Markku Aarnio

Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer

BACKGROUND & AIMS Identification of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome enables prevention of colorectal cancer (CRC) by means of colonoscopy and polypectomies. We evaluated the efficacy of screening in a controlled trial over 15 years. METHODS Incidence of CRC and survival were compared in 2 cohorts of at-risk members of 22 families with HNPCC. Colonic screening at 3-year intervals was arranged for 133 subjects; 119 control subjects had no screening. Genetic testing was offered to subjects in whose families the causative mutation was known. RESULTS CRC developed in 8 screened subjects (6%) compared with 19 control subjects (16 %; P = 0.014). The CRC rate was reduced by 62%. In mutation-positive subjects alone, the CRC rates were 18% in screened subjects and 41% in controls (P = 0.02). The decrease resulted from the removal of adenomas in 13 mutation-positive individuals (30%) and in 6 subjects with unknown mutation status (40%). All CRCs in the study group were local, causing no deaths, compared with 9 deaths caused by CRC in the controls. The overall death rates were 10 vs. 26 subjects in the study and control groups (P = 0.003), 4 vs. 12 in mutation-positive subjects (P = 0.05). CONCLUSIONS Colonoscopic screening at 3-year intervals more than halves the risk of CRC, prevents CRC deaths, and decreases overall mortality by about 65% in HNPCC families.

Cancer risk in mutation carriers of DNA‐mismatch‐repair genes

Excessive incidence of various cancers is a challenging feature of the hereditary‐non‐polyposis‐colorectal‐cancer (HNPCC) syndrome. This study estimated the cancer incidences in HNPCC compared with the general population. Individuals in a cohort of 1763 members of 50 genetically diagnosed families were categorized according to their genetic status as mutation carriers, non‐carriers, or individuals at 50 or 25% risk of being a carrier. Incidences of cancers in these groups were compared with those in the Finnish population overall. In 360 mutation carriers, standardized incidence ratios (SIR) were significantly increased for colorectal [68; 95% confidence intervals (CI), 56 to 81], endometrial (62; 95% CI, 44 to 86), ovarian (13; 95% CI, 5.3 to 25), gastric (6.9; 95% CI, 3.6 to 12), biliary tract (9.1; 95% CI, 1.1 to 33), uro‐epithelial (7.6; 95% CI, 2.5 to 18) and kidney (4.7; 95% CI, 1 to 14) cancers and for central‐nervous‐system tumours (4.5; 95% CI, 1.2 to 12). The SIR increased with increasing likelihood of being a mutation carrier. The cumulative cancer incidences were 82, 60, 13 and 12% for colorectal, endometrial, gastric and ovarian cancers respectively. For other tumours associated with increased risk, corresponding incidences were below 4%. Interestingly, the incidence of endometrial cancer (60%) exceeded that for colorectal cancer in women (54%). The tumour spectrum associated with germline mutations of DNA‐mismatch‐repair genes involves 8 or more organ sites, suggesting a need to develop methods to screen for extra‐colonic cancer also. Int. J. Cancer 81:214–218, 1999.

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.

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.

Is gastric cancer part of the tumour spectrum of hereditary non‐polyposis colorectal cancer? A molecular genetic study

