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H Järvinen

Publications and source records attributed to H Järvinen.

At least 19 recordsLinked to original sources
PubMed2006

No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer.

Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations in mismatch repair (MMR) genes, mostly MLH1 and MSH2. Somatic inactivation of the wild-type allele of the respective MMR gene is required for tumor development. Unexpectedly, a recent study utilizing DNA from paraffin-embedded tissue material detected frequent loss of the mutant MMR gene allele in HNPCC tumors. Dual role for loss of heterozygosity (LOH) was proposed. If somatic loss of the wild-type MMR gene allele had occurred through point mutation or promoter hypermethylation, frequent somatic deletions at the region of the MMR gene locus, perhaps targeting other relevant cancer genes, could quite commonly lead to loss of the mutant allele. To test this hypothesis, we studied a population-based series of 25 fresh-frozen HNPCC tumors with a germline mutation in MLH1 or MSH2 for LOH. Fourteen of the 25 tumors (56%) showed LOH at the respective locus, and all 14 losses targeted the wild-type allele (P=0.00006). These results strongly support the traditional two-hit model of HNPCC gene inactivation.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2006

Serrated carcinomas form a subclass of colorectal cancer with distinct molecular basis.

Serrated colorectal carcinomas (CRCs) are morphologically different from conventional CRCs and have been proposed to follow a distinct pathway of CRC formation. Despite studies of single molecular events in this tumor type, the diagnosis of serrated CRC relies on morphology and the putative unique biological character of these tumors has not been established. Here we show that the gene expression profiling of 37 CRCs separated serrated and conventional CRCs into two distinct branches in unsupervised hierarchical clustering (P-value 7.8 x 10(-7)), and revealed 201 differentially expressed genes representing potential biomarkers for serrated CRC. Immunohistochemistry was utilized to verify the key findings in the 37 CRCs examined by expression profiling, and a separate validation set of 37 serrated and 86 conventional CRCs was examined to evaluate the candidate biomarkers in an extended sample material. Ephrin receptor B2, hypoxia-inducible factor 1-alpha and patched appeared as proteins important for genesis of serrated CRC. This study establishes serrated CRCs as a biologically distinct subclass of CRC and represents a step forward in the molecular classification of these cancers. The study also provides a platform to understand the molecular basis of serrated CRC and in long term may contribute to the development of specific treatment options for this tumor type.

Adenocarcinoma, Mucinous↗
PubMed2006

LKB1 exonic and whole gene deletions are a common cause of Peutz-Jeghers syndrome.

BACKGROUND: LKB1/STK11 germline mutations cause Peutz-Jeghers syndrome (PJS). The existence of a second PJS locus is controversial, the evidence in its favour being families unlinked to LKB1 and the low frequency of LKB1 mutations found using conventional methods in several studies. Exonic and whole gene deletion or duplication events cannot be detected by routine mutation screening methods. OBJECTIVE: To seek evidence for LKB1 germline deletions or duplications by screening patients meeting clinical criteria for PJS but without detected mutations on conventional screening. METHODS: From an original cohort of 76 patients, 48 were found to have a germline mutation by direct sequencing; the remaining 28 were examined using multiplex ligation dependent probe amplification (MLPA) analysis to detect LKB1 copy number changes. RESULTS: Deletions were found in 11 of the 28 patients (39%)--that is, 14% of all PJS patients (11/76). Five patients had whole gene deletions, two had the promoter and exon 1 deleted, and in one patient exon 8 was deleted. Other deletions events involved: loss of exons 2-10; deletion of the promoter and exons 1-3; and loss of part of the promoter. No duplications were detected. Nine samples with deletions were sequenced at reported single nucleotide polymorphisms to exclude heterozygosity; homozygosity was found in all cases. No MLPA copy number changes were detected in 22 healthy individuals. CONCLUSIONS: These results lessen the possibility of a second PJS locus, as the detection rate of germline mutations in PJS patients was about 80% (59/76). It is suggested that MLPA, or a suitable alternative, should be used for routine genetic testing of PJS patients in clinical practice.

