Davide Brunetti

Expression of cyclin-dependent kinases and CDC25a phosphatase is related with recurrences and survival in women with peri- and post-menopausal breast cancer

Progression through the mammalian cell cycle is regulated by cyclin—cyclin-dependent kinase (CDKs) complexes that are activated throughout the cell cycle. Alteration in cell cycle control could lead to proliferation and tumourogenesis. This study was designed to analyse, at messenger RNA (mRNA) level, cyclins and CDKs involved in the retinoblastoma pathway, as well as cell division cycle 25a phosphatase (CDC25a), which activates some of the CDKs that were analysed. The aim of the study was to determine the possible prognostic relevance of these molecules in 73 women with peri- and post-menopausal breast cancer. Cyclins A, D1 and E; CDKs 2, 4 and 6 and phosphatase CDC25a expression status were analysed in primary tumours at mRNA level, by reverse transcriptase polymerase chain reaction analysis in paraffin-embedded primary breast cancers. High expression levels of CDK2, CDK4 and CDC25a were related to tumour recurrence. Over-expression of CDK2 and CDC25a was also associated with reduced overall survival; moreover, the CDK2 expression level was able to define a short-living cohort of patients with tumour-positive lymph nodes. CDK2, CDK4 and CDC25a can be used as reliable biomarkers to predict prognosis in women with peri- and post-menopausal breast cancer.

Evidence of multiple infectious agents in mycosis fungoides lesions

The etiology of mycosis fungoides (MF) remains to be determined. Several studies have proposed a viral etiology with controversial results. In this case-control study we investigated the presence of Epstein-Barr virus (EBV) and the debated presence of Human T-cell lymphotrophic virus I (HTLV-I) sequences, by polymerase chain reaction on nucleic acid extracts from formalin-fixed paraffin-embedded skin biopsies. Moreover, by a multivariate approach we analyzed in the same case-control study also the contribution of two previously examined pathogens: Hepatitis C virus (HCV) and Borrelia burgdorferi (Bb). Significant differences in the frequency of infectious agents in cases and controls were detected for Bb, HTLV-I and EBV. In MF patients we found the concurrent presence of two or three of these pathogen sequences in 21 out of 83 cases, but only in 1 out of 83 healthy controls. Our results suggest that the persistence of multiple infectious agents may cause a long-term antigenic stimulation contributing to the malignant transformation of T lymphocytes, especially when associated with HTLV-I like sequences. However, these infectious agents do not seem to have effects on disease progression.

Malignant tumors in first-degree relatives of cancer patients aged 0–25 years (province of Trieste, Italy)

To determine whether the occurrence of first and second primary malignancies in first‐degree relatives of cancer patients aged 0–25 years (probands) differed from that in the general population, a cohort study was carried out on 860 relatives of 265 probands living in the province of Trieste, Italy. During the follow‐up period (median duration = 28 years, 25th–75th percentile = 20–34), the relatives developed 103 first primary cancers vs. 88.9 expected for a standardized incidence ratio (SIR) of 1.2 (p = 0.2). Significantly elevated risks were found for melanoma in the parents of probands aged 15–25 years with melanoma (SIR = 15.0, p = 0.002), for hemolymphatic malignancies in the fathers of probands aged 0–14 years with brain tumors (SIR = 13.3, p = 0.0005) and for hemolymphatic cancers in relatives as a whole of probands aged 15–25 years with lymphomas (SIR = 4.5, p = 0.01). During the follow‐up period, 7 relatives with a first primary cancer had a subsequent malignancy vs. 4.2 expected for an SIR of 1.7 (p = 0.3). Our results indicate that young cancer patients per se should not to be considered as a factor that usually increases the risk of developing malignant tumors among their first‐degree relatives, except when a known cancer family syndrome or predisposition is recognized.

Cancer risk in first-degree relatives of children with malignant tumours (Province of Trieste, Italy).

