Impact of Mesh and Fixation on Chronic Inguinal Pain in Lichtenstein Hernia Repair: 5-Year Outcomes from the Finn Mesh Study.

OBJECTIVE: To find out the mesh fixation technique that minimises chronic pain in Lichtenstein hernioplasty. Mesh fixation may affect chronic pain and recurrence after inguinal hernia surgery, but long-term results of comparative trials are lacking. METHODS: Lichtenstein hernioplasty was performed under local anaesthesia on 625 patients in day care units. The patients were randomised to receive either a cyanoacrylate glue (n = 216), self-gripping mesh (n = 202) or non-absorbable 3-0 polypropylene sutures (n = 216) for the fixation of mesh. A standardised telephone interview or postal questionnaire was conducted 5 years after the index operation. The patients with complaints suggesting recurrence or chronic pain (visual analogue scale ≥ 3, 0-10) were examined clinically. The rate of occasional pain, chronic severe pain, recurrence, re-operations, daily use of analgesics, overall patient satisfaction and sensation of a foreign object were recorded. RESULTS: A total of 82% of patients (n = 514) completed the 5-year audit including 177, 167 and 170 patients in the glue, self-fixation and suture groups, respectively. There were no significant differences in the incidence of pain (7-8%), operated recurrences (2-4%), overall re-operations (4-5%), need for analgesics (1-2%), patient's satisfaction (93-97%) or in the feeling of a foreign object (11-18%) between the study groups. CONCLUSION: The choice of the mesh or fixation method had no effect on the overall long-term outcome, pain or recurrence of hernia. Less penetrating fixation (glue or self-gripping mesh) is a safe option for the fixation of mesh in Lichtenstein hernia repair.

Correction to: Factors predicting chronic pain after open inguinal hernia repair: a regression analysis of randomized trial comparing three different meshes with three fixation methods (FinnMesh Study).

In the original publication, co-authors affiliations were incorrect.

Factors predicting chronic pain after open inguinal hernia repair: a regression analysis of randomized trial comparing three different meshes with three fixation methods (FinnMesh Study).

BACKGROUND: Chronic pain after inguinal hernioplasty is the foremost side-effect up to 10-30% of patients. Mesh fixation may influence on the incidence of chronic pain after open anterior mesh repairs. METHODS: Some 625 patients who underwent open anterior mesh repairs were randomized to receive one of the three meshes and fixations: cyanoacrylate glue with low-weight polypropylene mesh (n = 216), non-absorbable sutures with partially absorbable mesh (n = 207) or self-gripping polyesther mesh (n = 202). Factors related to chronic pain (visual analogue scores; VAS ≥ 30, range 0-100) at 1 year postoperatively were analyzed using logistic regression method. A second analysis using telephone interview and patient records was performed 2 years after the index surgery. RESULTS: At index operation, all patient characteristics were similar in the three study groups. After 1 year, chronic inguinal pain was found in 52 patients and after 2 years in only 16 patients with no difference between the study groups. During 2 years' follow-up, three (0.48%) patients with recurrences and five (0.8%) patients with chronic pain were re-operated. Multivariate regression analysis indicated that only new recurrent hernias and high pain scores at day 7 were predictive factors for longstanding groin pain (p = 0.001). Type of mesh or fixation, gender, pre-operative VAS, age, body mass index or duration of operation did not predict chronic pain. CONCLUSION: Only the presence of recurrent hernia and early severe pain after index operation seemed to predict longstanding inguinal pain.

Does Nissen Fundoplication Provide Lifelong Reflux Control? Symptomatic Outcome After 31-33 Years.

