Effect of Oral Moxifloxacin vs Intravenous Ertapenem Plus Oral Levofloxacin for Treatment of Uncomplicated Acute Appendicitis: The APPAC II Randomized Clinical Trial.

Importance: Antibiotics are an effective and safe alternative to appendectomy for managing uncomplicated acute appendicitis, but the optimal antibiotic regimen is not known. Objective: To compare oral antibiotics with combined intravenous followed by oral antibiotics in the management of computed tomography-confirmed uncomplicated acute appendicitis. Design, Setting, and Participants: The Appendicitis Acuta (APPAC) II multicenter, open-label, noninferiority randomized clinical trial was conducted from April 2017 until November 2018 in 9 Finnish hospitals. A total of 599 patients aged 18 to 60 years with computed tomography-confirmed uncomplicated acute appendicitis were enrolled in the trial. The last date of follow-up was November 29, 2019. Interventions: Patients randomized to receive oral monotherapy (n = 295) received oral moxifloxacin (400 mg/d) for 7 days. Patients randomized to receive intravenous antibiotics followed by oral antibiotics (n = 288) received intravenous ertapenem (1 g/d) for 2 days followed by oral levofloxacin (500 mg/d) and metronidazole (500 mg 3 times/d) for 5 days. Main Outcomes and Measures: The primary end point was treatment success (≥65%) for both groups, defined as discharge from hospital without surgery and no recurrent appendicitis during 1-year follow-up, and to determine whether oral antibiotics alone were noninferior to intravenous and oral antibiotics, with a margin of 6% for difference. Results: Among 599 patients who were randomized (mean [SD] age, 36 [12] years; 263 [44%] women), 581 (99.7%) were available for the 1-year follow-up. The treatment success rate at 1 year was 70.2% (1-sided 95% CI, 65.8% to ∞) for patients treated with oral antibiotics and 73.8% (1-sided 95% CI, 69.5% to ∞) for patients treated with intravenous followed by oral antibiotics. The difference was -3.6% ([1-sided 95% CI, -9.7% to ∞]; P = .26 for noninferiority), with the confidence limit exceeding the noninferiority margin. Conclusion and Relevance: Among adults with uncomplicated acute appendicitis, treatment with 7 days of oral moxifloxacin compared with 2 days of intravenous ertapenem followed by 5 days of levofloxacin and metronidazole resulted in treatment success rates greater than 65% in both groups, but failed to demonstrate noninferiority for treatment success of oral antibiotics compared with intravenous followed by oral antibiotics. Trial Registration: ClinicalTrials.gov Identifier: NCT03236961; EudraCT Identifier: 2015-003633-10.

Five-Year Follow-up of Antibiotic Therapy for Uncomplicated Acute Appendicitis in the APPAC Randomized Clinical Trial.

