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Biomedical subjects

H J Järvinen

Publications and source records attributed to H J Järvinen.

At least 19 recordsLinked to original sources
PubMed2005

The MDM2 promoter polymorphism SNP309T-->G and the risk of uterine leiomyosarcoma, colorectal cancer, and squamous cell carcinoma of the head and neck.

BACKGROUND: MDM2 acts as a principal regulator of the tumour suppressor p53 by targeting its destruction through the ubiquitin pathway. A polymorphism in the MDM2 promoter (SNP309) was recently identified. SNP309 was shown to result, via Sp1, in higher levels of MDM2 RNA and protein, and subsequent attenuation of the p53 pathway. Furthermore, SNP309 was proposed to be associated with accelerated soft tissue sarcoma formation in both hereditary (Li-Fraumeni) and sporadic cases in humans. METHODS: We evaluated the possible contribution of SNP309 to three tumour types known to be linked with the MDM2/p53 pathway, using genomic sequencing or restriction fragment length polymorphism as screening methods. Three separate Finnish tumour materials (population based sets of 68 patients with early onset uterine leiomyosarcomas and 1042 patients with colorectal cancer, and a series of 162 patients with squamous cell carcinoma of the head and neck) and a set of 185 healthy Finnish controls were analysed for SNP309. RESULTS: Frequencies of SNP309 were similar in all four cohorts. In the colorectal cancer series, SNP309 was somewhat more frequent in women and in patients with microsatellite stable tumours. Female SNP309 carriers were diagnosed with colorectal cancer approximately 2.7 years earlier than those carrying the wild type gene. However, no statistically significant association of SNP309 with patients' age at disease onset or to any other clinicopathological parameter was found in these three tumour materials. CONCLUSION: SNP309 had no significant contribution to tumour formation in our materials. Possible associations of SNP309 with microsatellite stable colorectal cancer and with earlier disease onset in female carriers need to be examined in subsequent studies.

Adult↗
PubMed2005

Fate of the rectum after colectomy with ileorectal anastomosis in ulcerative colitis.

OBJECTIVE: Aim of the study was to evaluate the cumulative success of colectomy and ileorectal anastomosis in 20 patients with ulcerative colitis. PATIENTS AND METHODS: Data were collected from patient histories and cumulative success was calculated by the Kaplan-Meier method. RESULTS: Seven of 20 (35%) ileorectal anastomoses were lost. Cumulative success rate was 84% at 5 years, 69% at 10 years and 56% at 20 years. Most common indication for proctectomy was disabling proctitis. Other reasons for failure were postoperative ileal necrosis and persisting presacral infection. Patients with advanced colonic cancer managed relatively well with ileorectal anastomosis until death. No cases of rectal cancer were detected during postoperative follow-up but one moderate dysplasia was treated locally. CONCLUSION: Ileorectal anastomosis can be chosen for patients who are not suitable for ileoanal operation. Rectal endoscopies are mandatory postoperatively.

Adult↗
PubMed2003

Female fecundity before and after operation for familial adenomatous polyposis.

BACKGROUND: Knowledge about the fertility of women suffering from familial adenomatous polyposis (FAP) is scarce and inconclusive. The purpose of this study was to investigate the fecundity of women with FAP before and after operation, and to compare the findings with those of a general population database and women with ulcerative colitis. METHODS: A questionnaire concerning reproductive experiences and waiting times to pregnancy was sent to all 230 women on the polyposis registers in Denmark, Finland, Sweden and Norway in whom primary surgery had consisted of ileorectal anastomosis or ileal pouch-anal anastomosis. Data on the general population and women with ulcerative colitis came from an existing database. Cox regression and Kaplan-Meier plots were used for analysis. RESULTS: The fecundity of women with FAP before operation and after colectomy with ileorectal anastomosis was similar to that of the general population. However, fecundity dropped to 54 per cent (P = 0.015) following proctocolectomy with ileal pouch-anal anastomosis, although it was greater than the postoperative fecundity of women with ulcerative colitis. CONCLUSION: The significant reduction in female fecundity after ileal pouch-anal anastomosis should be communicated to young women with FAP before it is decided which surgical option to follow.

