Genetic Determinants of Outcome in Intrahepatic Cholangiocarcinoma.

BACKGROUND AND AIM: Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well characterized, but their impact on outcome and prognosis remains unknown. APPROACH AND RESULTS: This bi-institutional study of patients with confirmed iCCA (n = 412) used targeted next-generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were isocitrate dehydrogenase 1 (IDH1; 20%), AT-rich interactive domain-containing protein 1A (20%), tumor protein P53 (TP53; 17%), cyclin-dependent kinase inhibitor 2A (CDKN2A; 15%), breast cancer 1-associated protein 1 (15%), FGFR2 (15%), polybromo 1 (12%), and KRAS (10%). IDH1/2 mutations (mut) were mutually exclusive with FGFR2 fusions, but neither was associated with outcome. For all patients, TP53 (P < 0.0001), KRAS (P = 0.0001), and CDKN2A (P < 0.0001) alterations predicted worse overall survival (OS). These high-risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n = 209), TP53mut (HR, 1.82; 95% CI, 1.08-3.06; P = 0.03) and CDKN2A deletions (del; HR, 3.40; 95% CI, 1.95-5.94; P < 0.001) independently predicted shorter OS, as did high-risk clinical variables (multifocal liver disease [P < 0.001]; regional lymph node metastases [P < 0.001]), whereas KRASmut (HR, 1.69; 95% CI, 0.97-2.93; P = 0.06) trended toward statistical significance. The presence of both or neither high-risk clinical or genetic factors represented outcome extremes (median OS, 18.3 vs. 74.2 months; P < 0.001), with high-risk genetic alterations alone (median OS, 38.6 months; 95% CI, 28.8-73.5) or high-risk clinical variables alone (median OS, 37.0 months; 95% CI, 27.6-not available) associated with intermediate outcome. TP53mut, KRASmut, and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high-risk clinical features were notable for limited survival and no benefit of resection over chemotherapy. CONCLUSIONS: TP53, KRAS, and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Because genetic profiling can be integrated into pretreatment therapeutic decision-making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.

Volume-outcome relationship of liver surgery: a nationwide analysis.

BACKGROUND: Evidence for an association between hospital volume and outcomes for liver surgery is abundant. The current Dutch guideline requires a minimum volume of 20 annual procedures per centre. The aim of this study was to investigate the association between hospital volume and postoperative outcomes using data from the nationwide Dutch Hepato Biliary Audit. METHODS: This was a nationwide study in the Netherlands. All liver resections reported in the Dutch Hepato Biliary Audit between 2014 and 2017 were included. Annual centre volume was calculated and classified in categories of 20 procedures per year. Main outcomes were major morbidity (Clavien-Dindo grade IIIA or higher) and 30-day or in-hospital mortality. RESULTS: A total of 5590 liver resections were done across 34 centres with a median annual centre volume of 35 (i.q.r. 20-69) procedures. Overall major morbidity and mortality rates were 11·2 and 2·0 per cent respectively. The mortality rate was 1·9 per cent after resection for colorectal liver metastases (CRLMs), 1·2 per cent for non-CRLMs, 0·4 per cent for benign tumours, 4·9 per cent for hepatocellular carcinoma and 10·3 per cent for biliary tumours. Higher-volume centres performed more major liver resections, and more resections for hepatocellular carcinoma and biliary cancer. There was no association between hospital volume and either major morbidity or mortality in multivariable analysis, after adjustment for known risk factors for adverse events. CONCLUSION: Hospital volume and postoperative outcomes were not associated.

