Triplet repeat instability correlates with dinucleotide instability in primary breast cancer.

The expansion of triplet repeat microsatellite sequences is the molecular correlate of anticipation in a number of rare Mendelian neurodegenerative disorders. This finding prompted us to study these sequences in primary breast cancer in which there is evidence of genetic anticipation. We used a PCR/silver stain method to determine whether triplet-repeat instability (TRI) was present in DNA from malignant breast tumors, and analyzed microsatellite instability (MSI) in triplets SCA1, SCA2, SCA3, SCA6, HD, DRPLA and X25-GAA. We studied 54 consecutive primary breast cancers previously analyzed for dinucleotide instability (DI) at 9 loci. Microsatellite instability (TRI and/or DI) was found in 28/54 (52%) cases, ranging from 0 to 56% in each patient. Dinucleotide instability occurred at > or =2 loci in 19/54 (35%) cases and TRI in 6/54 (11%). Considering single locus instability, we found DI in 26/54 (48%) tumors and TRI in 13/54 (24%). Triplets DRPLA and X25-GAA were most frequently unstable (14% of cases); SCA2 instability was not detected. Interestingly, most tumors with TRI had DI (11/13, 85%). There was a correlation between TRI and DI in the same tumor (42 vs 7% in DI+ and DI- tumors respectively, p=0.0028). Furthermore, TRI appears more frequently associated with lymph node metastases and more advanced clinical stages and more frequent in patients <50 years old, with positive steroidal hormone receptor status, positive p185 and negative p53. These findings are of interest because they demonstrate a relationship between TRI and the clinicopathological characteristics of cancer aggressiveness. Triplet repeat alterations can interfere with gene expression and proteomic functions, which suggests they can play a role in the neoplastic progression of mammary cells. Furthermore, the association of TRI and DI in the same tumor suggests that alterations in the DNA repair gene could culminate in selective phenotypes and breast cancer progression in a considerable number of patients.

Loss of hMSH2 expression in primary breast cancer with p53 alterations.

Inactivation of DNA mismatch repair genes (MRG) is a recently described pathway of cancer development and progression resulting in genetic instability. Germline mutations in MRG have been studied predominantly in patients with hereditary non-polyposis colorectal cancer (HNPCC) where it is associated with microsatellite instability (MSI). The expression of MRG in primary breast cancer is still largely unexplored. The hMSH2 MRG encodes a protein that recognizes and binds to mismatch sequences of DNA. We investigated the relation-ship between hMSH2 expression and clinicopathological and biological characteristics, including p53 and p185 expression, in 44 primary invasive breast cancers. hMSH2 was not expressed in 11 cases (25%). Interestingly, p53 (p=0.05), p185 and steroidal receptor expression (p=0.07) were more frequent in tumors without hMSH2 expression. Furthermore, in 30 of 44 cases we analyzed hMSH2 expression in relation to MSI at 9 dinucleotide loci, and found that MRG expression was not significantly related to MSI. The presence of hMSH2 and p53 alterations in the same tumor suggests that the two oncoproteins act through a common mutational pathway, whereas the absence of a correlation between hMSH2 and MSI suggests that oncogenetic mechanisms of progression in primary breast cancer differ from those in HNPCC.

Differential TAG-72 epitope expression in breast cancer and lymph node metastases: a marker of a more aggressive phenotype.

We analysed the differential expression pattern of the three distinct TAG-72 carbohydrate epitopes detected by monoclonal antibodies (MAbs) B72.3, CC83 and CC49 in a consecutive series of 114 patients with primary breast cancer and in 39 synchronous lymph node metastases. B72.3, CC83 and CC49 were expressed in respectively 81 (71%), 68 (60%) and 96 (84%) of the 114 cases. Interestingly, MAb B72.3 was significantly expressed in a subgroup of patients characterised by larger tumour size (p=0.013), lymph node metastasis (p=0.0002), high histopathological grade (p=0.006), high cell kinetics (p=0.04) and advanced clinical stage (p=0.0019). In 20 (51%) of the 39 pairs of matched primary breast cancers and synchronous lymph node metastases, TAG-72 was expressed in the tumour but not in the corresponding metastatic lymph node; tumours with TAG-72-negative lymph nodes appeared to be clinicopathologically more aggressive. CC49, the most immunoreactive and widely used MAb, was not detected in 34% of the metastases of expressing primary tumours. All three MAbs were found in a significantly lower per cent of synchronous metastases with respect to primary tumours (p<0.001).

Low-dose recombinant IL-2 induces psychological changes: monitoring by Minnesota Multiphasic Personality Inventory (MMPI).