Importance: Short-term results support antibiotics as an alternative to surgery for treating uncomplicated acute appendicitis, but long-term outcomes are not known. Objective: To determine the late recurrence rate of appendicitis after antibiotic therapy for the treatment of uncomplicated acute appendicitis. Design, Setting, and Participants: Five-year observational follow-up of patients in the Appendicitis Acuta (APPAC) multicenter randomized clinical trial comparing appendectomy with antibiotic therapy, in which 530 patients aged 18 to 60 years with computed tomography-confirmed uncomplicated acute appendicitis were randomized to undergo an appendectomy (n = 273) or receive antibiotic therapy (n = 257). The initial trial was conducted from November 2009 to June 2012 in Finland; last follow-up was September 6, 2017. This current analysis focused on assessing the 5-year outcomes for the group of patients treated with antibiotics alone. Interventions: Open appendectomy vs antibiotic therapy with intravenous ertapenem for 3 days followed by 7 days of oral levofloxacin and metronidazole. Main Outcomes and Measures: In this analysis, prespecified secondary end points reported at 5-year follow-up included late (after 1 year) appendicitis recurrence after antibiotic treatment, complications, length of hospital stay, and sick leave. Results: Of the 530 patients (201 women; 329 men) enrolled in the trial, 273 patients (median age, 35 years [IQR, 27-46]) were randomized to undergo appendectomy, and 257 (median age, 33 years, [IQR, 26-47]) were randomized to receive antibiotic therapy. In addition to 70 patients who initially received antibiotics but underwent appendectomy within the first year (27.3% [95% CI, 22.0%-33.2%]; 70/256), 30 additional antibiotic-treated patients (16.1% [95% CI, 11.2%-22.2%]; 30/186) underwent appendectomy between 1 and 5 years. The cumulative incidence of appendicitis recurrence was 34.0% (95% CI, 28.2%-40.1%; 87/256) at 2 years, 35.2% (95% CI, 29.3%-41.4%; 90/256) at 3 years, 37.1% (95% CI, 31.2%-43.3%; 95/256) at 4 years, and 39.1% (95% CI, 33.1%-45.3%; 100/256) at 5 years. Of the 85 patients in the antibiotic group who subsequently underwent appendectomy for recurrent appendicitis, 76 had uncomplicated appendicitis, 2 had complicated appendicitis, and 7 did not have appendicitis. At 5 years, the overall complication rate (surgical site infections, incisional hernias, abdominal pain, and obstructive symptoms) was 24.4% (95% CI, 19.2%-30.3%) (n = 60/246) in the appendectomy group and 6.5% (95% CI, 3.8%-10.4%) (n = 16/246) in antibiotic group (P < .001), which calculates to 17.9 percentage points (95% CI, 11.7-24.1) higher after surgery. There was no difference between groups for length of hospital stay, but there was a significant difference in sick leave (11 days more for the appendectomy group). Conclusions and Relevance: Among patients who were initially treated with antibiotics for uncomplicated acute appendicitis, the likelihood of late recurrence within 5 years was 39.1%. This long-term follow-up supports the feasibility of antibiotic treatment alone as an alternative to surgery for uncomplicated acute appendicitis. Trial Registration: ClinicalTrials.gov Identifier: NCT01022567.

Clinical and laboratory findings in the diagnosis of right lower quadrant abdominal pain: outcome analysis of the APPAC trial.

BACKGROUND: The current research on acute appendicitis aims to improve the diagnostics and to clarify to whom antibiotic treatment might be the treatment of choice. METHODS: The present study is a retrospective analysis of a prospectively collected data in our randomized multicenter trial comparing surgery and antibiotic treatment for acute uncomplicated appendicitis (APPAC trial, NCTO1022567). We evaluated 1321 patients with a clinical suspicion of acute appendicitis, who underwent computed tomography (CT). Age, gender, body temperature, pain scores, the duration of symptoms, white blood cell count (WBC) and C-reactive protein (CRP) were recorded on admission. RESULTS: CT confirmed the diagnosis of acute appendicitis in 73% (n=970) and in 27% (n=351) it revealed no or other diagnosis. Acute appendicitis patients had significantly higher WBC levels than patients without appendicitis (median 12.2 and 10.0, respectively, p<0.0001), whereas CRP levels did not differ between the two groups. Ideal cut-off points were assessed with receiver operating characteristic (ROC) curves, but neither these markers or neither their combination nor any clinical characteristic could accurately differentiate between patients with acute appendicitis and those without. The proportion of patients with normal WBC count and CRP was significantly (p=0.0007) lower in patients with acute appendicitis than in patients without appendicitis. CONCLUSIONS: Both clinical findings and laboratory tests are unable to reliably distinguish between patients with acute appendicitis and those without. If both WBC count and CRP are normal, acute appendicitis is very unlikely. The current results emphasize the role of CT imaging in patients with suspected acute appendicitis.

Antibiotic Therapy vs Appendectomy for Treatment of Uncomplicated Acute Appendicitis: The APPAC Randomized Clinical Trial.

