Hein B A C Stockmann

Kennemer Gasthuis, Haarlem, North Holland, Netherlands

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Publications (27)70.62 Total impact

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    ABSTRACT: Colorectal cancer (CRC) is the third most prevalent cancer type worldwide with a mortality rate of approximately 50%. Elevated cell-surface expression of truncated carbohydrate structures such as Tn antigen (GalNAcα-Ser/Thr) is frequently observed during tumor progression. We have previously demonstrated that the C-type lectin macrophage galactose-type lectin (MGL), expressed by human antigen presenting cells, can distinguish healthy tissue from CRC through its specific recognition of Tn antigen. Both MGL binding and oncogenic BRAF mutations have been implicated in establishing an immunosuppressive microenvironment. Here we aimed to evaluate whether MGL ligand expression has prognostic value and whether this was correlated to BRAFV600E mutation status. Using a cohort of 386 colon cancer patients we demonstrate that high MGL binding to stage III tumors is associated with poor disease-free survival, independent of microsatellite instability or adjuvant chemotherapy. In vitro studies using CRC cell lines showed an association between MGL ligand expression and the presence of BRAFV600E. Administration of specific BRAFV600E inhibitors resulted in decreased expression of MGL-binding glycans. Moreover, a positive correlation between induction of BRAFV600E and MGL binding to epithelial cells of the gastrointestinal tract was found in vivo using an inducible BRAFV600E mouse model. We conclude that the BRAFV600E mutation induces MGL ligand expression, thereby providing a direct link between oncogenic transformation and aberrant expression of immunosuppressive glycans. The strong prognostic value of MGL ligands in stage III colon cancer patients, i.e. when tumor cells disseminate to lymph nodes, further supports the putative immune evasive role of MGL ligands in metastatic disease.
    Oncotarget 07/2015; · 6.63 Impact Factor
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    ABSTRACT: Current guidelines recommend routine follow-up colonoscopy after acute diverticulitis to confirm the diagnosis and exclude malignancy. Its value, however, has recently been questioned because of contradictory study results. Our objective was to compare the colonoscopic detection rate of advanced colonic neoplasia (ACN), comprising colorectal cancer (CRC) and advanced adenoma (AA), in patients after a CT-proven primary episode of uncomplicated acute diverticulitis with average risk participants in a primary colonoscopy CRC screening program. A retrospective comparison was performed of prospectively collected data from cohorts derived from two multicenter randomized clinical trials executed in the Netherlands between 2009 and 2013. 401 uncomplicated diverticulitis patients and 1,426 CRC screening participants underwent colonic evaluation by colonoscopy. Main outcome was the diagnostic yield for ACN, calculated as number of diverticulitis patients and screening participants with ACN relative to their totals, with differences expressed as odds ratios (OR). The histopathology outcome of removed lesions during colonoscopy was used as definitive diagnosis. AA detection was similar [5.5 vs. 8.7 %; OR 0.62 (95 % CI 0.38-1.01); P = 0.053]. CRC was detected in 1.2 % (5/401) of diverticulitis patients versus 0.6 % (9/1,426) of screening participants [OR 1.30 (95 % CI 0.39-4.36); P = 0.673]. ACN was diagnosed in 6.7 % (27/401) of diverticulitis patients versus 9.1 % (130/1,426) of screening participants [OR 0.71 (95 % CI 0.45-1.11); P = 0.134]. ORs were adjusted for age, family history of CRC, smoking, BMI, and cecal intubation rate. ACN detection does not differ significantly between patients with recent uncomplicated diverticulitis and average risk screening participants. Routine follow-up colonoscopy after primary CT-proven uncomplicated left-sided acute diverticulitis can be omitted; these patients can participate in CRC screening programs. Follow-up colonoscopy may be beneficial when targeted at high-risk patients, but such an approach first needs prospective evaluation.
