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3.  Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial 
BMC Cancer  2015;15:428.
The peritoneum is the second most common site of recurrence in colorectal cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult. Patients eventually presenting with clinically apparent PC have a poor prognosis. Median survival is only about five months if untreated and the benefit of palliative systemic chemotherapy is limited. Only a quarter of patients are eligible for curative treatment, consisting of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC). However, the effectiveness depends highly on the extent of disease and the treatment is associated with a considerable complication rate.
These clinical problems underline the need for effective adjuvant therapy in high-risk patients to minimize the risk of outgrowth of peritoneal micro metastases. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) seems to be suitable for this purpose. Without the need for cytoreductive surgery, adjuvant HIPEC can be performed with a low complication rate and short hospital stay.
The aim of this study is to determine the effectiveness of adjuvant HIPEC in preventing the development of PC in patients with colon cancer at high risk of peritoneal recurrence. This study will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible for inclusion are patients who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. After resection of the primary tumour, 176 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously or shortly after the primary resection. Oxaliplatin will be used as chemotherapeutic agent, for 30 min at 42-43 °C. Just before HIPEC, 5-fluorouracil and leucovorin will be administered intravenously. Primary endpoint is peritoneal disease-free survival at 18 months. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA.
Adjuvant HIPEC is assumed to reduce the expected 25 % absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10 %. This reduction is likely to translate into a prolonged overall survival.
Trial registration number
NCT02231086 (
PMCID: PMC4492087  PMID: 26003804
Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC); Colon cancer; Peritoneal carcinomatosis (PC)
4.  Neo-adjuvant chemotherapy followed by surgery versus surgery alone in high-risk patients with resectable colorectal liver metastases: the CHARISMA randomized multicenter clinical trial 
BMC Cancer  2015;15:180.
Efforts to improve the outcome of liver surgery by combining curative resection with chemotherapy have failed to demonstrate definite overall survival benefit. This may partly be due to the fact that these studies often involve strict inclusion criteria. Consequently, patients with a high risk profile as characterized by Fong’s Clinical Risk Score (CRS) are often underrepresented in these studies. Conceptually, this group of patients might benefit the most from chemotherapy. The present study evaluates the impact of neo-adjuvant chemotherapy in high-risk patients with primary resectable colorectal liver metastases, without extrahepatic disease. Our hypothesis is that adding neo-adjuvant chemotherapy to surgery will provide an improvement in overall survival (OS) in patients with a high-risk profile.
CHARISMA is a multicenter, randomized, phase III clinical trial. Patients will be randomized to either surgery alone (standard treatment, arm A) or to 6 cycles of neo-adjuvant oxaliplatin-based chemotherapy, followed by surgery (arm B). Patients must be ≥ 18 years of age with liver metastases of histologically confirmed primary colorectal carcinoma. Patients with extrahepatic metastases are excluded. Liver metastases must be deemed primarily resectable. Only patients with a CRS of 3–5 are eligible. The primary study endpoint is OS. Secondary endpoints are progression free survival (PFS), quality of life, morbidity of resection, treatment response on neo-adjuvant chemotherapy, and whether CEA levels can predict treatment response.
CHARISMA is a multicenter, randomized, phase III clinical trial that will provide an answer to the question if adding neo-adjuvant chemotherapy to surgery will improve OS in a well-defined high-risk patient group with colorectal liver metastases.
Trial registration
The CHARISMA is registered at European Union Clinical Trials Register (EudraCT), number: 2013-004952-39, and in the “Netherlands national Trial Register (NTR), number: 4893.
PMCID: PMC4377036  PMID: 25884448
Colorectal liver metastases; Neo-adjuvant chemotherapy; Surgical resection; Clinical risk score
5.  The ACCURE-trial: the effect of appendectomy on the clinical course of ulcerative colitis, a randomised international multicenter trial (NTR2883) and the ACCURE-UK trial: a randomised external pilot trial (ISRCTN56523019) 
BMC Surgery  2015;15:30.
