Clinical added value of MRI to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO): study protocol for an international multicentre prospective diagnostic accuracy study.

BACKGROUND: Abdominal computed tomography (CT) is the standard imaging method for patients with suspected colorectal liver metastases (CRLM) in the diagnostic workup for surgery or thermal ablation. Diffusion-weighted and gadoxetic-acid-enhanced magnetic resonance imaging (MRI) of the liver is increasingly used to improve the detection rate and characterization of liver lesions. MRI is superior in detection and characterization of CRLM as compared to CT. However, it is unknown how MRI actually impacts patient management. The primary aim of the CAMINO study is to evaluate whether MRI has sufficient clinical added value to be routinely added to CT in the staging of CRLM. The secondary objective is to identify subgroups who benefit the most from additional MRI. METHODS: In this international multicentre prospective incremental diagnostic accuracy study, 298 patients with primary or recurrent CRLM scheduled for curative liver resection or thermal ablation based on CT staging will be enrolled from 17 centres across the Netherlands, Belgium, Norway, and Italy. All study participants will undergo CT and diffusion-weighted and gadoxetic-acid enhanced MRI prior to local therapy. The local multidisciplinary team will provide two local therapy plans: first, based on CT-staging and second, based on both CT and MRI. The primary outcome measure is the proportion of clinically significant CRLM (CS-CRLM) detected by MRI not visible on CT. CS-CRLM are defined as liver lesions leading to a change in local therapeutical management. If MRI detects new CRLM in segments which would have been resected in the original operative plan, these are not considered CS-CRLM. It is hypothesized that MRI will lead to the detection of CS-CRLM in ≥10% of patients which is considered the minimal clinically important difference. Furthermore, a prediction model will be developed using multivariable logistic regression modelling to evaluate the predictive value of patient, tumor and procedural variables on finding CS-CRLM on MRI. DISCUSSION: The CAMINO study will clarify the clinical added value of MRI to CT in patients with CRLM scheduled for local therapy. This study will provide the evidence required for the implementation of additional MRI in the routine work-up of patients with primary and recurrent CRLM for local therapy. TRIAL REGISTRATION: The CAMINO study was registered in the Netherlands National Trial Register under number NL8039 on September 20th 2019.

Locoregional recurrences after transanal total mesorectal excision of rectal cancer during implementation.

BACKGROUND: Transanal total mesorectal excision (TaTME) has been proposed as an approach in patients with mid and low rectal cancer. The TaTME procedure has been introduced in the Netherlands in a structured training pathway, including proctoring. This study evaluated the local recurrence rate during the implementation phase of TaTME. METHODS: Oncological outcomes of the first ten TaTME procedures in each of 12 participating centres were collected as part of an external audit of procedure implementation. Data collected from a cohort of patients treated over a prolonged period in four centres were also collected to analyse learning curve effects. The primary outcome was the presence of locoregional recurrence. RESULTS: The implementation cohort of 120 patients had a median follow up of 21·9 months. Short-term outcomes included a positive circumferential resection margin rate of 5·0 per cent and anastomotic leakage rate of 17 per cent. The overall local recurrence rate in the implementation cohort was 10·0 per cent (12 of 120), with a mean(s.d.) interval to recurrence of 15·2(7·0) months. Multifocal local recurrence was present in eight of 12 patients. In the prolonged cohort (266 patients), the overall recurrence rate was 5·6 per cent (4·0 per cent after excluding the first 10 procedures at each centre). CONCLUSION: TaTME was associated with a multifocal local recurrence rate that may be related to suboptimal execution rather than the technique itself. Prolonged proctoring, optimization of the technique to avoid spillage, and quality control is recommended.