    Surgical Endoscopy 12/2014; DOI:10.1007/s00464-014-3977-9 · 3.31 Impact Factor
  • 11/2014; 2(Suppl 3):P237-P237. DOI:10.1186/2051-1426-2-S3-P237
  • British Journal of Cancer 08/2014; 111(4):749-755. DOI:10.1038/bjc.2014.354 · 4.82 Impact Factor
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    ABSTRACT: Disease-specific variations in intestinal microbiome composition have been found for a number of intestinal disorders, but little is known about diverticulitis. The purpose of this study was to compare the fecal microbiota of diverticulitis patients with control subjects from a general gastroenterological practice and to investigate the feasibility of predictive diagnostics based on complex microbiota data. Thirty-one patients with computed tomography (CT)-proven left-sided uncomplicated acute diverticulitis were included and compared with 25 control subjects evaluated for a range of gastrointestinal indications. A high-throughput polymerase chain reaction (PCR)-based profiling technique (IS-pro) was performed on DNA isolates from baseline fecal samples. Differences in bacterial phylum abundance and diversity (Shannon index) of the resulting profiles were assessed by conventional statistics. Dissimilarity in microbiome composition was analyzed with principal coordinate analysis (PCoA) based on cosine distance measures. To develop a prediction model for the diagnosis of diverticulitis, we used cross-validated partial least squares discriminant analysis (PLS-DA). Firmicutes/Bacteroidetes ratios and Proteobacteria load were comparable among patients and controls (p = 0.20). The Shannon index indicated a higher diversity in diverticulitis for Proteobacteria (p < 0.00002) and all phyla combined (p = 0.002). PCoA based on Proteobacteria profiles resulted in visually separate clusters of patients and controls. The diagnostic accuracy of the cross-validated PLS-DA regression model was 84 %. The most discriminative species derived largely from the family Enterobacteriaceae. Diverticulitis patients have a higher diversity of fecal microbiota than controls from a mixed population, with the phylum Proteobacteria defining the difference. The analysis of intestinal microbiota offers a novel way to diagnose diverticulitis.
    European Journal of Clinical Microbiology 06/2014; 33(11). DOI:10.1007/s10096-014-2162-3 · 2.67 Impact Factor
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    ABSTRACT: Objectives The objective was to identify a set of clinical features that can rule out appendicitis in patients with suspected acute appendicitis and nondiagnostic ultrasound (US) results, allowing safe discharge and next-day reevaluation without initial computed tomography (CT) or magnetic resonance imaging (MRI). Methods Data on clinical and US evaluation, including a number of prespecified variables potentially associated with acute appendicitis, were prospectively collected in two diagnostic accuracy studies of imaging. These studies included patients with suspected appendicitis seen in the emergency department (ED). For development and validation of the clinical decision rule (CDR), only patients with inconclusive or negative US results were included. There were 199 (of 422) patients in the development cohorts and 120 (of 211) patients in the validation cohort. Logistic regression analysis was used for data from patients with inconclusive or negative US results, and profiles were created of all possible combinations of predictors retained in the multivariable model. A final diagnosis was assigned by an expert panel based on perioperative data, histopathology, and clinical follow-up of at least 3months. ResultsThe CDR selected patients after negative or inconclusive US for discharge and next-day reevaluation without initial CT or MRI if fewer than two of the following predictors were present: male sex, migration of pain to the right lower quadrant, vomiting, and white blood cell (WBC) count higher than 12.0 x 10(9)/L. Applying the CDR in the development set selected 126 of 199 (63%) patients with negative or inconclusive US results for discharge without further imaging. This rule reduced the probability of appendicitis from 26% (51 of 199) in the total group of patients with negative or inconclusive US results to 12% (15 of 126) in the group that would be discharged based on the rule (p = 0.001). In the validation set (n = 120), the decision rule selected 72 (60%) patients for discharge