nine participants were randomised. The trial was stopped early and none of the planned statistical analyses was performed. The key issues inhibiting recruitment included fewer than anticipated patients eligible for both treatments, misconceptions about the eligibility criteria for the trial, surgeons' preference for one of the treatments ('lack of clinical equipoise' among some of the surgeons in the centre) with unconscious bias towards surgery, patients' preference for one of the treatments, and lack of dedicated research nurses for the trial., Conclusions: Recruitment feasibility was not demonstrated during the pilot stage of the trial; therefore, the trial closed early. In future, comparisons involving two very different treatments may benefit from an initial feasibility study or a longer period of internal pilot study to resolve these difficulties. Sufficient time should be allowed to set up arrangements through National Institute for Health Research (NIHR) Research Networks., Trial Registration: Current Controlled Trials ISRCTN52040363., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 21. See the NIHR Journals Library website for further project information., Competing Interests: Julia Brown is a member of Health Technology Assessment (HTA) Mental, Psychological and Occupational Health Methods Group, HTA Clinical Trials Committee, HTA Prioritisation Committee Methods Group and HTA Funding Committee Policy Group. Stephen Morris was formerly a member of the National Institute for Health Research (NIHR) Health Services and Delivery Research (HSDR) Research Funding Board, the NIHR HSDR Commissioned Board, the NIHR HSDR Evidence Synthesis Sub Board, the NIHR Unmet Need Sub Board, the NIHR HTA Clinical Evaluation and Trials Board, the NIHR HTA Commissioning Board, the NIHR Public Health Research (PHR) Research Funding Board and the NIHR Programme Grants for Applied Research (PGfAR) expert subpanel. Maureen Twiddy is a member of the Research for Patient Benefit North East and Yorkshire Advisory Panel. Brian Davidson is chairperson of the London NIHR Research for Patient Benefit panel. Daniel Hochhauser reports Medical Research Council CASE studentship with Merck Serono (Darmstadt, Germany). Kurinchi Gurusamy reports grants from NIHR, Cancer Research UK Multidisciplinary Award, UK Oncology Nursing Society, University College London and Wellcome Trust/Department of Health and Social Care – Health Innovation Challenge Fund 4 – Smart Surgery, during the conduct of the study.

Background: Decision making on optimal treatment strategy in patients with initially unresectable colorectal cancer liver metastases (CRLM) remains complex because uniform criteria for (un)resectability are lacking. This study reports on the feasibility and short-term outcomes of The Dutch Colorectal Cancer Group Liver Expert Panel., Study Design: The Expert Panel consists of 13 hepatobiliary surgeons and 4 radiologists. Resectability assessment is performed independently by 3 randomly assigned surgeons, and CRLM are scored as resectable, potentially resectable, or permanently unresectable. In absence of consensus, 2 additional surgeons are invited for a majority consensus. Patients with potentially resectable or unresectable CRLM at baseline are evaluated every 2 months of systemic therapy. Once CRLM are considered resectable, a treatment strategy is proposed., Results: Overall, 398 panel evaluations in 183 patients were analyzed. The median time to panel conclusion was 7 days (interquartile range [IQR] 5-11 days). Intersurgeon disagreement was observed in 205 (52%) evaluations, with major disagreement (resectable vs permanently unresectable) in 42 (11%) evaluations. After systemic treatment, 106 patients were considered to have resectable CRLM, 84 of whom (79%) underwent a curative procedure. R0 resection (n = 41), R0 resection in combination with ablative treatment (n = 26), or ablative treatment only (n = 4) was achieved in 67 of 84 (80%) patients., Conclusions: This study analyzed prospective resectability evaluation of patients with CRLM by a panel of radiologists and liver surgeons. The high rate of disagreement among experienced liver surgeons reflects the complexity in defining treatment strategies for CRLM and supports the use of a panel rather than a single-surgeon decision., (Copyright © 2019 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: The aim of this study was to assess the effect of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on tumor response to preoperative chemoradiation for rectal cancer., Materials and Methods: Data on patients who received chemoradiation prior to surgery for rectal cancer between 2010 and 2015 were retrieved from linkage between the PHARMO Database Network, Dutch Pathology Registry and Netherlands Cancer Registry. Pathological complete response rates (pCR) were compared between patients who did or did not use ACEIs/ARBs during treatment. Multivariable analysis was performed using logistic regression., Results: Out of 345 patients, 92 patients (26.7%) used ACEIs/ARBs during treatment. Median age was 65 years (range 30-85). Older and male patients were more likely to use ACEIs/ARBs. pCR (ypT0N0) was observed in 17.4% of patients using ACEIs/ARBs compared to 14.6% of patients who did not use ACEIs/ARBs (p = 0.595). A good response (ypT0-1N0) was observed in 21.7% of ACEIs/ARBs patients vs. 19.4% of patients who did not use ACEIs/ARBs (p = 0.724). Multivariable analysis, taking into account background variables and co-medication, showed increased pCR in patients using beta-blockers (odds ratio 2.3, 95% confidence interval 1.0-5.4)., Conclusion: In this retrospective cohort, the use of ACEIs/ARBs was not associated with tumor response to preoperative chemoradiation in rectal cancer patients. Thereby, the suggested potentiating effect of ACEIS/ARBs could not be confirmed in our study. Further research could be directed to investigate a possible benefit of beta-blockers or other anti-hypertensive drugs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To assess the influence of endorectal filling (EF) on rectal cancer staging., Methods: 47 patients who underwent a staging MRI of rectal cancer in the period from 2011 to 2014 were included. The MRI protocol included T 2 weighted fast spin echo sequences without and with EF at 3 T (EF-MRI). Images were scored by two readers for T-stage, distance of the lower pole of the tumour to the anorectal junction, distance to the mesorectal fascia (MRF), and number of (suspicious) lymph nodes. Agreement in T-staging was calculated using the Cohen's κ value. Comparison of continuous variables was performed using Wilcoxon matched pairs signed-rank test., Results: The interobserver agreement for T-staging with and without EF-MRI showed a poor agreement between both readers (weighted κ = 0.156, weighted κ = 0.037, respectively). Tumours tended to be overstaged more prominently with EF-MRI. The accuracy of predicting the pathological T-stage slightly improved from 55% with EF to 64% without EF for Reader 1 and from 59 to 68% for Reader 2, respectively. The distance of the tumour to the anorectal junction increased from 33.9 to 49.3 mm (p < 0.001) after EF for Reader 2. EF-MRI did not significantly influence the number of (suspicious) lymph nodes and distance to the mesorectal fascia., Conclusion: EF-MRI did not lead to an improved tumour staging and it has the potential to influence the distance to a key anatomical landmark. EF-MRI is therefore not recommended in primary staging rectal cancer. Advances in knowledge: EF-MRI may not be used as an additional tool to stage rectal cancer patients, as it does not seem to facilitate in locoregionally staging the disease.