ANTECEDENTES: La asociación entre el volumen hospitalario y los resultados de la cirugía hepática no está clara. Según la recomendación actual de las guías holandesas se requiere un volumen mínimo de 20 procedimientos anuales por centro. El objetivo de este estudio fue analizar la asociación entre el volumen hospitalario con los resultados postoperatorios en la auditoría hepatobiliar obligatoria holandesa a nivel nacional. MÉTODOS: Se realizó un estudio a nivel nacional en los Países Bajos. Se incluyeron todas las resecciones hepáticas registradas en la auditoría hepatobiliar holandesa entre 2014 y 2017. El volumen anual del centro se calculó y se clasificó en categorías de 20 procedimientos por año. Los objetivos principales fueron la morbilidad de mayor grado (Clavien-Dindo grado IIIA o superior) y la mortalidad hospitalaria o la mortalidad a los 30 días. RESULTADOS: Se realizaron un total de 5.590 resecciones en 34 centros con una mediana (rango intercuartílico) de volumen anual de 35 procedimientos (20-69). La tasa global de morbilidad mayor fue del 11% y la mortalidad del 2%. La mortalidad fue de 1,9% después de la resección por metástasis hepáticas colorrectales (colorectal liver metastases, CRLM), 1,2% para no CRLM, 0,4% para tumores benignos, 4,9% para carcinoma hepatocelular, y 10,3% para tumores biliares. Los centros de mayor volumen realizaron más resecciones hepáticas mayores y más resecciones por carcinoma hepatocelular y cáncer biliar. En el análisis multivariable después de ajustar por factores de riesgo conocidos de eventos adversos, no se observó ninguna asociación entre el volumen hospitalario y la morbilidad o mortalidad mayor. CONCLUSIÓN: No hubo asociación entre el volumen hospitalario y los resultados postoperatorios de la cirugía hepática en los Países Bajos.

Interconnectivity between molecular subtypes and tumor stage in colorectal cancer.

BACKGROUND: There are profound individual differences in clinical outcomes between colorectal cancers (CRCs) presenting with identical stage of disease. Molecular stratification, in conjunction with the traditional TNM staging, is a promising way to predict patient outcomes. We investigated the interconnectivity between tumor stage and tumor biology reflected by the Consensus Molecular Subtypes (CMSs) in CRC, and explored the possible value of these insights in patients with stage II colon cancer. METHODS: We performed a retrospective analysis using clinical records and gene expression profiling in a meta-cohort of 1040 CRC patients. The interconnectivity of tumor biology and disease stage was assessed by investigating the association between CMSs and TNM classification. In order to validate the clinical applicability of our findings we employed a meta-cohort of 197 stage II colon cancers. RESULTS: CMS4 was significantly more prevalent in advanced stages of disease (stage I 9.8% versus stage IV 38.5%, p < 0.001). The observed differential gene expression between cancer stages is at least partly explained by the biological differences as reflected by CMS subtypes. Gene signatures for stage III-IV and CMS4 were highly correlated (r = 0.77, p < 0.001). CMS4 cancers showed an increased progression rate to more advanced stages (CMS4 compared to CMS2: 1.25, 95% CI: 1.08-1.46). Patients with a CMS4 cancer had worse survival in the high-risk stage II tumors compared to the total stage II cohort (5-year DFS 41.7% versus 100.0%, p = 0.008). CONCLUSIONS: Considerable interconnectivity between tumor biology and tumor stage in CRC exists. This implies that the TNM stage, in addition to the stage of progression, might also reflect distinct biological disease entities. These insights can potentially be utilized to optimize identification of high-risk stage II colon cancers.

Improving clinical management of colon cancer through CONNECTION, a nation-wide colon cancer registry and stratification effort (CONNECTION II trial): rationale and protocol of a single arm intervention study.