and next-day reevaluation and reduced the probability of appendicitis from 20% (24 of 120) in the total group to 6% (4 of 72) in the patients selected on the rule (p = 0.001). The negative predictive value of the decision rule in the validation set was 94% (95% confidence interval [CI] = 87% to 98%). In comparison, the negative predictive value of CT in the same group was 99% (95% CI = 93% to 100%, p = 0.14), and that of MRI was 99% (95% CI = 94% to 100%, p = 0.12). Alternative decision rules based on combinations of the present decision rule with C-reactive protein (CRP) results did not improve selection. Conclusions This newly developed CDR significantly reduces the probability of appendicitis in a large subgroup of patients with negative or inconclusive US results. These patients can be safely discharged for outpatient reevaluation without further initial imaging if proper follow-up is available. This could assist in lowering the number of ED imaging investigations in patients with suspected appendicitis. Resumen ObjetivosIdentificar un conjunto de hallazgos clinicos que pueda descartar una apendicitis en pacientes con sospecha de apendicitis aguda y resultados ecograficos no diagnosticos, de manera que permitan dar de alta de forma segura y reevaluarlos al dia siguiente sin una tomografia computarizada (TC) o resonancia magnetica (RM) inicial. MetodologiaSe recogieron de forma prospectiva datos sobre la evaluacion clinica y la ecografia, que incluia un numero de variables prestablecidas potencialmente asociadas con apendicitis aguda, en dos estudios de precision de diagnostico por imagen. Estos estudios incluyeron a pacientes con sospecha de apendicitis visitados en el servicio de urgencias (SU). Se incluyeron solo los pacientes con resultados ecograficos negativos o no concluyentes para el desarrollo y la validacion de la regla de decision clinica (RDC). Hubo 199 pacientes (de 422) en la cohorte de desarrollo, y 120 pacientes (de 211) en la cohorte de validacion. Se utilizo un analisis de regresion logistica para los datos de pacientes con resultados ecograficos negativos o no concluyentes, y se crearon los perfiles de todas las posibles combinaciones de factores predictivos introducidos en el modelo multivariable. Se asigno un diagnostico final por un panel de expertos en base a los datos de la cirugia e histopatologicos y del seguimiento clinico durante al menos tres meses. ResultadosLa RDC selecciono pacientes tras una ecografia negativa o no concluyente para dar de alta y reevaluar al dia siguiente sin una TC o una RM inicial si presentaban al menos dos de los siguientes factores predictivos: sexo masculino, migracion del dolor al cuadrante inferior derecho, vomitos y recuento de leucocitos por encima de 12,0 x 10(9)/L. Aplicando la RDC en la cohorte de desarrollo, se selecciono a 126 de 199 (63%) pacientes con resultados ecograficos negativos o no concluyentes para dar de alta sin mas pruebas de imagen. Esta regla redujo la probabilidad de apendicitis de un 26% (51/199) en el grupo total de pacientes con resultados ecograficos negativos o no concluyentes, a un 12% (15/126) en el grupo que se habria dado de alta basandose en la regla (p = 0,001). En la cohorte de validacion (n = 120), la regla de decision selecciono a 72 (60%) pacientes para dar de alta y reevaluar al dia siguiente, y redujo la probabilidad de apendicitis de un 20% (24/120) en el grupo total a un 6% (4/72) de los pacientes seleccionados basandose en la regla (p=0,001). El valor predictivo negativo de la regla de decision en la cohorte de validacion fue de un 94% (intervalo de confianza [IC] 95% = 87% a 98%). En comparacion, el valor predictivo negativo de la TC en el mismo grupo fue de un 99% (IC 95% = 93% a 100%, p = 0,14), y el de la RM fue de un 99% (IC 95% = 94% a 100%, p = 0,12). Las reglas de decision alternativas basadas en las combinaciones de la presente RDC inicial junto con resultados de proteina C-reactiva no mejoraron la seleccion. ConclusionesEsta RDC recientemente desarrollada reduce significativamente la probabilidad de apendicitis en un gran subgrupo de pacientes con resultado ecografico negativo o no concluyente. Estos pacientes pueden ser dados de alta de forma segura para reevaluar de forma ambulatoria sin mas pruebas de imagen iniciales si se dispone de un correcto seguimiento. Esto podria ayudar a reducir el numero de pruebas de imagen en el SU en pacientes con sospecha de apendicitis.