Purpose: Locally advanced breast cancer (LABC) includes inflammatory breast cancer (IBC) as well as non-inflammatory LABC (NI-LABC). The aim of this population-based study was to compare the tumour characteristics, treatment and relative survival of IBC and NI-LABC patients., Methods: Patients with either IBC (cT4d) or NI-LABC (cT4a-c) were identified from the nationwide Netherlands Cancer Registry from the period 1989-2015. In each group, patients are divided into three time periods in order to perform a trend analysis: 1989-1997, 1998-2006, and 2007-2015., Results: IBC comprised 1.1% and NI-LABC 4.6% of all diagnosed breast cancer patients. IBC patients showed more nodal metastases (77.8 vs. 69.7%, P < 0.001) and distant metastases (39.7 vs. 34.1%, P < 0.001). IBC tumours were more often triple negative (23.2 vs. 12.8%, P < 0.001) and poorly differentiated (69.8 vs. 53.8%, P < 0.001). Trimodality therapy (neoadjuvant chemotherapy, surgery and adjuvant radiotherapy) was more often applied over time in both groups (IBC: 23.7%-56.0%-68.6%; NI-LABC: 3.7%-25.9%-43.6%; P trend  < 0.001). In IBC patients, relative 5-year survival was significantly shorter than in patients with NI-LABC (30.2 vs. 45.1%, P < 0.001). The relative survival significantly improved for IBC from 17.2% (1989-1997) to 30.0 and 38.9% for the last two time periods (1998-2006: P < 0.001; 2007-2015: P < 0.001). In contrast, survival did not significantly improve in NI-LABC breast cancer: from 44.7% (1989-1997) to 44.0 and 48.4% (1998-2006: P = 0.483; 2007-2015: P = 0.091)., Conclusions: IBC has tumour characteristics that determine its aggressive biology compared to NI-LABC. Trimodality therapy was increasingly applied in both groups, but did not improve survival in NI-LABC. Although relative survival in IBC patients has improved during the last decades, it remains a disease with a dismal prognosis.

Purpose: Preoperative therapy reduces local recurrences and may facilitate surgery in rectal cancer patients. However, in patients with inflammatory bowel disease (IBD) this treatment is often withheld due to the perceived risk of excessive side-effects, even though evidence is limited. The purpose of this study is to investigate the effects of preoperative therapy on acute toxicity and post-operative complications in IBD patients with rectal cancer., Methods: The Dutch pathology registry (PALGA) was searched for patients with IBD and rectal cancer treated between January 1991 and May 2010. Histopathology and clinical charts were reviewed to confirm IBD diagnosis and evaluate clinical and pathological characteristics., Results: Out of 161 patients, 66 received preoperative therapy (41%), including short-course radiation therapy (SC-RT), long course radiation therapy (LC-RT), and chemoradiation therapy (CRT) in 32, 13, and 21 patients respectively. Grade≥3 acute toxicity occurred in 0 patients (0.0%), 1 patient (7.7%), and 6 patients (28.6%) respectively (p=0.004). Systemic corticosteroids were used by 10.5% of patients at time of treatment. Grade≥3 post-operative 30-day complication rate (28.1% overall) was not associated with type of preoperative therapy., Conclusion: Results did not show excessive rates of toxicity or post-operative complications and support the use of standard preoperative therapies for rectal cancer (especially SC-RT) in IBD patients with relatively indolent disease. Caution is warranted in patients with active IBD, since the exact impact of active bowel inflammation could not be determined retrospectively. Prospective studies should investigate the influence of active IBD on acute and late toxicity in patients receiving pelvic irradiation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to investigate the incidence of parastomal hernias (PSHs) after end-colostomy formation using a polypropylene mesh in a randomized controlled trial versus conventional colostomy formation., Background: A PSH is the most frequent complication after stoma formation. Symptoms may range from mild abdominal pain to life-threatening obstruction and strangulation. The treatment of a PSH is notoriously difficult and recurrences up to 20% have been reported despite the use of mesh. This has moved surgical focus toward prevention., Methods: Augmentation of the abdominal wall with a retro-muscular lightweight polypropylene mesh was compared with the traditional formation of a colostomy. In total, 150 patients (1:1 ratio) were included. The incidence of a PSH, morbidity, mortality, quality of life, and cost-effectiveness was measured after 1 year of follow-up., Results: There was no difference between groups regarding demographics and predisposing factors for PSH. Three out of 67 patients (4.5%) in the mesh group and 16 out of 66 patients (24.2%) in the nonmesh group developed a PSH (P = 0.0011). No statistically significant difference was found in infections, concomitant hernias, SF-36 questionnaire, Von Korff pain score, and cost-effectiveness between both study groups., Conclusion: Prophylactic augmentation of the abdominal wall with a retromuscular lightweight polypropylene mesh at the ostomy site significantly reduces the incidence of PSH without a significant difference in morbidity, mortality, quality of life, or cost-effectiveness.

Background: Laparoscopic left lateral sectionectomy (LLLS) has been associated with shorter hospital stay and reduced overall morbidity compared with open left lateral sectionectomy (OLLS). Strong evidence has not, however, been provided., Methods: In this multicentre double-blind RCT, patients (aged 18-80 years with a BMI of 18-35 kg/m 2 and ASA fitness grade of III or below) requiring left lateral sectionectomy (LLS) were assigned randomly to OLLS or LLLS within an enhanced recovery after surgery (ERAS) programme. All randomized patients, ward physicians and nurses were blinded to the procedure undertaken. A parallel prospective registry (open non-randomized (ONR) versus laparoscopic non-randomized (LNR)) was used to monitor patients who were not enrolled for randomization because of doctor or patient preference. The primary endpoint was time to functional recovery. Secondary endpoints were length of hospital stay (LOS), readmission rate, overall morbidity, composite endpoint of liver surgery-specific morbidity, mortality, and reasons for delay in discharge after functional recovery., Results: Between January 2010 and July 2014, patients were recruited at ten centres. Of these, 24 patients were randomized at eight centres, and 67 patients from eight centres were included in the prospective registry. Owing to slow accrual, the trial was stopped on the advice of an independent Data and Safety Monitoring Board in the Netherlands. No significant difference in median (i.q.r.) time to functional recovery was observed between laparoscopic and open surgery in the randomized or non-randomized groups: 3 (3-5) days for OLLS versus 3 (3-3) days for LLLS; and 3 (3-3) days for ONR versus 3 (3-4) days for LNR. There were no significant differences with regard to LOS, morbidity, reoperation, readmission and mortality rates., Conclusion: This RCT comparing open and laparoscopic LLS in an ERAS setting was not able to reach a conclusion on time to functional recovery, because it was stopped prematurely owing to slow accrual. Registration number: NCT00874224 ( https://www.clinicaltrials.gov)., (© 2017 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: Shoulder complaints are frequently reported after surgical treatment for thyroid carcinoma. However, no specific literature on this topic is available for these patients and, hence, its impact on quality of life (QOL) is unknown and there are no known predictors of shoulder complaints in this specific patient population. Therefore, the purpose of this study was to assess the prevalence of shoulder-related complaints and its relation to QOL and clinical characteristics after thyroid carcinoma surgery by means of a cross-sectional case control study in a tertiary referral center., Methods: The prevalence of shoulder complaints and its relation to clinical characteristics and QOL after thyroid carcinoma surgery (n = 109) was compared to a healthy control group (n = 81). Main outcome measures are prevalence of self-reported shoulder complaints, results of the Disabilities of the Arm, Shoulder, and Hand questionnaire (DASH), and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30-questions (EORTC-QLQ-C30)., Results: Patients with thyroid carcinoma, on average 10.2 years after thyroid surgery, reported a 58.7% prevalence of shoulder-related complaints, which was significantly more than the 13.6% reported by healthy controls (p < .01). Patients with thyroid carcinoma scored worse than healthy controls on most of the different subscales of the DASH and EORTC-QLQ-C30. Bivariate association analysis identified level V neck dissection as being associated with the prevalence of shoulder complaints and the DASH score, and spinal accessory nerve damage and employment status as being associated with the DASH score. Prevalence of shoulder complaints and the DASH scores were significantly correlated to several EORTC-QLQ-C30 scores. Only 11.9% of patients with thyroid carcinoma retrospectively reported having received preoperative information on possible shoulder complaints and only 34.9% of patients with thyroid carcinoma retrospectively reported having received additional care for their shoulder complaints., Conclusion: Shoulder complaints represent and underestimated problem and are reported by many patients who had surgery for thyroid carcinoma. Information provision to the patient should be improved, shoulder complaints should be registered, and additional care should be provided after thyroid carcinoma surgery to improve QOL. © 2016 Wiley Periodicals, Inc. Head Neck 39: 260-268, 2017., (© 2016 Wiley Periodicals, Inc.)