Adenomatous Polyposis Coli↗
PubMed2003

Worldwide survey among polyposis registries of surgical management of severe duodenal adenomatosis in familial adenomatous polyposis.

BACKGROUND: The lifetime risk of developing duodenal cancer in familial adenomatous polyposis (FAP) is about 5 per cent. When and to what extent surgical intervention should be undertaken to prevent death from invasive carcinoma is controversial. The aim of this study was to determine the effectiveness of various surgical treatments for cancer and severe duodenal adenomatosis. METHODS: A questionnaire was mailed to the members of the Leeds Castle Polyposis Group to obtain data on patients with FAP, treated for duodenal cancer or severe duodenal adenomatosis after 1990. RESULTS: Sixty-nine patients were included. The indication for surgery was invasive cancer in 13 patients, of whom six died from metastatic disease. Fifty-six patients were initially treated for severe duodenal adenomatosis, five (9 per cent) of whom died from metastatic disease (P = 0.002). In surviving patients, adenomas recurred after ampullectomy (six of eight, at mean follow-up of 11 months), after duodenotomy with polypectomy (17 of 21, at mean 29 months) and after pancreatoduodenectomy (six of 25, at mean 47 months). None of six patients who underwent a pancreas-sparing duodenectomy had recurrence of adenoma (mean follow-up 11 months). CONCLUSION: Surgery for duodenal adenomatosis should take place before endoscopic biopsy reveals invasive cancer. Even after extensive surgical procedures, small bowel adenomas may occur, emphasizing the need for chemoprevention.

Adenoma↗
PubMed2003

Delayed sphincter repair for obstetric ruptures: analysis of failure.

OBJECTIVE: The aim of this study was to examine the clinical results after anterior anal sphincter repair in patients with obstetric trauma and to evaluate possible risk factors for poor outcome. PATIENTS AND METHODS: In years 1990-99 anterior anal sphincter repair for anal incontinence due to obstetric trauma was performed in 39 patients at Helsinki University Central Hospital. Clinical examination with Parks' classification and patients' questionnaire with endoanal ultrasound (EAUS) were done before and after surgery. Pudendal nerve terminal motor latency (PNTML) was measured postoperatively. The median follow-up time after the operation was 22 months (range 2-99). RESULTS: The follow-up results of the patients' questionnaire for 12 patients (31%) were good, for 15 patients (38%) acceptable and for 12 patients (31%) poor. Postoperative EAUS showed sphincter overlap in 28 (72%) patients but a defect was still found in 11 (28%) patients. A defect found on postoperative EAUS correlated with poor clinical result according to Parks' (R = 0.8, P < 0.01) and patients' questionnaire results (R = 0.7, P < 0.01). Patients with poor clinical results (Parks III/IV) were statistically significantly older (median 63 years, range 26-73) than those with favourable results (Parks I/II) (median 45 years, range 27-79) (P < 0.05). Further, the duration of incontinence symptoms correlated with poor functional results (R=0.4, P < 0.05). CONCLUSION: After obstetric trauma anterior anal repair gives acceptable short-term clinical results. EAUS investigation is easy and harmless to perform and should be used pre- and post-operatively. Advanced age, pre-operative signs of perineal descent, long-lasting severe incontinence symptoms and a persistent defect on postoperative EAUS seem to be related to poor clinical result.

Adult↗
PubMed2003

Genetic testing for polyposis: practical and ethical aspects.

The three autosomal dominant inherited polyposis syndromes, familial adenomatous polyposis, juvenile polyposis, and Peutz-Jeghers polyposis predispose to colorectal cancer as does hereditary non-polyposis colorectal cancer syndrome. Uncovering the genetic background of these four cancer traits provides the possibility for genetic testing of the family members of an affected patient. Before testing identification of the underlying family specific pathogenic mutation is mandatory. This is possible in about 60% to 95% of families. Endoscopic surveillance can be safely discontinued in mutation negative family members and surveillance or prophylactic surgery can be targeted to mutation positive members alone. Testing requires genetic counselling and written informed consent to prevent misunderstanding and to minimise untoward effects such as anxiety. Permanent surveillance and adequate prophylactic treatment for all mutation positive subjects and families is best ensured in national or regional polyposis registries with the capacity to take care of long term follow up from generation to generation.