BACKGROUND: Chronic subcutaneous rIL-2 at low doses produces long-lasting immunomodulatory effects and is considered an effective treatment for renal cell carcinoma with marginal activity in malignant melanoma and colorectal cancer. PATIENTS AND METHODS: In this study we evaluated, by Minnesota Multiphasic Personality Inventory (MMPI), the psychological changes induced by rIL-2 in 10 patients with advanced tumors. RESULTS: After 3 months of rIL-2 treatment, 80% of the patients had a significantly increased score on the clinical scale of depression (D) and psychasthenia (Pt) (p<0.01), 70% on the scale of conversion hysteria (Hy) and 60% on the scales of schizophrenia (Sc) and psychopathic deviate (Pd), (p<0.05). These MMPI changes were however not paralleled by disease progression or clinical-overt psychological disease. CONCLUSION: These findings demonstrate that low-dose rIL-2 is a psychoactive treatment, which deserves psychological monitoring The MMPI is feasible for the evaluation of subclinical psychological modifications induced by cytokine immunotherapy.

Cancer prevalence in the city of Naples: Contribution of the GP database analyses to the cancer registries network.

The Italian cancer registries network has not been sufficiently developed in the Southern regions. General practitioners (GPs) are knowledgeable about the prevalence, incidence and mortality for different types of cancer in their patient populations. The aim of this pilot study was to verify the feasibility and reliability of the characterization of cancer populations using GP databases in order to evaluate the impact of cancer in the general population of Naples. The characteristics of the cases studied have been collected by interview or electronic health record and recorded on paper or magnetic supports, appropriately conforming to the current privacy law. Databases are centralized, stored and codified on electronic data-sheets and periodically elaborated by the 'Consorzio Nazionale delle Cooperative Mediche' and 'Federico II' University. The present study was initiated on September 15, 2004. The analysed geographical area included the suburbs of 'Stella' and 'San Carlo all'Arena', situated in the historical center of Naples and corresponding to Health Care District 29 of the local health service. The analysis included 16,927 men and women (age range, 6-97 years) from the outpatient offices of 12 GPs who agreed to participate in the study. Results showed that the analysed population represents 16.3% of the general population residing in the area under study. We identified 342 (2%) patients with cancer, 143 (0.8%) of whom were men and 199 (1.2%) women (M/F ratio of 0.7). Of the 342 patients, 10 (5 men and 5 women) had a double cancer; thus, a total of 352 malignancies was characterized. Cancer prevalence was 2,020/100,000 inhabitants. This estimate is lower compared to the national prevalence (2,683/100,000 inhabitants) but higher compared to that in other southern Italian areas. Results, stratified by International Classification of Disease, ninth revision (ICD-IX), based on factors including gender and age, demonstrated that breast cancer, urogenital tumours and colorectal cancer are the most frequently occurring types of cancer identified among the inhabitants of Naples. Cancer prevalence in the historical center of Naples is in concordance with national estimates and projections and National Cancer Registries may be easily and accurately supported by GP medical databases.

Incidence and pathological characteristics of prostate cancer in Italy: a contribution to the screening debate.

BACKGROUND: The scientific, social and financial aspects of prostate cancer (PC) organized or opportunistic screening to identify early PC are hotly debated. The incidence of prostate cancer is lower in Italy than in America and North Europe and data on PC incidence and pathological characteristics are scarce. METHODS: To determine PC incidence and whether screening would be beneficial, we studied 1008 consecutive symptomatic patients from the Southern Italy who underwent transrectal ultrasonography; 170 of them (age range: 48-93 years; median: 70 years) were at risk and underwent transrectal biopsy. RESULTS: Adenomatous hyperplasia was detected in 105 patients (62%), PC in 51 (30%), prostate intraepithelial neoplasia (PIN) in 5 (3%) and inflammatory disease in 5 (3%). The median age of patients with PC was 73.5 and tumors were generally well to moderately differentiated (76%, Gleason score < or =7). Prostate cancer (or PIN) was more frequent in patients over 70 (p<0.0001). The Gleason score also increased with age: >7 in 92% and 8% of patients aged >70 and < or =70, respectively (p<0.05). CONCLUSIONS: On the basis of our results organized or opportunistic PC screening of elderly men does not appear justified because: invasive carcinoma is detected in less than 1/3 of symptomatic "healthy" men; patients became symptomatic when their life expectancy is often less than 10 years; and PC is more frequent and more aggressive after 70 years.

p53 expression is decreased in primary breast carcinomas with microsatellite instability.

p53 and p185 expression in primary breast cancer with microsatellite instability (MSI) is still largely unexplored. To investigate the relationship between these oncoproteins and the pathways of genomic instability, we examined 52 primary invasive breast cancers stratified by the presence and absence of MSI. We determined the status of eight microsatellite loci using radioactive and silver staining methods, and evaluated the immunohistochemical expression of p53 and p185 in a consecutive series of Italian cancer patients characterized by clinical-pathological and biological parameters. Nineteen cases (36.5%) were MSI-positive in at least two loci. p53 was expressed in 15 cases (28.8%) and p185 in eight (15.4%). MSI-positive tumors were inversely correlated with p53 expression (p = 0.0007); in addition, the percent of p53-expressing cells decreased as the number of MSI-positive loci increased. MSI-positive tumors were correlated with a larger tumor size (p = 0.04), lymph-node metastasis (p = 0.001), and advanced clinical stage (p = 0.0006). These data demonstrate the existence of two subsets of primary breast cancers: one characterized by MSI, the other by p53 expression. MSI-positive patients had a more advanced and/or aggressive disease.