Purpose: In order to understand the multidimensional mechanism of fear of cancer recurrence (FCR) and to identify potential targets for interventions, it is important to empirically test the theoretical model of FCR. This study aims at assessing the validity of Lee-Jones et al.'s FCR model., Methods: A total of 1205 breast cancer survivors were invited to participate in this study. Participants received a questionnaire booklet including questionnaires on demographics and psychosocial variables including FCR. Data analysis consisted of the estimation of direct and indirect effects in mediator models., Results: A total of 460 women (38 %) participated in the study. Median age was 55.8 years (range 32-87). Indirect effects of external and internal cues via FCR were found for all mediation models with limited planning for the future (R 2  = .28) and body checking (R 2  = .11-.15) as behavioral response variables, with the largest effects for limited planning for the future. A direct relation was found between feeling sick and seeking professional advice, not mediated by FCR., Conclusions: In the first tested models of FCR, all internal and external cues were associated with higher FCR. In the models with limited planning for the future and body checking as behavioral response, an indirect effect of cues via FCR was found supporting the theoretical model of Lee-Jones et al., Implications for Cancer Survivors: An evidence-based model of FCR may facilitate the development of appropriate interventions to manage FCR in breast cancer survivors., Competing Interests: Compliance with ethical standards Funding This study was funded by Pink Ribbon, the Netherlands, Grant No. 2011.WO11.C106 Conflict of interest The authors declare that they have no conflict of interest Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study.

Background: The influence of physical activity on patient-reported recovery of physical functioning after colorectal cancer (CRC) surgery is unknown. Therefore, we studied recovery of physical functioning after hospital discharge by (a) a relative increase in physical activity level and (b) absolute activity levels before and after surgery., Methods: We included 327 incident CRC patients (stages I-III) from a prospective observational study. Patients completed questionnaires that assessed physical functioning and moderate-to-vigorous physical activity shortly after diagnosis and 6 months later. Cox regression models were used to calculate prevalence ratios (PRs) of no recovery of physical functioning. All PRs were adjusted for age, sex, physical functioning before surgery, stage of disease, ostomy and body mass index., Results: At 6 months post-diagnosis 54% of CRC patients had not recovered to pre-operative physical functioning. Patients who increased their activity by at least 60 min/week were 43% more likely to recover physical function (adjusted PR 0.57 95%CI 0.39-0.82), compared with those with stable activity levels. Higher post-surgery levels of physical activity were also positively associated with recovery (P for trend = 0.01). In contrast, activity level before surgery was not associated with recovery (P for trend = 0.24)., Conclusions: At 6 month post-diagnosis, about half of CRC patients had not recovered to preoperative functioning. An increase in moderate-to-vigorous physical activity after CRC surgery was associated with enhanced recovery of physical functioning. This benefit was seen regardless of physical activity level before surgery. These associations provide evidence to further explore connections between physical activity and recovery from CRC surgery after discharge from the hospital.

Background: The objective of this study was to map referral patterns in patients with synchronous colorectal liver metastases (SCLM) and to investigate if type, volume and location of the hospital of diagnosis are associated with whether or not patients underwent liver resection., Methods: This population-based study includes all patients diagnosed with SCLM between 2008 and 2012, based on the Netherlands Cancer Registry. To study inter-hospital variation, the proportion of patients undergoing liver surgery was calculated per hospital of diagnosis. Multivariable multilevel logistic regression analysis was used to investigate the association between hospital characteristics and liver resection., Results: Of 10,520 patients with SCLM, 12% (n = 1259) underwent liver surgery. Of these patients, 58% (n = 733) were referred to another hospital to undergo liver surgery. In 53% of the patients (n = 647), liver resection was performed in a university hospital, in 39% (n = 482) in a dedicated liver centre and in 8% (n = 102) in a general hospital. There was a large inter-hospital variation in the proportion of patients undergoing liver resection (2-26%). In a multilevel logistic regression model, the odds of undergoing liver surgery were higher when patients were diagnosed in hospitals where liver surgery was performed compared with the general hospitals (dedicated liver centre: odds ratio 1.36 [95% confidence intervals 1.08-1.70], university hospital: odds ratio 1.69 [95% confidence intervals 1.22-2.34])., Conclusion: There is a large inter-hospital and inter-regional variation in the utilisation of liver resection. Patients diagnosed with SCLM in expert centres had a higher chance of undergoing liver resection., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Although synchronous and metachronous metastases are considered as separate entities of metastatic colorectal cancer (mCRC) with different outcomes, its proportion is reported infrequently. We compared inclusion rates and survival of synchronous versus metachronous mCRC in different types of studies investigating initial systemic therapy or surgical treatment of mCRC., Methods: We searched PubMed and EMBASE (January 2004 - February 2016) for mCRC studies investigating first-line systemic therapy or surgical treatment of mCRC including information on synchronous versus metachronous metastases. Outcomes were the proportion of synchronous mCRC, and estimated median overall survival (OS) of the total study population. Spearman analysis (r s ) was used to study correlations between outcomes and median year of study enrolment., Results: We included 46 articles, reporting data from 23 phase 3 randomised controlled trials (RCTs), twenty cohort and three population-based studies (total: 25,941 patients). Seventeen different definitions for synchronous mCRC were identified. In systemic therapy RCTs, we observed an increased proportion of synchronous mCRC during recent years (r s .77, p < .001). In these trials, estimated median OS slightly improved over time (r s .48, p = .03). No significant inclusion or survival trends were observed in included cohort and population-based studies., Conclusions: In recent years, the proportion of patients with synchronous compared with metachronous mCRC enrolled in first-line systemic therapy RCTs increased. Estimated median OS of the total study population in these RCTs slightly increased over time. Many different definitions of synchronous disease were used. Uniform definitions and consistent reporting of the proportion of synchronous versus metachronous metastases could improve cross-study comparisons and interpretation of reported data in all mCRC studies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Fine Needle Aspiration Biopsy (FNAB), Core Needle biopsy (CNB) and hybrid techniques including Core Wash Cytology (CWC) are available for same-day diagnosis in breast lesions. In CWC a washing of the biopsy core is processed for a provisional cytological diagnosis, after which the core is processed like a regular CNB. This study focuses on the reliability of CWC in daily practice., Methods: All consecutive CWC procedures performed in a referral breast centre between May 2009 and May 2012 were reviewed, correlating CWC results with the CNB result, definitive diagnosis after surgical resection and/or follow-up. Symptomatic as well as screen-detected lesions, undergoing CNB were included., Results: 1253 CWC procedures were performed. Definitive histology showed 849 (68%) malignant and 404 (32%) benign lesions. 80% of CWC procedures yielded a conclusive diagnosis: this percentage was higher amongst malignant lesions and lower for benign lesions: 89% and 62% respectively. Sensitivity and specificity of a conclusive CWC result were respectively 98.3% and 90.4%. The eventual incidence of malignancy in the cytological 'atypical' group (5%) was similar to the cytological 'benign' group (6%)., Conclusion: CWC can be used to make a reliable provisional diagnosis of breast lesions within the hour. The high probability of conclusive results in malignant lesions makes CWC well suited for high risk populations., (Copyright © 2016 Elsevier Ltd, BASO ~ the Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Aims: Changes in rectal cancer treatment include increasing emphasis on organ preservation. Local excision after chemoradiotherapy (CRT) for rectal cancer with excellent clinical response reduces morbidity and mortality compared to total mesorectal excision, although residual lymph node metastases (LNM) may cause local recurrence. Our aim is to identify clinicopathological factors predicting the presence of residual LNM in rectal cancer patients with ypT0-2 tumours after neoadjuvant CRT. These risk factors may help to select patients who can be spared radical surgery without compromising oncological outcomes., Methods and Results: Rectal cancer patients with ypT0-2 tumours after CRT and radical resection from five centres treated between June 1999 and February 2012 were included. Histopathology was reviewed extensively. Clinicopathological characteristics and their association with residual LNM were investigated. Of 657 consecutive CRT-treated rectal cancer patients 210 with ypT0-2 disease were included. Residual nodal disease was found in 44 cases (21.0%). Independent predictors of LNM were clinical nodal involvement (cN + ) [odds ratio (OR): 2.79, 95% confidence interval (CI): 1.04-7.48, P = 0.042], high-grade histopathology assessed in the post-CRT resection specimen (OR: 6.46, 95% CI: 1.23-34.02, P = 0.028) and residual tumour diameter (RTD) ≥10 mm (OR: 2.54, 95% CI: 1.06-6.09, P = 0.036). An algorithm combining these factors stratified patients adequately according to LNM risk, independently of ypT category., Conclusions: Clinical nodal involvement, high-grade histopathology and RTD ≥10 mm are strong and independent predictors of residual nodal disease in rectal cancer patients with ypT0-2 tumours after CRT. Risk stratification based on these factors may help to identify patients suitable for organ preserving therapy and should be validated in appropriately selected populations., (© 2016 John Wiley & Sons Ltd.)

