Identification of germline MLH1 alterations in familial prostate cancer.

Several linkage and loss of heterozygosity (LOH) analyses suggest that the region 3p21-p26, which is a chromosomal location of MLH1, could harbour a susceptibility gene for prostate cancer (PRCA). Furthermore, in a recent candidate single nucleotide polymorphism (SNP) analysis the I219V variation of the MLH1 gene was associated with PRCA. Microsatellite instability (MSI) and germ-line MLH1 mutations were originally demonstrated in hereditary non-polyposis colorectal cancer (HNPCC) but MSI and loss of MLH1 function have also been detected in PRCA. To assess the contribution of MLH1 germline mutations to the development of PRCA in Finland different approaches were used. First, the samples from 11 PRCA-colon cancer patients were screened for MLH1, MSH2 and MSH6 protein expression by immunohistochemistry (IHC). IHC revealed one patient with a putative MLH1 aberration and sequencing of this sample revealed five sequence variants including two missense variants P434L and I219V. Second, the samples from Finnish hereditary prostate cancer (HPC) families were used for the screening of MLH1 mutations which produced twelve MLH1 sequence variants including two missense mutations, I219V, as in the PRCA-colon cancer patient, and V647M. P434L and V647 were both novel, rare variants. Carrier frequencies of the I219V mutation were compared between hereditary prostate cancer (HPC) patients, unselected PRCA cases, patients with benign prostate hyperplasia and controls, but no differences between the sample groups were found. P434L was not present in this study population and V647M was a very rare variant found only in one HPC family. According to the present results, MLH1 does not have a major role in PRCA causation in Finland.

Lack of analgesic effect of parecoxib following laparoscopic cholecystectomy.

BACKGROUND: The cyclo-oxygenase-2 inhibitor, parecoxib, can be administered parenterally. The recommended dose for post-operative use is 40 mg twice daily, which may not be the appropriate dose for the treatment of visceral pain. We studied the effect of a single dose of parecoxib of either 40 or 80 mg in laparoscopic cholecystectomy, and its effect on opioid-induced side-effects. METHODS: Seventy-three patients scheduled for elective laparoscopic cholecystectomy were enrolled in this prospective, randomized, double-blind study. Patients were randomized into three groups: a placebo-treated control group, a 40-mg parecoxib-treated group (P40) and an 80-mg parecoxib-treated group (P80). We recorded the cumulative fentanyl consumption during the first 20 h post-operatively by patient-controlled analgesia equipment, the pain scores during rest, coughing and mobilization (visual analogue scale, 0-10), the worst pain during the first 2 h post-operatively and in the following 18 h, and the side-effects by questionnaire. RESULTS: No significant differences in fentanyl consumption between the three groups could be detected. The worst pain experienced between 2 and 20 h post-operatively on the ward was significantly lower in the P80 group than in the control group. CONCLUSION: The recommended dose of parecoxib, 40 mg, is not effective for the treatment of pain during the early post-operative period after laparoscopic cholecystectomy. Doubling the dose to 80 mg seems to improve the results.

CHEK2 variants associate with hereditary prostate cancer.

Recently, variants in CHEK2 gene were shown to associate with sporadic prostate cancer in the USA. In the present study from Finland, we found that the frequency of 1100delC, a truncating variant that abrogates the kinase activity, was significantly elevated among 120 patients with hereditary prostate cancer (HPC) (four out of 120 (3.3%); odds ratio 8.24; 95% confidence interval 1.49-45.54; P=0.02) compared to 480 population controls. Suggestive evidence of segregation between the 1100delC mutation and prostate cancer was seen in all positive families. In addition, I157T variant had significantly higher frequency among HPC patients (13 out of 120 (10.8%); odds ratio 2.12; 95% confidence interval 1.06-4.27; P=0.04) than the frequency 5.4% seen in the population controls. The results suggest that CHEK2 variants are low-penetrance prostate cancer predisposition alleles that contribute significantly to familial clustering of prostate cancer at the population level.

ELAC2/HPC2 involvement in hereditary and sporadic prostate cancer.

The ELAC2/HPC2 gene at 17p11 is the first candidate gene identified for human prostate cancer (PRCA) based on linkage analysis and positional cloning (S. V. Tavtigian et al. Nat. Genet., 27:172-180, 2001). A truncating mutation was found in one hereditary prostate cancer (HPC) family, whereas two missense variants, Ser217Leu and Ala541Thr, were reported to be associated with increased PRCA risk in the general population. Here, we screened for mutations of the ELAC2/HPC2 gene in 66 Finnish HPC families. Several sequence variants, including a new exonic variant (Glu622Val) were found, but none of the mutations were truncating. We then analyzed the frequency of the three found missense variants in 1365 individuals, including hereditary (n = 107) and unselected (n = 467) PRCA, benign prostatic hyperplasia (n = 223), and population controls (568 healthy male blood donors). Ser217Leu and Ala541Thr variants carried no significantly elevated risk for HPC or PRCA, although the latter variant was associated with benign prostatic hyperplasia. The previously undescribed Glu622Val variant had a 1.0% population prevalence, but a significantly higher frequency in PRCA cases (3.0% odds ratio, 2.94; 95% confidence interval, 1.05-8.23). We conclude that ELAC2/HPC2 truncating mutations are rare in HPC, but that rare variants of the ELAC2/HPC2 require additional study as risk factors for PRCA in the general population.

Colon interposition in the treatment of carcinoma of the esophagus and gastric cardia.