IMPORTANCE: An increasing amount of evidence supports the use of antibiotics instead of surgery for treating patients with uncomplicated acute appendicitis. OBJECTIVE: To compare antibiotic therapy with appendectomy in the treatment of uncomplicated acute appendicitis confirmed by computed tomography (CT). DESIGN, SETTING, AND PARTICIPANTS: The Appendicitis Acuta (APPAC) multicenter, open-label, noninferiority randomized clinical trial was conducted from November 2009 until June 2012 in Finland. The trial enrolled 530 patients aged 18 to 60 years with uncomplicated acute appendicitis confirmed by a CT scan. Patients were randomly assigned to early appendectomy or antibiotic treatment with a 1-year follow-up period. INTERVENTIONS: Patients randomized to antibiotic therapy received intravenous ertapenem (1 g/d) for 3 days followed by 7 days of oral levofloxacin (500 mg once daily) and metronidazole (500 mg 3 times per day). Patients randomized to the surgical treatment group were assigned to undergo standard open appendectomy. MAIN OUTCOMES AND MEASURES: The primary end point for the surgical intervention was the successful completion of an appendectomy. The primary end point for antibiotic-treated patients was discharge from the hospital without the need for surgery and no recurrent appendicitis during a 1-year follow-up period. RESULTS: There were 273 patients in the surgical group and 257 in the antibiotic group. Of 273 patients in the surgical group, all but 1 underwent successful appendectomy, resulting in a success rate of 99.6% (95% CI, 98.0% to 100.0%). In the antibiotic group, 70 patients (27.3%; 95% CI, 22.0% to 33.2%) underwent appendectomy within 1 year of initial presentation for appendicitis. Of the 256 patients available for follow-up in the antibiotic group, 186 (72.7%; 95% CI, 66.8% to 78.0%) did not require surgery. The intention-to-treat analysis yielded a difference in treatment efficacy between groups of -27.0% (95% CI, -31.6% to ∞) (P = .89). Given the prespecified noninferiority margin of 24%, we were unable to demonstrate noninferiority of antibiotic treatment relative to surgery. Of the 70 patients randomized to antibiotic treatment who subsequently underwent appendectomy, 58 (82.9%; 95% CI, 72.0% to 90.8%) had uncomplicated appendicitis, 7 (10.0%; 95% CI, 4.1% to 19.5%) had complicated acute appendicitis, and 5 (7.1%; 95% CI, 2.4% to 15.9%) did not have appendicitis but received appendectomy for suspected recurrence. There were no intra-abdominal abscesses or other major complications associated with delayed appendectomy in patients randomized to antibiotic treatment. CONCLUSIONS AND RELEVANCE: Among patients with CT-proven, uncomplicated appendicitis, antibiotic treatment did not meet the prespecified criterion for noninferiority compared with appendectomy. Most patients randomized to antibiotic treatment for uncomplicated appendicitis did not require appendectomy during the 1-year follow-up period, and those who required appendectomy did not experience significant complications. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01022567.

A prospective randomized controlled multicenter trial comparing antibiotic therapy with appendectomy in the treatment of uncomplicated acute appendicitis (APPAC trial).

BACKGROUND: Although the standard treatment of acute appendicitis (AA) consists of an early appendectomy, there has recently been both an interest and an increase in the use of antibiotic therapy as the primary treatment for uncomplicated AA. However, the use of antibiotic therapy in the treatment of uncomplicated AA is still controversial. METHODS/DESIGN: The APPAC trial is a randomized prospective controlled, open label, non-inferiority multicenter trial designed to compare antibiotic therapy (ertapenem) with emergency appendectomy in the treatment of uncomplicated AA. The primary endpoint of the study is the success of the randomized treatment. In the antibiotic treatment arm successful treatment is defined as being discharged from the hospital without the need for surgical intervention and no recurrent appendicitis during a minimum follow-up of one-year (treatment efficacy). Treatment efficacy in the operative treatment arm is defined as successful appendectomy evaluated to be 100%. Secondary endpoints are post-intervention complications, overall morbidity and mortality, the length of hospital stay and sick leave, treatment costs and pain scores (VAS, visual analoque scale). A maximum of 610 adult patients (aged 18-60 years) with a CT scan confirmed uncomplicated AA will be enrolled from six hospitals and randomized by a closed envelope method in a 1:1 ratio either to undergo emergency appendectomy or to receive ertapenem (1 g per day) for three days continued by oral levofloxacin (500 mg per day) plus metronidazole (1.5 g per day) for seven days. Follow-up by a telephone interview will be at 1 week, 2 months and 1, 3, 5 and 10 years; the primary and secondary endpoints of the trial will be evaluated at each time point. DISCUSSION: The APPAC trial aims to provide level I evidence to support the hypothesis that approximately 75-85% of patients with uncomplicated AA can be treated with effective antibiotic therapy avoiding unnecessary appendectomies and the related operative morbidity, also resulting in major cost savings.