BACKGROUND: It is estimated that around 15-30% of patients with early stage colon cancer benefit from adjuvant chemotherapy. We are currently not capable of upfront selection of patients who benefit from chemotherapy, which indicates the need for additional predictive markers for response to chemotherapy. It has been shown that the consensus molecular subtypes (CMSs), defined by RNA-profiling, have prognostic and/or predictive value. Due to postoperative timing of chemotherapy in current guidelines, tumor response to chemotherapy per CMS is not known, which makes the differentiation between the prognostic and predictive value impossible. Therefore, we propose to assess the tumor response per CMS in the neoadjuvant chemotherapy setting. This will provide us with clear data on the predictive value for chemotherapy response of the CMSs. METHODS: In this prospective, single arm, multicenter intervention study, 262 patients with resectable microsatellite stable cT3-4NxM0 colon cancer will be treated with two courses of neoadjuvant and two courses of adjuvant capecitabine and oxaliplatin. The primary endpoint is the pathological tumor response to neoadjuvant chemotherapy per CMS. Secondary endpoints are radiological tumor response, the prognostic value of these responses for recurrence free survival and overall survival and the differences in CMS classification of the same tumor before and after neoadjuvant chemotherapy. The study is scheduled to be performed in 8-10 Dutch hospitals. The first patient was included in February 2020. DISCUSSION: Patient selection for adjuvant chemotherapy in early stage colon cancer is far from optimal. The CMS classification is a promising new biomarker, but a solid chemotherapy response assessment per subtype is lacking. In this study we will investigate whether CMS classification can be of added value in clinical decision making by analyzing the predictive value for chemotherapy response. This study can provide the results necessary to proceed to future studies in which (neo) adjuvant chemotherapy may be withhold in patients with a specific CMS subtype, who show no benefit from chemotherapy and for whom possible new treatments can be investigated. TRIAL REGISTRATION: This study has been registered in the Netherlands Trial Register (NL8177) at 11-26-2019, https://www.trialregister.nl/trial/8177 . The study has been approved by the medical ethics committee Utrecht (MEC18/712).

Effects of bariatric surgery on telomere length and T-cell aging.

BACKGROUND: Obesity adversely affects health and is associated with subclinical systemic inflammation and features of accelerated aging, including the T-cell immune system. The presence of metabolic syndrome (MetS) may accelerate, while bariatric surgery might reverse these phenomena. To examine the effects of MetS and bariatric surgery on T-cell aging, we measured relative telomere length (RTL) and T-cell differentiation status in obese patients before and after bariatric surgery. METHODS: WHO II/III classified obese patients scheduled for bariatric surgery were included: 41 without MetS and 67 with MetS. RTL and T-cell differentiation status were measured in circulating CD4+ and CD8+ T cells via flow cytometry. T-cell characteristics were compared between patients with and without MetS prior to and at 3, 6, and 12 months after surgery considering effects of age, cytomegalovirus-serostatus, and weight loss. RESULTS: Thymic output, represented by numbers of CD31-expressing naive T cells, showed an age-related decline in patients with MetS. MetS significantly enhanced CD8+ T-cell differentiation. Patients with MetS had significant lower CD4+ RTL than patients without MetS. Within the first 6 months after bariatric surgery, RTL increased in CD4+ T cells after which it decreased at month 12. A decline in both thymic output and more differentiated T cells was seen following bariatric surgery, more pronounced in the MetS group and showing an association with percentage of body weight loss. CONCLUSIONS: In obese patients, MetS results in attrition of RTL and accelerated T-cell differentiation. Bariatric surgery temporarily reverses these effects. These data suggest that MetS is a risk factor for accelerated aging of T cells and that MetS should be a more prominent factor in the decision making for eligibility for bariatric surgery.

Safety and efficacy of transarterial embolization of hepatocellular adenomas.

BACKGROUND: Hepatocellular adenoma (HCA) larger than 5 cm in diameter has an increased risk of haemorrhage and malignant transformation, and is considered an indication for resection. As an alternative to resection, transarterial embolization (TAE) may play a role in prevention of complications of HCA, but its safety and efficacy are largely unknown. The aim of this study was to assess outcomes and postembolization effects of selective TAE in the management of HCA. METHODS: This retrospective, multicentre cohort study included patients aged at least 18 years, diagnosed with HCA and treated with TAE. Patient characteristics, 30-day complications, tumour size before and after TAE, symptoms before and after TAE, and need for secondary interventions were analysed. RESULTS: Overall, 59 patients with a median age of 33.5 years were included from six centres; 57 of the 59 patients were women. Median tumour size at time of TAE was 76 mm. Six of 59 patients (10 per cent) had a major complication (cyst formation or sepsis), which could be resolved with minimal therapy, but prolonged hospital stay. Thirty-four patients (58 per cent) were symptomatic at presentation. There were no significant differences in symptoms before TAE and symptoms evaluated in the short term (within 3 months) after TAE (P = 0·134). First follow-up imaging was performed a median of 5·5 months after TAE and showed a reduction in size to a median of 48 mm (P < 0·001). CONCLUSION: TAE is safe, can lead to adequate size reduction of HCA and, offers an alternative to resection in selected patients.