AMP-Activated Protein Kinase Kinases↗
PubMed2005

Gene expression signatures for colorectal cancer microsatellite status and HNPCC.

The majority of microsatellite instable (MSI) colorectal cancers are sporadic, but a subset belongs to the syndrome hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability is caused by dysfunction of the mismatch repair (MMR) system that leads to a mutator phenotype, and MSI is correlated to prognosis and response to chemotherapy. Gene expression signatures as predictive markers are being developed for many cancers, and the identification of a signature for MMR deficiency would be of interest both clinically and biologically. To address this issue, we profiled the gene expression of 101 stage II and III colorectal cancers (34 MSI, 67 microsatellite stable (MSS)) using high-density oligonucleotide microarrays. From these data, we constructed a nine-gene signature capable of separating the mismatch repair proficient and deficient tumours. Subsequently, we demonstrated the robustness of the signature by transferring it to a real-time RT-PCR platform. Using this platform, the signature was validated on an independent test set consisting of 47 tumours (10 MSI, 37 MSS), of which 45 were correctly classified. In a second step, we constructed a signature capable of separating MMR-deficient tumours into sporadic MSI and HNPCC cases, and validated this by a mathematical cross-validation approach. The demonstration that this two-step classification approach can identify MSI as well as HNPCC cases merits further gene expression studies to identify prognostic signatures.

Adenocarcinoma↗
PubMed2005

The C/C-13910 genotype of adult-type hypolactasia is associated with an increased risk of colorectal cancer in the Finnish population.

BACKGROUND AND AIMS: The role of nutrition in the pathogenesis of colorectal cancer is not fully understood. Milk products are an essential part of human nutrition in Western countries. Absorption of lactose, the main sugar of milk, is regulated by the activity of the lactase enzyme in the gut wall. The activity of lactase is genetically determined and is associated with a C/T single nucleotide polymorphism residing 13910 bp upstream of the lactase coding sequence. Here we have studied the relationship between the C/T(-13910) polymorphism and colorectal cancer in Finnish, British, and Spanish populations. PATIENTS AND METHODS: A total of 2766 subjects, including 963 Finnish, 283 British, and 163 Spanish subjects with colorectal cancer, and 773 Finnish, 363 British, and 221 Spanish control subjects, were genotyped for the C/T(-13910) variant by polymerase chain reaction minisequencing. RESULTS: The C/C(-13910) genotype, which is a robust molecular marker of low lactase activity (lactase non-persistence), was found to significantly associate with the risk of colorectal cancer (p = 0.015) in the Finnish subjects, with an odds ratio of 1.40 (95% confidence interval 1.07-1.85). No association was found with site, histology, or stage of the tumour. No significant risk was detected in the British or Spanish populations. CONCLUSION: Low lactase enzyme activity, defined by genotyping of the C/T(-13910) variant, may increase the risk of colorectal cancer. Further studies are warranted to investigate the role of milk and other dairy products in the pathogenesis of colon cancer in different populations.

Adult↗
PubMed2004

Factors associated with disease activity of pouchitis after surgery for ulcerative colitis.

BACKGROUND: Pouchitis occurs in 20% to 59% of patients operated on for ulcerative colitis. Several risk factors have been identified for the development of pouchitis. This study was undertaken to assess the incidence of pouchitis at least 5 years after ileal pouch-anal anastomosis for ulcerative colitis, and to evaluate possible predictive factors for inflammation activity. METHODS: A total of 107 subjects were enrolled (54 M, 53 F, mean age 45 years, range 23-69) with a J-pouch created between 1985 and 1994. Preoperative medical history was determined, an endoscopy performed, and biopsies taken from the pouch and neoterminal ileum above the pouch. Sera from all patients were tested for perinuclear antineutrophil cytoplasmic antibodies (pANCAs). RESULTS: After a mean 7.5-years' follow-up time, the cumulative incidence of pouchitis was 58%. Risk for development of active inflammation (PDAI > or = 7) was significantly higher in patients with preoperative extraintestinal manifestations (OR 2.7, 95% CI 1.1-6.4, P=0.03). Patients who had had ankylosing spondylitis (AS) (OR 11.7, P=0.006) or iritis (OR 9.8, P=0.013) were especially at risk. Positive titres of pANCAs were associated with inflammation in the neoterminal ileum; 80% of patients with high pANCA levels (>100) had pouchitis. Current smokers tended to have a more benign disease course. CONCLUSIONS: A correlation existed between the prevalence and titre of pANCAs and extent and disease activity of pouchitis. Chronic pouchitis may continuously stimulate the immunological process, keeping pANCAs at detectable levels. A strong correlation between AS, iritis and pouchitis suggests a common link in their pathogenesis.