Adenomatous Polyposis Coli↗
PubMed2002

No support for endoscopic surveillance for gastric cancer in hereditary non-polyposis colorectal cancer.

BACKGROUND: The DNA mismatch repair gene mutations underlying hereditary non-polyposis colorectal cancer syndrome (HNPCC) also predispose, besides colorectal and endometrial cancer, to gastric cancer. usually of the intestinal type. The carcinogenetic pathway behind the elevated gastric cancer risk is largely unknown. METHODS: The aim of this study was to determine whether there are any premalignant lesions to search for in gastric surveillance in HNPCC by comparing gastric histopathology between mutation-positive and mutation-negative family members. We searched for differences in occurrence of Helicobacter pylori, inflammation, atrophy, intestinal metaplasia and dysplastic changes. Upper gastrointestinal endoscopy was performed for 73 mutation-positive and 32 mutation-negative family members. RESULTS: One case of duodenal cancer was detected in the mutation-positive group, but no gastric neoplastic lesions were seen in either group. There were no differences in the occurrence of polyps, H. pylori, inflammation, activity, atrophy nor intestinal metaplasia tested with binaric, logistic, regression analysis. CONCLUSIONS: We conclude that surveillance gastroscopy may not be beneficial in HNPCC, since neither cases of early cancer nor premalignant lesions could be detected in our series of 73 mutation-positive subjects.

Adult↗
PubMed2001

MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer.

A set of 90 nonpolypotic colon cancer families in which germ-line mutations of MSH2 and MLH1 had been excluded were screened for mutations in two additional DNA mismatch repair genes, MSH6 and MSH3. Kindreds fulfilling and not fulfilling the Amsterdam I criteria, showing early and late onset colorectal (and other) cancers, and having microsatellite stable and unstable tumors were included. Two partly parallel approaches were used: genetic linkage analysis (19 large families) and the protein truncation test (85, mostly smaller, families). Whereas MSH3 was not involved in any family, a large Amsterdam-positive, late-onset family showed a novel germ-line mutation in MSH6 (deletion of CT at nucleotide 3052 in exon 4). The mutation was identified through genetic linkage (multipoint lod score 2.4) and subsequent sequencing of MSH6. Furthermore, the entire MSH6 gene was sequenced exon by exon in families with frameshift mutations in the (C)8 tract in tumors, previously suggested as a predictor of MSH6 germ-line mutations; no mutations were found. We conclude that germ-line involvement of MSH6 and MSH3 is rare and that other genes are likely to account for a majority of MSH2-, MLH1-mutation negative families with nonpolypotic colon cancer.

Adult↗
PubMed2001

The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer.

OBJECTIVE: Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary cancer susceptibility disorder associated with a very high risk for carcinoma of the colon and an elevated risk for certain extracolonic cancers including ovarian cancer. Our aim in this study was to describe the clinicopathologic features of ovarian cancer in HNPCC family members. METHODS: . Members of the International Collaborative Group on HNPCC collected retrospective data on 80 ovarian cancer patients who were members of HNPCC families, including 31 known mutation carriers, 35 presumptive carriers (by colorectal/endometrial cancer status), and 14 at-risk family members. RESULTS: Mean age at diagnosis of ovarian cancer was 42.7. Nonepithelial tumors made up only 6.4% of the cancers, and borderline tumors comprised just 4.1% of the epithelial cancers. Among frankly malignant epithelial cases, most cancers were well or moderately differentiated, and 85% were FIGO stage I or II at diagnosis. Synchronous endometrial cancer was reported in 21.5% of cases. CONCLUSIONS: Ovarian cancer in HNPCC differs from ovarian cancer in the general population in several clinically important respects. It occurs at a markedly earlier age. It is more likely to be epithelial. If it is a frankly invasive epithelial cancer, it is more likely to be well or moderately differentiated. HNPCC patients with ovarian cancer are more likely to have a synchronous endometrial cancer than other ovarian cancer patients and are more likely to be diagnosed at an early stage.

