Fiebo J. ten Kate

Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: Long-term results of a randomized controlled trial

BackgroundThis is a randomized, controlled trial of preoperative chemotherapy in patients undergoing surgery for oesophageal squamous cell carcinoma (OSCC). Patients were allocated to chemotherapy, consisting of 2-4 cycles of cisplatin and etoposide, followed by surgery (CS group) or surgery alone (S group). Initial results reported only in abstract form in 1997, demonstrated an advantage for overall survival in the CS group. The results of this trial have been updated and discussed in the timeframe in which this study was performed.MethodsThis trial recruited 169 patients with OSCC, 85 patients assigned to preoperative chemotherapy and 84 patients underwent immediate surgery. The primary study endpoint was overall survival (OS), secondary endpoints were disease free survival (DFS) and pattern of failure. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test.ResultsThere were 148 deaths, 71 in the CS and 77 in the S group. Median OS time was 16 months in the CS group compared with 12 months in the S group; 2-year survival rates were 42% and 30%; and 5-year survival rates were 26% and 17%, respectively. Intention to treat analysis showed a significant overall survival benefit for patients in the CS group (P = 0.03, by the log-rank test; hazard ratio [HR] 0.71; 95%CI 0.51-0.98). DFS (from landmark time of 6 months after date of randomisation) was also better in the CS-group than in the S group (P = 0.02, by the log-rank test; HR 0.72; 95%CI 0.52-1.0). No difference in failure pattern was observed between both treatment arms.ConclusionsPreoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC.

Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy versus open transthoracic esophagectomy for resectable esophageal cancer, a randomized controlled trial (ROBOT trial)

BackgroundFor esophageal cancer patients, radical esophagolymphadenectomy is the cornerstone of multimodality treatment with curative intent. Transthoracic esophagectomy is the preferred surgical approach worldwide allowing for en-bloc resection of the tumor with the surrounding lymph nodes. However, the percentage of cardiopulmonary complications associated with the transthoracic approach is high (50 to 70%).Recent studies have shown that robot-assisted minimally invasive thoraco-laparoscopic esophagectomy (RATE) is at least equivalent to the open transthoracic approach for esophageal cancer in terms of short-term oncological outcomes. RATE was accompanied with reduced blood loss, shorter ICU stay and improved lymph node retrieval compared with open esophagectomy, and the pulmonary complication rate, hospital stay and perioperative mortality were comparable. The objective is to evaluate the efficacy, risks, quality of life and cost-effectiveness of RATE as an alternative to open transthoracic esophagectomy for treatment of esophageal cancer.Methods/designThis is an investigator-initiated and investigator-driven monocenter randomized controlled parallel-group, superiority trial. All adult patients (age ≥18 and ≤80 years) with histologically proven, surgically resectable (cT1-4a, N0-3, M0) esophageal carcinoma of the intrathoracic esophagus and with European Clinical Oncology Group performance status 0, 1 or 2 will be assessed for eligibility and included after obtaining informed consent. Patients (n = 112) with resectable esophageal cancer are randomized in the outpatient department to either RATE (n = 56) or open three-stage transthoracic esophageal resection (n = 56). The primary outcome of this study is the percentage of overall complications (grade 2 and higher) as stated by the modified Clavien–Dindo classification of surgical complications.DiscussionThis is the first randomized controlled trial designed to compare RATE with open transthoracic esophagectomy as surgical treatment for resectable esophageal cancer. If our hypothesis is proven correct, RATE will result in a lower percentage of postoperative complications, lower blood loss, and shorter hospital stay, but with at least similar oncologic outcomes and better postoperative quality of life compared with open transthoracic esophagectomy. The study started in January 2012. Follow-up will be 5 years. Short-term results will be analyzed and published after discharge of the last randomized patient.Trial registrationDutch trial register: NTR3291 ClinicalTrial.gov: NCT01544790