BACKGROUND: A substantial number of people are suffering from gastroesophageal reflux disease (GERD). The indication for surgical treatment is the failure of medical treatment in patients with objectively verified GERD. The use of PPIs has been noted to increase with the length of follow-up after fundoplication, raising questions concerning the durability of surgical results. The aim of the study was to investigate the results of open Nissen fundoplication (ONF) over a follow-up of more than 31 years. METHODS: ONF was performed for 38 consecutive patients. Questionnaires concerning long-term outcome were sent on December 14, 2015, to the 24 patients still living. Long-term symptom evaluation was carried out using the Gastrointestinal Symptom Rating Scale (GSRS), Visick grading, a Visual Analog Scale (VAS), the DeMeester-Johnson reflux scale, and the 15D tool. RESULTS: Seventeen (70.8%) of the 24 patients still living participated in the study. The typical symptoms of GERD had resolved significantly. Dysphagia was graded as none or minimal by 13 (81.3%) patients. The mean 15D score of the patient group was clinically and statistically the same (0.896 vs. 0.899) as that of the age- and sex-standardized general population (p = 0.912). Six (15.8%) patients had used antireflux medication after the operation and 4 of them (10.6%) continuously. CONCLUSIONS: Patients in the present study used PPIs less frequently than what has been reported in previous long-term follow-up studies. Our results indicate that successful surgery may provide lifelong relief of GERD symptoms and normalize the health-related quality of life in GERD patients.

Randomized Clinical Trial Comparing Cyanoacrylate Glue Versus Suture Fixation in Lichtenstein Hernia Repair: 7-Year Outcome Analysis.

BACKGROUND: Lichtenstein hernioplasty has relatively low recurrence rate, but chronic inguinal pain may cause harm to the patient. The aim of our study was to compare long-term results of cyanoacrylate glue versus absorbable sutures for mesh fixation in Lichtenstein hernioplasty. METHODS: Lichtenstein hernioplasty (n = 302) was performed under local anesthesia in three hospitals. The patients were randomized to receive either 1 ml of butyl-2-cyanoacrylate tissue glue (Glubran®; 151 hernias) or absorbable polyglycolic acid sutures (Dexon®; 151 hernias) for mesh fixation (Optilene® mesh). Short-term results were published previously. Chronic groin pain, foreign body sensation, use of analgesics, recurrence and re-operations were analyzed 7 years after surgery. RESULTS: We reached 236 patients (78%) to present study. In the glue group (n = 115), there were five (4.3%) and in the suture group (n = 121) three (2.5%) recurrent hernias (p = 0.491). The prevalence of chronic pain (NRS ≥ 3) in the patients without re-operations was similar in two groups: 15/118 (13%) and 13/111 (12%), respectively (p = 0.843). There were no significant differences in the foreign body sensation (8/14, p = 0.267) or in the need of analgesics (2/2, p = 1.00) between the two study groups. CONCLUSION: Both cyanoacrylate glue and mesh fixation with absorbable sutures were equal in terms of chronic pain and rate of recurrences in Lichtenstein hernioplasty after 7-year follow-up. TRIAL REGISTRATION NUMBER: NCT00659542.

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.

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.

Germline mutations in the ribonuclease L gene in families showing linkage with HPC1.

Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States, little is known about inherited factors that influence its genetic predisposition. Here we report that germline mutations in the gene encoding 2'-5'-oligoadenylate(2-5A)-dependent RNase L (RNASEL) segregate in prostate cancer families that show linkage to the HPC1 (hereditary prostate cancer 1) region at 1q24-25 (ref. 9). We identified RNASEL by a positional cloning/candidate gene method, and show that a nonsense mutation and a mutation in an initiation codon of RNASEL segregate independently in two HPC1-linked families. Inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway and has been suggested to be a candidate tumor suppressor gene. We found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozyogous individuals compared with family members who were homozygous with respect to the wildtype allele. Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway might provide opportunities for developing therapies for those with prostate cancer.

Association of E-cadherin germ-line alterations with prostate cancer.

