Comorbidity has large impact on colorectal cancer (CRC) treatment and outcomes and may increase as the population ages. We aimed to evaluate the prevalence and time trends of comorbid diseases in... Show moreComorbidity has large impact on colorectal cancer (CRC) treatment and outcomes and may increase as the population ages. We aimed to evaluate the prevalence and time trends of comorbid diseases in patients with CRC from 1995 to 2010. The Eindhoven Cancer Registry registers comorbidity in all patients with primary CRC in the South of the Netherlands. We analyzed the prevalence of serious comorbid diseases in four time frames from 1995 to 2010. Thereby, we addressed its association with age, gender and socio-economic status (SES). The prevalence of comorbidity was registered in 27,339 patients with primary CRC. During the study period, the prevalence of comorbidity increased from 47% to 62%, multimorbidity increased from 20% to 37%. Hypertension and cardiovascular diseases were most prevalent and increased largely over time (respectively 16-29% and 12-24%). Pulmonary diseases increased in women, but remained stable in men. Average age at diagnosis increased from 68.3 to 69.5 years (p = 0.004). A low SES and male gender were associated with a higher risk of comorbidity (not changing over time). This study indicates that comorbidity among patients with CRC is common, especially in males and patients with a low SES. The prevalence of comorbidity increased from 1995 to 2010, in particular in presumably nutritional diseases. Ageing, increased life expectancy and life style changes may contribute to more comorbid diseases. Also, improved awareness among health care providers on the importance of comorbidity may have resulted in better registration. The increasing burden of comorbidity in patients with CRC emphasizes the need for more focus on individualized medicine. Show less
Because of its antitumor effect, the immunosuppressant rapamycin holds great promise for organ transplant recipients in that it may lower their cancer risk. In a mouse model, we showed previously... Show moreBecause of its antitumor effect, the immunosuppressant rapamycin holds great promise for organ transplant recipients in that it may lower their cancer risk. In a mouse model, we showed previously that rapamycin inhibits the outgrowth of primary skin carcinomas induced by UV radiation. However, the tumors that did grow out showed an altered p53 mutation spectrum. Here, we investigated whether this shift in p53 mutations already occurred in the smallest tumors, which were not affected in onset. We found that rapamycin did not alter the mutational spectrum in small tumors and in preceding microscopic clusters of cells expressing mutant-p53. However, rapamycin did reduce the number of these cell clusters. As this reduction did not affect tumor onset, we subsequently investigated whether rapamycin merely suppressed expression of mutated p53. This was not the case, as we could demonstrate that switching from a diet with rapamycin to one without, or vice versa, did not affect the number of existing mutant-p53 expressing cell clusters. Hence, rapamycin actually reduced the formation of mutant-p53 cell clusters. In wild-type and p53-mutant mice, we could not measure a significant enhancement of UV-induced apoptosis, but we did observe clear enhancement in human skin equivalents. This was associated with a clear suppression of HIF1α accumulation. Thus, we conclude that rapamycin reduces the formation of mutant-p53-expressing cell clusters without affecting tumor onset, suggesting that tumors grow out of a minor subset of cell clusters, the formation of which is not affected by rapamycin. Show less
Middeldorp, A.; Eijk, R. van; Oosting, J.; Forte, G.I.; Puijenbroek, M. van; Nieuwenhuizen, M. van; ... ; Wezel, T. van 2012
Many hereditary nonpolyposis colorectal cancers (CRCs) cannot be explained by Lynch syndrome. Other high penetrance genetic risk factors are likely to play a role in these mismatch repair (MMR)... Show moreMany hereditary nonpolyposis colorectal cancers (CRCs) cannot be explained by Lynch syndrome. Other high penetrance genetic risk factors are likely to play a role in these mismatch repair (MMR)-proficient CRC families. Because genomic profiles of CRC tend to vary with CRC susceptibility syndromes, our aim is to analyze the genomic profile of MMR-proficient familial CRC to obtain insight into the biological basis of MMR-proficient familial CRC. We studied 30 MMR-proficient familial colorectal carcinomas, from 15 families, for genomic aberrations, including gains, physical losses, and copy-neutral loss of heterozygosity LOH (cnLOH) using SNP array comparative genomic hybridization. In addition, we performed somatic mutation analysis for KRAS, BRAF, PIK3CA and GNAS. The frequency of 20q gain (77%) is remarkably increased when compared with sporadic CRC, suggesting that 20q gain is involved in tumor progression of familial CRC. There is also a significant increase in the frequency of cnLOH and, as a consequence, a reduced frequency of physical loss compared with sporadic CRC. The most frequent aberrations observed included gains of 7p, 7q, 8q, 13q, 20p and 20q as well as physical losses of 17p, 18p and 18q. Most of these changes are also observed in sporadic CRC. Mutations in KRAS were identified in 37% of the MMR-proficient CRCs, and mutations in BRAF were identified in 16%. No mutations were identified in PIK3CA or chromosome 20 candidate gene GNAS. We show that the patterns of chromosomal instability of MMR-proficient familial CRC are clearly distinct from those from sporadic CRC. Both the increased gain on chromosome 20 and the increased levels of cnLOH suggest the presence of yet undiscovered germline defects that can, in part, underlie the cancer risk in these families. Show less