As the value of palliative primary tumor resection in stage IV colorectal cancer (CRC) is still under debate, the purpose of this population-based study was to investigate if palliative primary tumor resection as the initial treatment after diagnosis was associated with improved overall survival. All patients with stage IV colorectal adenocarcinoma (2008-2011) were selected from the Netherlands Cancer Registry, and patients undergoing treatment with curative intent (i.e., metastasectomy, radiofrequency ablation and/or hyperthermic intraperitoneal chemotherapy), or best supportive care were excluded. After propensity score matching, a multivariable Cox proportional hazard model was performed to determine the association between treatment strategy and mortality. From a total group of 10,371 patients with stage IV CRC, 2,746 patients (26%) underwent an elective palliative resection of the primary tumor, whether or not followed by systemic therapy, and 3,345 patients (32%) were initially treated with palliative systemic therapy. After propensity score matching, median overall survival in these groups was 17.2 months (95% CI 16.3-18.1) and 11.5 months (95% CI 11.0-12.0), respectively. In Cox regression analysis, primary tumor resection was significantly associated with improved overall survival (hazard ratio of death = 0.44 [95% CI 0.35-0.55], p < 0.001). This large population-based study shows an overall survival benefit for patients with incurable stage IV CRC who underwent primary tumor resection as the initial treatment after diagnosis, compared to patients who started systemic therapy with the primary tumor in situ. This result is an argument in favor of resection of the primary tumor, even when patients have little to no symptoms., (© 2016 UICC.)

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 K trans using automatically determined arterial input functions (AIFs). Fifteen patients with colorectal liver metastases were measured twice with a T 1 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 K trans 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 K trans (p < 0.05) and lower coefficient of repeatability of K trans in liver metastases compared with an analysis without correction. SSIM correction improves the reproducibility of the DCE-MRI parameter K trans in liver metastasis and reduces contamination of K trans values of lesions by that of surrounding normal liver tissue., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: High-volume hospitals have been associated with improved patient outcomes for tumors with a relatively low incidence that require complex surgeries, such as esophageal and pancreatic cancer. The volume-outcome association for colorectal cancer is under debate., Objective: This study investigated whether hospital volume for colorectal cancer is associated with surgical care characteristics and 5-year overall survival., Design: This is a population-based study., Setting: Data were gathered from the Netherlands Cancer Registry. Hospitals were grouped by volume for colon (<50, 50-74, 75-99, and ≥100 resections per year) and rectum (<20, 20-39, and ≥40 resections per year)., Patients: All of the patients with primary nonmetastatic colorectal cancer who underwent resection between 2005 and 2012 were included., Main Outcome Measures: Differences in surgical approach, anastomotic leakage, and postoperative 30-day mortality between hospital volumes were analyzed using χ tests and multivariable logistic regression analyses. Cox proportional hazard models were used to investigate the effect of hospital volume on overall survival., Results: This study included 61,394 patients with colorectal cancer. In 2012, 31 of the 91 hospitals performed less than 50 colon cancer resections per year, and 21 of the 90 hospitals performed less than 20 rectal cancer resections per year. No differences in anastomotic leakage rates between hospital volumes were observed. Only small differences between hospital volumes were revealed for conversion of laparoscopic to open resection (OR of less than 50 versus 100 or more resections per year = 1.25 (95% CI, 1.06-1.46)) and postoperative 30-day mortality (colon: OR of less than 50 versus 100 or more resections per year = 1.17 (95% CI, 1.02-1.35); rectum: OR of less than 20 versus 40 or more resections per year = 1.42 (95% CI, 1.09-1.84)). No differences in overall survival were found between hospital volumes., Limitations: Although we adjusted for several patient and tumour characteristics, data regarding comorbidity, surgeon volume, local recurrences, and specific postoperative complications other than anastomotic leakage were not available., Conclusions: In the Netherlands, no differences in 5-year survival rates were revealed between hospital volumes for patients with nonmetastatic colorectal cancer.

Introduction: Liver metastases are common in patients with gastrointestinal stromal tumors (GIST). In the absence of randomized controlled clinical trials, the effectiveness of surgery as a treatment modality is unclear. This study identifies safety and outcome in a nationwide study of all patients who underwent resection of liver metastases from GIST., Methods: Patients were included using the national registry of histo- and cytopathology (PALGA) of the Netherlands from 1999. Kaplan Meier survival analysis was used for calculating survival outcome. Univariate and multivariate regression analyses were carried out for the assessment of potential prognostic factors., Results: A total of 48 patients (29 male, 19 female) with a median age of 58 (range 28-81) years were identified. Preoperative and postoperative tyrosine kinase inhibitor therapy was given to 30 (63%) and 36 (75%) patients, respectively. A minor liver resection was performed in 32 patients, 16 patients underwent major liver resection. Median follow-up was 27 (range 1-146) months. Median progression-free survival (PFS) was 28 (range 1-121) months. One-, three-, and five-year PFS was 93%, 67%, and 59% respectively. Median overall survival (OS) was 90 (range 1-146) months from surgery. The one-, three-, and five-year OS was 93%, 80%, and 76% respectively. R0 resection was the only independent significant prognostic factor for DFS and OS at multivariate analysis., Conclusion: Resection of liver metastases in GIST patients combined with imatinib may be associated with prolonged overall survival when a complete resection is achieved., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The liver is a common metastatic site for a large variety of primary tumors. For both patients with known and unknown primary tumors it is important to understand metastatic patterns to provide tailored therapies., Objective: To perform a nationwide exploration of the origins of histological confirmed liver metastases., Results: A total of 23,154 patients were identified. The majority of liver metastases were carcinomas (n=21,400; 92%) of which adenocarcinoma was the most frequent subtype (n=17,349; 75%). Most common primary tumors in patients with adenocarcinoma were from colorectal (n=8,004), pancreatic (n=1,755) or breast origin (n=1,415). In women of 50 years and younger, metastatic adenocarcinoma originated more frequently from breast cancer, while in women older than 70 years liver metastases originated more frequently from gastrointestinal tumors. Liver metastases in men older than 70 years originated often from squamous cell lung carcinoma. An unknown primary tumor was detected in 4,209 (18%) patients, although tumor type could be determined in 3,855 (92%) of them., Methods: Data were collected using the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA). All histological confirmed liver metastases between January 2001 and December 2010 were evaluated for tumor type, origin of the primary tumor and were correlated with patient characteristics (age, gender)., Conclusion: The current study provides an overview of the origins of liver metastases in a series of 23,154 patients.