In our recent cancer registry-based study, the incidence of gastric carcinoma was increased up to 5-fold in male relatives of early-onset prostate cancer (PCA) patients. This association may reflect the influence of genetic factors predisposing individuals to both tumor types. Germ-line mutations of the CDH1 gene at 16q have recently been associated with familial gastric cancer. Furthermore, two genome-wide linkage studies of PCA recently reported positivity at 16q. We therefore identified families and individual patients with both gastric and PCA and investigated whether the CDH1 gene mutations were involved in cancer predisposition in these cases. Fifteen of the 180 Finnish hereditary PCA families (8.3%) had one or more gastric cancer cases. No truncating or splice site CDH1 mutations were identified by PCR single-strand conformational polymorphism in these families or in eight individual patients who had both prostate and gastric cancer. However, a novel S270A missense mutation in exon 6 of the CDH1 gene was seen in a single family with four prostate and two gastric cancers. A large-scale population-based survey indicated a higher prevalence of S270A among both familial PCA cases (3.3%; n = 120; P = 0.01) and unselected PCA patients (1.5%; n = 472; P = 0.12) as compared with blood donors serving as population controls (0.5%; n = 923). We conclude that individual rare mutations and polymorphisms in the CDH1 gene, such as S270A, may contribute to the onset of PCA and warrant further investigations in other populations. However, the CDH1 gene does not appear to explain the link between prostate and gastric cancer.

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.

Dysphagia and oesophageal clearance after laparoscopic versus open Nissen fundoplication. A randomized, prospective trial.

BACKGROUND: An increase in postoperative dysphagia has been reported after laparoscopic fundoplication. Our aim was to compare laparoscopic Nissen-Rossetti fundoplication to open fundoplication regarding oesophageal clearance and dysphagia in a prospective, randomized study. METHODS: Twenty-eight consecutive patients with objectively observed gastro-oesophageal reflux disease referred to operative treatment were randomized to laparoscopic (13) or open (15) fundoplication. A standard formula was used in pre- and postoperative interview. Oesophageal clearance was measured by liquid bolus radionuclide transit before and 3 days, 1 month and 1 year after fundoplication. Endoscopy was done preoperatively and 1 year after the operation. RESULTS: Heartburn, regurgitation and ooesophagitis were cured with equal effectiveness (p = 0.001). New-onset dysphagia was observed in nine (69%) of the patients in the laparoscopic group and in nine (60%) in the open group during the first postoperative month. Food impaction occurred in four (31%) cases after laparoscopic and in two (13%) after open surgery (ns). One year after the operation, one patient (8%) in both groups had more than mild symptoms. Oesophageal radionuclide transit remained normal after open fundoplication, but after the laparoscopic procedure oesophageal clearance was disturbed--only one patient did not have a pathologic result during the first postoperative month. One year after the operation, clearance was normal. CONCLUSIONS: After laparoscopic operation, a tendency to more severe new-onset dysphagia was observed, and oesophageal clearance was transiently disturbed. Efforts should be made to minimize postoperative swallowing and clearance disturbances after laparoscopic fundoplication in order to get the full value out of otherwise more rapid recovery.

Immunoaffinity purification and reconstitution of human alpha(2)-adrenergic receptor subtype C2 into phospholipid vesicles.

Large quantities of correctly folded, pure alpha(2)-adrenergic receptor protein are needed for structural analysis. We report here the first efficient method to purify human alpha(2)-adrenergic receptor subtype C2 to homogeneity from recombinant yeast Saccharomyces cerevisiae by one-step purification using a monoclonal antibody column (specific for alpha(2)C2). We show that the adrenoceptor antagonist phentolamine stabilized the receptor during purification. We used a very effective chaotropic agent, NaSCN, to elute the receptor from the immunoaffinity column with an overall yield of 34% before reconstitution. Ligand binding of detergent-solubilized, immunoaffinity-purified receptors could not be demonstrated, but partial recovery of ligand binding activity was achieved when purified receptors were reconstituted into phospholipid vesicles. The reconstituted receptors still bound radioligand after storage on ice for 4 weeks. This purification procedure can be easily scaled-up and thus demonstrates the utility of a monoclonal antibody column and NaSCN elution to purify large quantities of G-protein-coupled receptors.