Breast carcinoma and Lynch syndrome: molecular analysis of tumors arising in mutation carriers, non-carriers, and sporadic cases.

INTRODUCTION: Breast carcinoma is the most common cancer in women, but its incidence is not increased in Lynch syndrome (LS) and studies on DNA mismatch repair deficiency (MMR) in LS-associated breast cancers have arrived at conflicting results. This study aimed to settle the question as to whether breast carcinoma belongs to the LS tumor spectrum. METHODS: MMR status and epigenetic profiles were determined for all available breast carcinomas identified among 200 LS families from a nation-wide registry (23 tumors from mutation carriers and 18 from non-carriers). Sporadic breast carcinomas (n = 49) and other cancers (n = 105) from MMR gene mutation carriers were studied for comparison. RESULTS: The proportion of breast carcinomas that were MMR-deficient based on absent MMR protein, presence of microsatellite instability, or both was significantly (P = 0.00016) higher among breast carcinomas from mutation carriers (13/20, 65%) compared to non-carriers (0/14, 0%). While the average age at breast carcinoma diagnosis was similar in carriers (56 years) and non-carriers (54 years), it was lower for MMR-deficient versus proficient tumors in mutation carriers (53 years versus 61 years, P = 0.027). Among mutation carriers, absent MMR protein was less frequent in breast carcinoma (65%) than in any of seven other tumor types studied (75% to 100%). Tumor suppressor promoter methylation patterns were organ-specific and similar between breast carcinomas from mutation carriers and non-carriers. CONCLUSIONS: Breast carcinoma from MMR gene mutation carriers resembles common breast carcinoma in many respects (for example, general clinicopathological and epigenetic profiles). MMR status makes a distinction: over half are MMR-deficient typical of LS spectrum tumors, while the remaining subset which is MMR-proficient may develop differently. The results are important for appropriate surveillance in mutation carriers and may be relevant for LS diagnosis in selected cases.