Adult↗
PubMed2004

Duodenal adenomatosis in familial adenomatous polyposis.

BACKGROUND: The prevalence of duodenal carcinoma is much higher in familial adenomatous polyposis (FAP) than in the background population, and duodenal adenomatosis is found in most polyposis patients. AIMS: To describe the long term natural history of duodenal adenomatosis in FAP and evaluate if cancer prophylactic surveillance of the duodenum is indicated. METHODS: A prospective five nation study was carried out in the Nordic countries and the Netherlands. PATIENTS: A total of 368 patients were examined by gastroduodenoscopy at two year intervals during the period 1990-2001. RESULTS: At the first endoscopy, 238 (65%) patients had duodenal adenomas at a median age of 38 years. Median follow up was 7.6 years. The cumulative incidence of adenomatosis at age 70 years was 90% (95% confidence interval (CI) 79-100%), and of Spigelman stage IV 52% (95% CI 28-76%). The probability of an advanced Spigelman score increased during the study period (p<0.0001) due to an increasing number and size of adenomas. Two patients had asymptomatic duodenal carcinoma at their first endoscopy while four developed carcinoma during the study at a median age of 52 years (range 26-58). The cumulative incidence rate of cancer was 4.5% at age 57 years (95% CI 0.1-8.9%) and the risk was higher in patients with Spigelman stage IV at their first endoscopy than in those with stages 0-III (p<0.01). CONCLUSIONS: The natural course of duodenal adenomatosis has now been described in detail. The high incidence and increasing severity of duodenal adenomatosis with age justifies prophylactic examination, and a programme is presented for upper gastrointestinal endoscopic surveillance.

Adenomatous Polyposis Coli↗
PubMed2002

Familial and sporadic inflammatory bowel disease: comparison of clinical features and serological markers in a genetically homogeneous population.

BACKGROUND: The familial occurrence of inflammatory bowel disease (IBD) and the clinical features of familial and sporadic IBD in the genetically homogeneous Finnish population are evaluated. METHODS: 257 patients with Crohn disease (CD) and 436 with ulcerative colitis (UC) participated in the study. They were asked whether IBD was present (familial IBD) or absent (sporadic IBD) in their first-degree relatives. Data on the clinical course of the disease were collected from the patient records. Antibodies to Saccharomyces cerevisiae (ASCA) and anti-neutrophil cytoplasmic antibodies (ANCA) were determined from serum samples. RESULTS: Affected first-degree relatives were found in 15.6% of patients with CD and in 13.8% of patients with UC. In familial cases CD was more often located in the ileum (38% versus 21%) and less often in the ileocolon (35% versus 50%) (P< 0.05) than in sporadic cases. A greater percentage of CD patients than UC patients were smokers (47% versus 13%; P < 0.01). An elevated level of IgA and/or IgG antibodies for ASCA was found more often in CD patients than in UC patients (59% versus 14%; P < 0.01), while pANCA were found more often in UC than in CD patients (48% versus 12%; P < 0.01). The combination of pANCA-ASCA+ yielded a sensitivity, specificity and positive predictive value of 48%, 92% and 90%, respectively, for CD, and the combination of pANCA + ASCA- of 55%, 94% and 90%, respectively, for UC. CONCLUSIONS: The percentage of familial IBD cases in Finland is comparable to that reported elsewhere in Europe. No important clinical differences between patients with familial and sporadic forms of the disease were found. ASCA is associated with both familial and sporadic CD and pANCA with UC, but low sensitivity diminishes their value as a serological marker of IBD or as a differential diagnostic test between CD and UC.