Purpose: Parastomal hernia (PSH) is a common complication after colostomy formation. Recent studies indicate that mesh implantation during formation of a colostomy might prevent a PSH. To determine if placement of a retromuscular mesh at the colostomy site is a feasible, safe and effective procedure in preventing a parastomal hernia, we performed a multicentre randomized controlled trial in 11 large teaching hospitals and three university centres in The Netherlands., Methods: Augmentation of the abdominal wall with a retromuscular light-weight polypropylene mesh (Parietene Light™, Covidien) around the trephine was compared with traditional colostomy formation. Patients undergoing elective open formation of a permanent end-colostomy were eligible. 150 patients were randomized between 2010 and 2012. Primary endpoint of the PREVENT trial is the incidence of parastomal hernia. Secondary endpoints are morbidity, pain, quality of life, mortality and cost-effectiveness. This article focussed on the early results of the PREVENT trial and, therefore, operation time, postoperative morbidity, pain, and quality of life were measured., Results: Outcomes represent results after 3 months of follow-up. A total of 150 patients were randomized. Mean operation time of the mesh group (N = 72) was significantly longer than in the control group (N = 78) (182.6 vs. 156.8 min; P = 0.018). Four (2.7 %) peristomal infections occurred of which one (1.4 %) in the mesh group. No infection of the mesh occurred. Most of the other infections were infections of the perineal wound, equally distributed over both groups. No statistical differences were discovered in stoma or mesh-related complications, fistula or stricture formation, pain, or quality of life., Conclusions: During open and elective formation of an end-colostomy, primary placement of a retromuscular light-weight polypropylene mesh for prevention of a parastomal hernia is a safe and feasible procedure. The PREVENT trial is registered at: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2018 .

Background: Rectal cancer surgery is accompanied with high morbidity and poor long term functional outcome. Screening programs have shown a shift towards more early staged cancers. Patients with early rectal cancer can potentially benefit significantly from rectal preserving therapy. For the earliest stage cancers, local excision is sufficient when the risk of lymph node disease and subsequent recurrence is below 5 %. However, the majority of early cancers are associated with an intermediate risk of lymph node involvement (5-20 %) suggesting that local excision alone is not sufficient, while completion radical surgery, which is currently standard of care, could be a substantial overtreatment for this group of patients., Methods/study Design: In this multicentre randomised trial, patients with an intermediate risk T1-2 rectal cancer, that has been locally excised using an endoluminal technique, will be randomized between adjuvant chemo-radiotherapylimited to the mesorectum and standard completion total mesorectal excision (TME). To strictly monitor the risk of locoregional recurrence in the experimental arm and enable early salvage surgery, there will be additional follow up with frequent MRI and endoscopy. The primary outcome of the study is three-year local recurrence rate. Secondary outcomes are morbidity, disease free and overall survival, stoma rate, functional outcomes, health related quality of life and costs. The design is a non inferiority study with a total sample size of 302 patients., Discussion: The results of the TESAR trial will potentially demonstrate that adjuvant chemoradiotherapy is an oncological safe treatment option in patients who are confronted with the difficult clinical dilemma of a radically removed intermediate risk early rectal cancer by polypectomy or transanal surgery that is conventionally treated with subsequent radical surgery. Preserving the rectum using adjuvant radiotherapy is expected to significantly improve morbidity, function and quality of life if compared to completion TME surgery., Trial Registration: NCT02371304 , registration date: February 2015.

Adjuvant chemotherapy can be considered in high-risk stage II colon cancer comprising pT4, poor/undifferentiated grade, vascular invasion, emergency surgery and/or <10 evaluated lymph nodes (LNs). Adjuvant chemotherapy administration and its effect on survival was evaluated for each known risk factor. All patients with high-risk stage II colon cancer who underwent resection and were diagnosed in the Netherlands between 2008 and 2012 were included. After stratification by risk factor(s) (vascular invasion could not be included), Cox regression was used to discriminate the independent association of adjuvant chemotherapy with the probability of death. Relative survival was used to estimate disease-specific survival. A total of 4,940 of 10,935 patients with stage II colon cancer were identified as high risk, of whom 790 (16%) patients received adjuvant chemotherapy. Patients with a pT4 received adjuvant chemotherapy more often (37%). Probability of death in pT4 patients receiving chemotherapy was lower compared to non-recipients (3-year overall survival 91% vs. 73%, HR 0.43, 95% CI 0.28-0.66). The relative excess risk (RER) of dying was also lower for pT4 patients receiving chemotherapy compared to non-recipients (3-year relative survival 94% vs. 85%, RER 0.36, 95% CI 0.17-0.74). For patients with only poor/undifferentiated grade, emergency surgery or <10 LNs evaluated, no association between receipt of adjuvant chemotherapy and survival was observed. In high-risk stage II colon cancer, adjuvant chemotherapy was associated with higher survival in pT4 only. To prevent unnecessary chemotherapy-induced toxicity, further refinement of patient subgroups within stage II colon cancer who could benefit from adjuvant chemotherapy seems indicated., (© 2016 UICC.)

The majority of colorectal cancers (CRCs) are classified as adenocarcinoma not otherwise specified (AC). Mucinous carcinoma (MC) is a distinct form of CRC and is found in 10-15% of patients with CRC. MC differs from AC in terms of both clinical and histopathological characteristics, and has long been associated with an inferior response to treatment compared with AC. The debate concerning the prognostic implications of MC in patients with CRC is ongoing and MC is still considered an unfavourable and unfamiliar subtype of the disease. Nevertheless, in the past few years epidemiological and clinical studies have shed new light on the treatment and management of patients with MC. Use of a multidisciplinary approach, including input from surgeons, pathologists, oncologists and radiologists, is beginning to lead to more-tailored approaches to patient management, on an individualized basis. In this Review, the authors provide insight into advances that have been made in the care of patients with MC. The prognostic implications for patients with colon or rectal MC are described separately; moreover, the predictive implications of MC regarding responses to commonly used therapies for CRC, such as chemotherapy, radiotherapy and chemoradiotherapy, and the potential for, and severity of, metastasis are also described.

Purpose: To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specific immunological responses in stage III melanoma patients., Experimental Design: Retrospective analysis of stage III melanoma patients, vaccinated with autologous monocyte-derived DC loaded with tumor-associated antigens (TAA) gp100 and tyrosinase after radical lymph node dissection. Skin-test infiltrating lymphocytes (SKILs) obtained from delayed-type hypersensitivity skin-test biopsies were analyzed for the presence of TAA-specific CD8(+) T cells by tetrameric MHC-peptide complexes and by functional TAA-specific T cell assays, defined by peptide-recognition (T2 cells) and/or tumor-recognition (BLM and/or MEL624) with specific production of Th1 cytokines and no Th2 cytokines., Results: Ninety-seven patients were analyzed: 21 with stage IIIA, 34 with stage IIIB, and 42 had stage IIIC disease. Tetramer-positive CD8(+) T cells were present in 68 patients (70%), and 24 of them showed a response against all 3 epitopes tested (gp100:154-162, gp100:280-288, and tyrosinase:369-377) at any point during vaccinations. A functional T cell response was found in 62 patients (64%). Rates of peptide-recognition of gp100:154-162, gp100:280-288, and tyrosinase:369-377 were 40%, 29%, and 45%, respectively. Median recurrence-free survival and distant metastasis-free survival of the whole study population were 23.0 mo and 36.8 mo, respectively., Conclusions: DC vaccination induces a functional TAA-specific T cell response in the majority of stage III melanoma patients, indicating it is more effective in stage III than in stage IV melanoma patients. Furthermore, performing multiple cycles of vaccinations enhances the chance of a broader immune response.