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative.

BACKGROUND: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. MATERIAL AND METHODS: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. RESULTS: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. CONCLUSION: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting.

Long-term outcomes of patients with 10 or more colorectal liver metastases.

BACKGROUND: Although the number of colorectal liver metastases (CLM) is decreasingly considered as a contraindication to surgery, patients with 10 CLM or more are often denied liver surgery. This study aimed to evaluate the outcome after liver surgery and to identify prognostic factors of survival in such patients. METHODS: The study population consisted of a multicentre cohort of patients with CLM (N=12 406) operated on, with intention to resect, from January 2005-June 2013 and whose data were prospectively collected in the LiverMetSurvey registry. RESULTS: Overall, the group ⩾10 CLM (N=529, 4.3%) experienced a 5-year overall survival (OS) of 30%. A macroscopically complete (R0/R1) resection (72.8% of patients) was associated with a 3- and 5-year OS of 61% and 39% vs 29% and 5% for R2/no resection patients (P<0.0001). At multivariate analysis, R0/R1 resection emerged as the strongest favourable factor of OS (HR 0.35 (0.26-0.48)). Other independent favourable factors were as follows: maximal tumour size <40 mm (HR 0.67 (0.49-0.92)); age <60 years (HR 0.66 (0.50-0.88)); preoperative MRI (HR 0.65 (0.47-0.89)); and adjuvant chemotherapy (HR 0.73 (0.55-0.98)). The model showed that 5-year OS rates of 30% was possible provided R0/R1 resection associated with at least an additional favourable factor. CONCLUSIONS: Liver resection might provide long-term survival in patients with ⩾10 CLM staged with preoperative MRI, provided R0/R1 resection followed by adjuvant therapy. A validation of these results in another cohort is needed.

Retrospective study on timing of resection of hepatocellular adenoma.

BACKGROUND: Hepatocellular adenoma (HCA) is a benign liver tumour that may be complicated by bleeding or malignant transformation. Present guidelines advise cessation of oral contraceptives and surgical resection if the lesion is still larger than 5 cm at 6 months after diagnosis. The aim of this study was to evaluate whether this 6-month interval is sufficient to expect regression of a large HCA to 5 cm or smaller. METHODS: This retrospective cohort study included all patients with an HCA larger than 5 cm diagnosed between 1999 and 2015 with follow-up of at least 6 months. Medical records were reviewed for patient characteristics, clinical presentation, lesion characteristics, management and complications. Differences in characteristics were assessed between patients kept under surveillance and those who underwent treatment for an HCA larger than 5 cm. RESULTS: Some 194 patients were included, of whom 192 were women. Eighty-six patients were kept under surveillance and 108 underwent HCA treatment. Patients in the surveillance group had a significantly higher BMI (P = 0·029), smaller baseline HCA diameter (P < 0·001), more centrally located lesions (P < 0·001) and were more likely to have multiple lesions (P = 0·001) than those in the treatment group. There were no significant differences in sex, age at diagnosis, symptoms, complication rates and HCA subtype distribution. Time-to-event analysis in patients managed conservatively and those still undergoing treatment more than 6 months after diagnosis showed that 69 of 118 HCAs (58·5 per cent) regressed to 5 cm or smaller after a median of 104 (95 per cent c.i. 80-128) weeks. Larger HCAs took longer to regress (P < 0·001). No complications were documented during follow-up. CONCLUSION: This study suggests that a 6-month cut-off point for assessment of regression of HCA larger than 5 cm to no more than 5 cm is too early. As no complications were documented during follow-up, the cut-off point in women with typical, non-ß-catenin-activated HCA could be prolonged to 12 months, irrespective of baseline diameter.