Over the past 20 years evidence has accumulated confirming the immunomodulatory role of the appendix in ulcerative colitis (UC). This led to the idea that appendectomy might alter the clinical course of established UC. The objective of this body of research is to evaluate the short-term and medium-term efficacy of appendectomy to maintain remission in patients with UC, and to establish the acceptability and cost-effectiveness of the intervention compared to standard treatment.
These paired phase III multicenter prospective randomised studies will include patients over 18 years of age with an established diagnosis of ulcerative colitis and a disease relapse within 12 months prior to randomisation. Patients need to have been medically treated until complete clinical (Mayo score <3) and endoscopic (Mayo score 0 or 1) remission. Patients will then be randomised 1:1 to a control group (maintenance 5-ASA treatment, no appendectomy) or elective laparoscopic appendectomy plus maintenance treatment. The primary outcome measure is the one year cumulative UC relapse rate - defined both clinically and endoscopically as a total Mayo-score ≥5 with endoscopic subscore of 2 or 3. Secondary outcomes that will be assessed include the number of relapses per patient at 12 months, the time to first relapse, health related quality of life and treatment costs, and number of colectomies in each arm.
The ACCURE and ACCURE-UK trials will provide evidence on the role and acceptability of appendectomy in the treatment of ulcerative colitis and the effects of appendectomy on the disease course.
Trial registration
NTR2883; ISRCTN56523019
PMCID: PMC4393565  PMID: 25887789
Inflammatory bowel disease; Ulcerative colitis; Appendectomy; Surgery; Disease course
6.  Randomized controlled multicentre study comparing biological mesh closure of the pelvic floor with primary perineal wound closure after extralevator abdominoperineal resection for rectal cancer (BIOPEX-study) 
BMC Surgery  2014;14:58.
Primary perineal wound closure after conventional abdominoperineal resection (cAPR) for rectal cancer has been the standard of care for many years. Since the introduction of neo-adjuvant radiotherapy and the extralevator APR (eAPR), oncological outcome has been improved, but at the cost of increased rates of perineal wound healing problems and perineal hernia. This has progressively increased the use of biological meshes, although not supported by sufficient evidence. The aim of this study is to determine the effectiveness of pelvic floor reconstruction using a biological mesh after standardized eAPR with neo-adjuvant (chemo)radiotherapy compared to primary perineal wound closure.
In this multicentre randomized controlled trial, patients with a clinical diagnosis of primary rectal cancer who are scheduled for eAPR after neo-adjuvant (chemo)radiotherapy will be considered eligible. Exclusion criteria are prior radiotherapy, sacral resection above S4/S5, allergy to pig products or polysorbate, collagen disorders, and severe systemic diseases affecting wound healing, except for diabetes. After informed consent, 104 patients will be randomized between standard care using primary wound closure of the perineum and the experimental arm consisting of suturing a biological mesh derived from porcine dermis in the pelvic floor defect, followed by perineal closure similar to the control arm. Patients will be followed for one year after the intervention and outcome assessors and patients will be blinded for the study treatment. The primary endpoint is the percentage of uncomplicated perineal wound healing, defined as a Southampton wound score of less than II on day 30. Secondary endpoints are hospital stay, incidence of perineal hernia, quality of life, and costs.
The BIOPEX-study is the first randomized controlled multicentre study to determine the additive value of using a biological mesh for perineal wound closure after eAPR with neo-adjuvant radiotherapy compared to primary perineal wound closure with regard to perineal wound healing and the occurrence of perineal hernia.
Trail registration number
NCT01927497 (
PMCID: PMC4158342  PMID: 25163547
Abdominoperineal resection; Rectal cancer; Radiotherapy; Primary perineal wound closure; Biological mesh; perineal wound infection; Perineal wound healing
7.  Intentionally curative treatment of locally recurrent rectal cancer: a systematic review 
Canadian Journal of Surgery  2013;56(2):135-144.