Purpose: Traditionally, total thyroidectomy has been advocated for patients with tumors larger than 1 cm. However, according to the ATA and NCCN guidelines (2015, USA), patients with tumors up to 4 cm are now eligible for lobectomy. A rationale for adhering to total thyroidectomy might be the presence of contralateral carcinomas. The purpose of this study was to describe the characteristics of contralateral carcinomas in patients with differentiated thyroid cancer (DTC) larger than 1 cm., Methods: A retrospective study was performed including patients from 17 centers in 5 countries. Adults diagnosed with DTC stage T1b-T3 N0-1a M0 who all underwent a total thyroidectomy were included. The primary endpoint was the presence of a contralateral carcinoma., Results: A total of 1313 patients were included, of whom 426 (32 %) had a contralateral carcinoma. The contralateral carcinomas consisted of 288 (67 %) papillary thyroid carcinomas (PTC), 124 (30 %) follicular variant of a papillary thyroid carcinoma (FvPTC), 5 (1 %) follicular thyroid carcinomas (FTC), and 3 (1 %) Hürthle cell carcinomas (HTC). Ipsilateral multifocality was strongly associated with the presence of contralateral carcinomas (OR 2.62). Of all contralateral carcinomas, 82 % were ≤10 mm and of those 99 % were PTC or FvPTC. Even if the primary tumor was a FTC or HTC, the contralateral carcinoma was (Fv)PTC in 92 % of cases., Conclusions: This international multicenter study performed on patients with DTC larger than 1 cm shows that contralateral carcinomas occur in one third of patients and, independently of primary tumor subtype, predominantly consist of microPTC.

Background: Prior abdominal surgery increases complexity of abdominal operations. Effort to prevent injury during adhesiolysis might result in less extensive bowel resection in colorectal cancer surgery. The aim of this study was to evaluate the effect of prior abdominal surgery on the outcome of colorectal cancer surgery., Methods: A nationwide prospective database of patients with primary colorectal cancer resection in The Netherlands between 2010 and 2012 was reviewed for histopathology, morbidity and mortality in patients with compared to patients without prior abdominal surgery., Results: 9042 patients with and 17,679 without prior abdominal surgery were analyzed. After prior abdominal surgery 20.7 % had less than 10 lymph nodes in the histopathological specimen compared to 17.8 % without prior abdominal surgery (adjusted OR 1.17, 95 % CI 1.09-1.26). Adjusted ORs for less than 10 and 12 lymph nodes were significant in colon cancer resection and not in rectal cancer resection. Subgroups of patients who had previous hepatobiliary surgery or other abdominal surgery had a higher incidence of inadequate number of harvested lymph nodes. Prior colorectal surgery increased the percentage of positive circumferential rectal resection margin by 64 % (12.5 and 7.6 %; adjusted OR 1.70, 95 % CI 1.21-2.39). For colon cancer morbidity was significantly higher in patients with prior surgery (33.2 and 29.7 %; adjusted OR 1.18, 95 % CI 1.10-1.26), 30-day mortality was comparable (4.7 % prior surgery and 3.8 % without prior surgery; adjusted OR 1.01, 95 % CI 0.88-1.17)., Conclusions: Prior abdominal surgery compromises the quality of resection and increases postoperative morbidity in patients with primary colorectal cancer.

Objective: To evaluate and compare the overall survival (OS) in case-matched patient groups treated either with systemic therapy or surgery for colorectal liver metastases (CRLM)., Methods: Patients with CRLM, without extra-hepatic disease, treated with chemotherapy with or without targeted therapy in two phase III studies (n = 480) were selected and case-matched to patients who underwent liver resection (n = 632). Matching criteria were sex, age, established prognostic factors for survival (clinical risk score). Available computed tomography (CT)-scans of patients treated with systemic therapies were reviewed by three independent liver surgeons for resectability. Survival was compared between patients with resectable CRLM (based on CT-scan review) who were treated with systemic therapy versus patients who underwent liver resection., Results: A total of 96 patients treated with systemic therapy were included. Pre-treatment CT-scans of the liver were available for review in 56 of the systemically treated patients, and metastases were unanimously considered resectable in 36 patients (64.3%) (complex resectable: n = 25; 69%). These 36 patients were case-matched with 36 patients who underwent liver resection (wedge resection or segmentectomy: n = 26; 72%). Median OS in the patient group treated with systemic therapy was 26.5 months (range 0-81 months), which was significantly lower than that in case-matched patients who underwent liver resection (median OS 56 months; range 6-116) (p = 0.027)., Conclusions: In this case-matched control study, surgery provided superior OS rates compared to systemic therapy for CRLM. Resection of CRLM should always be considered, preferably in a dedicated liver centre, since not all patients that qualify for resection are identified as such., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: The combination of resection and radiofrequency ablation (RFA) may provide an alternative treatment for patients with unresectable colorectal liver metastases (CRLM). Although the results in literature look promising, uncertainty exists with regard to complication risks and survival for this therapy., Methods: From January 2000 to May 2013, patients were included in a prospective multicenter database when treated for CRLM. Exclusion criteria were: two-staged treatment, synchronous resection of liver metastases and primary tumor, loss to follow-up or extrahepatic metastases. Patients were divided in a resection-only group (ROG) and combination group (CG). Outcome variables were retrospectively analyzed., Results: In CG, 98 patients were included versus 534 patients in ROG. There were no differences in general patient characteristics. Patients in CG had a higher Fong clinical risk score (CRS; P = 0.001), better ASA classification (P = 0.04) and received more neoadjuvant chemotherapy (P = 0.001). There was no difference in postoperative morbidity or 90-day mortality. The 5-year disease-free survival (DFS) for CG and ROG was 25% and 36.1% (P = 0.03), respectively. For the 5-year overall survival (OS) this was respectively 42% and 62.2% (P = 0.001). On multivariate analysis, Fong CRS was a significant predictor for DFS. For OS, Fong CRS, ASA class IV and the combination therapy were significant predictors., Conclusion: The combination of hepatic resection and intraoperative RFA is a safe procedure, without increase in postoperative morbidity or mortality. Combining RFA and resection in one session is a valid treatment option for patients who would otherwise be inoperable., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Multidrug resistance-associated proteins (MRPs) belong to the C-family of ATP-binding cassette (ABC) transport proteins and are known to transport a variety of physiologically important compounds and to be involved in the extrusion of pharmaceuticals. Rodent malaria parasites encode a single ABC transporter subfamily C protein, whereas human parasites encode two: MRP1 and MRP2. Although associated with drug resistance, their biological function and substrates remain unknown. To elucidate the role of MRP throughout the parasite life cycle, Plasmodium berghei and Plasmodium falciparum mutants lacking MRP expression were generated. P. berghei mutants lacking expression of the single MRP as well as P. falciparum mutants lacking MRP1, MRP2 or both proteins have similar blood stage growth kinetics and drug-sensitivity profiles as wild type parasites. We show that MRP1-deficient parasites readily invade primary human hepatocytes and develop into mature liver stages. In contrast, both P. falciparum MRP2-deficient parasites and P. berghei mutants lacking MRP protein expression abort in mid to late liver stage development, failing to produce mature liver stages. The combined P. berghei and P. falciparum data are the first demonstration of a critical role of an ABC transporter during Plasmodium liver stage development., (© 2015 John Wiley & Sons Ltd.)