A missense substitution A49T in the steroid 5-alpha-reductase gene (SRD5A2) is not associated with prostate cancer in Finland.

Prostatic steroid 5-alpha-reductase gene (SRD5A2) encodes a critical enzyme involved in the conversion of testosterone to dihydrotestosterone. A germline mis-sense substitution (A49T) leads to a variant SRD5A2 protein, which has a 5-fold higher in vitro V(max)than the wild-type protein (Ross et al, 1998; Makridakis et al, 1999). The A49T variant was recently associated with 2.5 to 3.28-fold increased risk of prostate cancer (PC) in African-American and Hispanic men (Makridakis et al, 1999). Also, Jaffe et al (2000) reported an association between A49T and more aggressive disease among Caucasian patients. Here, we report that the prevalence of the A49T variant in 449 Finnish PC patients was 6.0%, not significantly different from 6.3% observed in 223 patients with benign prostatic hyperplasia or 5.8% in 588 population-based controls (odds ratio for PC 1.04, 95% C.I. 0.62-1.76, P = 0.89). There was no association between A49T and the family history of the patients nor with tumour stage or grade. Our results argue against a prominent role of the A49T variant as a genetic risk factor for prostate cancer development and progression in the Finnish population.

Genetic changes in familial prostate cancer by comparative genomic hybridization.

BACKGROUND: Germline mutations in recessive cancer predisposition genes are uncovered by somatic genetic deletions during tumor development. Analysis of genetic changes in tumor tissues from patients with an inherited predisposition may therefore highlight regions of the genome containing susceptibility or modifier genes. Our aim was to characterize genetic changes in familial prostate cancer METHODS: Twenty-one primary prostate cancers from 19 Finnish prostate cancer families were analyzed for somatic genetic changes by comparative genomic hybridization (CGH). RESULTS: The average number of genetic alterations per tumor was 4.0 +/- 1.9, distributed equally among losses and gains. The most common losses were found at chromosomal regions 13q14-q22 (29%), 8p12-pter (24%), and 6q13-q16 (14%), and the most common gains at 19p (25%), 19q (14%) and 7q (14%). CONCLUSIONS: These results suggest that prostate cancers in genetically predisposed individuals arise for the most part through similar somatic genetic progression pathways as sporadic prostate cancers. This also implies that the biological properties of tumors from the two groups may not be different from one another.

Post-ERCP pancreatitis: reduction by routine antibiotics.

Cholangitis and pancreatitis are severe complications of endoscopic retrograde cholangiopancreatography (ERCP). Antibiotics have been considered important in preventing cholangitis, especially in those with jaundice. Some have suggested that bacteria may play a role in the induction of post-ERCP pancreatitis. It is not clear, however, whether the incidence of post-ERCP pancreatitis could be reduced by antibiotic prophylaxis, as is the case with septic complications. In this prospective study, a total of 321 consecutive patients were randomized to the following two groups: (1) a prophylaxis group (n = 161) that was given 2 g of cephtazidime intravenously 30 minutes before ERCP, and (2) a control group (n = 160) that received no antibiotics. All patients admitted to the hospital for ERCP who had not taken any antibiotics during the preceding week were included. Patients who were allergic to cephalosporins, patients with immune deficiency or any other condition requiring antibiotic prophylaxis, patients with clinical jaundice, and pregnant patients were excluded. In the final analysis six patients were excluded because of a diagnosis of bile duct obstruction but with unsuccessful biliary drainage that required immediate antibiotic treatment. The diagnosis of cholangitis was based on a rising fever, an increase in the C-reactive protein (CRP) level, and increases in leukocyte count and liver function values, which were associated with bacteremia in some. The diagnosis of acute pancreatitis was based on clinical findings, and increases in the serum amylase level (>900 IU/L), CRP level, and leukocyte count with no increase in liver chemical values. The control group had significantly more patients with post-ERCP pancreatitis (15 of 160 in the prophylaxis group vs. 4 of 155 in the control group; P = 0.009) and cholangitis (7 of 160 vs. 0 of 155; P = 0.009) compared to the prophylaxis group. Nine patients in the prophylaxis group (6%) and 15 patients in the control group (9%) had remarkably increased serum amylase levels (>900 IU/L) after ERCP, but clinical signs of acute pancreatitis with leukocytosis, CRP reaction, and pain developed in four of nine patients in the prophylaxis group compared to 15 of 15 patients with hyperamylasemia in the control group (P = 0.003). In a multivariate analysis, the lack of antibiotic prophylaxis (odds ratio 6.63, P = 0.03) and sphincterotomy (odds ratio 5.60, P = 0.05) were independent risk factors for the development of post-ERCP pancreatitis. We conclude that antibiotic prophylaxis effectively decreases the risk of pancreatitis, in addition to cholangitis after ERCP, and can thus be routinely recommended prior to ERCP. These results suggest that bacteria could play a role in the pathogenesis of post-ERCP pancreatitis