Adult↗
PubMed2001

Expression of inducible and endothelial nitric oxide synthases in pouchitis.

To study the induction of nitric oxide synthase (NOS) in different forms of pouchitis, we divided patients in five groups: 1) ulcerative colitis, no pouch; 2) no-pouchitis; 3) chronic asymptomatic pouchitis; 4) chronic active pouchitis; and 5) acute pouchitis. Ileal biopsies were scored for NOS-2 (inducible) and NOS-3 (endothelial) immunoreactivity and acute inflammation. In group 1, most specimens lacked NOS-2 immunoreactivity. In group 2, some specimens showed NOS-2 immunoreactive epithelium. In group 3, areas of NOS-2-immunoreactive epithelium were consistently observed in most specimens. In groups 4 and 5, most specimens showed moderate-to-extensive epithelial NOS-2 staining. NOS-2 immunoreactivity scores of groups 1-5 were 0.25 +/- 0.16, 0.67 +/- 0.19, 1.19 +/- 0.40, 2.0 +/- 0.23, and 2.18 +/- 0.12, respectively. Corresponding acute inflammation scores were 0, 0.53 + 0.17, 1.00 +/- 0.33, 1.80 +/- 0.20, and 1.64 +/- 0.15. NOS-2 score correlated with acute inflammation score (p < 0.0001), indicating that NOS-2 induction correlates with both the clinical degree of pouchitis and the severity of acute inflammation. NOS-3 immunoreactivity increased in all pouchitis groups.

Colitis, Ulcerative↗
PubMed2001

Decision analysis in the surgical treatment of patients with familial adenomatous polyposis: a Dutch-Scandinavian collaborative study including 659 patients.

BACKGROUND AND AIMS: The choice of colorectal surgery in patients with familial adenomatous polyposis lies between the morbidity of proctocolectomy and ileum-pouch-anal anastomosis (IPAA) and the mortality from rectal cancer after total colectomy and ileorectal anastomosis (IRA). The aims of the present study were: (1) to assess the risk of dying from rectal cancer after IRA, (2) to compare the life expectancy between patients with an IRA and those with an IPAA, and (3) to investigate whether regular endoscopic examination of the rectum leads to detection of cancer at an earlier stage. METHODS: Clinical and pathological data on 659 patients who underwent colectomy and ileorectal anastomosis were collected from four national polyposis registries-that is, in Denmark, Finland, Sweden, and the Netherlands. Data were analysed using survival analysis methods. Decision analysis was used to compare the life expectancy between patients with an IRA and those with an IPAA. RESULTS: A total of 47 patients developed rectal cancer after IRA. The risk of dying from rectal cancer was 12.5% (95% confidence interval 7.1--17.9%) by age 65. Compared with IRA, IPAA would lead to an increase in life expectancy of 1.8 years. Seventy five per cent of patients with rectal cancer had a negative rectoscopy within 12 months before the diagnosis. CONCLUSION: IRA is associated with substantial mortality due to rectal cancer. Follow up examinations of the rectum does not have sufficient preventive effect on morbidity and mortality of rectal cancer.

Adenomatous Polyposis Coli↗
PubMed2001

Quantitative comparison of growth-associated protein-43 and substance P in ulcerative colitis.