Optical imaging is a promising technique to visualize cancer tissue during surgery. In this study, we explored the use of combinations of near-infrared fluorescence agents that emit fluorescence... Show moreOptical imaging is a promising technique to visualize cancer tissue during surgery. In this study, we explored the use of combinations of near-infrared fluorescence agents that emit fluorescence signal at different wavelengths and each target specific tumor characteristics. Two combinations of agents (ProSense680 combined with 2DG CW800 and MMPSense680 combined with EGF CW800) were used to detect hypopharyngeal cancer in an animal model. ProSense680 and MMPSense680 detect increased activity of cathepsins and matrix metalloproteinases, respectively. These enzymes are mainly found in the invasive tumor border due to degradation of the extracellular matrix. 2DG CW800 detects tumor cells with high glucose metabolism and EGF CW800 is internalized by the epidermal growth factor receptor of tumor cells. Whole-body imaging revealed clear demarcation of tumor tissue using all 4 agents. The tumor-to-background ratio (standard deviation, p-value) was 3.69 (0.72, p<0.001) for ProSense680; 4.26 (1.33, p<0.001) for MMPSense680; 5.81 (3.59, p=0.02) for 2DG CW800; and 4.84 (1.56, p<0.001) for EGF CW800. Fluorescence signal corresponded with histopathology and immunohistochemistry, demonstrating signal of ProSense680 and MMPSense680 in the invasive tumor border, and signal of 2DG CW800 and EGF CW800 in the tumor tissue. In conclusion, we demonstrated the feasibility of dual wavelength tumor detection using different targeting strategies simultaneously in an animal model. Combined targeting at different wavelengths allowed simultaneous imaging of different tumor characteristics. Near-infrared fluorescence optical imaging has the potential to be translated into the clinic in order to improve the complete removal of tumors by real-time image-guided surgery. Show less
Heusinkveld, M.; Goedemans, R.; Briet, R.J.P.; Gelderblom, H.; Nortier, J.W.R.; Gorter, A.; ... ; Burg, S.H. van der 2011
Squamous cell carcinomas of the head and neck (HNSCC), in particular those of the oropharynx, can be caused by human papilloma virus Type 16 (HPV16). Whereas these HPV-induced oropharyngeal... Show moreSquamous cell carcinomas of the head and neck (HNSCC), in particular those of the oropharynx, can be caused by human papilloma virus Type 16 (HPV16). Whereas these HPV-induced oropharyngeal carcinomas may express the HPV16 E6 and E7 oncoproteins and are associated with better survival, the nonvirally induced HNSCC are associated with overexpression of p53. In this study we assessed the presence of systemic and local T cells reactive against these oncoproteins in HNSCC. An exploratory study on the presence, type and function of HPV16- and/or p53-specific T cells in the blood, tumor and/or metastatic lymph node as measured by several immune assays was performed in an unselected group of 50 patients with HNSCC. Tumor tissue was tested for HPV DNA and the overexpression of p53 protein. Almost all HPV16+ tumors were located in the oropharynx. Circulating HPV16- and p53-specific T cells were found in 17/47 and 7/45 tested patients. T cells were isolated from tumor cultures and/or lymph nodes of 20 patients. HPV16-specific T cells were detected in six of eight HPV+ tumors, but in none of the 12 HPV-tumors. Tumor-infiltrating p53-specific T cells were not detected. In depth analysis of the HPV16-specific T-cell response revealed that this response comprised a broad repertoire of CD4+ T-helper Type 1 and 2 cells, CD4+ regulatory T cells and CD8+ T cells reactive to HPV16. The local presence of HPV16-specific T-cell immunity in HPV16-induced HNSCC implicates a role in the antitumor response and support the development of immunotherapy for HNSCC. Show less
Desmoid-type fibromatoses are neoplasms of fibroblastic origin, occurring sporadically or associated with familial adenomatous polyposis (FAP) coli. By comparing sporadic and FAP-associated desmoid... Show moreDesmoid-type fibromatoses are neoplasms of fibroblastic origin, occurring sporadically or associated with familial adenomatous polyposis (FAP) coli. By comparing sporadic and FAP-associated desmoid-type fibromatoses, we tried to identify clinical characteristics, which may indicate FAP. Histopathology data of all Dutch patients with desmoid-type fibromatoses diagnosed between 1999 and 2009 were retrieved from PALGA, the nation-wide network and registry of histopathology in the Netherlands. For calculation of incidence rates, person-years from the general matched population were used. Based on polyp counts in pathological records, the cohort was divided into a FAP group and a non-FAP group. Patient-and tumor characteristics were compared between the two groups. A total number of 519 patients older than 10 years with a confirmed diagnosis of desmoid-type fibromatoses were included. Thirty-nine (7.5%) desmoid patients were documented of having FAP. The incidences of sporadic and FAP-related desmoid-type fibromatoses were 3.42 and 2,784 per million person-years, respectively. The majority of FAP patients developed desmoid-type fibromatoses after the diagnosis of FAP. Having FAP was associated with male gender [odds ratio (OR) 2.0, p = 0.034], desmoid diagnosis at an earlier age (mean 36 vs. 42 years, p = 0.031), and desmoid localization intra-abdominally (OR 18.9, p <= 0.001) or in the abdominal wall (OR 4.8, p <= 0.001), compared to extra-abdominal desmoid localization. In conclusion, patients with desmoid-type fibromatoses are at risk of underlying FAP. Especially cases with desmoid localization intra-abdominal or in the abdominal wall, and all patients younger than 60 years, have a substantial increased risk and should be referred for colonoscopy. Show less
