Ilmo Kellokumpu

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.

Impact of Functional Results on Quality of Life After Rectal Cancer Surgery

PurposeQuality of life is an important outcome measure that has to be considered when deciding treatment strategy for rectal cancer. The aim of this study was to find out the impact of surgery-related adverse effects on quality of life.MethodsThe RAND-36 questionnaire and questionnaires assessing urinary, sexual, and bowel dysfunction were administered to 94 patients with no sign of recurrence a minimum of one year after curative surgery. Results were compared with age-matched and gender-matched general population.ResultsEighty-two (87 percent) patients answered the questionnaires. Major bowel dysfunction was as common after high anterior resection as after low anterior resection. Urinary complaints occurred as often after anterior resection as after abdominoperineal resection, but sexual dysfunction was more common after abdominoperineal resection. Overall, the patients reported better general health perception but poorer social functioning than population controls. In particular, elderly patients reported a significantly better quality of life in many dimensions than their population controls. There was no significant difference in quality of life between treatment groups. Major bowel dysfunction after anterior resection impaired social functioning compared with that of patients without such symptoms. Urinary dysfunction impaired social functioning and impotence impaired physical and social functioning.ConclusionsQuality of life after rectal cancer surgery is not worse than that of the general population. The major adverse impact of bowel and urogenital dysfunction is on social functioning. These adverse effects need to be discussed with the patient and preoperative function needs to be taken into account when choosing between treatment options. Permanent colostomy is not always the factor that disrupts a persons quality of life most.

Day-Case Stapled (Circular) vs. Diathermy Hemorrhoidectomy

AbstractPURPOSE: Stapled hemorrhoidectomy may be associated with less pain and faster recovery than conventional hemorrhoidectomy for prolapsing hemorrhoids. Therefore, the outcome of stapled hemorrhoidectomy was compared with that of diathermy hemorrhoidectomy in a randomized, controlled trial. METHODS: Sixty patients with third-degree hemorrhoids were randomly assigned to stapled hemorrhoidectomy (n = 30) or to diathermy hemorrhoidectomy in a day-case setting. Visual analog scale was used for postoperative pain scoring. Surgical and functional outcome was assessed at six weeks and one year after surgery. RESULTS: Operation time was a median of 21 (range, 11–59) minutes in the stapled group vs. 22 (range, 14–40) minutes in the diathermy group. Day-case surgery was successful in 24 patients (80 percent) in the stapled group vs. 29 patients (97 percent) in the diathermy group. Average pain in the stapled group was significantly lower than in the diathermy group (median, 1.8 (0.1–4.8) vs. 4.3 (1.4–6.2), 95 percent confidence interval difference medians, 1.15–3.85, P = 0.0002, Mann-Whitney U test) as was the average pain expected by the patients (median −2.7 (−0.15–0.8) vs. 0.006 (−4.05–0.5) respectively, 95 percent confidence interval difference medians, 0.5–3.55, P = 0.0018, Mann-Whitney U test). Postoperative morbidity and time off work were not significantly different between the diathermy and stapled groups. Seven treatment failures in the stapled group and one in the diathermy group necessitated other treatments at a later date. Patient satisfaction scores in the stapled and diathermy group were similar. Symptoms attributed to difficult rectal evacuation decreased significantly after surgery. CONCLUSIONS: Stapled hemorrhoidectomy is a significantly less painful operation than diathermy hemorrhoidectomy, but does not seem to offer significant advantages in terms of hospital stay or symptom control in the long term. Hemorrhoidectomy may improve symptoms of difficult rectal evacuation.

Abnormal glycosylation and altered Golgi structure in colorectal cancer: dependence on intra‐Golgi pH

Abnormal glycosylation of cellular glycoconjugates is a common phenotypic change in many human tumors. Here, we explore the possibility that an altered Golgi pH may also be responsible for these cancer‐associated glycosylation abnormalities. We show that a mere dissipation of the acidic Golgi pH results both in increased expression of some cancer‐associated carbohydrate antigens and in structural disorganization of the Golgi apparatus in otherwise normally glycosylating cells. pH dependence of these alterations was confirmed by showing that an acidification‐defective breast cancer cell line (MCF‐7) also displayed a fragmented Golgi apparatus, whereas the Golgi apparatus was structurally normal in its acidification‐competent subline (MCF‐7/AdrR). Acidification competence was also found to rescue normal glycosylation potential in MCF‐7/AdrR cells. Finally, we show that abnormal glycosylation is also accompanied by similar structural disorganization and fragmentation of the Golgi apparatus in colorectal cancer cells in vitro and in vivo. These results suggest that an inappropriate Golgi pH may indeed be responsible for the abnormal Golgi structure and lowered glycosylation potential of the Golgi apparatus in malignant cells.