Whole slide images for primary diagnostics in dermatopathology: a feasibility study

Background During the last decade, whole slide images (WSI) have been used in many areas of pathology such as teaching, research, digital archiving, teleconsultation and quality assurance testing. However, WSI have not regularly been used for routine diagnosis, because of the lack of validation studies. Aim To test the validity of using WSI for primary diagnosis of skin diseases. Materials and methods 100 skin biopsies and resections which had been diagnosed light microscopically one year previously were scanned at 20× magnification, and rediagnosed by six pathologists (every pathologist assessed his own cases), having the original clinical information available, but blinded to the original diagnoses. The WSI diagnoses were compared to the initial light microscopy diagnosis and classified as concordant, slightly discordant (without clinical consequences) or discordant. Results The light microscopy and the WSI based diagnosis were concordant in 94% of the cases. The light microscopy and WSI diagnosis were slightly discordant in 6% of the cases. For one of the slightly discrepant cases the WSI diagnosis was considered better, while the original diagnosis was preferred for the other five cases. There were no discordant cases with clinical or prognostic implications. Conclusion Primary histopathological diagnosis of skin biopsies and resections can be done digitally using WSI.

microRNA-145 in Barrett's oesophagus: regulating BMP4 signalling via GATA6

Objective Barretts oesophagus (BE) is a metaplastic condition of the distal oesophagus which predisposes to oesophageal adenocarcinoma (EAC). It has been suggested that microRNAs (miRNAs) are involved in the process of development of BE and EAC; however, few functional miRNA data are available. The aim of the study was to perform a tissue-specific miRNA profile and, based on this, to examine the function of miRNA-145 in the oesophagus. Design miRNA expression profiling using microarray analysis in EAC, BE and normal squamous epithelium of the oesophagus (SQ) was performed and validated using real-time PCR in samples from 15 patients and in situ hybridisation in samples from 10 patients. The proliferative effect of miRNA-145 precursor transfection in the SQ (HET-1A) and BE cell line (BAR-T) was measured. Downstream targets of miRNA-145 were determined by analysing mRNA and protein expression from miRNA-145 transfected cells. Results Three unique miRNA expression profiles were found in tissue from EAC, BE and SQ, which showed that miRNA-145 was upregulated in BE compared with EAC and SQ. Overexpression of miRNA-145 in HET-1A and BAR-T cells reduced cell proliferation and inhibited GATA6, BMP4 and SOX9 mRNA expression. Furthermore, altered BMP4 signalling was observed in vitro on miRNA-145 overexpression. These effects were blocked when cells were co-transfected with a miRNA-145 specific inhibitor. Additionally, BMP4 incubation of HET-1A cells altered miRNA-145 and GATA6 expression over time. Conclusion These results imply that miRNA-145 indirectly targets BMP4 via GATA6 and is potentially involved in the development of BE.

Validation of tissue microarray technology in squamous cell carcinoma of the esophagus

Tissue microarray (TMA) technology has been developed to facilitate high-throughput immunohistochemical and in situ hybridization analysis of tissues by inserting small tissue biopsy cores into a single paraffin block. Several studies have revealed novel prognostic biomarkers in esophageal squamous cell carcinoma (ESCC) by means of TMA technology, although this technique has not yet been validated for these tumors. Because representativeness of the donor tissue cores may be a disadvantage compared to full sections, the aim of this study was to assess if TMA technology provides representative immunohistochemical results in ESCC. A TMA was constructed containing triplicate cores of 108 formalin-fixed, paraffin-embedded squamous cell carcinomas of the esophagus. The agreement in the differentiation grade and immunohistochemical staining scores of CK5/6, CK14, E-cadherin, Ki-67, and p53 between TMA cores and a subset of 64 randomly selected donor paraffin blocks was determined using kappa statistics. The concurrence between TMA cores and donor blocks was moderate for Ki-67 (κ = 0.42) and E-cadherin (κ = 0.47), substantial for differentiation grade (κ = 0.65) and CK14 (κ = 0.71), and almost perfect for p53 (κ = 0.86) and CK5/6 (κ = 0.93). TMA technology appears to be a valid method for immunohistochemical analysis of molecular markers in ESCC provided that the staining pattern in the tumor is homogeneous.