    Academic Emergency Medicine 05/2014; 21(5). DOI:10.1111/acem.12374 · 2.20 Impact Factor
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    ABSTRACT: Improved prognostic stratification of patients with TNM stage II colorectal cancer is desired, since 20-30% of high-risk stage II patients may die within five years of diagnosis. This study was conducted to investigate REarranged during Transfection (RET) gene promoter CpG island methylation as a possible prognostic marker for TNM stage II colorectal cancer patients (CRC) patients. The utility of RET promoter CpG island methylation in tumors of stage II CRC patients as a prognostic biomarker for CRC related death was studied in three independent series (including 233, 231, and 294 TNM stage II patients, respectively) by using MSP and pyrosequencing. The prognostic value of RET promoter CpG island methylation was analyzed by using Cox regression analysis. In the first series, analyzed by MSP, CRC stage II patients (n=233) with RET methylated tumors, had a significantly worse overall survival as compared to those with unmethylated tumors (HRmultivariable = 2.51, 95%-CI: 1.42-4.43). Despite a significant prognostic effect of RET methylation in stage III patients of a second series, analyzed by MSP, the prognostic effect in stage II patients (n=231) was not statistically significant (HRmultivariable = 1.16, 95%-CI 0.71-1.92). The third series (n=294), analyzed by pyrosequencing, confirmed a statistically significant association between RET methylation and poor overall survival in stage II patients (HRmultivariable = 1.91, 95%-CI: 1.03-3.52). Our results show that RET promoter CpG island methylation, analyzed by two different techniques, is associated with a poor prognosis in stage II CRC in two independent series and a poor prognosis in stage III CRC in one series. RET methylation may serve as a useful and robust tool for clinical practice to identify high-risk stage II CRC patients with a poor prognosis. This merits further investigation.
    Molecular oncology 05/2014; DOI:10.1016/j.molonc.2014.01.011 · 5.94 Impact Factor
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    ABSTRACT: Infectious complications and especially anastomotic leakage (AL) severely impede the recuperation of patients following colorectal cancer (CRC) surgery. When the normal gut barrier fails, as in AL, pathogenic microorganisms can enter the circulation and may cause severe sepsis which is associated with substantial mortality. Moreover, AL has a negative impact on the CRC prognosis. Selective decontamination of the digestive tract (SDD) employs oral nonabsorbable antibiotics to eradicate pathogenic microorganisms before elective tumour resection. In this multicentre randomised clinical trial, perioperative SDD in addition to standard antibiotic prophylaxis is compared with standard antibiotic prophylaxis alone in patients with CRC who undergo elective surgical resection with a curative intent. The SDD regimen consists of colistin, tobramycin and amphotericin B. The primary objectives of this randomised clinical trial are to evaluate if perioperative SDD reduces the incidence of clinical AL and its septic consequences as well as other infectious complications. A main secondary objective is improvement of the cancer-free survival. A total of 762 patients will be included in total for sufficient power. It is hypothesised that SDD will reduce clinical AL thereby reducing the morbidity and the mortality in CRC patients. The trial is investigator-initiated, investigator-driven and supported by the Dutch Digestive Foundation (WO 11-06) and the private Posthumus Meyes Fund. The trial is registered at ClinicalTrials.gov: NCT01740947.
    Danish Medical Journal 04/2014; 61(4):A4695. · 0.61 Impact Factor
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    ABSTRACT: Deregulation of apoptosis related genes may be associated with poor outcome in cancer. Aim of the present study was to investigate the prognostic role of expression levels of apoptosis related proteins in stage II and III colon cancer. From tumor samples of 386 stage II and III colon cancer patients, DNA was isolated and tissue microarrays were constructed. Expression of Bcl-2, Bcl-X, BAX, XIAP, Fas, FasL and c-FLIP was evaluated and PCR-based microsatellite instability analysis was performed. High FasL expressing tumors were associated with high disease recurrence rates in stage II colon cancer patients overall, as was low Bcl-X expression in microsatellite stable stage II patients. In stage II patients, a multivariable model based on FasL and Bcl-XL expression revealed a significant association with disease free survival (DFS). In stage III colon cancer patients, low Bcl-2, low BAX and low Fas expression levels were associated with worse outcome. In these patients a multivariable model based on angioinvasion and Bcl-2, Fas and FasL expression was significantly associated with DFS. Stage II patients with low Bcl-X and high FasL protein expression levels and stage III patients with low Fas, high FasL and low Bcl-2 expression could be considered as high risk for disease recurrence. J. Surg. Oncol. © 2013 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 03/2014; 109(3). DOI:10.1002/jso.23495 · 2.84 Impact Factor