Histological and macroscopic changes in the pelvic pouch: long-term follow up after restorative proctocolectomy for ulcerative colitis (UC).

OBJECTIVE: Our aim was to evaluate macroscopic and histological (inflammatory) changes in ileal pouch mucosa after restorative proctocolectomy with J-pouch-ileoanal anastomosis for UC during long-term follow up. PATIENTS AND METHODS: Thirty-six (56%) out of 64 consecutive patients operated at our Institute during 1985-90 underwent endoscopy of the reservoir in the years 1994 and 1998. Functional outcome and macroscopic changes were recorded and histological samples taken from the three levels of the pelvic pouch. Acute and chronic inflammation were graded in accordance with a well-established histopathologic scoring system. RESULTS: The functional outcome was unchanged in 26 (72%), became worse in eight (22%) and better in two (6%) cases during follow up. The number of macroscopic changes increased during follow up and there was a tendency for them to become more common in the distal pouch. Microscopic acute and chronic inflammation decreased during follow up. There were more severe inflammatory changes in the distal pouch. Both acute and chronic inflammatory scores were higher through the reservoir in the cases of chronic pouchitis. Chronic pouchitis occurred more often in males. CONCLUSION: Macroscopic and inflammatory changes in the pelvic pouch seem to have separate progress during long-term follow up. In chronic pouchitis both acute and chronic inflammation are pronounced and spread over the entire pelvic pouch mucosa.

Analysis of p53 tumor suppressor gene in families with multiple glioma patients.

The high incidence of gliomas in Li-Fraumeni families and the high frequency of somatic p53 mutations in sporadic glial tumors have raised the possibility that germline p53 mutations could play an important role in familial aggregation of gliomas. In the present study, 18 families with two or more gliomas were screened for germline p53 mutation. The families were identified through questionnaires sent to 369 consecutive glioma patients operated at Tampere University Hospital during 1983-1994. In these families, a family history of cancer was verified through the Finnish Cancer Registry. Interestingly, the questionnaires reveled only 15 of 57 cancers (index gliomas excluded) retrieved through the Cancer Registry. None of the 18 families fufilled the criteria for classic Li-Fraumeni syndrome. Immunostaining analysis of p53 protein accumulation suggested that alterations of the p53 gene are as common in familial as in sporadic gliomas. Sequencing analysis of exons 4-10 of the p53 gene revealed no germline mutations in any of the 18 families. Thus, although occasional glioma families carrying germline p53 mutations have been identified in earlier studies, systematic evaluation of familial glioma patients suggests that the p53 gene is not a common susceptibility gene in case of familial gliomas. The p53 tumor suppressor gene seems to have a similar role in the tumorigenesis of most familial and sporadic gliomas.