Adolescent↗
PubMed2002

Risk of osteopenia after proctocolectomy and ileal pouch-anal anastomosis for ulcerative colitis.

BACKGROUND: The aim of our study was to evaluate the influence of pouchitis and villous atrophy on bone mineral density and metabolism at least 5 years after ileal pouch-anal anastomosis for ulcerative colitis (UC). METHODS: Eighty-eight subjects with a J-pouch operated on between 1985 and 1994, and 20 ulcerative colitis subjects with a conventional ileostomy were enrolled. Endoscopy was performed and spine and femoral neck bone mineral densities measured. Bone metabolism was assessed by measurement of serum levels of parathyroid hormone, osteocalcin, 25-hydroxyvitamin D3, calcium, alkaline phosphatase and urinary N-telopeptide cross-linked of type I collagen (NTX). RESULTS: In the lumbar spine, 37% of the J-pouch subjects with subtotal to total villous atrophy had osteopenia (Z score <-1), whereas none of the subjects with normal villous structure had reduced bone densities in the spine or femoral neck. The highest prevalence of osteopenia (66.7%) and the lowest spine (mean -0.89+/-0.36; P = 0.006) and femoral neck (mean -0.63+/-0.29; P = 0.07) Z scores were found among the patients (n = 12) with inflammation in the proximal limb of the pouch. No biochemical parameters were found to predict osteopenia and in stepwise regression analysis, the only independent risk factors for osteopenia were low body mass index and villous atrophy. CONCLUSIONS: Patients with a J-pouch showing high inflammatory activity and villous atrophy in the pouch need long-term follow-up and should be ensured adequate intake of calcium and vitamin D.

Bone Density↗
PubMed2002

Genetic and clinical characterisation of familial adenomatous polyposis: a population based study.

BACKGROUND: Familial adenomatous polyposis (FAP) is a rare autosomal dominantly inherited disease predisposing to colon cancer and caused by germline mutations in the APC (adenomatous polyposis coli) gene. AIMS: We conducted a population based study to evaluate the prevalence and clinical implications of APC mutations among Finnish FAP kindreds. A possible founder effect in parallel with previous observations in hereditary non-polyposis colon cancer (HNPCC) was addressed. PATIENTS: Affected individuals from 65 kindreds were included. METHODS: The APC gene was screened for mutations using the protein truncation test and heteroduplex analysis. Haplotype analysis was performed with four flanking microsatellite markers. Families that failed to show any mutations were scrutinised with Southern blot hybridisation and allelic expression analysis. RESULTS: Thirty eight different germline mutations in APC were identified in 47 kindreds (72%). The majority of these mutations were novel and unique to each family. Although sharing the classical polyposis phenotype, families without detectable APC mutations differed from mutation positive families in the following respects: firstly, mean age at polyposis diagnosis was higher (38.6 years (48 individuals) v 30.0 years (140 individuals); p=0.001); and secondly, the proportion of kindreds lacking extracolonic disease was higher (6/18 v. 5/47; p=0.04). CONCLUSIONS: Our results may pave the way for predictive testing in mutation positive families and should stimulate further molecular studies in mutation negative families. No founder effect was observed, which is in contrast with HNPCC in the same population.

Adenomatous Polyposis Coli↗
PubMed2002

Frequent loss of SMAD4/DPC4 protein in colorectal cancers.