The stomach is the organ most used for restoring esophageal continuity after esophageal resection for malignancy. In the present series, we report our experience over a 20-year period (1965 through 1984) with an alternative method, colon interposition. Two hundred forty-eight patients (124 men and 124 women) underwent colon interposition. Seventy-one percent (175) of the tumors were squamous cell carcinomas, and 23% (58) were adenocarcinomas in the gastric cardia and lower esophagus. The left colon was the substitute of first choice and was used in 54% of the patients. Of the interpositions, 59% were antiperistaltic. Esophagectomy without thoracotomy was the method in 146 patients. The operative mortality was 16% (40 patients), and 3% (8 patients) sustained colon graft necrosis. Leakage in the upper anastomosis occurred in 4% (10). No dysphagia was experienced by 85%, 80%, and 76% of the patients during reexaminations 3, 6, and 12 months, respectively, after operation. The 1-year and 5-year survival for patients with squamous cell carcinoma was 40% and 10%, respectively, and for patients with adenocarcinoma, 50% and 12%, respectively. The data from this study suggest that colon interposition offers a good alternative for long-term relief of dysphagia in patients with carcinoma of the esophagus. The rate of complications is acceptable.

Hepatic coma resulting from diaphragmatic rupture and hepatic herniation.

We treated a unique case of blunt rupture of the right hemidiaphragm that produced acute hepatic failure with jaundice and coma. Laparotomy showed total eventration of the liver into the chest. The hepatic failure was caused by strangulation of the extrahepatic biliary and venous structures. Surgical repair was followed by recovery and normalization of hepatic function. This case stresses the need to diagnose and treat diaphragmatic ruptures promptly to prevent such threatening complications. The diagnosis of right diaphragmatic rupture must be suspected in instances of blunt injury, with an awareness of misleading presentations.

Complications after pancreatic resection for acute necrotizing pancreatitis.

The risks of pancreatic resection for acute necrotizing pancreatitis were evaluated in 37 patients, all with greater than or equal to 3 positive Ranson signs, most with extensive peripancreatic fat necrosis and almost half with extensive parenchymal necrosis. The mortality (43%), though comparable with most other reports, was higher than in the authors' earlier experience. The reason was not clear. Postoperative bleeding from the surgical field was the most common problem, being responsible for half of the deaths. Septicaemia due to abscess or fistulation occurred in eight patients and was fatal in five. Pulmonary and renal complications were common, but caused only three deaths. Time from onset of symptoms to operation did not influence complications or age-matched mortality. With increasing extent of resection, lung complications diminished, but not other complications or mortality. All patients older than 60 died. Resection thus should be avoided for the elderly, and its role in younger cases remains far from clear. The postoperative complications and insignificantly lower death rate than after other treatments have diminished the former enthusiasm for resection in acute necrotizing pancreatitis.

Clinicobiochemical factors in predicting gallstones in necrotizing pancreatitis.

Sixty-one patients with acute necrotizing pancreatitis were studied for age, sex, ASAT, ALAT, alkaline phosphatase, bilirubin and amylase 48 hours after admission, these factors having recently been found to be significant in predicting this gallstone-associated disease. Age, ASAT, ALAT and alkaline phosphatase were found to be significant. However, 38 per cent of the patients with pancreatitis and gallstones remained unidentified with these criteria only. Thus, more intensive methods of investigation should be used whenever gallstone-associated pancreatitis is suspected. Increased hepatic chemistry could seldom be explained by the necrotizing form of pancreatitis if there was no biliary tract cause.

Determination of necrosis in necrotizing pancreatitis.

The diagnosis of necrosis and its extent in acute necrotizing pancreatitis is one main problem in establishing criteria for possible pancreatectomy. With this in mind a clinicopathological analysis was carried out on 54 patients who had undergone pancreatic resection for acute necrotizing pancreatitis. The macroscopic appearance of the gland correlated poorly with its histology. Parenchymal necrosis varied from 0 to 100 per cent of the resected specimen though all the glands were considered totally or subtotally necrotic. In the clinicobiochemical status no criteria were found determining the extent of necrosis. Obesity, hypotension, hypocalcaemia and elevated serum creatinine in severely ill patients (as determined by Ranson criteria) strongly supported extensive peripancreatic and septal necrosis; however, 38 per cent of patients developed necrosis without those stigmata. While waiting for new methods to determine necrosis we prefer conservative treatment. In contrast to our previous tactics we think that resection should be limited to extreme cases in order to avoid resection of glands with limited necrosis and thus mainly reversible parenchymal damage.

Resection of the pancreas for acute hemorrhagic and necrotizing pancreatitis.

The role of surgery in the treatment of acute hemorrhagic or necrotizing pancreatitis is discussed on the basis of a series of 996 patients with all types of acute pancreatitis who were treated in the years 1967--1976. Pancreatic resection was performed in 29 patients with hemorrhagic or necrotizing pancreatitis during the past 3 years. The extent of resection ranged from 60 to 100% of the pancreas. Eight patients died, for a mortality rate of 28%. Eight of 21 surviving patients developed diabetes requiring substitution therapy. During a follow-up period of 6 to 36 months, 17 patients were able to resume work, 3 are still convalescing, and 1 has retired.

The intensive care of acute pancreatitis.

The results of medical and surgical treatment of 115 cases of acute pancreatitis treated in the surgical intensive care unit over a period of 8 years are reviewed. The death rate from acute pancreatitis fell during the period of study in the intensive care unit from 42.6% between 1969 and 1973, when drainage was used, to 22.9% between 1974 and 1976 when resection was performed, and in hospital from 8.2% to 5.8% respectively. The results improved as a consequence of adequate treatment of shock, complete intravenous feeding, accurate timing of surgery and the successful choice of operative procedures.