Quality of Life and Patient Satisfaction at 7-Year Follow-up of Antibiotic Therapy vs Appendectomy for Uncomplicated Acute Appendicitis: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Long-term results support antibiotics for uncomplicated acute appendicitis as an alternative to appendectomy. To our knowledge, treatment-related long-term patient satisfaction and quality of life (QOL) are not known. Objective: To determine patient satisfaction and QOL after antibiotic therapy and appendectomy for treating uncomplicated acute appendicitis. Interventions: Open appendectomy vs antibiotics with intravenous ertapenem, 1 g once daily, for 3 days followed by 7 days of oral levofloxacin, 500 mg once daily, and metronidazole, 500 mg 3 times per day. Design, Setting, and Participants: This observational follow-up of the Appendicitis Acuta (APPAC) multicenter randomized clinical trial comparing appendectomy with antibiotics included 530 patients age 18 to 60 years with computed tomography-confirmed uncomplicated acute appendicitis who were randomized to undergo appendectomy (273 [52%]) or receive antibiotics (257 [49%]). The trial was conducted from November 2009 to June 2012; the last follow-up was May 9, 2018. The data were analyzed in February 2019. Main Outcomes and Measures: In this analysis, post hoc secondary end points of postintervention QOL (EQ-5D-5L) and patient satisfaction and treatment preference were evaluated. Results: Of the 530 patients enrolled in the trial (appendectomy group: 273 [174 men (64%)] with a median age of 35 years; (antibiotic group: 257 [155 men (60%)] with a median age of 33 years), 423 patients (80%) were available for phone interview at a median follow-up of 7 years; 206 patients (80%) took antibiotics and 217 (79%) underwent appendectomy. Of the 206 patients taking antibiotics, 81 (39%) had undergone appendectomy. The QOL between appendectomy and antibiotic group patients was similar (median health index value, 1.0 in both groups; 95% CI, 0.86-1.0; P = .96). Patients who underwent appendectomy were more satisfied in the treatment than patients taking antibiotics (68% very satisfied, 21% satisfied, 6% indifferent, 4% unsatisfied, and 1% very unsatisfied in the appendectomy group and 53% very satisfied, 21% satisfied, 13% indifferent, 7% unsatisfied, and 6% very unsatisfied in the antibiotic group; P < .001) and in a subgroup analysis this difference was based on the antibiotic group patients undergoing appendectomy. There was no difference in patient satisfaction after successful antibiotic treatment compared with appendectomy (cumulative odds ratio [COR], 7.8; 95% CI, 0.5-1.3; P < .36). Patients with appendectomy or with successful antibiotic therapy were more satisfied than antibiotic group patients who later underwent appendectomy (COR, 7.7; 95% CI, 4.6-12.9; P < .001; COR, 9.7; 95% CI, 5.4-15.3; P < .001, respectively). Of the 81 patients taking antibiotics who underwent appendectomy, 27 (33%) would again choose antibiotics as their primary treatment. Conclusions and Relevance: In this analysis, long-term QOL was similar after appendectomy and antibiotic therapy for the treatment of uncomplicated acute appendicitis. Patients taking antibiotics who later underwent appendectomy were less satisfied than patients with successful antibiotics or appendectomy. Trial Registration: Clinicaltrials.gov Identifier: NCT01022567.

Cost analysis of antibiotic therapy versus appendectomy for treatment of uncomplicated acute appendicitis: 5-year results of the APPAC randomized clinical trial.

BACKGROUND: The efficacy and safety of antibiotic treatment for uncomplicated acute appendicitis has been established at long-term follow-up with the majority of recurrences shown to occur within the first year. Overall costs of antibiotics are significantly lower compared with appendectomy at short-term follow-up, but long-term durability of these cost savings is unclear. The study objective was to compare the long-term overall costs of antibiotic therapy versus appendectomy in the treatment of uncomplicated acute appendicitis in the APPAC (APPendicitis ACuta) trial at 5 years. METHODS AND FINDINGS: This multicentre, non-inferiority randomized clinical trial randomly assigned 530 adult patients with CT-confirmed uncomplicated acute appendicitis to appendectomy or antibiotic treatment at six Finnish hospitals. All major costs during the 5-year follow-up were recorded, whether generated by the initial visit and subsequent treatment or possible recurrent appendicitis. Between November 2009 and June 2012, 273 patients were randomized to appendectomy and 257 to antibiotics. The overall costs of appendectomy were 1.4 times higher (p<0.001) (€5716; 95% CI: €5510 to €5925) compared with antibiotic therapy (€4171; 95% CI: €3879 to €4463) resulting in cost savings of €1545 per patient (95% CI: €1193 to €1899; p<0.001) in the antibiotic group. At 5 years, the majority (61%, n = 156) of antibiotic group patients did not undergo appendectomy. CONCLUSIONS: At 5-year follow-up antibiotic treatment resulted in significantly lower overall costs compared with appendectomy. As the majority of appendicitis recurrences occur within the first year after the initial antibiotic treatment, these results suggest that treating uncomplicated acute appendicitis with antibiotics instead of appendectomy results in lower overall costs even at longer-term follow-up.

The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome.