BACKGROUND AND AIMS: Loss of DNA sequences from chromosome 18q21 is a major genetic change in colorectal tumorigenesis. Multiple genes have been identified in this area. One of these, DPC4 (deleted in pancreatic cancer 4, also known as SMAD4), is mutated in a minor subset of colorectal carcinomas as well as in germlines of humans predisposed to colon tumours. PATIENTS AND METHODS: The involvement of SMAD4 in sporadic colorectal neoplasia was evaluated by immunohistochemistry in 53 unselected cases and 27 cases displaying microsatellite instability. RESULTS: SMAD4 expression was absent in 20 of 53 (38%) unselected colorectal carcinomas, and reduced in another 15 (28%) cases. However, 26 of 27 cancers displaying microsatellite instability and TGF-betaIIR mutations were positive for SMAD4 immunostaining. CONCLUSIONS: Loss of SMAD4 expression may play a more prominent role in colon cancer than anticipated based on genetic evidence, but not in mutator phenotype tumours.

Chromosomes, Human, Pair 18↗
PubMed2001

Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes.

Juvenile polyposis syndrome (JPS) is an inherited hamartomatous-polyposis syndrome with a risk for colon cancer. JPS is a clinical diagnosis by exclusion, and, before susceptibility genes were identified, JPS could easily be confused with other inherited hamartoma syndromes, such as Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Cowden syndrome (CS). Germline mutations of MADH4 (SMAD4) have been described in a variable number of probands with JPS. A series of familial and isolated European probands without MADH4 mutations were analyzed for germline mutations in BMPR1A, a member of the transforming growth-factor beta-receptor superfamily, upstream from the SMAD pathway. Overall, 10 (38%) probands were found to have germline BMPR1A mutations, 8 of which resulted in truncated receptors and 2 of which resulted in missense alterations (C124R and C376Y). Almost all available component tumors from mutation-positive cases showed loss of heterozygosity (LOH) in the BMPR1A region, whereas those from mutation-negative cases did not. One proband with CS/CS-like phenotype was also found to have a germline BMPR1A missense mutation (A338D). Thus, germline BMPR1A mutations cause a significant proportion of cases of JPS and might define a small subset of cases of CS/BRRS with specific colonic phenotype.

Abnormalities, Multiple↗
PubMed2001

Microsatellite marker analysis in screening for hereditary nonpolyposis colorectal cancer (HNPCC).

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant cancer predisposition syndrome caused by germ-line mutations in DNA mismatch repair genes. It is relevant to identify HNPCC patients because colonoscopic screening of individuals with HNPCC mutations reduces cancer morbidity and mortality. Microsatellite instability (MSI) is characteristic of HNPCC tumors. A panel of five markers (BAT25, BAT26, D2S123, D5S346, and D17S250, the so-called Bethesda markers) has been proposed for screening for MSI. To test a hypothesis that the use of BAT26 alone is feasible in screening for MLH1/MSH2 mutation-positive HNPCC patients, we compared the MSI results of 494 colorectal cancer patients obtained using BAT26 with results obtained using the Bethesda markers. BAT26 was able to identify all 27 mutation-positive individuals in this series. The marker failed to identify 2 high MSI tumors and 20 low MSI tumors, all of which expressed MLH1, MSH2, and MSH6 when scrutinized by immunohistochemistry.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Infrequent isolation of multiresistant Acinetobacter baumannii from the staff tending a colonized patient with severe burns.

A patient with severe burns who was colonized by multiresistant Acinetobacter baumannii was cared for in contact isolation by staff intensively trained on hospital hygiene. Of the 1,907 postexposure cultures from the staff and 425 environmental samples, only 0.7% and 4%, respectively, yielded this microorganism. These data show that strict hygienic measures may limit staff colonization and contamination of the environment byA baumannii.

Acinetobacter↗
PubMed2001

Long term metabolic consequences of ileal pouch-anal anastomosis for ulcerative colitis.