Multicenter fresh frozen tissue sampling in colorectal cancer: does the quality meet the standards for state of the art biomarker research?

The growing interest in the molecular subclassification of colorectal cancers is increasingly facilitated by large multicenter biobanking initiatives. The quality of tissue sampling is pivotal for successful translational research. This study shows the quality of fresh frozen tissue sampling within a multicenter cohort study for colorectal cancer (CRC) patients. Each of the seven participating hospitals randomly contributed ten tissue samples, which were collected following Standard Operating Procedures (SOP) using established techniques. To indicate if the amount of intact RNA is sufficient for molecular discovery research and prove SOP compliance, the RNA integrity number (RIN) was determined. Samples with a RIN < 6 were measured a second time and when consistently low a third time. The highest RIN was used for further analysis. 91% of the tissue samples had a RIN ≥ 6 (91%). The remaining six samples had a RIN between 5 and 6 (4.5%) or lower than 5 (4.5%). The median overall RIN was 7.3 (range 2.9-9.0). The median RIN of samples in the university hospital homing the biobank was 7.7 and the median RIN for the teaching hospitals was 7.3, ranging from 6.5 to 7.8. No differences were found in the outcome of different hospitals (p = 0.39). This study shows that the collection of high quality fresh frozen samples of colorectal cancers is feasible in a multicenter design with complete SOP adherence. Thus, using basic sampling techniques large patient cohorts can be organized for predictive and prognostic (bio)marker research for CRC.

Systematic Review and Meta-Analysis of the Impact of Computed Tomography-Assessed Skeletal Muscle Mass on Outcome in Patients Awaiting or Undergoing Liver Transplantation.

Liver transplant outcome has improved considerably as a direct result of optimized surgical and anesthesiological techniques and organ allocation programs. Because there remains a shortage of human organs, strict selection of transplant candidates remains of paramount importance. Recently, computed tomography (CT)-assessed low skeletal muscle mass (i.e. sarcopenia) was identified as a novel prognostic parameter to predict outcome in liver transplant candidates. A systematic review and meta-analysis on the impact of CT-assessed skeletal muscle mass on outcome in liver transplant candidates were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Nineteen studies, including 3803 patients in partly overlapping cohorts, fulfilled the inclusion criteria. The prevalence of sarcopenia ranged from 22.2% to 70%. An independent association between low muscle mass and posttransplantation and waiting list mortality was described in 4 of the 6 and 6 of the 11 studies, respectively. The pooled hazard ratios of sarcopenia were 1.84 (95% confidence interval 1.11-3.05, p = 0.02) and 1.72 (95% confidence interval 0.99-3.00, p = 0.05) for posttransplantation and waiting list mortality, respectively, independent of Model for End-stage Liver Disease score. Less-consistent evidence suggested a higher complication rate, particularly infections, in sarcopenic patients. In conclusion, sarcopenia is an independent predictor for outcome in liver transplantation patients and could be used for risk assessment.

Improving the outcome of kidney transplantation by ameliorating renal ischemia reperfusion injury: lost in translation?

Kidney transplantation is the treatment of choice in patients with end stage renal disease. During kidney transplantation ischemia reperfusion injury (IRI) occurs, which is a risk factor for acute kidney injury, delayed graft function and acute and chronic rejection. Kidneys from living donors show a superior short- and long-term graft survival compared with deceased donors. However, the shortage of donor kidneys has resulted in expansion of the donor pool by using not only living- and brain death donors but also kidneys from donation after circulatory death and from extended criteria donors. These grafts are associated with an increased sensitivity to IRI and decreased graft outcome due to prolonged ischemia and donor comorbidity. Therefore, preventing or ameliorating IRI may improve graft survival. Animal experiments focus on understanding the mechanism behind IRI and try to find methods to minimize IRI either before, during or after ischemia. This review evaluates the different experimental strategies that have been investigated to prevent or ameliorate renal IRI. In addition, we review the current state of translation to the clinical setting. Experimental research has contributed to the development of strategies to prevent or ameliorate IRI, but promising results in animal studies have not yet been successfully translated to clinical use.