There is a lack of outcome data beyond local recurrence rates after primary treatment in rectal cancer, despite more information being necessary for clinical decision-making. We sought to determine patient selection, therapeutic modalities and outcomes of locally recurrent rectal cancer treated with curative intent.
We searched MEDLINE (1990–2010) using the medical subject headings “rectal neoplasms” and “neoplasm recurrence, local.” Selection of cohort studies was based on the primary intention of treatment and availability of at least 1 outcome variable.
We included 55 cohort studies comprising 3767 patients; 8 studies provided data on the rate of intentionally curative treatment from an unselected consecutive cohort of patients (481 of 1188 patients; 40%). Patients were symptomatic with pain in 50% (796 of 1607) of cases. Overall, 3088 of 3767 patients underwent resection. The R0 resection rate was 56% (1484 of 2637 patients). The rate of external beam radiotherapy was 100% in 9 studies, 0% in 5 studies, and ranged from 12% to 97% in 37 studies. Overall postoperative mortality was 2.2% (57 of 2515 patients). Five-year survival was at least 25%, with an upper limit of 41% in 11 of 18 studies including at least 50 resections. We found a significant increase in reported survival rates over time (r2 = 0.214, p = 0.007).
More uniformity in treatment protocols and reporting on outcomes for locally recurrent rectal cancer is warranted. The observed improvement of reported survival rates in time is probably related to better patient selection and optimized multimodality treatment in specialized centres.
PMCID: PMC3617119  PMID: 23517634
8.  The CARTS study: Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery 
BMC Surgery  2011;11:34.
The CARTS study is a multicenter feasibility study, investigating the role of rectum saving surgery for distal rectal cancer.
Patients with a clinical T1-3 N0 M0 rectal adenocarcinoma below 10 cm from the anal verge will receive neoadjuvant chemoradiation therapy (25 fractions of 2 Gy with concurrent capecitabine). Transanal Endoscopic Microsurgery (TEM) will be performed 8 - 10 weeks after the end of the preoperative treatment depending on the clinical response.
Primary objective is to determine the number of patients with a (near) complete pathological response after chemoradiation therapy and TEM. Secondary objectives are the local recurrence rate and quality of life after this combined therapeutic modality. A three-step analysis will be performed after 20, 33 and 55 patients to ensure the feasibility of this treatment protocol.
The CARTS-study is one of the first prospective multicentre trials to investigate the role of a rectum saving treatment modality using chemoradiation therapy and local excision. The CARTS study is registered at (NCT01273051)
PMCID: PMC3295682  PMID: 22171697
9.  Less adhesiolysis and hernia repair during completion proctocolectomy after laparoscopic emergency colectomy for ulcerative colitis 
Surgical Endoscopy  2011;26(2):368-373.
The aim of this study was to determine whether the need for adhesiolysis during completion proctectomy (CP) with ileopouch anal anastomosis (IPAA) is influenced by the surgical approach of the initial emergency colectomy for ulcerative colitis and the hospital setting.
One hundred consecutive patients who underwent CP with IPAA in our center between January 1999 and April 2010 were included. Emergency colectomy had been performed laparoscopically in 30 of 52 patients at the Academic Medical Center Amsterdam and in 6 of 48 patients at referring hospitals. Case files of these patients were retrospectively reviewed.
Significantly more extensive adhesiolysis was performed after open compared to laparoscopic colectomy (47 vs. 6%, P < 0.001). In univariate analysis, emergency colectomy at a referring hospital was also predictive for adhesiolysis (P = 0.003), but the open approach for the initial colectomy was the only independent predictive factor for the need for adhesiolysis (P < 0.001) in a multivariable ordinal logistic regression analysis. Operating time of CP was significantly longer when limited [18 (95% CI = 0–36) min] or extensive [55 (35–75) min] adhesiolysis had to be performed. The interval to CP was longer after open colectomy and after colectomy performed at a referring hospital. Significantly more incisional hernia corrections during CP were performed after open emergency colectomy (14 vs. 0%, P = 0.024). Overall morbidity and postoperative hospital stay of CP were not related to the surgical approach or the hospital setting of the emergency colectomy.