Background: Local recurrence after rectal cancer treatment occurs in ≈5% to 10% of patients. Neoadjuvant (chemo)radiotherapy for primary rectal cancer renders treatment of recurrent disease more difficult., Objective: The purpose of this study was to review contemporary multimodality therapies, including their outcome, for locally recurrent rectal carcinoma after (chemo)radiotherapy and complete surgical resection of primary rectal cancer., Data Sources: A comprehensive literature search of PubMed and EMBASE was performed., Study Selection: All English language articles presenting original patient data regarding treatment and the respective outcome of previously irradiated locally recurrent rectal cancer were included., Interventions: All of the treatment modalities for locally recurrent rectal cancer were reviewed., Main Outcome Measures: Primary outcome parameters were local control, metastasis-free survival, and overall survival. Secondary outcome parameters were perioperative morbidity and mortality, and prognostic factors for treatment outcome., Results: Of 854 studies, 9 studies and 474 patients with locally recurrent rectal carcinoma were included. Various treatment regimens were used, most with curative intent. Reirradiation was composed of (neo-)adjuvant external beam radiotherapy (with or without concurrent chemotherapy), additional intraoperative radiotherapy, or intraoperative radiotherapy only. Surgical technique highly varied, depending on the extent of the lesion. Radiation toxicity, perioperative morbidity, and mortality were generally acceptable. Outcome was better after curative intent treatment, any surgical resection, and R0 resections in particular. Moreover, reirradiation is associated with increased complete resection rates, which in turn positively affected local control and overall survival., Limitations: Most studies were retrospectively designed, with highly variable therapies, patient populations, and duration of follow-up., Conclusions: A complete resection is the most important prognostic factor and should be the goal of treatment in locally recurrent rectal carcinoma. Reirradiation seems safe and of additional value in reaching a complete resection. Considering the available evidence, at present reirradiation should be given on a case-specific basis, with all of the patients entering an international prospective database.

Objective: The study aims to evaluate all patients who underwent liver resection for metastatic disease for demographics, characteristics of the primary tumor and metastasis, volume of liver resection specimens per pathology laboratory and to describe trends in surgical treatment., Methods: Data were prospectively collected using the Dutch nationwide pathology network. All pathology reports containing details on liver resections for metastatic disease between January 2001 and December 2010 were evaluated., Results: A total of 3,916 liver resections were performed in 3,699 patients with a median age of 63 years (range 1-91). The primary tumor was mainly colorectal (n = 3,256; 88.0%). The number of 'high volume liver centers' increased from 2 to 12 in the study period, whereas the number of 'low volume centers' decreased. The number of liver resections increased from 224 to 596 per year (p ≤ 0.0001). A significant increase was demonstrated in elderly patients, patients with multiple metastases, liver resections for smaller metastases and minor liver resections., Conclusion: Although the majority of patients were young and had solitary metastasis, indications for liver resection are expanding as indicated by increasing numbers of elderly and patients with multiple liver metastases. Patients with non-colorectal liver metastases were seldom candidates for resection., (© 2016 S. Karger AG, Basel.)

A 62-year-old female was admitted to the hospital with pain in the lower abdomen and fever since 1 week. A CT scan showed retroperitoneal air around the inferior mesenteric vein and diverticulitis of the sigmoid. We made the diagnosis of intramesocolic diverticular perforation of the sigmoid, a rare phenomenon, and performed an emergency sigmoidectomy.

Background/aims: Adhesiolysis is a frequent part of colorectal surgery, potentially impeding the operation and causing inadvertent bowel injury. Such difficulties might compromise convalescence and oncological quality of resection. The aim of this prospective cohort study was to assess the impact of adhesiolysis on clinical outcomes and histopathological results in colorectal surgery., Methods: Colorectal procedures were selected from a prospective cohort study of adhesiolysis-related problems. We compared the incidence of bowel injury, morbidity, costs, and the histopathology between patients undergoing elective colorectal surgery with or without adhesiolysis., Results: Two hundred and forty nine colorectal surgeries were analysed. Adhesiolysis was required in 59.0%. The mean adhesiolysis time was 28 min. In the adhesiolysis group, enterotomies occurred in 6.1% and seromuscular injuries in 27.2% compared to 0 and 6.9% respectively in the non-adhesiolysis group (p = 0.012 and p < 0.001). In patients requiring adhesiolysis, 29.9% had major surgery-related complications (MSRC) compared to 15.7% without adhesiolysis (p = 0.007). There were no statistically significant differences regarding inpatient costs and resection margin or number of harvested lymph nodes., Conclusions: Adhesiolysis during colorectal surgery is related to an increased incidence of iatrogenic bowel injuries and MSRC. Despite the technical challenges associated with adhesiolysis, good histopathological results were obtained in oncological resections., (© 2015 S. Karger AG, Basel.)

Background: For a selection of patients with colorectal liver metastases (CRLM), liver resection is a curative option. In order to predict long-term survival, clinicopathologic risk scores have been developed, but little is known about histologic factors and their prognostic value for disease-free and overall survival. The objective of the present study was to assess possible prognostic histologic factors in patients with solitary CRLM treated with liver resection who did not receive neoadjuvant treatment., Methods: Patients with solitary CRLM who underwent liver resection between 1992 and 2011 were evaluated for clinical prognostic factors. Histologic analyses on tumor thickness at the tumor-normal interface, presence of a fibrotic capsule, intrahepatic vascular invasion, lymphatic invasion, or bile duct invasion and perineural growth were performed, using immunohistochemistry., Results: A total of 124 patients were analyzed with a median follow-up of 41 months (range 1-232 months). There was no association between histologic factors and disease-free survival in multivariate analysis. In multivariate analysis, intrahepatic lymphatic invasion was associated with a decreased overall survival (41.9 vs. 61.0 months; p = 0.041), especially in combination with vascular invasion (n = 15) (28.1 vs. 62.2 months; p < 0.0001). In addition, size over 50 mm (29.2 vs. 65.9 months; p = 0.004) and interval less than 12 months between resection of the primary tumor and diagnosis of liver metastasis (49.0 vs. 91.5 months: p = 0.019) were also independent adverse prognostic factors., Conclusions: Intrahepatic lymphatic invasion, especially in combination with vascular invasion, is an important adverse prognostic factor for overall survival in patients with solitary CRLM after liver resection.