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    ABSTRACT: Objective To compare accuracy and interobserver agreement between radiologists with limited experience in the evaluation of abdominal MRI (non-experts), and radiologists with longer MR reading experience (experts), in reading MRI in patients with suspected appendicitis. Methods MR imaging was performed in 223 adult patients with suspected appendicitis and read independently by two members of a team of eight MR-inexperienced radiologists, who were trained with 100 MR examinations previous to this study (non-expert reading). Expert reading was performed by two radiologists with a larger abdominal MR experience (>500 examinations) in consensus. A final diagnosis was assigned after three months based on all available information, except MRI findings. We estimated MRI sensitivity and specificity for appendicitis and for all urgent diagnoses separately. Interobserver agreement was evaluated using kappa statistics. Results Urgent diagnoses were assigned to 147 of 223 patients; 117 had appendicitis. Sensitivity for appendicitis was 0.89 by MR-non-expert radiologists and 0.97 in MR-expert reading (p = 0.01). Specificity was 0.83 for MR-non-experts versus 0.93 for MR-expert reading (p = 0.002). MR-experts and MR-non-experts agreed on appendicitis in 89% of cases (kappa 0.78). Accuracy in detecting urgent diagnoses was significantly lower in MR-non-experts compared to MR-expert reading: sensitivity 0.84 versus 0.95 (p < 0.001) and specificity 0.71 versus 0.82 (p = 0.03), respectively. Agreement on urgent diagnoses was 83% (kappa 0.63). Conclusion MR-non-experts have sufficient sensitivity in reading MRI in patients with suspected appendicitis, with good agreement with MR-expert reading, but accuracy of MR-expert reading was higher.
    European journal of radiology 01/2014; 83(1):103–110. DOI:10.1016/j.ejrad.2013.09.022 · 2.16 Impact Factor
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    ABSTRACT: Gastrointestinal surgery is associated with a high incidence of infectious complications. Selective decontamination of the digestive tract is an antimicrobial prophylaxis regimen that aims to eradicate gastrointestinal carriage of potentially pathogenic microorganisms and represents an adjunct to regular prophylaxis in surgery. Relevant studies were identified using bibliographic searches of MEDLINE, EMBASE, and the Cochrane database (period from 1970 to November 1, 2012). Only studies investigating selective decontamination of the digestive tract in gastrointestinal surgery were included. Two randomized clinical trials and one retrospective case-control trial showed significant benefit in terms of infectious complications and anastomotic leakage in colorectal surgery. Two randomized controlled trials in esophageal surgery and two randomized clinical trials in gastric surgery reported lower levels of infectious complications. Selective decontamination of the digestive tract reduces infections following esophageal, gastric, and colorectal surgeries and also appears to have beneficial effects on anastomotic leakage in colorectal surgery. We believe these results provide the basis for a large multicenter prospective study to investigate the role of selective decontamination of the digestive tract in colorectal surgery.
    Journal of Gastrointestinal Surgery 10/2013; 17(12). DOI:10.1007/s11605-013-2379-y · 2.39 Impact Factor
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    ABSTRACT: Laparoscopic lavage has recently emerged as a promising alternative to sigmoid resection in the treatment of perforated diverticulitis. This study examined an early experience with this technique. The files of all patients with complicated diverticulitis were searched in 34 teaching hospitals of the Netherlands. Patients with perforated diverticulitis treated with laparoscopic lavage between 1 January 2008 and 31 December 2010 were included. Treatment with laparoscopic lavage was performed in only 38 patients in ten hospitals. Lavage was successful in controlling sepsis in 31 of the 38 included patients, with 32 per cent morbidity (10 of 31 patients) and fast recovery. Overall, 17 of 38 patients developed complications, of whom two had a missed overt sigmoid perforation. Two patients died from multiple organ failure and one from aspiration pneumonia; one other patient died after palliative management of inoperable lung carcinoma. Three patients in whom lavage was successful underwent subsequent sigmoid resection for recurrent diverticulitis. Patients in whom lavage was unsuccessful tended to have more co-morbidities, a higher preoperative C-reactive protein concentration and a higher Mannheim Peritonitis Index. Laparoscopic lavage for perforated diverticulitis was feasible in the majority of patients, but identification of an overt sigmoid perforation and patient selection are of critical importance. © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