Laparoscopic as opposed to open emergency colectomy is associated with less adhesiolysis, fewer incisional hernias, and a shorter interval to completion proctectomy.
PMCID: PMC3261391  PMID: 21993930
Restorative proctocolectomy; Ulcerative colitis; Abdominal adhesions; Laparoscopy; Incisional hernia
10.  Sexual and urinary functioning after rectal surgery: a prospective comparative study with a median follow-up of 8.5 years 
The purpose of this study was to prospectively compare rectal resection (RR) with colonic resection on sexual, urinary and bowel function and quality of life in both short-term and long-term.
Eighty-three patients who underwent RR were compared to 53 patients who underwent a colonic resection leaving the rectum in situ (RIS). A questionnaire assessing sexual, urinary and bowel functioning with a quality of life questionnaire (SF-36) was sent to all participants preoperatively, 3 and 12 months postoperatively and approximately 8 years after the onset of the study.
Short-term dysfunction included diminished sexual activity in female RR patients at 3 months and significantly more erectile dysfunction in RR patients 1 year postoperatively. Long-term dysfunction included more frequent and more severe erectile dysfunction in RR patients compared to RIS patients. These short-term and long-term outcomes did not influence overall quality of life. The incidence of urinary dysfunction was comparable between both groups. Bowel functioning was significantly better in the RIS group compared to the RR group 3 months and 1 year postoperatively.
Patients who underwent RR experienced up to 1 year postoperatively more sexual and bowel function problems than RIS patients. However, short-term and long-term dysfunction did not influence overall quality of life. Erectile dysfunction in male RR patients persisted in time, whereas other aspects of sexual, urinary and bowel function after RR and colonic resection are similar after a median follow-up of 8.5 years.
PMCID: PMC3219871  PMID: 21922200
Rectal resection; Colonic resection; Sexual function; Urinary function; Bowel function
11.  Alternative specimen extraction techniques after laparoscopic emergency colectomy in inflammatory bowel disease 
Surgical Endoscopy  2011;26(2):408-412.
Omitting the extraction site incision potentially further decreases the abdominal wall trauma in laparoscopic surgery. The purpose of this study was to report the results of alternative specimen extraction techniques after laparoscopic emergency colectomy in patients with inflammatory bowel disease (IBD).
Ten consecutive patients with IBD underwent (sub)acute emergency colectomy for refractory disease from October 2009 until December 2010. The specimen was retrieved via the stoma site in three and transrectally in seven patients. Patient data were prospectively collected. In case of later completion proctectomy and pouch procedure, adhesions were systematically scored.
The extraction techniques were all feasible. Median operative time was 219 (interquartile range (IQR), 197–232) min. The pain scores and morphine requirement in patients decreased quickly after surgery. No infectious complications occurred. In five patients, a completion proctectomy was performed at a median time of 7 (IQR, 3.8–9.3) months after colectomy. All patients showed absence of any adhesions in the pelvis. In two patients, limited adhesions of the cut side of the mesentery were present.
Specimen extraction via the rectum or stoma site is a safe, alternative way to extract the specimen after laparoscopic colectomy. No infectious complications were observed postoperatively and no pelvic adhesions were found during completion proctectomy.
PMCID: PMC3261408  PMID: 21909858
Colitis; Inflammatory bowel disease; Colectomy; Laparoscopy; Extraction
12.  Morbidity related to defunctioning ileostomy closure after ileal pouch-anal anastomosis and low colonic anastomosis 
Defunctioning ileostomies are widely performed in order to prevent or treat anastomotic leakage after colorectal surgery. The aim of the present study was to determine morbidity related to stoma closure and to identify predictive factors of a complicated postoperative course.