ANTECEDENTES: La escisión total del mesorrecto por vía transanal (Transanal Total Mesorectal Excision, TaTME) se ha propuesto como abordaje quirúrgico en pacientes con cáncer de recto medio e inferior. La técnica TaTME se ha introducido en los Países Bajos mediante un proceso de formación estructurado que incluye la supervisión. Este estudio evaluó el porcentaje de recidiva local durante la fase de implementación de TaTME. MÉTODOS: Se recogieron los resultados oncológicos de los primeros 10 procedimientos realizados mediante TaTME en cada uno de los 12 centros participantes como parte de una auditoría externa de implementación del procedimiento. Se reunió una cohorte más amplia de pacientes procedentes de 4 centros para analizar los efectos de la curva de aprendizaje. El criterio de valoración principal fue la presencia de recidiva locorregional. RESULTADOS: La cohorte de implementación de 120 pacientes tuvo una mediana de seguimiento de 21,9 meses. Los resultados a corto plazo incluyeron una tasa del margen de resección circunferencial positivo del 5% y una tasa de fuga anastomótica del 17,4%. La tasa global de recidiva local en la cohorte de implementación fue del 10% (12/120) con un intervalo medio de recidiva de 15,2 (DE 7) meses. El patrón de recidiva local fue multifocal en 8 de 12 casos (67%). En la cohorte ampliada (n = 266), la tasa global de recidiva fue del 5,6% (4,0%, excluyendo a los primeros 10 pacientes). CONCLUSIÓN: TaTME se asoció con un porcentaje de recidiva local multifocal que puede relacionarse con una ejecución subóptima, más que con la técnica en sí. Se recomienda una supervisión prolongada, la optimización de la técnica para evitar la diseminación tumoral, así como un control de calidad.

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.

Evaluation of PET and laparoscopy in STagIng advanced gastric cancer: a multicenter prospective study (PLASTIC-study).

BACKGROUND: Initial staging of gastric cancer consists of computed tomography (CT) and gastroscopy. In locally advanced (cT3-4) gastric cancer, fluorodeoxyglucose positron emission tomography with CT (FDG-PET/CT or PET) and staging laparoscopy (SL) may have a role in staging, but evidence is scarce. The aim of this study is to evaluate the impact and cost-effectiveness of PET and SL in addition to initial staging in patients with locally advanced gastric cancer. METHODS: This prospective observational cohort study will include all patients with a surgically resectable, advanced gastric adenocarcinoma (cT3-4b, N0-3, M0), that are scheduled for treatment with curative intent after initial staging with gastroscopy and CT. The modalities to be investigated in this study is the addition of PET and SL. The primary outcome of this study is the proportion of patients in whom the PET or SL lead to a change in treatment strategy. Secondary outcome parameters are: diagnostic performance, morbidity and mortality, quality of life, and cost-effectiveness of these additional diagnostic modalities. The study recently started in August 2017 with a duration of 36 months. At least 239 patients need to be included in this study to demonstrate that the diagnostic modalities are break-even. Based on the annual number of gastrectomies in the participating centers, it is estimated that approximately 543 patients are included in this study. DISCUSSION: In this study, it is hypothesized that performing PET and SL for locally advanced gastric adenocarcinomas results in a change of treatment strategy in 27% of patients and an annual cost-reduction in the Netherlands of €916.438 in this patient group by reducing futile treatment. The results of this study may be applicable to all countries with comparable treatment algorithms and health care systems. TRIAL REGISTRATION: NCT03208621 . This trial was registered prospectively on June 30, 2017.

Peri-operative bowel perforation in early stage colon cancer is associated with an adverse oncological outcome.

BACKGROUND: The presence of an inflammatory response resulting from bowel perforation or anastomotic leakage has been suggested to enhance recurrence rates in colorectal cancer patients. Currently, it is unknown if bowel perforation or anastomotic leakage has prognostic significance in early stage colon cancer patients. In this study, the impact of peri-operative bowel perforation including anastomotic leakage on disease-free survival of stage I/II colon cancer patients was investigated. METHODS: Prospective follow up data of 448 patients with stages I/II colon cancer that underwent resection were included. Patients who died within 3 months after initial surgery were excluded. RESULTS: Median follow up was 56.0 months. Patients with peri-operative bowel perforation (n = 25) had a higher recurrence rate compared to patients without perforation (n = 423), 36.0 % vs. 16.1 % (p = 0.01). Disease-free survival was significantly worse for the perforation group compared to patients without perforation (p = 0.004). Multivariate analysis including T-stage, histological grade, and adjuvant chemotherapy showed peri-operative bowel perforation to be an independent factor significantly associated with disease recurrence (odds ratio, 2.7; 95 % CI, 1.1-6.7). CONCLUSION: Peri-operative bowel perforation is associated with increased recurrence rates and impaired disease-free survival in early-stage colon cancer patients.

Deletion of chromosome 4q predicts outcome in stage II colon cancer patients.