Persons with the Lynch syndrome (LS) are at high risk for cancer, including cancers of the small bowel, stomach, upper urologic tract (renal pelvis and ureter), ovary, biliary tract and brain tumors, in addition to the more commonly observed colorectal and endometrial cancers. Cancer prevention strategies for these less common cancers require accurate, age-specific risk estimation. We pooled data from 4 LS research centers in a retrospective cohort study, to produce absolute incidence estimates for these cancer types, and to evaluate several potential risk modifiers. After elimination of 135 persons missing crucial information, cohort included 6,041 members of 261 families with LS-associated MLH1 or MSH2 mutations. All were either mutation carriers by test, probable mutation carriers (endometrial/colorectal cancer-affected), or first-degree relatives of these. Among mutation carriers and probable carriers, urologic tract cancer (N = 98) had an overall lifetime risk (to age 70) of 8.4% (95% CI: 6.6-10.8); risks were higher in males (p < 0.02) and members of MSH2 families (p < 0.0001). Ovarian cancer (N = 72) had an lifetime risk of 6.7% (95% CI: 5.3-9.1); risks were higher in women born after the median year of birth (p < 0.008) and in members of MSH2 families (p < 0.006). Brain tumors and cancers of the small bowel, stomach, breast and biliary tract were less common. Urologic tract cancer and ovarian cancer occur frequently enough in some LS subgroups to justify trials to evaluate promising prevention interventions. Other cancer types studied occur too infrequently to justify strenuous cancer control interventions.

Is preoperative distinction between complicated and uncomplicated acute appendicitis feasible without imaging?

BACKGROUND: One of the main aims of appendicitis research is the differential diagnostics between complicated and uncomplicated acute appendicitis that enable provision of the optimal treatment for each patient. METHODS: Data in the present study were collected prospectively in our randomized antibiotic treatment for uncomplicated acute appendicitis trial (APPAC) comparing surgery and antibiotic treatment for uncomplicated acute appendicitis (NCT01022567). We evaluated 705 patients who had acute appendicitis on computed tomography. Patients with uncomplicated acute appendicitis (n = 368) were compared with all complicated acute appendicitis patients (n = 337), and subgroup analyses were performed between uncomplicated acute appendicitis and an appendicolith appendicitis (CA1; n = 256) and uncomplicated acute appendicitis and perforation and/or abscess (CA2; n = 78). Age, sex, body temperature (°C), duration of symptoms, white blood cell count (E9/L), and C-reactive protein (mg/L) were recorded on admission. Receiver operating characteristic curves were calculated for white blood cell count, C-reactive protein, and temperature. RESULTS: CA2 patients had significantly greater C-reactive protein levels (mean 122 and 47, respectively, P < .001) and longer duration of symptoms than uncomplicated acute appendicitis patients; 81% of CA2 patients and 38% of uncomplicated acute appendicitis patients had symptoms >24 hours before admission (P < .001). In receiver operating characteristic analysis, C-reactive protein and temperature had clinically significant results only in comparison with uncomplicated acute appendicitis and CA2 (area under the curve >0.7), but no optimum cutoff points could be identified. CONCLUSION: In clinical decision making, neither clinical findings nor laboratory markers are reliable enough to estimate the severity of the acute appendicitis accurately or to determine the presence of an appendicolith. The current results emphasize the role of computed tomography in the differential diagnosis of complicated and uncomplicated acute appendicitis.

Clinicopathological features and management of cancers in lynch syndrome.

Lynch syndrome (LS) is characterized by an autosomal dominant inheritance of the early onset of colorectal cancer (CRC) and endometrial cancer, as well as increased risk for several other cancers including gastric, urinary tract, ovarian, small bowel, biliary tract, and brain tumors. The syndrome is due to a mutation in one of the four DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. The majority of LS patients and families can now be identified, and the underlying mutation detected using genetic diagnostics. Regular surveillance for CRC and endometrial cancer has proved beneficial for mutation carriers. However, screening for other tumors is also recommended even though experiences in the screening of these tumors is limited. Prophylactic colectomy, prophylactic hysterectomy, and bilateral salpingo-oophorectomy may be reasonable options for selected patients with LS. This paper describes the features and management of LS.