Laparoscopic repair of rectal prolapse: A prospective study evaluating surgical outcome and changes in symptoms and bowel function

AbstractBackground: There have been few large series that have focused on the feasibility of the laparoscopic approach for rectal prolapse. This single-institution study prospectively examines the surgical outcome and changes in symptoms and bowel function following the laparoscopic repair of rectal prolapse. Methods: In a selected group of 34 patients (total prolapse, 28; intussusception, six), 17 patients underwent laparoscopic-assisted resection rectopexy and 17 patients received a laparoscopic sutured rectopexy. Preoperative and postoperative evaluation at 3, 6, and 12 months included assessment of the severity of anal incontinence, constipation, changes in constipation-related symptoms, and colonic transit time. Results: Median operation time was 255 min (range, 180–360) in the resection rectopexy group and 150 min (range, 90–295) in the rectopexy alone group. Median postoperative hospital stay was 5 days (range, 3–15) and median time off work was 14 days (range, 12–21) in both groups. There were no deaths. Postoperative morbidity was 24%. Incontinence improved significantly regardless of which method was used. The main determinant of constipation was excessive straining at defecation. Constipation was cured in 70% of the patients in the rectopexy group and 64% in the resection rectopexy group. Symptoms of difficult evacuation improved, but the changes were significant only after resection rectopexy. Two patients (7%) developed recurrent total prolapse during a median follow-up of 2 years (range 12–60 months). Conclusions: Laparoscopic-sutured rectopexy and laparoscopic-assisted resection rectopexy are feasible and carry an acceptable morbidity rate. They eliminate prolapse and cure incontinence in the great majority of patients. Constipation and symptoms of difficult evacuation are alleviated.

SMAD genes in juvenile polyposis

Juvenile polyposis (JP) is a dominantly inherited condition characterized by the development of multiple hamartomatous tumors, juvenile polyps, in the gastrointestinal tract. The aim of this study was to clarify the role of SMAD4 in JP. DNA from four unrelated JP kindreds and three sporadic JP cases was available for mutation screening. Two truncating defects (one in a familial and one in a sporadic case) and one missense change (in a familial case) that was absent in 55 control samples were detected. To study the possibility that germline mutations in other genes encoding different components of the TGF‐β signaling pathway may be present in these JP patients, mutation analyses of the SMAD2, SMAD3, and SMAD7 genes were also performed. No mutations of these genes were detected in any of the patients. Our results confirm that SMAD4 is a gene predisposing to JP and suggest the existence of further JP loci other than the SMAD2, SMAD3, or SMAD7 genes. Genes Chromosomes Cancer 26:54–61, 1999.

Open vs. laparoscopic surgery for rectal prolapse: A case-controlled study assessing short-term outcome

PURPOSE This study was undertaken to evaluate the efficacy and safety of laparoscopic repair for rectal prolapse. METHODS A case-control study was undertaken. The case group consisted of a consecutive series of patients who underwent laparoscopic repair for rectal prolapse between February 1993 and June 2000. The control group underwent open prolapse repair between October 1987 and January 2000. RESULTS There were 53 patients in each group. The groups were matched according to operation type, gender, and age. Median operative time was longer in the case group than in the control group (resection rectopexy 210 vs. 117 minutes, rectopexy 127.5 vs. 72 minutes, respectively). Median postoperative hospital stay was shorter in the case group than in the control group (resection rectopexy 5 vs. 7 days, rectopexy 4.5 vs. 7 days, respectively). Median intraoperative bleeding was minor in the case group (resection rectopexy 35 vs. 300 ml, rectopexy 15 vs. 100 ml, respectively). Mortality (0 vs. 4 percent), complications (23 vs. 30 percent), late complications (4 vs. 13 percent), and the rate of recurrent prolapse (6 vs. 13 percent) did not differ significantly between the groups. CONCLUSIONS Laparoscopic repair for rectal prolapse is technically feasible and can be performed with mortality and morbidity rates comparable to those of the conventional technique. The main advantages of the laparoscopic approach appear to be a shorter hospital stay and lessened intraoperative blood loss. Recurrence rate is not increased in the short term.

Elevated Golgi pH in breast and colorectal cancer cells correlates with the expression of oncofetal carbohydrate T-antigen.