Whole slide images for primary diagnostics of gastrointestinal tract pathology: a feasibility study

During the last decade, whole slide images have been used in many areas of pathology such as teaching, research, digital archiving, teleconsultation, and quality assurance testing. However, whole slide images have as yet not much been used for up-front diagnostics because of the lack of validation studies. The aim of this study was, therefore, to test the feasibility of whole slide images for diagnosis of gastrointestinal tract specimens, one of the largest areas of diagnostic pathology. One hundred gastrointestinal tract biopsies and resections that had been diagnosed using light microscopy 1 year before were rediagnosed on whole slide images scanned at ×20 magnification by 5 pathologists (all reassessing their own cases), having the original clinical information available but blinded to their original light microscopy diagnoses. The original light microscopy and whole slide image-based diagnoses were compared and classified as concordant, slightly discordant (without clinical consequences), and discordant. The diagnoses based on light microscopy and the whole slide image-based rediagnoses were concordant in 95% of the cases. Light microscopy and whole slide image diagnosis in the remaining 5% of cases were slightly discordant, none of these were with clinical or prognostic implications. Up-front histopathologic diagnosis of gastrointestinal biopsies and resections can be done on whole slide images.

Pancreatic intraepithelial neoplasia and pancreatic tumorigenesis: of mice and men.

CONTEXT Pancreatic cancer has a poor prognosis with a 5-year survival of less than 5%. Early detection is at present the only way to improve this outlook. This review focuses on the recent advances in our understanding of pancreatic carcinogenesis, the scientific evidence for a multistaged tumor progression, and the role genetically engineered mouse models can play in recapitulating the natural course and biology of human disease. OBJECTIVES To illustrate the stepwise tumor progression of pancreatic cancer and genetic alterations within the different stages of progression and to review the findings made with genetically engineered mouse models concerning pancreatic carcinogenesis. DATA SOURCES A review of recent literature on pancreatic tumorigenesis and genetically engineered mouse models. CONCLUSIONS Pancreatic cancer develops through stepwise tumor progression in which preinvasive stages, called pancreatic intraepithelial neoplasia, precede invasive pancreatic cancer. Genetic alterations in oncogenes and tumor suppressor genes underlying pancreatic cancer are also found in pancreatic intraepithelial neoplasia. These mutations accumulate during progression through the consecutive stages of pancreatic intraepithelial neoplasia lesions. Also in genetically engineered mouse models of pancreatic ductal adenocarcinoma, tumorigenesis occurs through stepwise progression via consecutive mouse pancreatic intraepithelial neoplasia, and these models provide important tools for clinical applications. Nevertheless differences between mice and men still remain.

SMAD4 Immunohistochemistry Reflects Genetic Status in Juvenile Polyposis Syndrome

