Babs G. Taal

Clinical findings with implications for genetic testing in families with clustering of colorectal cancer.

BACKGROUND Germ-line mutations in DNA mismatch-repair genes (MSH2, MLH1, PMS1, PMS2, and MSH6) cause susceptibility to hereditary nonpolyposis colorectal cancer. We assessed the prevalence of MSH2 and MLH1 mutations in families suspected of having hereditary nonpolyposis colorectal cancer and evaluated whether clinical findings can predict the outcome of genetic testing. METHODS We used denaturing gradient gel electrophoresis to identify MSH2 and MLH1 mutations in 184 kindreds with familial clustering of colorectal cancer or other cancers associated with hereditary nonpolyposis colorectal cancer. Information on the site of cancer, the age at diagnosis, and the number of affected family members was obtained from all families. RESULTS Mutations of MSH2 or MLH1 were found in 47 of the 184 kindreds (26 percent). Clinical factors associated with these mutations were early age at diagnosis of colorectal cancer, the occurrence in the kindred of endometrial cancer or tumors of the small intestine, a higher number of family members with colorectal or endometrial cancer, the presence of multiple colorectal cancers or both colorectal and endometrial cancers in a single family member, and fulfillment of the Amsterdam criteria for the diagnosis of hereditary nonpolyposis colorectal cancer (at least three family members in two or more successive generations must have colorectal cancer, one of whom is a first-degree relative of the other two; cancer must be diagnosed before the age of 50 in at least one family member; and familial adenomatous polyposis must be ruled out). Multivariate analysis showed that a younger age at diagnosis of colorectal cancer, fulfillment of the Amsterdam criteria, and the presence of endometrial cancer in the kindred were independent predictors of germ-line mutations of MSH2 or MLH1. These results were used to devise a logistic model for estimating the likelihood of a mutation in MSH2 and MLH1. CONCLUSIONS Assessment of clinical findings can improve the rate of detection of mutations of DNA mismatch-repair genes in families suspected of having hereditary nonpolyposis colorectal cancer.

ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms of the Digestive System: Well-Differentiated Pancreatic Non-Functioning Tumors

ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms of the Digestive System : Well-Differentiated Pancreatic Non-Functioning Tumors

Consensus guidelines for the management of patients with liver metastases from digestive (neuro)endocrine tumors: Foregut, midgut, hindgut, and unknown primary

a DRK Kliniken Westend, Berlin , Germany; b UFR Bichat-Beaujon-Louis Mourier, Service de Chirurgie Digestive, Hopital Louis Mourier, Colombes , France; c Medicine and Surgery, General Surgery Section, MED/18 – General Surgery and d Department of Pathology, University of Verona, Verona , Italy; e Netherlands Cancer Centre, Amsterdam , and f Department of Nuclear Medicine, Erasmus University Medical Center, Rotterdam , The Netherlands;

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Towards a Standardized Approach to the Diagnosis of Gastroenteropancreatic Neuroendocrine Tumors and Their Prognostic Stratification

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors : towards a standardized approach to the diagnosis of gastroenteropancreatic neuroendocrine tumors and their prognostic stratification

A cost-effectiveness analysis of colorectal screening of hereditary nonpolyposis colorectal carcinoma gene carriers

It has been estimated that the prevalence of carriers of a mutated mismatch repair (MMR) gene among the general population in Western countries is between 5 and 50 per 10,000. These carriers have a risk of >85% of developing colorectal carcinoma (CRC) and therefore need careful follow‐up. The objective of this study was to analyze the cost‐effectiveness of CRC surveillance for carriers of a mutated MMR gene.

Surveillance for hereditary nonpolyposis colorectal cancer - A long-term study on 114 families