OBJECTIVES: Chronic inflammation in the ileal pouch is the most significant late complication after ileal pouch-anal anastomosis (IPAA). It leads to changes in mucosal morphology, with consequent decreased vitamin B12, bile acid and cholesterol absorption documented. The aims of this study were to evaluate long term metabolic consequences at least 5 yr after IPAA and the influence of pouchitis on pouch histology and on bile acid, lipid, and vitamin B12, A, E, and D metabolism. METHODS: A total of 104 patients with a J-pouch who were operated on between 1985 and 1994, as well as 21 ulcerative colitis patients with a conventional ileostomy were enrolled for the study. Routine blood tests, vitamin status, vitamin B12 levels, and bile acid absorption were determined, as well as endoscopy with biopsies. The pouchitis disease activity index (PDAI) was calculated. On the basis of histology, IPAA patients were divided into three subgroups: 1) those with no villous atrophy, 2) those with partial villous atrophy, and 3) those with subtotal or total villous atrophy. RESULTS: Incidence of pouchitis was 42.3%, and was strongly associated with villous atrophy. In IPAA patients with subtotal or total villous atrophy (32.7%), serum levels of albumin, calcium, total cholesterol, triglycerides, and vitamin E were significantly reduced (p < 0.05). The lowest bile acid and vitamin B12 absorption rates were seen in patients with inflammation in the proximal limb. Vitamin D deficiency was seen in 10.6%, and vitamin A and B12 deficiency in approximately 5% of IPAA patients. CONCLUSIONS: Metabolic consequences after IPAA are associated with pouchitis, grade of villous atrophy, and extent of inflammation in the remaining ileum. Patients with active chronic inflammation need long term follow-up.

Adult↗
PubMed2001

Dosimetry of beta-ray ophthalmic applicators: comparison of different measurement methods.

An international intercomparison of the dosimetry of three beta particle emitting ophthalmic applicators was performed, which involved measurements with radiochromic film, thermoluminescence dosimeters (TLDs), alanine pellets, plastic scintillators, extrapolation ionization chambers, a small fixed-volume ionization chambers, a diode detector and a diamond detector. The sources studied were planar applicators of 90Sr-90Y and 106Ru-106Rh, and a concave applicator of 106Ru-106Rh. Comparisons were made of absolute dosimetry determined at 1 mm from the source surface in water or water-equivalent plastic, and relative dosimetry along and perpendicular to the source axes. The results of the intercomparison indicate that the various methods yield consistent absolute dosimetry results at the level of 10%-14% (one standard deviation) depending on the source. For relative dosimetry along the source axis at depths of 5 mm or less, the agreement was 3%-9% (one standard deviation) depending on the source and the depth. Crucial to the proper interpretation of the measurement results is an accurate knowledge of the detector geometry, i.e., sensitive volume and amount of insensitive covering material. From the results of these measurements, functions which describe the relative dose rate along and perpendicular to the source axes are suggested.

Alanine↗
PubMed2001

Calculation of beta-ray dose distributions from ophthalmic applicators and comparison with measurements in a model eye.

Dose distributions throughout the eye, from three types of beta-ray ophthalmic applicators, were calculated using the EGS4, ACCEPT 3.0, and other Monte Carlo codes. The applicators were those for which doses were measured in a recent international intercomparison [Med. Phys. 28, 1373 (2001)], planar applicators of 106Ru-106Rh and 90Sr-90Y and a concave 106Ru-106Rh applicator. The main purpose was to compare the results of the various codes with average experimental values. For the planar applicators, calculated and measured doses on the source axis agreed within the experimental errors (<10%) to a depth of 7 mm for 106Ru-106Rh and 5 mm for 90Sr-90Y. At greater distances the measured values are larger than those calculated. For the concave 106Ru-106Rh applicator, there was poor agreement among available calculations and only those calculated by ACCEPT 3.0 agreed with measured values. In the past, attempts have been made to derive such dose distributions simply, by integrating the appropriate point-source dose function over the source. Here, we investigated the accuracy of this procedure for encapsulated sources, by comparing such results with values calculated by Monte Carlo. An attempt was made to allow for the effects of the silver source window but no corrections were made for scattering from the source backing. In these circumstances, at 6 mm depth, the difference in the results of the two calculations was 14%-18% for a planar 106Ru-l06Rh applicator and up to 30% for the concave applicator. It becomes worse at greater depths. These errors are probably caused mainly by differences between the spectrum of beta particles transmitted by the silver window and those transmitted by a thickness of water having the same attenuation properties.

Beta Particles↗