Purpose: Juvenile polyposis syndrome (JPS) can be caused by a germline defect of the SMAD4 gene. Somatic inactivation of SMAD4 occurs in pancreatic and colorectal cancers and is reflected by loss of SMAD4 immunohistochemistry. Here, SMAD4 immunohistochemistry as a marker of SMAD4 gene status and the role of SMAD4 in the adenoma-carcinoma sequence in neoplastic progression in JPS are studied. Experimental Design: Twenty polyps with a SMAD4 germline defect and 38 control polyps were studied by SMAD4 immunohistochemistry. Inactivation of the SMAD4 wild-type allele was studied in dysplastic epithelium and in areas with aberrant SMAD4 expression. APC, β-catenin, p53, and K-ras were studied to evaluate the adenoma-carcinoma sequence. Results: Nine of 20 polyps with a SMAD4 germline defect showed loss of epithelial SMAD4 expression. Loss of heterozygosity of SMAD4 was found in five polyps and a somatic stop codon mutation was found in two polyps without loss of heterozygosity. Remarkably, somatic inactivation of epithelial SMAD4 did not always coincide with dysplasia and aberrant p53 staining was found in four of six dysplastic polyps with normal SMAD4 staining. One K-ras mutation was found in nine juvenile polyps with dysplasia. No evidence for Wnt activation was found. Conclusions: SMAD4 immunohistochemistry mirrors genetic status and provides a specific adjunct in the molecular diagnosis of JPS. However, epithelial SMAD4 inactivation is not required for polyp formation and is not obligatory for neoplastic progression in JPS. Instead, different routes to neoplasia in JPS caused by germline SMAD4 mutation seem to be operative, including somatic loss of SMAD4 and p53 inactivation without somatic loss of SMAD4. Clin Cancer Res; 16(16); 4126–34. ©2010 AACR.

Misclassification of Dysplasia in Patients with Inflammatory Bowel Disease: Consequences for Progression Rates to Advanced Neoplasia

Background: The natural behavior of flat low‐grade (LGD) and indefinite dysplasia (IND) in patients with inflammatory bowel disease (IBD) remains uncertain and seems to be dependent on the interpretation of the pathologist. We studied the progression rate of flat LGD and IND to advanced neoplasia (high‐grade dysplasia [HGD] or colorectal cancer [CRC]) before and after histopathological review by a panel of gastrointestinal expert pathologists. Methods: A nationwide pathology database was used to identify IBD patients with dysplasia in six Dutch university medical centers between 1990 and 2006. Medical charts of patients with recorded flat LGD or IND were reviewed. Histological slides from three university medical centers were reviewed by a panel of three expert gastrointestinal pathologists. Results: We identified 113 flat LGD patients and 26 flat IND patients. Advanced neoplasia was found in 18 flat LGD patients (16%) after a median follow‐up of 48 months, resulting in a 5‐year progression rate of 12%. Five IND patients (19%) developed advanced neoplasia after a median follow‐up of 24 months, resulting in a 5‐year progression rate of 21%. Review of 1547 histological slides from 87 patients resulted in an increase of the 5‐year progression rate of flat LGD to advanced neoplasia to 37%, whereas the progression rate of IND decreased to 5%. Conclusions: A diagnosis of flat LGD that is confirmed by a panel of expert gastrointestinal pathologists is associated with a substantial risk of progression to advanced neoplasia, while confirmed IND is associated with a low risk of progression. (Inflamm Bowel Dis 2010;)

Reproducibility of the histological diagnosis of celiac disease.

Abstract Objective. A small intestinal biopsy is considered to be the gold standard for the diagnosis of celiac disease (CD). However, the assessment of small intestinal histology may vary between pathologists. Our aim was, therefore, to determine the interobserver variability in the histological diagnosis of CD. Material and methods. Biopsy specimens of 297 pediatric patients suspected of having CD were revised by a single experienced pathologist and compared to the original reports. Mucosal changes were scored using the Marsh classification. In patients with a discrepancy in diagnosis, clinical and serological data were used to determine the most probable diagnosis. Results. Although the interobserver variability for the Marsh classification was found to be moderate with a Kappa value of 0.486, the Kappa value for the diagnosis reached an almost perfect agreement (0.850). Nevertheless, in 22 patients a different diagnosis was made by the second observer. Interestingly, in this subgroup relatively more biopsies were classified to be of suboptimal quality. Based on clinical presentation, serology and follow-up, 19 of those patients truly had CD. In 14 of them the diagnosis was originally missed by the first observer while five cases were under-diagnosed by the second pathologist. Conclusions. CD can be missed histologically due to assessment variation between pathologists. A final diagnosis of CD should be based on histology, serology as well as response to the diet.