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BACKGROUND: Observational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer; we now report long-term follow-up of participants randomly assigned to aspirin or placebo. METHODS: In the CAPP2 randomised trial, carriers of Lynch syndrome were randomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was in blocks of 16 with provision for optional single-agent randomisation and extended postintervention double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. This trial is registered, ISRCTN59521990. RESULTS: 861 participants were randomly assigned to aspirin or aspirin placebo. At a mean follow-up of 55.7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 0.63 (95% CI 0.35-1.13, p=0.12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0.56 (95% CI 0.32-0.99, p=0.05). For participants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysis yielded an HR of 0.41 (0.19-0.86, p=0.02) and an IRR of 0.37 (0.18-0.78, p=0.008). No data for adverse events were available postintervention; during the intervention, adverse events did not differ between aspirin and placebo groups. INTERPRETATION: 600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55.7 months in carriers of hereditary colorectal cancer. Further studies are needed to establish the optimum dose and duration of aspirin treatment. FUNDING: European Union; Cancer Research UK; Bayer Corporation; National Starch and Chemical Co; UK Medical Research Council; Newcastle Hospitals trustees; Cancer Council of Victoria Australia; THRIPP South Africa; The Finnish Cancer Foundation; SIAK Switzerland; Bayer Pharma., link_to_OA_fulltext

Evidence supporting aspirin and resistant starch (RS) for colorectal cancer prevention comes from epidemiologic and laboratory studies (aspirin and RS) and randomized controlled clinical trials (aspirin). Familial adenomatous polyposis (FAP) strikes young people and, untreated, confers virtually a 100% risk of colorectal cancer and early death. We conducted an international, multicenter, randomized, placebo-controlled trial of aspirin (600 mg/d) and/or RS (30 g/d) for from 1 to 12 years to prevent disease progression in FAP patients from 10 to 21 years of age. In a 2 × 2 factorial design, patients were randomly assigned to the following four study arms: aspirin plus RS placebo; RS plus aspirin placebo; aspirin plus RS; RS placebo plus aspirin placebo; they were followed with standard annual clinical examinations including endoscopy. The primary endpoint was polyp number in the rectum and sigmoid colon (at the end of intervention), and the major secondary endpoint was size of the largest polyp. A total of 206 randomized FAP patients commenced intervention, of whom 133 had at least one follow-up endoscopy and were therefore included in the primary analysis. Neither intervention significantly reduced polyp count in the rectum and sigmoid colon: aspirin relative risk = 0.77 (95% CI, 0.54–1.10; versus nonaspirin arms); RS relative risk = 1.05 (95% CI, 0.73–1.49; versus non-RS arms). There was a trend toward a smaller size of largest polyp in patients treated with aspirin versus nonaspirin—mean 3.8 mm versus 5.5 mm for patients treated 1 or more years (adjusted P = 0.09) and mean 3.0 mm versus 6.0 mm for patients treated more than 1 year (P = 0.02); there were similar weaker trends with RS versus non-RS. Exploratory translational endpoints included crypt length (which was significantly shorter in normal-appearing mucosa in the RS group over time) and laboratory measures of proliferation (including Ki67). This clinical trial is the largest ever conducted in the setting of FAP and found a trend of reduced polyp load (number and size) with 600 mg of aspirin daily. RS had no clinical effect on adenomas. Cancer Prev Res; 4(5); 655–65. ©2011 AACR.

A C--A polymorphism within the CDH1 (E-cadherin) promoter seems to be associated with a reduced efficiency of gene transcription in vitro. Due to the crucial role of E-cadherin in epithelia, tissue-specific effect of C--A change on CDH1 transcription was tested and a case-control study was performed on patients affected with epithelial tumors.The -178/+93 CDH1 region containing either C or A nucleotide was inserted upstream of the Luciferase reporter gene in the pGL-2 vector, and the construct activity was assessed by transient transfection assay in HeLa and HCT116 cells.A significantly lower activity for pGL-2A was found compared to pGL-2C, both in HeLa (54% decrease) and in HCT116 (67% decrease) cells. Genotyping of 246 controls and 505 patients affected with breast, gastric, colorectal, cervical and endometrial cancers demonstrated an association between the A allele and an increased risk of colorectal, gastric and endometrial tumors (1.66-, 1.81- and 2.35-fold, respectively).Our data support the notion that the A allele may act as a low-penetrance cancer susceptibility gene.