The aim of this study was to compare immunoreactivities for substance P with other enteric neuropeptides and GAP-43, a general marker for enteric nerves, in normal human colon and in different stages of ulcerative colitis. Tissue samples from normal colon and regions of ulcerative colitis colon were obtained at surgery and immunostained for substance P, vasoactive intestinal polypeptide (VIP), somatostatin, calcitonin gene-related peptide (CGRP), enkephalin, galanin, GAP-43, and neuron-specific enolase (NSE). Visual examination and semiquantitative analysis revealed a clear increase in the immunoreactivity for substance P in ulcerative colitis, whereas no differences were observed in the distribution of the other peptides. Therefore, quantitative analysis was performed only for substance P immunoreactivity in the lamina propria, circular muscle layer, and myenteric ganglia. In the lamina propria, the score of total intensity of substance P immunoreactivity was 0.55 +/- 0.15 (mean +/- SEM) in normal colon, 1.30 +/- 0.35 (p = 0.087) in least affected colon, and 2.22 +/- 0.28 (p < 0.001) in moderately affected colon, whereas no significant differences were observed in immunoreactivities for GAP-43. Similar results were obtained for the mean substance P- or GAP-43-immunoreactive area. In the circular muscle layer, the number, density, total intensity, and perimeter of substance P- and GAP-43-immunoreactive fibers were essentially similar in normal colon, and in mild or moderately affected colon. We conclude that ulcerative colitis does not change the density of gut innervation as a whole. However, the density of substance P-containing nerves is specifically increased, probably due to increased peptide synthesis leading to better visibility of the fibers.

Adult↗
PubMed2001

Changes in distribution of three isoforms of nitric oxide synthase in ulcerative colitis.

BACKGROUND: Nitric oxide (NO) has an important role both in normal physiology and pathological events of the colon. Our aim was to study possible changes of the three nitric oxide synthases in ulcerative colitis (UC). METHODS: Tissue samples from normal colon and least and moderately affected regions of ulcerative colitis colon were obtained at surgery and immunostained for NOS-1, NOS-2, NOS-3, and GAP-43, a marker of nerve fibers. Quantitative analysis of NOS-1 immunoreactivity was performed on the circular muscle layer. RESULTS: NOS-1-immunoreactive fibers in the muscularis mucosae disappeared in least affected and moderately affected UC colon. Quantitative analysis of NOS-1-immunoreactive nerve fibers in the circular muscle showed no differences between normal and diseased colon. NOS-2 immunoreactivity appeared apically in the epithelial cells. In normal colon some specimens showed immunoreactivity in lower parts of crypts. NOS-2 immunoreactivity increased according to the severity of UC. NOS-3 immunoreactivity was exclusively localized in the vascular endothelium. The difference in NOS-3 staining intensity between the lamina propria and submucosa observed in normal tissue disappeared in moderately affected UC colon. The number of NOS-3-immunoreactive vascular profiles increased in the lamina propria of UC colon. CONCLUSIONS: All three NOS isoforms show specific changes in UC colon.

Aged↗
PubMed2000

Genetic reconstruction of individual colorectal tumor histories.

It is difficult to observe human tumor progression as precursor lesions are systematically removed. Alternatives to direct observations, commonly used to reveal the hidden past of species and populations, are sequence comparisons or molecular clocks. Noncoding microsatellite (MS) loci were employed as molecular tumor clocks in 13 human mutator phenotype (MSI(+)) colorectal tumors. Quantitative analysis revealed that specific patterns of somatic MS mutations accumulate with division after loss of mismatch repair (MMR). Tumors had unique patterns of MS mutation, and, therefore, based on this model, each tumor had its own unique history. Loss of MMR occurred very early relative to terminal clonal expansion, with an estimated average of 2,300 divisions since loss of MMR and 280 divisions since expansion. Contrary to the classical adenoma-cancer sequence, MSI(+) adenomas were nearly as old as cancers (2,000 versus 2,400 divisions since loss of MMR). Negative clinical examinations preceded six tumors, independently documenting an absence of visible precursors during early MSI(+) adenoma or cancer progression. These findings further extend a window beyond visible progression since loss of MMR appears to start a genetic phase involving clone sizes or phenotypes below a threshold of clinical detection. This previously occult prologue before visible neoplasia is longer and therefore likely more important than generally appreciated.

Adenocarcinoma↗