Kidney and liver transplantation in the elderly.

BACKGROUND: Transplant surgery is facing a shortage of deceased donor organs. In response, the criteria for organ donation have been extended, and an increasing number of organs from older donors are being used. For recipients, the benefits of transplantation are great, and the growing ageing population has led to increasing numbers of elderly patients being accepted for transplantation. METHODS: The literature was reviewed to investigate the impact of age of donors and recipients in abdominal organ transplantation, and to highlight aspects of the fine balance in donor and recipient selection and screening, as well as allocation policies fair to young and old alike. RESULTS: Overall, kidney and liver transplantation from older deceased donors have good outcomes, but are not as good as those from younger donors. Careful donor selection based on risk indices, and potentially biomarkers, special allocation schemes to match elderly donors with elderly recipients, and vigorous recipient selection, allows good outcomes with increasing age of both donors and recipients. The results of live kidney donation have been excellent for donor and recipient, and there is a trend towards inclusion of older donors. Future strategies, including personalized immunosuppression for older recipients as well as machine preservation and reconditioning of donor organs, are promising ways to improve the outcome of transplantation between older donors and older recipients. CONCLUSION: Kidney and liver transplantation in the elderly is a clinical reality. Outcomes are good, but can be optimized by using strategies that modify donor risk factors and recipient co-morbidities, and personalized approaches to organ allocation and immunosuppression.

Prospective Dutch colorectal cancer cohort: an infrastructure for long-term observational, prognostic, predictive and (randomized) intervention research.

BACKGROUND: Systematic evaluation and validation of new prognostic and predictive markers, technologies and interventions for colorectal cancer (CRC) is crucial for optimizing patients' outcomes. With only 5-15% of patients participating in clinical trials, generalizability of results is poor. Moreover, current trials often lack the capacity for post-hoc subgroup analyses. For this purpose, a large observational cohort study, serving as a multiple trial and biobanking facility, was set up by the Dutch Colorectal Cancer Group (DCCG). METHODS/DESIGN: The Prospective Dutch ColoRectal Cancer cohort is a prospective multidisciplinary nationwide observational cohort study in the Netherlands (yearly CRC incidence of 15 500). All CRC patients (stage I-IV) are eligible for inclusion, and longitudinal clinical data are registered. Patients give separate consent for the collection of blood and tumor tissue, filling out questionnaires, and broad randomization for studies according to the innovative cohort multiple randomized controlled trial design (cmRCT), serving as an alternative study design for the classic RCT. Objectives of the study include: 1) systematically collected long-term clinical data, patient-reported outcomes and biomaterials from daily CRC practice; and 2) to facilitate future basic, translational and clinical research including interventional and cost-effectiveness studies for both national and international research groups with short inclusion periods, even for studies with stringent inclusion criteria. RESULTS: Seven months after initiation 650 patients have been enrolled, eight centers participate, 15 centers await IRB approval and nine embedded cohort- or cmRCT-designed studies are currently recruiting patients. CONCLUSION: This cohort provides a unique multidisciplinary data, biobank, and patient-reported outcomes collection initiative, serving as an infrastructure for various kinds of research aiming to improve treatment outcomes in CRC patients. This comprehensive design may serve as an example for other tumor types.

[Organ donation after circulatory death]. / Organspende nach Herz- und Kreislauftod.

