Predictors of germline status for hereditary melanoma: 5 years of multi-gene panel testing within the Italian Melanoma Intergroup.

BACKGROUND: The incidence of cutaneous melanoma is increasing in Italy, in parallel with the implementation of gene panels. Therefore, a revision of national genetic assessment criteria for hereditary melanoma may be needed. The aim of this study was to identify predictors of susceptibility variants in the largest prospective cohort of Italian high-risk melanoma cases studied to date. MATERIALS AND METHODS: From 25 Italian centers, we recruited 1044 family members and germline sequenced 940 cutaneous melanoma index cases through a shared gene panel, which included the following genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP, MITF and ATM. We assessed detection rate according to familial status, region of origin, number of melanomas and presence and type of non-melanoma tumors. RESULTS: The overall detection rate was 9.47% (5.53% analyzing CDKN2A alone), ranging from 5.14% in sporadic multiple melanoma cases (spoMPM) with two cutaneous melanomas to 13.9% in familial cases with at least three affected members. Three or more cutaneous melanomas in spoMPM cases, pancreatic cancer and region of origin predicted germline status [odds ratio (OR) = 3.23, 3.15, 2.43, P < 0.05]. Conversely, age > 60 years was a negative independent predictor (OR = 0.13, P = 0.008), and was the age category with the lowest detection rate, especially for CDKN2A. Detection rate was 19% when cutaneous melanoma and pancreatic cancer clustered together. CONCLUSIONS: Gene panel doubled the detection rate given by CDKN2A alone. National genetic testing criteria may need a revision, especially regarding age cut-off (60) in the absence of strong family history, pancreatic cancer and/or a high number of cutaneous melanomas.

Surveillance of infectious diseases in the Italian military as pre-requisite for tailored vaccination programme.

Surveillance and control of infectious diseases in the Italian military include prompt reporting of all occurring cases and prophylaxis through compulsory vaccination practices. The last mandatory immunisation programme in the Italian military was launched in 1998 (more than 10 years after the previous programme was introduced in 1986-1987) and it was planned according to the epidemiological data herein reported. The incidence rates (number of cases x 100000 subjects) of infectious diseases notified during the period 1976-1980 were compared with the corresponding figures notified 15 years later (1991-1995). An increase of three airborne-transmitted viral diseases--varicella, rubella and measles--counterbalanced by a decrease of other infectious diseases, such as mumps, typhoid fever, tuberculosis, viral hepatitis, scabies, syphilis and gonorrhea, was observed. This may be related to improvements in the general hygienic conditions and more responsible sexual behaviour among Italian military recruits. Moreover, incidence rates of cases notified in the military were compared with those notified in the general population of the same sex- and similar age-range (15-24 years) over a 12-year period (1986-1997), to monitor the epidemiological situation in relation to (a) potential risk factors specifically linked to military life and (b) protective effects induced by specific vaccinations. Airborne-transmitted viral diseases, such as varicella, rubella, measles and mumps--which are usually underreported among civilians--show higher incidence rates in the military. Meningococcal meningitis shows higher incidence rates in the military in 1986 and 1987 (before the introduction of mandatory specific vaccination) as well as in 1995-1997 (main etiologic agent N. meningitidis serogroup B); similar rates were instead observed in the other years. Incidence rates for typhoid fever are generally lower in the military, despite the community life, probably reflecting the protective efficacy of specific vaccine. Hepatitis A and B show similar rates between military and civilian population. Finally, pulmonary tuberculosis generally shows higher rates in the military. These data therefore allow the conclusion that the only infectious diseases, for which possible risk factors in the military life may be hypothesised, seem to be meningococcal meningitis and perhaps pulmonary tuberculosis. Epidemiological surveillance of infectious diseases in the military as a pre-requisite for appropriate public health intervention strategy represents a good model to be followed also in larger contexts.

Tuberculin skin reactivity in Italian military recruits tested in 1996-1997.

In 1996-1997 data was collected and a Mantoux tuberculin test performed in 2882 Italian military recruits aged 18-23 years in order to establish the prevalence of tuberculin reactivity. In addition, the annual risk of infection, defined as the probability that a non-infected individual would be infected during the following year, was calculated. Of the 2882 recruits, 513 had received a BCG vaccination, the remaining 2369 had not. The overall prevalence of subjects with a tuberculin skin reaction size >5 mm (the cut-off point for positivity corresponding to the antimode in the reaction size frequency curve) was 6.1% (144/2369). The prevalence of skin reactivity increased with age but remained similar when related to area of residence, duration of father's school education and family size. The same general trend was observed if the standard pre-established cut-off point of 10 mm was used. In this case the overall prevalence of a positive skin reaction was 4% (95/2369). The annual risk of infection was 0.3% for a prevalence of tuberculin skin reactivity of 6.1% (cut-off point 5 mm) and 0.19% for a prevalence of 4% (cut-off point 10 mm). Analysis of the population sample vaccinated with BCG showed a lack of correlation between the positive reaction after vaccination reported retrospectively by the subject and the current skin reaction observed by the physician in this study (K = 0.254). Moreover, a significant difference was observed between the skin reaction in subjects vaccinated with BCG in 1993-1994 (average size 12.5 mm) and that of subjects vaccinated in 1995-1996 (average size 10.1 mm, P<0.01), probably as a consequence of mycobacteria circulating in the general population which act as a natural booster in people already vaccinated with BCG. A booster effect of tuberculin in Mantoux assays also cannot be excluded.

Prevalence of markers of exposure to Bordetella pertussis among Italian young adults.

Titers of serum antibody and cell-mediated immunity (CMI) to Bordetella pertussis antigens were assessed in a cohort of Italian military school students for whom the coverage of pertussis vaccination was low. The overall prevalence of IgG antibody above the minimum level of detection (MLD) was 71.6% for pertussis toxin (PT), 81% for pertactin (PRN), and 99% for filamentous hemagglutinin (FHA). Levels of IgA antibody to PT above the MLD were detected in 15.9% of the study participants. CMI to FHA, PRN, and PT was positive in 97%, 100%, and 82% of tested individuals, respectively. Only 9.7% of the participants had neither antibody nor CMI specific to B. pertussis antigens. In the 5-month clinical, microbiological, and serological follow-up conducted during a high-risk period of pertussis, no cases of pertussis were detected. These data, in particular CMI, demonstrate that most Italian young adults are specifically primed against B. pertussis, which should be taken into consideration when future policy on pertussis vaccination is being made in Italy.

Synthesis and in vitro antitumor activity evaluation of 9-substituted 1,2,3,4-tetrahydrocarbazoles.

A series of 9-acetamido-1,2,3,4-tetrahydrocarbazoles (2) and 9-(aminoalkyloxyethyl)-1,2,3,4-tetrahydrocarbazoles (4) were prepared and tested for their in vitro antitumor activity. Compounds 4 are highly cytotoxic in almost all subpanel cell lines when tested at 10(-4) M, but showed a weak activity at the lowest concentrations employed.

Synthesis and antihypertensive activity evaluation of indole derivatives N-acetamido substituted.

The synthesis of a series of 1-(alkyl- or aryl-aminocarbonylmethyl)-2-methyl- or 2-phenyl-indoles are described. All compounds were tested for antihypertensive activity on spontaneously hypertensive rats (SHR) and some of them showed a significant reduction of the arterial pressure.