BackgroundRecent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy... Show moreBackgroundRecent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal.MethodsTo inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers.ResultsStage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within <1.5, 1.5-2.5, 2.5-3.5 and at >3.5years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively (p=0.34). The cancers detected more than 2.5years after the last colonoscopy were not more advanced than those diagnosed earlier (p=0.14).ConclusionsThe CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers. Show less
Clostridium difficile infection (CDI) was discovered in 1978 as an important cause of antibiotic-associated diarrhoea. CDI became the most common healthcare-associated infection in Northern-America... Show moreClostridium difficile infection (CDI) was discovered in 1978 as an important cause of antibiotic-associated diarrhoea. CDI became the most common healthcare-associated infection in Northern-America and Europe during the antibiotic era, especially after global spread of a fluoroquinoloneresistant ribotype 027 strain in 2003. The rise of CDI urged the use of epidemiological surveillance systems to monitor disease dynamics and rapidly detect outbreaks. However, valid estimations of the infection burden of CDI in Europe were hampered by the heterogeneity and insufficiency of diagnostic algorithms for CDI, lack of standardised typing systems and incomplete surveillance methodologies. This thesis includes two studies conducted within a project named ‘the European CDI Surveillance Network’ focussing on enhancement of CDI surveillance and laboratory capacity for CDI in Europe. In the Netherlands, a sentinel surveillance system monitors the incidence of CDI in hospitals. This thesis describes (spatial) trends in the epidemiology of CDI in the Netherlands, in particular for children and the potentially zoonotic C. difficile ribotype 078. Data of a community-based case-control study was used to apply spatial scan statistics to detect CDI clustering beyond the hospital setting. Finally, this thesis provides directions for future epidemiological surveillance systems of CDI, both in the Netherlands and Europe. Show less
The Dutch Hereditary Cancer Registry was established in 1985 with the support of the Ministry of Health (VWS). The aims of the registry are: (1) to promote the identification of families with... Show moreThe Dutch Hereditary Cancer Registry was established in 1985 with the support of the Ministry of Health (VWS). The aims of the registry are: (1) to promote the identification of families with hereditary cancer, (2) to encourage the participation in surveillance programs of individuals at high risk, (3) to ensure the continuity of lifelong surveillance examinations, and (4) to promote research, in particular the improvement of surveillance protocols. During its early days the registry provided assistance with family investigations and the collection of medical data, and recommended surveillance when a family fulfilled specific diagnostic criteria. Since 2000 the registry has focused on family follow-up, and ensuring the quality of surveillance programs and appropriate clinical management. Since its founding, the registry has identified over 10,000 high-risk individuals with a diverse array of hereditary cancer syndromes. All were encouraged to participate in prevention programmes. The registry has published a number of studies that evaluated the outcome of surveillance protocols for colorectal cancer (CRC) in Lynch syndrome, as well as in familial colorectal cancer. In 2006, evaluation of the effect of registration and colonoscopic surveillance on the mortality rate associated with colorectal cancer (CRC) showed that the policy led to a substantial decrease in the mortality rate associated with CRC. Following discovery of MMR gene defects, the first predictive model that could select families for genetic testing was published by the Leiden group. In addition, over the years the registry has produced many cancer risk studies that have helped to develop appropriate surveillance protocols. Hereditary cancer registries in general, and the Lynch syndrome registry in particular, play an important role in improving the clinical management of affected families. Show less
Being a member of a melanoma family is a major risk factor for cutaneous malignant melanoma. In this thesis clinical characteristics and management of melanoma families are discussed. In the first... Show moreBeing a member of a melanoma family is a major risk factor for cutaneous malignant melanoma. In this thesis clinical characteristics and management of melanoma families are discussed. In the first part of the thesis clinical and histological characteristics of melanoma (patients) from families with a (p16-Leiden) mutation in the high penetrance melanoma susceptibility gene CDKN2A were compared with the general population. Significant differences with respect to several characteristics are reported. In the second part of the thesis the yield, effectiveness, and causes for failure of surveillance of melanoma families are discussed. We report that surveillance is associated with a more favorable tumor stage. Several aspects of surveillance, including interval melanomas, surveillance interval, noncompliance, and overdiagnosis are discussed. Based on analyses of melanoma detection rates in families with different family and genetic characteristics, we propose a risk stratification for members of melanoma families. In the third part of the thesis we investigate the impact of dermoscopy on management decisions. It is demonstrated that dermoscopy by dermoscopy experts in the setting of melanoma family surveillance resulted in a considerable reduction of unnecessary excisions. This effect was considerably less in the setting of dermoscopy non-experts examining patients in general dermatology clinics. Show less
Surgical site infections (SSI) are the most-common healthcare-associated infections among surgical patients and have severe adverse consequences. Surveillance is the ongoing systematic collection,... Show moreSurgical site infections (SSI) are the most-common healthcare-associated infections among surgical patients and have severe adverse consequences. Surveillance is the ongoing systematic collection, analysis, interpretation, and feedback of data, and has been accepted worldwide as a primary step toward prevention of healthcare-associated infections. In the Netherlands, a national network for the surveillance of healthcare-associated infections was set up in 1996 and called PREZIES (__PREventie van ZIEkenhuisinfecties door Surveillance__). In this thesis, the quality of the SSI surveillance within this network is evaluated. The method for postdischarge surveillance recommended by PREZIES seemed feasible and effective, and the mandatory validation visits ensured reliability and robustness of the surveillance data. Furthermore, the predictive power of the NNIS risk index was sufficient for several surgical procedures and could not be significantly improved by using other procedure-specific determinants. Analysis of the time-trend in SSI rates for five surgical procedures showed encouraging decreasing trends, although mostly not statistically significant. Comparison of the Dutch and German SSI surveillance data revealed that even though similar infection surveillance protocols were used, differences occurred in the implementation which hampered the comparison of SSI rates. Additionally, PREZIES contributed to a multi-center intervention project to improve the quality of surgical prophylaxis. Show less
Colorectal cancer is one of the most common malignancies in the world. A family history of colon cancer has been shown to increase an individual’s risk of developing the disease. Approximately 2-3%... Show moreColorectal cancer is one of the most common malignancies in the world. A family history of colon cancer has been shown to increase an individual’s risk of developing the disease. Approximately 2-3% of all colorectal cancers occur in the setting of a well described autosomal dominant inherited syndrome: The Lynch syndrome. It is essential to identify individuals at increased risk to offer adequate surveillance programs to prevent the development of tumors or recognize them at an early stage. This thesis gives a laboratory workup of suspected Lynch syndrome, including analysis of tumor tissue by microsatellite instability analysis and immunohistochemistry, and germline DNA analysis. Several aspects of surveillance in Lynch syndrome are described. The appropriate screening interval is discussed and the effect on mortality because of surveillance is shown. Further, we sought to establish whether individuals from dominant families without mismatch repair deficiency are also at increased risk by examining the incidence of advanced neoplasia during surveillance. Finally, the prevalence of the frequency of a positive family history for CRC, within a random cohort among the Dutch population is presented and also the prevalence of adenomas among young individuals at average risk for colorectal cancer is shown. Show less