Approximately 17 million inhabitants live in the Netherlands. The number of potential organ donors in 1999 was the lowest in Europe with only 10 donors per million inhabitants. Medical associations, public health services, health insurance companies and the government had to find common solutions in order to improve organ allocation, logistics of donations and to increase the number of transplantations. After a prolonged debate on medical ethical issues of organ transplantation, all participants were able to agree on socio-medico-legal regulations for organ donation and transplantation. In addition to improving the procedure for organ donation after brain death (DBD) the most important step was the introduction of organ donation after circulatory death (DCD). Measures such as the introduction of a national organ donor database, improved information to the public, further education on intensive care units (ICU), guidelines for end of life care on the ICU, establishment of transplantation coordinators on site, introduction of autonomous explantation teams and strict procedures on the course of organ donations, answered many practical issues about logistics and responsibilities for DBD and DCD. In 2014 the number of postmortem organ donations rose to 16.4 per million inhabitants. Meanwhile, up to 60 % of organ donations in the Netherlands originate from a DCD procedure compared to approximately 10 % in the USA. This overview article discusses the developments and processes of deceased donation in the Netherlands after 15 years of experience with DCD.

Tumour antigen expression in hepatocellular carcinoma in a low-endemic western area.

BACKGROUND: Identification of tumour antigens is crucial for the development of vaccination strategies against hepatocellular carcinoma (HCC). Most studies come from eastern-Asia, where hepatitis-B is the main cause of HCC. However, tumour antigen expression is poorly studied in low-endemic, western areas where the aetiology of HCC differs. METHODS: We constructed tissue microarrays from resected HCC tissue of 133 patients. Expression of a comprehensive panel of cancer-testis (MAGE-A1, MAGE-A3/4, MAGE-A10, MAGE-C1, MAGE-C2, NY-ESO-1, SSX-2, sperm protein 17), onco-fetal (AFP, Glypican-3) and overexpressed tumour antigens (Annexin-A2, Wilms tumor-1, Survivin, Midkine, MUC-1) was determined by immunohistochemistry. RESULTS: A higher prevalence of MAGE antigens was observed in patients with hepatitis-B. Patients with expression of more tumour antigens in general had better HCC-specific survival (P=0.022). The four tumour antigens with high expression in HCC and no, or weak, expression in surrounding tumour-free-liver tissue, were Annexin-A2, GPC-3, MAGE-C1 and MAGE-C2, expressed in 90, 39, 17 and 20% of HCCs, respectively. Ninety-five percent of HCCs expressed at least one of these four tumour antigens. Interestingly, GPC-3 was associated with SALL-4 expression (P=0.001), an oncofetal transcription factor highly expressed in embryonal stem cells. SALL-4 and GPC-3 expression levels were correlated with vascular invasion, poor differentiation and higher AFP levels before surgery. Moreover, patients who co-expressed higher levels of both GPC-3 and SALL-4 had worse HCC-specific survival (P=0.018). CONCLUSIONS: We describe a panel of four tumour antigens with excellent coverage and good tumour specificity in a western area, low-endemic for hepatitis-B. The association between GPC-3 and SALL-4 is a novel finding and suggests that GPC-3 targeting may specifically attack the tumour stem-cell compartment.

Vascular management during live donor nephrectomy: an online survey among transplant surgeons.

In 2006, a survey from the American Society of Transplant Surgeons disclosed significant and sometimes fatal hemorrhagic events in live donor nephrectomies (LDN) related to failure of clips, leading to the contraindication of the Weck® Hem-o-lok® clip for control of the renal artery during LDN. A survey regarding vascular control techniques, their perceived safety ratings and their failures was sent to 645 European Society for Organ Transplantation members who profiled their profession as "surgeon" and selected "kidney" as organ type. Two hundred forty-three (41%) members responded, of whom 171 (63.3%) independently perform LDN. Their responses were analyzed. For arterial and venous vascular control, the GIA™ and TA™stapler are used most frequently, and were rated the safest. Of the 121 reported hemorrhagic events, slippage and dislodgement of clips occurred at least 58 times, while stapler malfunction occurred at least 40 times. One donor death from hemorrhage related to clip dysfunction was reported. Hemorrhagic complications of LDN with fatal and non-fatal outcomes still occur. Strikingly, many surgeons do not use the vascular closing technique that they consider most safe. Failure of non-transfixion techniques is associated with greater risks for the donor. Control of major vessels in LDN must employ transfixion techniques for optimal donor safety.

Kidney retransplantation in the ipsilateral iliac fossa: a surgical challenge.