    British Journal of Surgery 04/2013; 100(5):704-10. DOI:10.1002/bjs.9063 · 5.21 Impact Factor
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    ABSTRACT: Abstract Background: After promising results were obtained from studies in large animals, a technique using indocyanine green (ICG) is being introduced for sentinel lymph node (SLN) biopsy in colon cancer patients. Subjects and Methods: Colon cancer patients without clinical signs of metastatic disease, presenting at the VU University Medical Center (Amsterdam, The Netherlands) or Kennemer Gasthuis (Haarlem, The Netherlands), were asked to participate in the study. During laparoscopy, a subserosal injection of 2.5 mg of ICG diluted in 1 mL of 0.9% NaCl plus 2% human albumin was performed using a percutaneously inserted long rigid or flexible needle. After injection, a near-infrared laparoscope (Olympus Corp., Tokyo, Japan) was used for lymph flow and SLN visualization. The SLNs were laparoscopically harvested and analyzed by a senior pathologist using multisectioning and immunohistochemistry. Results: Fourteen patients were included (six women, eight men), with a median age of 75.5 (interquartile range [IQR], 67.8-81.0) years and a median body mass index of 25.1 (IQR, 22.7-26.0) kg/m2. Median tumor diameter was 4.5 (IQR, 3.4-7.0) cm. At least one SLN was identified in all patients, with a median number of 2.0 (IQR, 2.0-3.3) SLNs. The median time between injection and identification of the SLN was 15.0 (IQR, 13.3-29.3) minutes. Positioning of the needle tip into the subserosal layer was found to be more effective using the flexible needle. When this flexible needle was used, less spill of dye was observed. All SLNs were negative. We observed four false-negative nodes, all after using a rigid needle. None of the patients showed an adverse reaction to the ICG injection. Conclusions: Preliminary results of laparoscopic sentinel node identification using a near-infrared dye show this procedure is safe and feasible. It was possible to detect lymph nodes in all patients. Large tumor size, drainage to adjacent lymphatic vessels, and the use of a rigid needle might contribute to false-negative nodes.
    Journal of Laparoendoscopic & Advanced Surgical Techniques 03/2013; 23(4). DOI:10.1089/lap.2012.0407 · 1.19 Impact Factor
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    ABSTRACT: BACKGROUND: Tumor stroma plays an important role in the progression and metastasis of colon cancer. The glycoproteins versican and lumican are overexpressed in colon carcinomas and are associated with the formation of tumor stroma. The aim of the present study was to investigate the potential prognostic value of versican and lumican expression in the epithelial and stromal compartment of Union for International Cancer Control (UICC) stage II and III colon cancer. METHODS: Clinicopathological data and tissue samples were collected from stage II (n = 226) and stage III (n = 160) colon cancer patients. Tissue microarrays were constructed with cores taken from both the center and the periphery of the tumor. These were immunohistochemically stained for lumican and versican. Expression levels were scored on digitized slides. Statistical evaluation was performed. RESULTS: Versican expression by epithelial cells in the periphery of the tumor, i.e., near the invasive front, was correlated to a longer disease-free survival for the whole cohort (P = 0.01), stage III patients only (P = 0.01), stage III patients with microsatellite-instable tumors (P = 0.04), and stage III patients with microsatellite-stable tumors who did not receive adjuvant chemotherapy (P = 0.006). Lumican expression in epithelial cells overall in the tumor was correlated to a longer disease-specific survival in stage II patients (P = 0.05) and to a longer disease-free survival and disease-specific survival in microsatellite-stable stage II patients (P = 0.02 and P = 0.004). CONCLUSIONS: Protein expression of versican and lumican predicted good clinical outcome for stage III and II colon cancer patients, respectively.