BACKGROUND: Around 30% of all stage II colon cancer patients will relapse and die of their disease. At present no objective parameters to identify high-risk stage II colon cancer patients, who will benefit from adjuvant chemotherapy, have been established. With traditional histopathological features definition of high-risk stage II colon cancer patients is inaccurate. Therefore more objective and robust markers for prediction of relapse are needed. DNA copy number aberrations have proven to be robust prognostic markers, but have not yet been investigated for this specific group of patients. The aim of the present study was to identify chromosomal aberrations that can predict relapse of tumor in patients with stage II colon cancer. MATERIALS AND METHODS: DNA was isolated from 40 formaldehyde fixed paraffin embedded stage II colon cancer samples with extensive clinicopathological data. Samples were hybridized using Comparative Genomic Hybridization (CGH) arrays to determine DNA copy number changes and microsatellite stability was determined by PCR. To analyze differences between stage II colon cancer patients with and without relapse of tumor a Wilcoxon rank-sum test was implemented with multiple testing correction. RESULTS: Stage II colon cancers of patients who had relapse of disease showed significantly more losses on chromosomes 4, 5, 15q, 17q and 18q. In the microsatellite stable (MSS) subgroup (n = 28), only loss of chromosome 4q22.1-4q35.2 was significantly associated with disease relapse (P < 0.05, FDR < 0.15). No differences in clinicopathological characteristics between patients with and without relapse were observed. CONCLUSION: In the present series of MSS stage II colon cancer patients losses on 4q22.1-4q35.2 were associated with worse outcome and these genomic alterations may aid in selecting patients for adjuvant therapy.

Deletion of chromosome 4q predicts outcome in stage II colon cancer patients.

BACKGROUND: Around 30% of all stage II colon cancer patients will relapse and die of their disease. At present no objective parameters to identify high-risk stage II colon cancer patients, who will benefit from adjuvant chemotherapy, have been established. With traditional histopathological features definition of high-risk stage II colon cancer patients is inaccurate. Therefore more objective and robust markers for prediction of relapse are needed. DNA copy number aberrations have proven to be robust prognostic markers, but have not yet been investigated for this specific group of patients. The aim of the present study was to identify chromosomal aberrations that can predict relapse of tumor in patients with stage II colon cancer. MATERIALS AND METHODS: DNA was isolated from 40 formaldehyde fixed paraffin embedded stage II colon cancer samples with extensive clinicopathological data. Samples were hybridized using Comparative Genomic Hybridization (CGH) arrays to determine DNA copy number changes and microsatellite stability was determined by PCR. To analyze differences between stage II colon cancer patients with and without relapse of tumor a Wilcoxon rank-sum test was implemented with multiple testing correction. RESULTS: Stage II colon cancers of patients who had relapse of disease showed significantly more losses on chromosomes 4, 5, 15q, 17q and 18q. In the microsatellite stable (MSS) subgroup (n=28), only loss of chromosome 4q22.1-4q35.2 was significantly associated with disease relapse (p<0.05, FDR<0.15). No differences in clinicopathological characteristics between patients with and without relapse were observed. CONCLUSION: In the present series of MSS stage II colon cancer patients losses on 4q22.1-4q35.2 were associated with worse outcome and these genomic alterations may aid in selecting patients for adjuvant therapy.

Mortality and morbidity of planned relaparotomy versus relaparotomy on demand for secondary peritonitis.

BACKGROUND: Planned relaparotomy (PR) and relaparotomy on demand (ROD) are both frequently used in the treatment of secondary peritonitis. The aim of this study was to evaluate the mortality, morbidity and long-term outcome associated with PR compared with ROD in patients with secondary peritonitis admitted to a university hospital. METHOD: This retrospective study included 278 consecutive patients who underwent emergency laparotomy for secondary peritonitis between January 1994 and January 2000. Outcome was analysed based on the decision made by the surgeon during the first operation to perform either ROD (197 patients) or PR (81). RESULTS: The Acute Physiology And Chronic Health Evaluation II score was comparable in ROD and PR groups (10.8 versus 11.7; P = 0.222). The in-hospital mortality rate was significantly lower with ROD than PR (21.8 versus 36 per cent; P = 0.016). Two-year survival(s.e.) was 65.8(3.4) per cent in the ROD group and 55.5(5.5) per cent in the PR group (P = 0.031). CONCLUSION: The in-hospital and long-term survival rates were higher in patients with secondary peritonitis treated by ROD than in those with disease of comparable severity treated by PR. Choice of treatment strategy was an independent predictor of survival.