Absence of cytomegalovirus from the gastrointestinal tract of patients with active Crohn's disease.

BACKGROUND: Cytomegalovirus (CMV) infection reportedly is detectable in the gastrointestinal mucosa of patients with chronic inflammatory bowel disease. One view is that CMV infection is of clinical significance in patients with Crohn's disease with severe colitis not responding to steroid therapy. In this study, we evaluated the prevalence of CMV infection in our own patients with Crohn's disease treated with colon resection. PATIENTS AND METHODS: The study included 16 consecutive patients with Crohn's disease with colitis who underwent surgery for colonic disease. Histology and immunohistochemistry were used to examine the CMV infection in their surgical specimens by means of enzymatic antigen retrieval, mouse monoclonal antibody, clone CMV01, and a sensitive polymer detection system. RESULTS: All 16 patients underwent colon resection, three of them undergoing emergency surgery. No CMV infection was found in their surgical specimens. CONCLUSION: CMV infection seems not to play a major role in the pathogenesis of Crohn's colitis requiring surgery. However, further prospective studies with larger number of patients are needed to determine the role of CMV in active Crohn's colitis.

Uroepithelial and kidney carcinoma in Lynch syndrome.

Increased risk for urological tumors has been observed in mutation carriers with Lynch syndrome (LS). In this study, we evaluated the clinical features of uroepithelial (bladder and ureter) and kidney cancers in 974 Finnish mutation carriers. Altogether 30 patients had a total of 34 urological tumors: 12 ureter, 12 bladder, and 10 kidney cancers. Urological tumor was the only tumor in 9 (30 %) patients, and metachronous other tumor occurred in 21 (70 %). The occurrence of uroepithelial cancers was significantly higher in MSH2 mutation carriers (6 %; 95 % CI, 2.7-11.0) than in MLH1 carriers (2 %; 95 % CI, 1.1-3.2) and MSH6 mutation carriers (0 %) (p = 0.014). The mean ages of patients at the time of diagnosis were: bladder cancer, 57 years; ureter cancer, 58 years; and kidney cancer, 64 years. Overall 5-year survival rates were 70 % (95 % CI, 0.32-0.89) in bladder cancer, 81 % (95 % CI, 0.45-0.95) in ureter cancer, and 75 % (95 % CI, 0.31-0.93) in kidney cancer. Cancer-specific 5-year survival rates were 70 % (95 % CI, 0.32-0.89) in bladder cancer, 91 % (95 % CI, 0.51-0.98) in ureter cancer, and 100 % in kidney cancer. In conclusion, early age of onset was observed in patients with uroepithelial tumors, but not in patients with kidney cancer. The frequency of uroepithelial tumors was significantly higher in MSH2 mutation carriers than in MLH1 carriers. Further studies with larger numbers of patients, however, are needed to evaluate the potential benefit of surveillance of urological tumors in LS.

Molecular analysis of endometrial tumorigenesis: importance of complex hyperplasia regardless of atypia.

PURPOSE: Endometrial carcinoma (EC) is common in the population and the most frequent extracolonic malignancy in hereditary nonpolyposis colorectal carcinoma (HNPCC)/Lynch syndrome. We characterized precursor lesions of endometrioid EC to identify markers of malignant transformation and tumor progression. EXPERIMENTAL DESIGN: Serial specimens of normal endometrium, simple hyperplasia, complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma obtained during a 10-year surveillance of DNA mismatch repair (MMR) gene mutation carriers (together 110 samples) were molecularly profiled and compared with a sporadic reference series of endometrial specimens taken for nonmalignant reasons (62 samples). RESULTS: Among MMR gene mutation carriers, decreased MMR protein expression was present in 7% in normal endometrium, 40% in simple hyperplasia, 100% in complex hyperplasia without atypia, 92% in complex hyperplasia with atypia, and 100% in endometrial carcinoma. Microsatellite instability frequencies were lower (6%, 17%, 67%, 38%, and 64%, respectively). Among 24 tumor suppressor genes, the number of methylated loci increased from normal endometrium to simple hyperplasia to complex hyperplasia (complex hyperplasia without atypia/complex hyperplasia with atypia) in both Lynch syndrome and reference series. The most frequently methylated genes were CDH13, RASSF1A, and GSTP1. In MMR gene mutation carriers, MMR and methylation defects appeared up to 12 years before endometrial carcinoma. CONCLUSIONS: Molecular changes in endometrial tissue are detectable several years before endometrial carcinoma in genetically predisposed individuals. Abnormal MMR and methylation classify normal endometrium and simple hyperplasia into one category and complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma into another, suggesting that, contrary to a traditional view, complex hyperplasia without atypia and complex hyperplasia with atypia are equally important as precursor lesions of endometrial carcinoma.