PURPOSE Hereditary nonpolyposis colorectal cancer is caused by germline mutations in DNA mismatch repair genes. Mutation carriers have a 60 to 85 percent risk of developing colorectal cancer. In the Netherlands hereditary nonpolyposis colorectal cancer families are monitored in an intensive surveillance program. The aim of this study was to examine the stage of the screening-detected tumors in relation to the surveillance interval and to assess the risk of developing colorectal cancer while on the program. METHODS The Dutch hereditary nonpolyposis colorectal cancer family registry was used. A total of 114 families had a mismatch repair gene defect and/or met the clinical criteria for hereditary nonpolyposis colorectal cancer. The interval between surveillance and colorectal cancer was investigated in initially healthy family members who underwent at least one surveillance examination without showing evidence for colorectal cancer (surveillance group) and in family members who previously underwent partial or subtotal colectomy for colorectal cancer. The risk of colorectal cancer was calculated for proven mutation carriers (surveillance group) and for putative carriers after partial or subtotal colectomy. RESULTS A total of 35 cancers were detected while on the program. With intervals between colorectal cancer and the preceding surveillance examination of two years or less, tumors were at Dukes Stage A (n = 4), B (n = 11), and C (1). With intervals of more than two years, tumors were at Dukes Stage A (n = 3), B (n = 10), and C (n = 6). The 10-year cumulative risk of developing colorectal cancer was 10.5 (95 percent confidence interval, 3.8–17.2) percent in proven mutation carriers, 15.7 (95 percent confidence interval, 4.1–27.3) percent after partial colectomy, and 3.4 percent after subtotal colectomy. CONCLUSION There is a substantial risk of developing colorectal cancer while on the program. However, all tumors but one of subjects who underwent a surveillance examination two years or less before detection were at a local stage. We recommend surveillance for hereditary nonpolyposis colorectal cancer with an interval of two years or less.

Histological grading in gastric lymphoma: Pretreatment criteria and clinical relevance

BACKGROUND & AIMS Stomach-conserving therapy in primary gastric non-Hodgkins lymphoma (mucosa-associated lymphoid tissue [MALT]-NHL) is increasingly gaining importance as an alternative to surgery. As a consequence, surgical pathologists have to define histological criteria in pretreatment endoscopic biopsy specimen samples not only to make the diagnosis but also to recognize minor tumor components that may infer a significantly adverse impact on prognosis. The aim of this study was to define histological criteria for clinically significant tumor progression in pretreatment endoscopic biopsy specimens. METHODS In a consecutive series of 106 patients with gastric MALT-NHL, the prognostic impact of large cell components was assessed by semiquantitative analysis of clusters and diffusely intermingled malignant blasts. RESULTS In low-grade MALT-NHL, a category with a diffuse large cell component of 1%-10% with or without nonconfluent clusters of blasts could be separated with a significantly worse prognosis (10-year disease-specific survival, 90% vs. 75%). No clinical parameters of known prognostic significance could account for this difference. CONCLUSIONS It is possible to define criteria in endoscopic biopsy specimens to recognize clinically relevant tumor progression. To serve as a guideline in the choice of treatment, these criteria should be validated prospectively in future clinical trials.

Epidemiology of Neuroendocrine Tumours

Neuroendocrine tumours account for only 0.5% of all malignancies. The incidence is approximately 2/100,000 with a female preponderance under the age of 50 years due to appendiceal location. The main primary sites are the gastrointestinal tract (62–67%) and the lung (22–27%). Presentation with metastatic disease accounts for 12–22%. In the last decades, the incidence has been rising. This might be due to more awareness, improved diagnostic tools or a change in definition. Most neuroendocrine tumours are mainly sporadic, but association with the multiple endocrine neoplasia type 1 syndrome and clustering within families is known. Also an increased risk of secondary cancers has been reported, but numbers are small. The 5-year survival is mainly associated with stage: 93% in local disease, 74% in regional disease and 19% in metastatic disease. In metastatic disease, survival increased since 1992, when treatment with octreotide became largely available in the Netherlands.

Probabilities for a probabilistic network: a case study in oesophageal cancer

With the help of two experts in gastrointestinal oncology from The Netherlands Cancer Institute, Antoni van Leeuwenhoekhuis, a decision-support system is being developed for patient-specific therapy selection for oesophageal cancer. The kernel of the system is a probabilistic network that describes the presentation characteristics of cancer of the oesophagus and the pathophysiological processes of invasion and metastasis. While the construction of the graphical structure of the network was relatively straightforward, probability elicitation with existing methods proved to be a major obstacle. To overcome this obstacle, we designed a new method for eliciting probabilities from experts that combines the ideas of transcribing probabilities as fragments of text and of using a scale with both numerical and verbal anchors for marking assessments. In this paper, we report experiences with our method in eliciting the probabilities required for the oesophagus network. The method allowed us to elicit many probabilities in reasonable time. To gain some insight in the quality of the probabilities obtained, we conducted a preliminary evaluation study of our network, using data from real patients. We found that for 85% of the patients, the network predicted the correct cancer stage.

ENETS consensus guidelines for the standards of care in neuroendocrine tumors: Somatostatin receptor imaging with IIIIn-pentetreotide

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors : Somatostatin Receptor Imaging with In-111-Pentetreotide