We conducted a population‐based cohort study in the province of Trieste, Italy, to assess whether the first‐degree relatives of children with malignancies had an increased risk of cancer compared with the general population. We examined cancers occurring in all first‐degree relatives of children who experienced malignancies under the age of 15 years between 1971 and 1993 (probands). A cohort of the 394 relatives of the 125 probands contributed 7,939 person–years of observation. Among the relatives as a whole, we found a statistically significant increased risk of developing all malignancies except non‐melanoma skin carcinoma (21 observed relatives with cancer and 12.46 expected, for a standardized incidence ratio [SIR] of 1.69), of developing breast cancer (SIR = 3.09) and of developing haemolymphatic system neoplasms (SIR = 4.03). This was mainly due to the excess cancer risk in the relatives of probands with intracranial tumours, who showed a significant 3.1‐fold risk for developing all cancers but non‐melanoma skin tumours. Our findings and the previously reported steep rise in the incidence of childhood brain tumours in our area may imply that not only genetic factors but also shared environmental agents might be involved in the observed aggregation of cancer in the families of probands with intracranial tumours. Int. J. Cancer 73:822–827, 1997.

Family history of cancer and risk of second malignancies in young cancer patients in Trieste, Italy

We carried out a cohort study in the Italian province of Trieste (2001 population, 242,000) to ascertain whether the risk of a subsequent primary cancer among 265 individuals diagnosed with a first malignancy at ages up to 25 years between 1971 and 1993 differed from that in the general population and to evaluate the effect of cancer family history, quantified by the family risk index (FRI), on the occurrence of second primaries. During the follow‐up (median duration = 10 years; 25th–75th percentile = 2–16), 15 cohort members developed a second cancer vs. 1.60 expected for a standardized incidence ratio (SIR) of 9.4 (p < 0.0001). The overall SIR fell to 4.7 (p = 0.004) after excluding the 8 patients with well‐known cancer‐predisposing conditions (SIR = 300.0; p < 0.0001) and the 50 with a positive family history (FRI ≥ 1.0) of malignant tumors (SIR = 20.0; p < 0.0001). Among 114 patients treated with radiotherapy and chemotherapy for their first neoplasms and not affected by predisposing disorders, 23 with a positive family history of cancer showed a 6.4‐fold excess risk of second primaries (p = 0.008) compared with 91 with a negative history (FRI < 1.0). It is imperative that clinicians carefully and regularly evaluate cancer family history of young patients with malignancies. This would enable them to identify possible individual and familial features in patients at higher risk of multiple primaries and to adopt more suitable preventive and therapeutic measures.

Metformin and aspirin treatment could lead to an improved survival rate for Type 2 diabetic patients with stage II and III colorectal adenocarcinoma relative to non-diabetic patients

Metformin, the drug of choice in the treatment of type 2 diabetes mellitus (DM2), in addition to aspirin (ASA), the drug prescribed for cardioprotection of diabetic and non-diabetic patients, have an inhibitory effect on cancer cell survival. The present population-based study conducted in the province of Trieste (Italy), aimed to investigate the prevalence of DM2 in patients with colorectal adenocarcinoma (CRC) and survival for CRC in diabetic and nondiabetic patients. All permanent residents diagnosed with a CRC between 2004 and 2007 were ascertained through the regional health information system. CRC-specific and relative survival probabilities were computed for each group of patients defined by CRC stage, presence or absence of DM2 treated with metformin, and presence or absence of daily ASA therapy. A total of 515 CRC patients without DM2 and 156 with DM2 treated with metformin were enrolled in the study. At the time of CRC diagnosis, 71 (14%) nondiabetic and 39 (25%) diabetic patients were taking ASA daily. The five-year relative survival for stage III CRC was 101% [95% confidence interval (CI)=76-126] in the 18 patients with DM2 treated with metformin and ASA, 55% (95% CI=31-78) in the 23 without DM2 treated with ASA, 55% (95% CI=45-65) in the 150 without DM2 not taking ASA, and 29% (95% CI=13-45) in the 43 with DM2 treated with metformin, however not with ASA. The findings support the hypothesis of a possible inhibitory effect of metformin and ASA on CRC cells. Randomized controlled trials are required to verify this hypothesis.