Background: With evolving treatment possibilities for peritoneal metastases (PM) from colorectal cancer (CRC), adequate prognostication and patient selection for treatment becomes increasingly important. We investigated the prognostic relevance of commonly identified histological subtypes in PM of CRC (adenocarcinoma [AC], mucinous AC [MC], and signet-ring cell carcinoma [SC]), which is currently unclear., Patients and Methods: This study involved 4277 patients diagnosed with synchronous PM from CRC between 2005 and 2012 in The Netherlands. Kaplan-Meier analysis and log-rank testing were performed to estimate survival. Subsequently a Cox proportional hazard model was used to calculate hazard ratios for the risk of death., Results: Most of the CRC patients were diagnosed with AC (n = 3008; 70%), whereas MC and SC were found in 958 (22%) and 311 (7%) patients, respectively. SC was associated with the highest risk of death in colon and rectal cancer, with median survival rates of respectively, 6.6 and 6.9 months. For MC, median survival varied from 10.9 months in colon and 9.8 months in rectal cancer (P > .05). In colon cancer, MC was associated with a significantly lower risk of death compared with AC (hazard ratio, 0.9; 95% confidence interval, 0.79-0.95). In rectal cancer, no such effect was observed. AC was associated with a significantly poorer survival rate in the case of primary colonic tumor localization (7.4 months in colon vs. 10.9 months in rectal cancer)., Conclusion: Histological subtype is an important prognostic factor in patients with synchronous PM of colorectal origin. This knowledge will aid clinicians in counseling of patients and clinical decision-making regarding possible treatment options., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Patients with palpable melanoma groin metastases have a poor prognosis. There is debate whether a combined superficial and deep groin dissection (CGD) is necessary or if superficial groin dissection (SGD) alone is sufficient., Aim: The aim of this study was to analyze risk factors for deep pelvic nodal involvement in a retrospective, multicenter cohort of palpable groin melanoma metastases. This could aid in the development of an algorithm for selective surgery in the future., Methods: This study related to 209 therapeutic CGDs from four tertiary centers in The Netherlands (1992-2013), selected based on complete preoperative imaging and pathology reports. Analyzed risk factors included baseline and primary tumor characteristics, total and positive number of inguinal nodes, inguinal lymph node ratio (LNR) and positive deep pelvic nodes on imaging (computed tomography [CT] ± positron emission tomography [PET], or PET - low-dose CT)., Results: Median age was 57 years, 54 % of patients were female, and median follow-up was 21 months (interquartile range [IQR] 11-46 months). Median Breslow thickness was 2.10 mm (IQR 1.40-3.40 mm), and 26 % of all primary melanomas were ulcerated. Positive deep pelvic nodes occurred in 35 % of CGDs. Significantly fewer inguinal nodes were positive in case of negative deep pelvic nodes (median 1 [IQR 1-2] vs. 3 [IQR 1-4] for positive deep pelvic nodes; p < 0.001), and LNR was significantly lower for negative versus positive deep pelvic nodes [median 0.15 (IQR 0.10-0.25) vs. 0.33 (IQR 0.14-0.54); p < 0.001]. A combination of negative imaging, low LNR, low number of positive inguinal nodes, and no extracapsular extension (ECE) could accurately predict the absence of pelvic nodal involvement in 84 % of patients., Conclusions: Patients with negative imaging, few positive inguinal nodes, no ECE, and low LNR have a low risk of positive deep pelvic nodes and may safely undergo SGD alone.

Background: Since the introduction of total mesorectal surgery the outcome of rectal cancer patients has improved significantly. Involvement of the circumferential resection margin (CRM) is an important predictor of increased local recurrence, distant metastases and decreased overall survival. Abdomino perineal excision (APE) is associated with increased risk of CRM involvement. Aim of this study was to analyze reporting of CRM and to identify predictive factors for CRM involvement., Methods: A population-based dataset was used selecting 2153 patients diagnosed between 2008 and 2013 with primary rectal cancer undergoing surgery. Variation in CRM reporting was assessed and predictive factors for CRM involvement were calculated and used in multivariate analyses., Results: Large variation in CRM reporting was found between pathology departments, with missing cases varying from 6% to 30%. CRM reporting increased from 77% in 2008 to 90% in 2012 (p < 0.001). CRM involvement significantly decreased from 12% to 6% over the years (p < 0.001). In multivariate analysis type of operation, low anterior resection or APE, did not influence the risk of CRM involvement. Clinical T4-stage [odds ratio (OR) = 3.51; 95% confidence interval (CI) = 1.85-6.65) was associated with increased risk of CRM involvement, whereas neoadjuvant treatment (5 × 5 gray radiotherapy [OR 0.39; CI 0.25-0.62] or chemoradiation therapy [OR 0.30; CI 0.17-0.53]) were associated with significant decreased risk of CRM involvement., Conclusion: Although significant improvements are made during the last years there still is variation in reporting of CRM involvement in the Southern Netherlands. In multivariate analysis APE was no longer associated with increased risk of CRM involvement., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The Z0011 trial demonstrated no difference in overall survival (OS) and locoregional recurrence in breast cancer patients with a positive sentinel lymph node (SLN) randomized to axillary lymph node dissection (ALND) or no further surgery. The aim of this study was to evaluate locoregional recurrence in a nonrandomized group of SLN positive patients, in whom cALND was not performed, that were retrospectively categorized by the Z0011 eligibility criteria. From two hospital breast cancer databases consisting of 656 consecutive SLN positive breast cancer patients, 88 patients, who did not undergo cALND, were identified. This population was categorized by the Z0011 inclusion criteria (e.g., eligible versus ineligible) and the groups were compared. Thirty-four patients (38.6%) were retrospectively eligible for omitting cALND according to the Z0011 criteria and 54 (61.4%) were not. The median number of SLNs removed in both groups was 1 (range 1-5). The number of positive SLNs did not differ between the groups. Tumor size was slightly larger in the ineligible group (21 mm versus 19 mm) and 76% of patients in the ineligible group underwent a mastectomy. At a median follow-up of 26 months (range 1-84 months), one axillary recurrence was observed in the ineligible group versus 0 in the eligible group. Axillary recurrence was low, even in patients who did not meet the Z0011 inclusion criteria. Future trials that randomize Z0011 ineligible patients are needed to investigate long-term results., (© 2015 Wiley Periodicals, Inc.)

Background: Mucinous carcinoma (MC) is found in 10%-15% of colorectal cancer (CRC) patients. It differs from the common adenocarcinoma (AC) in histopathological appearance and clinical behavior., Methods: Genome-wide DNA copy number and survival data from MC and AC primary CRC samples from patients from two phase III trials (CAIRO and CAIRO2) was compared. Chromosomal copy number data from The Cancer Genome Atlas (TCGA) was used for validation. Altogether, 470 ACs were compared to 57 MCs., Results: MC showed a reduced amount of copy number aberrations (CNAs) compared with AC for the CAIRO/CAIRO2 cohort, with a median amount of CNAs that was 1.5-fold lower (P = 0.002). Data from TCGA also showed a reduced amount of CNAs for MC. MC samples in both cohorts displayed less gain at chromosome 20q and less loss of chromosome 18p. A high rate of chromosomal instability was a strong negative prognostic marker for survival in MC patients from the CAIRO cohorts (hazard ratio 15.60, 95% CI 3.24-75.05)., Conclusions: Results from this study indicate that the distinct MC phenotype is accompanied by a different genetic basis when compared with AC and show a strong association between the rate of chromosomal instability and survival in MC patients.

Background: Trials failed to demonstrate additional value of completion axillary lymph node dissection in case of limited sentinel lymph node metastases in breast cancer patients undergoing breast conserving therapy. It has been suggested that the low regional recurrence rates in these trials might partially be ascribed to accidental irradiation of part of the axilla by whole breast radiation therapy, which precludes extrapolation of results to mastectomy patients. The aim of the randomized controlled BOOG 2013-07 trial is therefore to investigate whether completion axillary treatment can be safely omitted in sentinel lymph node positive breast cancer patients treated with mastectomy., Design: This study is designed as a non-inferiority randomized controlled multicentre trial. Women aged 18 years or older diagnosed with unilateral invasive clinically T1-2 N0 breast cancer who are treated with mastectomy, and who have a maximum of three axillary sentinel lymph nodes containing micro- and/or macrometastases, will be randomized for completion axillary treatment versus no completion axillary treatment. Completion axillary treatment can consist of completion axillary lymph node dissection or axillary radiation therapy. Primary endpoint is regional recurrence rate at 5 years. Based on a 5-year regional recurrence free survival rate of 98 % among controls and 96 % for study subjects, the sample size amounts 439 per arm (including 10 % lost to follow-up), to be able to reject the null hypothesis that the rate for study and control subjects is inferior by at least 5 % with a probability of 0.8. Results will be reported after 5 and 10 years of follow-up., Discussion: We hypothesize that completion axillary treatment can be safely omitted in sentinel node positive breast cancer patients undergoing mastectomy. If confirmed, this study will significantly decrease the number of breast cancer patients receiving extensive treatment of the axilla, thereby diminishing the risk of morbidity and improving quality of life, while maintaining excellent regional control and without affecting survival., Trial Registration: The BOOG 2013-07 study is registered in the register of ClinicalTrials.gov since April 10, 2014, Identifier: NCT02112682 .