A consecutive series of 138 patients were retrospectively analyzed after stoma reversal. Data collection included general demographics and surgery-related aspects. Morbidity related to stoma closure was retrieved from our prospectively collected registry of complications.
In 74 of 138 patients, defunctioning ileostomy was performed after restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA). The remaining ileostomies (n = 64) were constructed after a low colorectal or coloanal anastomosis. A total of 46 complications were recorded in 28 patients resulting in an overall complication rate of 20.3%. Anastomotic leakage rate was 4.3%, and reoperation rate was 8.0%. The number of complications according to the Clavien–Dindo classification was 5 for grade I (10.9%), 26 for grade II (56.5%), 13 for grade III (28.3%), 1 for grade IV (2.2%), and 1 for grade V (2.2%). Multivariate analysis revealed a significantly higher ASA score in the complicated group (P = 0.015, odds ratio 2.6, 95% confidence interval 1.2–5.6).
Closure of a defunctioning ileostomy is associated with 20% morbidity and a reoperation rate of 8%. There is an urgent need for criteria on which a more selective use of a defunctioning ileostomy after low colonic anastomosis or IPAA can be based given its associated morbidity.
PMCID: PMC3249166  PMID: 21761119
Defunctioning ileostomy; Stoma; Ileostomy; Morbidity
13.  Surgical Treatment of Renal Cell Cancer Liver Metastases: A Population-Based Study 
Annals of Surgical Oncology  2011;18(7):1932-1938.
To evaluate outcomes of surgical treatment in patients with hepatic metastases from renal-cell carcinoma in the Netherlands, and to identify prognostic factors for survival after resection. Renal-cell carcinoma has an incidence of 2,000 new patients in the Netherlands each year (12.5/100,000 inhabitants). According to literature, half of these patients ultimately develop distant metastases with 20% involvement of the liver. Resection of renal-cell carcinoma liver metastases (RCCLM) is performed in only a minority of patients. Hence, little is known about outcome of resectable RCCLM.
Patients were retrieved from local databases of theNetherlands Task Force for Liver Surgery (14 centers) and from the Dutch collective pathology database. Survival and prognostic factors were determined by Kaplan–Meier analysis and log rank test.
Thirty-three patients were identified who underwent resection (n = 29) or local ablation (n = 4) of RCCLM in the Netherlands between 1990 and 2008. These patients comprise 0.5% to 1% of the total population of patients diagnosed with RCCLM in that period. There was no operative mortality. The overall survival at 1, 3, and 5 years was 79, 47, and 43%, respectively. Metachronous metastases (n = 23, P = 0.03) and radical resection (n = 19, P < 0.001) were statistically significant prognosticators of overall survival. Size < 50 mm (n = 18, P = 0,54), solitary metastases (n = 19, P = 0.93), and presence of extrahepatic metastases (n = 11, P = 0.28) did not have a statistically significant impact on survival.
The favorable 5-year survival rate of 43% without operative mortality as found in this nationwide study indicates that selected patients with RCCLM can benefit from surgical treatment.
PMCID: PMC3115064  PMID: 21347794
14.  History of sentinel node and validation of the technique 
Breast Cancer Research  2001;3(2):109-112.
Sentinel node biopsy is a minimally invasive technique to select patients with occult lymph node metastases who may benefit from further regional or systemic therapy. The sentinel node is the first lymph node reached by metastasising cells from a primary tumour. Attempts to remove this node with a procedure based on standard anatomical patterns did not become popular. The development of the dynamic technique of intraoperative lymphatic mapping in the 1990s resulted in general acceptance of the sentinel node concept. This hypothesis of sequential tumour dissemination seems to be valid according to numerous studies of sentinel node biopsy with confirmatory regional lymph node dissection. This report describes the history and the validation of the technique, with particular reference to breast cancer.
PMCID: PMC139441  PMID: 11250756
history; lymphatic dissemination; review; sentinel node

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