Development of colorectal tumors in colonoscopic surveillance in Lynch syndrome.

BACKGROUND & AIMS: Mutation carriers in Lynch syndrome families have a high risk for developing colorectal cancer during their lifetime. This study was designed to assess the cumulative risk for the development of colorectal adenoma or carcinoma in prospective colonoscopic surveillance. METHODS: Data from the Finnish Hereditary Colorectal Cancer Registry electronic database on 420 Lynch syndrome mutation carriers without previous colorectal tumors were reviewed. Between March 1982 and May 2005 the mutation carriers underwent a total of 1252 colonoscopies. The total follow-up time was 3150 years (mean, 6.7 y/patient). RESULTS: The cumulative risk of adenoma by age 60 was estimated as 68% (95% confidence interval [CI], 50%-80%) in men and 48% (95% CI, 29%-62%) in women. The estimated cumulative risk up to age 60 years for the development of cancer found as a result of surveillance at an interval of 2-3 years was 35% (95% CI, 16%-49%) in men and 22% (95% CI, 7%-34%) in women. Half of the adenomas were located proximal to the splenic flexure. Extracolonic cancer was diagnosed in 73 patients (18%). CONCLUSIONS: Adenoma would appear to be the most important lesion preceding cancer formation in Lynch syndrome and removal of adenomas decreases the risk for colorectal cancer (CRC). The Finnish surveillance protocol of colonoscopies at 2- to 3-year intervals facilitates patient adherence but includes an essential risk for CRC up to 60 years of age, but without CRC-related mortality when the surveillance instructions are followed.

Immediate repair of obstetric anal sphincter rupture: medium-term outcome of the overlap technique.

PURPOSE: Overlap sphincteroplasty is gaining popularity in the primary repair of obstetric sphincter ruptures. This study was designed to evaluate the medium-term outcome of the overlap technique. METHODS: Between August 1997 and October 2001, 31 consecutive females who were diagnosed with a complete third-degree or fourth-degree anal sphincter rupture underwent overlap sphincteroplasty immediately after delivery. Thirty of the females were followed-up for a median of 24 months. The outcome was assessed by clinical examination, anal endosonography, Wexner score, and pelvic floor electromyography. RESULTS: Median 24 (range, 12-63) months after delivery, 23 females (77 percent) were free of symptoms of anal incontinence. Occasional incontinence to flatus and liquid stool occurred in 17 and 7 percent of patients, respectively. Seven percent of patients had a Wexner incontinence score of > 9. The maximum mean resting pressure was 55 (range, 20-90) mmHg, and the maximum mean incremental squeeze pressure was 37 (range, 14-95) mmHg. On anal endosonography, an unrecognized internal sphincter rupture was found in one and a failed repair in two females. Overlap of the external sphincter was demonstrated in 29 patients (97 percent). One female with anal incontinence and persisting external sphincter rupture underwent redo sphincteroplasty. CONCLUSIONS: The median-term outcome of primary overlap repair for obstetric sphincter rupture is good; however, larger, randomized studies with a longer follow-up are needed to evaluate the advantage of this technique over the end-to-end technique.