The APC gene is a putative human tumor-suppressor gene responsible for adenomatous polyposis coli (APC), an inherited, autosomal dominant predisposition to colon cancer. It is also implicated in the development of sporadic colorectal tumors. The characterization of APC gene mutations in APC patients is clinically important because DNA-based tests can be applied for presymptomatic diagnosis once a specific mutation has been identified in a family. Moreover, the identification of the spectrum of APC gene mutations in patients is of great interest in the study of the biological properties of the APC gene product. We analyzed the entire coding region of the APC gene by the PCR–single-strand conformation polymorphism method in 42 unrelated Italian APC patients. Mutations were found in 12 cases. These consist of small (5–14 bp) base-pair deletions leading to frameshifts; all are localized within exon 15. Two of these deletions, a 5-bp deletion at position 3183–3187 and a 5-bp deletion at position 3926–3930, are present in 3/42 and 7/42 cases of our series, respectively, indicating the presence of mutational hot spots at these two sites.

The chronology of first recurrences, their topographic distribution and survival from mastectomy were retrospectively studied in a series of 800 mastectomized women with special reference to the relationship between these data and treatment delay, T N categories and free interval. Visceral metastases were more frequent in patients under 50 years, whereas local recurrences were more common in patients over 50. The average free interval was 26 months (over 5 years in 18% of cases) and seemed to be influenced little by the treament delay or by tumor size; it was shorter in patients under 50 years and shorter still in patients with lymph node involvement at operation. A similar correlation exists between these parameters and survival. The 5 year survival rate of the 800 cases with recurrence was 52%, which is quite different from the rate generally indicated for surgical cases, and much higher than the rate for the natural history of untreated breast cancer. The survival rate in cases with first metastases confined to the soft tissues is much higher than in those with bone and/or with visceral metastases. The survival after recurrence proves to be significantly influenced by the length of the free interval, but much more by the presence or absence of regional lymph node involvement, so that the lymph nodes status (N–- or N+) turns out to be a prognostic item of primary importance, even after the onset of recurrence.

One hundred and fifty-five cases of scintigraphically "cold" thyroid nodules were examined telethermographically to determine their thermal gradient. All nodules hyperthermic greater than or equal to 1.5 degrees C were successively removed, as were those (regardless of the thermal gradient) present in men, those in women younger than 21 years and older than 45 years of age, and those clinically suspect, the latter regardless of age or sex of the patient. Of 95 operated cases, 79 proved to be benign or nontumoral nodules, and 16 were carcinomas at histology. Hyperthermia greater than or equal to 1.5 degrees C had been present in 43% of the benign cases and in only 25% of the carcinomas. Out of ten cases were hyperthermia greater than or equal to 2 degrees C, none was a carcinoma. A malignancy was found in 26% of 23 normothermic cases, 17.6% of 34 slightly hyperthermic cases, and only 10.5% of 38 markedly hyperthermic (greater than or equal to 1.5 degrees C) cases. There was no evident correlation between the thermal gradient and the clinical diameter of the thyroid nodule. Our study affirms that thermography is not reliable when used to select cold thyroid nodules for surgical removal.

In the present study we report the long-term results for 120 female patients who underwent mastectomy for breast cancer, from 1955 to 1965, and in whom the first relapse was represented by a skin recurrence or a supraclavicular lymph node metastastis. Eighty-nine patients had been submitted only to local therapy, 11 had also undergone bilateral oophorectomy, and in the remaining 20 hormonal compounds had been administered in addition to local therapy. The disease-free interval between the first and the second relapse, and survival after the treatment of the first relapse were strictly related to the presence and the number of axillary lymph node metastases at the time of the mastectomy (N category). In fact, the median survival was 19.5 months for 63 cases with more than 3 metastatic lymph nodes, 29 months for 24 cases with 1–3 involved lymph nodes, and 59 months for 38 cases without axillary involvement. No significant difference in survival was observed in relation to chronological age and menopausal status of the patients or to the lenght of the disease-free interval. The association of endocrine therapies to local treatment of the recurrences also did not increase the survival rate in these cases. The present data indicate that the prognosis for patients with recurrent breast cancer is mainly related to the N category.

Aims and Background Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients. Methods A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLH1-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family. Results Five-year survival rates were 0.73 (95% CI, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% CI, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P = 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% CI, 0.51-0.98) for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006). Conclusions Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related colorectal carcinoma patients depends on the associated constitutional mismatch repair genotype.