Altered glycosylation has turned out to be a universal feature of cancer cells, and in many cases, to correlate with altered expression or localization of relevant glycosyltransferases. However, no such correlation exists between observed enzymatic changes and the expression of the oncofetal Thomsen‐Friedenreich (T)‐antigen, a core 1 (Gal‐β1 → 3‐GalNAc‐ser/thr) carbohydrate structure. Here we report that T‐antigen expression, instead, correlates with elevated Golgi pH in cancer cells. Firstly, using a Golgi‐targeted green fluorescent protein (GT‐EGFP) as a probe, we show that the medial/trans‐Golgi pH (pHG) in a high proportion of breast (MCF‐7) and colorectal (HT‐29, SW‐48) cancer cells is significantly more alkaline (pHG ≥ 6.75) than that of control cells (pHG 5.9–6.5). The pH gradient between the cytoplasm and the Golgi lumen is also markedly reduced in MCF‐7 cells, suggesting a Golgi acidification defect. Secondly, we show that T‐antigen expression is highly sensitive to changes in Golgi pH, as only a 0.2 pH unit increase was sufficient to increase T‐antigen expression in control cells. Thirdly, we found that T‐antigen expressing MCF‐7 cells have 0.3 pH units more alkaline Golgi pH than non‐expressing MCF‐7 cells. Fourthly, in all cell types examined, we observed significant correlation between the number of T‐antigen expressing cells and cells with a markedly elevated Golgi pH (pHG ≥ 6.75). Consistent with these observations in cultured cells, cells in solid tumors also heterogenously expressed the T‐antigen. Thus, elevated Golgi pH appears to be directly linked to T‐antigen expression in cancer cells, but it may also act as a more general factor for altered glycosylation in cancer by affecting the distribution of Golgi‐localized glycosyltransferases.

Effect of temperature of insufflated CO2 during and after prolonged laparoscopic surgery

AbstractBackground: Pneumoperitoneum with room temperature carbon dioxide (CO2) has been shown to decrease core temperature and urine output. Methods: The effect of 37°C (warm) and room temperature (cool) CO2 pneumoperitoneum on core temperature, urine output, and central hemodynamics was compared in 26 randomized patients undergoing prolonged laparoscopic surgery (>90 min). Results: The core temperature (p < 0.05) and cardiac index (p < 0.05) were significantly higher after warm than after cool pneumoperitoneum. Urine output was significantly higher during warm (2.3 ± 1.6 ml/kg/h) than during cool (0.9 ± 0.7 ml/kg/h) insufflation (p < 0.05). Two of 13 patients with warm and 11 of 13 patients with cool pneumoperitoneum needed mannitol to maintain adequate diuresis (p < 0.05). Conclusions: Warm insufflation probably causes a local vasodilation in the kidneys and may be beneficial to patients with borderline renal function.

Frequency of hereditary nonpolyposis colorectal cancer

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant cancer syndrome characterized by early onset of colorectal carcinomas (CRC). Recently, two HNPCC genes have been mapped and cloned, one in the short arm of chromosome 2 and another in the short arm of chromosome 3. There has been a major controversy about the frequency of HNPCC. The few estimates available have been based on series selected by age or series representing local area. The purpose of the present study was to design a nonselected, prospective, multicenter study, taking into account the family background and other risk factors of CRC. METHODS: The proportion of HNPCC of all (N=406) CRC cases was evaluated in a prospective multicenter study. Family history and other risk factors were investigated over a 12-month period for all new CRC patients in ten hospitals. These cases constituted 23 percent of all CRCs diagnosed in Finland during the study period. RESULTS: Three (0.7 percent) cases of verified and seven (1.7 percent) cases of suspected HNPCC were identified, following the evaluation of all families with features indicative of susceptibility to cancer. The proportion of identifiable risk factors of CRC was 5.8–7.5 percent (HNPCC, 0.7-2.4 percent; previous CRC, 3.4 percent; ulcerative colitis, 1.0 percent; familial adenomatous polyposis coli, 0.7 percent). CONCLUSION. This prospective multicenter study revealed that the frequency of hereditary colorectal cancer is lower than in some previous studies, when diagnosis is based on extensive pedigree analysis. This result with recent findings of common ancestral founding mutation in Finnish HNPCC families indicates that there may be geographic differences in the occurrence of HNPCC. However, this does not change the fact that identification of HNPCC—perhaps one of the most common inherited diseases identified in humans—has become a question of vital importance now when diagnosis of the syndrome and largescale screening of gene carriers using specific tests are on the horizon.