    Annals of Surgical Oncology 06/2012; 20(Suppl 3). DOI:10.1245/s10434-012-2441-0 · 3.94 Impact Factor
  • Cancer Research 06/2012; 72(8 Supplement):4526-4526. DOI:10.1158/1538-7445.AM2012-4526 · 9.28 Impact Factor
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    ABSTRACT: To investigate the prognostic value of multiple cell cycle-associated proteins in a large series of stage II and III colon cancers. From formalin-fixed, paraffin-embedded tumor samples of 386 patients with stage II and III colon cancer, DNA was isolated and tissue microarrays were constructed. Tissue microarray slides were immunohistochemically stained for p21, p27, p53, epidermal growth factor receptor, Her2/Neu, β-catenin, cyclin D1, Ki-67, thymidylate synthase, and Aurora kinase A (AURKA). Polymerase chain reaction-based microsatellite instability analysis was performed to allow for stratification of protein expression by microsatellite instability status. Overall, low p21, high p53, low cyclin D1, and high AURKA expression were significantly associated with recurrence (P = 0.01, P < 0.01, P = 0.04, and P < 0.01, respectively). In stage II patients who did not receive adjuvant chemotherapy (n = 190), significantly more recurrences were observed in case of low-p21 and high-p53-expressing tumors (P < 0.01 and P = 0.03, respectively). In stage III patients who did not receive chemotherapy, high p53 expression was associated with recurrence (P = 0.02), and in patients who received chemotherapy, high AURKA expression was associated with relapse (P < 0.01). In patients with microsatellite stable tumors, high levels of p53 and AURKA were associated with recurrence (P = 0.01 and P < 0.01, respectively). Multivariate analysis showed p21 (odds ratio 1.6, 95% confidence interval 0.9-2.8) and AURKA (odds ratio 2.7, 95% confidence interval 1.3-5.6) to be independently associated with disease recurrence. p21, p53, cyclin D1, and AURKA could possibly be used as prognostic markers to identify colon cancer patients with high risk of disease recurrence.
    Annals of Surgical Oncology 02/2012; 19 Suppl 3(3):S682-92. DOI:10.1245/s10434-012-2216-7 · 3.94 Impact Factor
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    ABSTRACT: The sentinel lymph node (SLN) is an emerging focus for immunological research in breast cancer. Cryopreservation of SLN single-cell suspensions allows for simultaneous phenotypic multi-parameter analyses and minimizes operator dependent variability. This is of particular importance for immunomonitoring of large multicenter trials. However, little data are available regarding the influence of cryopreservation on phenotypic characteristics of lymph node dendritic cells and T cells. In this study we assessed the feasibility of cryopreservation of viable SLN cell samples for flowcytometric analysis, by comparing quantitative analyses of SLN cell samples after freeze-thawing with direct analysis of fresh SLN cell samples. SLN were collected from nine breast cancer patients. From each SLN cell sample, half was used for immediate analysis and half was analyzed after cryopreservation and thawing. Conventional dendritic cell (cDC) and T cell subsets were quantified and phenotypically characterized by flow cytometry.
    Journal of immunological methods 10/2011; 375(1-2):189-95. DOI:10.1016/j.jim.2011.10.011 · 2.01 Impact Factor
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    ABSTRACT: The median laparotomy is frequently used by abdominal surgeons to gain rapid and wide access to the abdominal cavity with minimal damage to nerves, vascular structures and muscles of the abdominal wall. However, incisional hernia remains the most common complication after median laparotomy, with reported incidences varying between 2-20%. Recent clinical and experimental data showed a continuous suture technique with many small tissue bites in the aponeurosis only, is possibly more effective in the prevention of incisional hernia when compared to the common used large bite technique or mass closure. The STITCH trial is a double-blinded multicenter randomized controlled trial designed to compare a standardized large bite technique with a standardized small bites technique. The main objective is to compare both suture techniques for incidence of incisional hernia after one year. Secondary outcomes will include postoperative complications, direct costs, indirect costs and quality of life. A total of 576 patients will be randomized between a standardized small bites or large bites technique. At least 10 departments of general surgery and two departments of oncological gynaecology will participate in this trial. Both techniques have a standardized amount of stitches per cm wound length and suture length wound length ratio's are calculated in each patient. Follow up will be at 1 month for wound infection and 1 year for incisional hernia. Ultrasound examinations will be performed at both time points to measure the distance between the rectus muscles (at 3 points) and to objectify presence or absence of incisional hernia. Patients, investigators and radiologists will be blinded during follow up, although the surgeon can not be blinded during the surgical procedure. The STITCH trial will provide level 1b evidence to support the preference for either a continuous suture technique with many small tissue bites in the aponeurosis only or for the commonly used large bites technique.
    BMC Surgery 08/2011; 11(1):20. DOI:10.1186/1471-2482-11-20 · 1.24 Impact Factor
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    Journal of Gastrointestinal Surgery 07/2011; 15(10):1904-5; author reply 1906-7. DOI:10.1007/s11605-011-1602-y · 2.39 Impact Factor
  • Annual Meeting of the American-Society-of-Colon-and-Rectal-Surgeons; 05/2011