The aim of this study is to review the surgical outcome of kidney retransplantation in the ipsilateral iliac fossa in comparison to first kidney transplants. The database was screened for retransplantations between 1995 and 2013. Each study patient was matched with 3 patients with a first kidney transplantation. Just for graft and patient survival analyses, we added an extra control group including all patients receiving a second transplantation in the contralateral iliac fossa. We identified 99 patients who received a retransplantation in the ipsilateral iliac fossa. There was significantly more blood loss and longer operative time in the retransplantation group. The rate of vascular complications and graft nephrectomies within 1 year was significantly higher in the study group. The graft survival rates at 1 year and 3, 5, and 10 years were 76%, 67%, 61%, and 47% in the study group versus 94%, 88%, 77%, and 67% (p < 0.001) in the first control group versus 91%, 86%, 78%, and 57% (p = 0.008) in the second control group. Patient survival did not differ significantly between the groups. Kidney retransplantation in ipsilateral iliac fossa is surgically challenging and associated with more vascular complications and graft loss within the first year after transplantation. Whenever feasible, the second renal transplant (first retransplant) should be performed contralateral to the prior failed one.

Mental health among living kidney donors: a prospective comparison with matched controls from the general population.

The impact of living kidney donation on donors' mental health has not been sufficiently nor comprehensively studied. Earlier studies demonstrated that mental health did not change in the majority of donors, however they often lacked a suitable control group and/or had other methodological limitations. Consequently, it remains unclear whether changes in mental health found among a minority of donors reflect normal fluctuations. In this study we matched 135 donors with individuals from the general Dutch population on gender and baseline mental health and compared changes in mental health over time. Mental health was measured using the Brief Symptom Inventory and Mental Health Continuum Short Form. Primary analyses compared baseline and 6 months follow-up. Secondary analyses compared baseline and 9 (controls) or 15 months (donors) follow-up. Primary multilevel regression analyses showed that there was no change in psychological complaints (p = 0.20) and wellbeing (p = 0.10) over time and donors and controls did not differ from one another in changes in psychological complaints (p = 0.48) and wellbeing (p = 0.85). Secondary analyses also revealed no difference in changes between the groups. We concluded that changes in mental health in the short term after donation do not significantly differ from normal fluctuations found in the Dutch general population.

Systematic review of sarcopenia in patients operated on for gastrointestinal and hepatopancreatobiliary malignancies.

BACKGROUND: Preoperative risk assessment in cancer surgery is of importance to improve treatment and outcome. The aim of this study was to assess the impact of CT-assessed sarcopenia on short- and long-term outcomes in patients undergoing surgical resection of gastrointestinal and hepatopancreatobiliary malignancies. METHODS: A systematic search of Embase, PubMed and Web of Science was performed to identify relevant studies published before 30 September 2014. PRISMA guidelines for systematic reviews were followed. Screening for inclusion, checking the validity of included studies and data extraction were carried out independently by two investigators. RESULTS: After screening 692 records, 13 observational studies with a total of 2884 patients were included in the analysis. There was wide variation in the reported prevalence of sarcopenia (17.0-79 per cent). Sarcopenia was independently associated with reduced overall survival in seven of ten studies, irrespective of tumour site. Hazard ratios (HRs) of up to 3.19 (hepatic cancer), 1.63 (pancreatic cancer), 1.85 (colorectal cancer) and 2.69 (colorectal liver metastases, CLM) were reported. For oesophageal cancer, the HR was 0.31 for increasing muscle mass. In patients with colorectal cancer and CLM, sarcopenia was independently associated with postoperative mortality (colorectal cancer: odds ratio (OR) 43.3), complications (colorectal cancer: OR 0.96 for increasing muscle mass; CLM: OR 2.22) and severe complications (CLM: OR 3.12). CONCLUSION: Sarcopenia identified before surgery by single-slice CT is associated with impaired overall survival in gastrointestinal and hepatopancreatobiliary malignancies, and increased postoperative morbidity in patients with colorectal cancer with or without hepatic metastases.