Background: Gastric cancer is the second most common extracolonic malignancy in individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome. As gastric cancer is relatively common in the general population as well, it is not clear whether or not gastric cancer is a true HNPCC spectrum malignancy. Aim: To determine whether or not gastric cancer is a true HNPCC spectrum malignancy. Subjects and methods: The molecular and clinicopathological profiles of gastric cancers (n = 13) from HNPCC mutation carriers were evaluated and compared with the profiles of sporadic gastric cancers (n = 46) stratified by histology and microsatellite instability (MSI) status. Results: This study on sporadic and HNPCC gastric cancers revealed several important universal associations. Loss of heterozygosity in the adenomatous polyposis coli (APC) region was associated with intestinal histology regardless of the MSI (p = 0.007). KRAS-mutations (p = 0.019) and frameshift mutations in repeat tracts of growth-regulatory genes (p<0.001) were associated with MSI tumours being absent in microsatellite stable (MSS) tumours. The average number of methylated tumour suppressor gene loci among the 24 genes studied (methylation index) was higher in MSI than in MSS tumours regardless of histology (p<0.001). Gastric cancers from HNPCC mutation carriers resembled sporadic intestinal MSI gastric cancers, except that MLH1 promoter methylation was absent (p<0.001) and the general methylation index was lower (p = 0.038), suggesting similar, but not identical, developmental pathways. All these lacked the mismatch repair protein corresponding to the germline mutation and displayed high MSI. Conclusion: The present molecular evidence, combined with the previous demonstration of an increased incidence relative to the general population, justify considering gastric cancers as true HNPCC spectrum malignancies.

Prognosis of colorectal cancer varies in different high-risk conditions

Variation in prognosis between different colorectal cancer (CRC) patient groups was studied by comparing the survival rates of patients belonging to three cancer predisposition groups with those with sporadic CRC. The high-risk groups included 43 members of hereditary nonpolyposis colorectal cancer (HNPCC) families, 25 patients with familial adenomatous polyposis (FAP) and 33 patients with underlying ulcerative colitis (UC). The control group included 122 consecutive sporadic CRC patients. Cumulative 5-year survival was highest in HNPCC (86%), which is significantly better than in sporadic colorectal cancer (59%, hazard ratio 0.41, P = 0.02). Cancer associated with UC had a 5-year survival rate of 39%, which is significantly less than in sporadic cancer (hazard ratio 1.83, P = 0.03). There was no significant difference in the survival between patients with FAP and patients with sporadic CRC (hazard ratio 1.27, P = 0.5). Exclusion of cases detected by screening examinations slightly reduced the survival rates; 85% for HNPCC, 53% for FAP and 28% for UC. However, the differences between the groups remained significant. The survival of patients with HNPCC was found to be better than that among other groups in this study, which probably relates to the specific tumourigenesis involving DNA mismatch repair dysfunction.

Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors

Hereditary non-polyposis colorectal carcinoma (Lynch syndrome) is among the most common hereditary cancers in man and a model of cancers arising through deficient DNA mismatch repair (MMR). Lynch syndrome patients are predisposed to different cancers in a non-random fashion, the basis of which is poorly understood. We addressed this issue by determining the molecular profiles for different tumors from a nationwide cohort of Lynch syndrome families (approximately 150 tumors in total). We focused on some less prevalent cancers, affecting the brain (n = 7) and urinary tract (five bladder and five ureter uroepithelial cancers and four kidney adenocarcinomas), and compared their molecular characteristics to those of the most common cancers, colorectal, gastric and endometrial adenocarcinomas, from the same families. Despite origin from verified MMR gene mutation carriers, the frequency of high-level microsatellite instability in tumors varied between high (100-96% for ureter, stomach and colon), intermediate (63-60% for endometrium and bladder) and low (25-0% for kidney and brain). In contrast to gastrointestinal and endometrial carcinomas, active (nuclear) beta-catenin was rare and KRAS mutations were absent in brain and urological tumors. Compared with other tumors, frequent stabilization of p53 protein characterized urinary tract cancers. Promoter methylation of tumor suppressor genes discriminated the tumors in an organ-specific manner. Our findings suggest that different Lynch syndrome tumors develop along different routes. Uroepithelial cancers of the ureter (and bladder to lesser extent) share many characteristics of MMR deficiency-driven tumorigenesis, whereas brain tumors and kidney adenocarcinomas follow separate pathways.

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. (Clin Cancer Res 2009;15(18):5772–83)

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

BackgroundAlthough 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/designThe 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.DiscussionThe 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.Trial registrationClinicaltrials.govhttp://NCT01022567

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

IntroductionBreast 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.MethodsMMR 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.ResultsThe 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.ConclusionsBreast 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.