Gender-related differences in patients with carcinoid syndrome: new insights from an Italian multicenter cohort study.

BACKGROUND: The incidence of neuroendocrine neoplasm (NEN) and related carcinoid syndrome (CaS) has increased markedly in recent decades, and women appear to be more at risk than men. As per other tumors, gender may be relevant in influencing the clinical and prognostic characteristics of NEN-associated CS. However, specific data on carcinoid syndrome (CaS) are still lacking. PURPOSE: To evaluate gender differences in clinical presentation and outcome of CaS. METHODS: Retrospective analysis of 144 CaS patients from 20 Italian high-volume centers was conducted. Clinical presentation, tumor characteristics, therapies, and outcomes (progression-free survival, PFS, overall survival, OS) were correlated to gender. RESULTS: Ninety (62.5%) CaS patients were male. There was no gender difference in the site of primary tumor, tumor grade and clinical stage, as well as in treatments. Men were more frequently smokers (37.2%) and alcohol drinkers (17.8%) than women (9.5%, p = 0.002, and 3.7%, p = 0.004, respectively). Concerning clinical presentation, women showed higher median number of symptoms (p = 0.0007), more frequent abdominal pain, tachycardia, and psychiatric disorders than men (53.3% vs 70.4%, p = 0.044; 6.7% vs 31.5%, p = 0.001; 50.9% vs. 26.7%, p = 0.003, respectively). Lymph node metastases at diagnosis were more frequent in men than in women (80% vs 64.8%; p = 0.04), but no differences in terms of PFS (p = 0.51) and OS (p = 0.64) were found between gender. CONCLUSIONS: In this Italian cohort, CaS was slightly more frequent in males than females. Gender-related differences emerged in the clinical presentation of CaS, as well as gender-specific risk factors for CaS development. A gender-driven clinical management of these patients should be advisable.

Lynch syndrome-associated endometrial cancer patient with a rare novel germline likely pathogenic variant of MSH2 gene: A case report.

The Lynch syndrome (LS) is an autosomal dominant condition usually characterized by germline pathogenic variants in DNA mismatch repair (MMR) genes. Despite the guidelines now available, determining the pathogenicity of rare variants remains challenging, as the clinical significance of a genetic variant could be uncertain, but it may represent a disease-associated variation in the aforementioned genes. In this case report we will describe the case of a 47 years-old female affected by endometrial cancer (EC) with an extremely rare germline heterozygous variant in the MSH2 gene (c.562G > T p. (Glu188Ter), exon 3) that is likely pathogenic, and a family history consistent with LS.

Hypersensitivity to platinum salts according to BRCA status in ovarian cancer: A retrospective analysis of clinical outcomes and systematic review of literature.

BACKGROUND: Hypersensitivity reactions (HSRs) to platinum are an important issue in the treatment of patients (pts) with ovarian cancer (OC). Germline BRCA mutations have been proposed as a risk factor. We aimed at evaluating the incidence and severity of HSRs to platinum in OC pts. with known BRCA status. PATIENTS AND METHODS: We retrospectively analyzed 432 pts. from 5 Italian Centers. In addition, we performed a systematic review and meta-analysis of published series. RESULTS: Four hundred nine pts. received at least one prior platinum-based treatment line: 314 were BRCA wild type (77%) and 95 were BRCA mutated (23%). There was no statistical difference in exposure to platinum. Incidence of any grade HSRs was higher among BRCA mutated pts. [9% vs 18%, p = 0.019] and the time-to-HSRs curves show that the risk increases with the duration of platinum exposure, in BRCA mutated pts. more than in BRCA wild type. A multivariable analysis showed that harboring a germline BRCA mutation was related to a higher incidence of HSRs (HR: 1.84, 95% CI 1.00-3.99, p = 0.05) while having received pegylated liposomal doxorubicin (PLD) was related to a lower incidence of HSRs (HR: 0.03 95% CI 0.004-0.22, p = 0.001). The systematic review confirmed the higher incidence of HSRs in BRCA mutated pts., though heterogeneity among series was significant. CONCLUSIONS: In OC pts. with BRCA mutations, there is a significantly higher incidence of HSRs to carboplatin, not justified by longer drug exposure. On the other hand, PLD exerted a protective role in our series.

Accuracy of CT and MRI to assess resection margins in primary malignant bone tumours having histology as the reference standard.

AIM: To evaluate the accuracy of magnetic resonance imaging (MRI) and computed tomography (CT) in assessing the resection margins of primary malignant bone tumours. MATERIALS AND METHODS: Resected primary malignant bone tumour specimens removed from 46 patients (27 male; mean age: 48±22 years) were imaged using MRI (fat-saturated proton density-weighted and three-dimensional fat-suppressed T1-weighted gradient-recalled-echo) and CT immediately after surgery. A radiologist and an orthopaedist evaluated bone and soft-tissue margins of the specimens on both examinations. Histological evaluation was performed by a senior orthopaedic oncology pathologist. Margins were classified as R0 (safe margins), R1 (residuals between 0 and 1 mm), and R2 (macroscopic residuals). Cohen's k, chi-square, and McNemar's statistics were used. RESULTS: Having histology as the reference standard, reproducibility of the radiologist ranged from moderate (k=0.544) to substantial (k=0.741) for bone and soft-tissue margins on CT, respectively, while that of the orthopaedist ranged from fair (k=0.316) to moderate (k=0.548). When comparing R2 and R0+R1 scores, reproducibility of readers' evaluation of bone margins increased ranging from substantial (k=0.655) to perfect (k=1.000). Inter-reader agreement ranged from fair (k=0.308) to substantial (k=0.633). Accuracy of the radiologist and orthopaedist ranged from 76% to 83% and from 68% to 72%, respectively. When comparing R2 and R0+R1 scores, the accuracy of both readers ranged from 83% to 100%. There was no association between local recurrence and margin scores of histology, MRI, and CT (p≥0.058). CONCLUSIONS: MRI and CT may be useful for extemporaneous analysis of resection margins of primary malignant bone tumours, although wide accuracy variability between the different imaging methods was observed.

Epidemiological and clinical features of HEV infection: a survey in the district of Foggia (Apulia, Southern Italy).

In this study we assessed the seroprevalence of hepatitis E virus (HEV) infection in both the Italian population and immigrants from developing countries in Foggia (Apulia, Southern Italy). The seroprevalence of HEV was determined in 1217 subjects [412 (34%) immigrants and 805 Italian subjects (blood donors, general population, HIV-positive, haemodialysis patients)]. Serum samples were tested for anti-HEV and confirmed by Western blot assay; in positive patients HEV RNA and genotype were also determined. There were 8·8% of patients that were positive to anti-HEV, confirmed by Western blot. The prevalence in immigrants was 19·7%, and in Italians 3·9% (blood donors 1·3%, general population 2·7%, HIV-positive patients 2·0%, haemodialysis patients 9·6%). Anti-HEV IgM was found in 38/107 (35·5%) of the anti-HEV-positive serum samples (34 immigrants, four Italians). This study indicates a higher circulation of HEV in immigrants and Italian haemodialysis patients, whereas a low prevalence of HEV antibodies was seen in the remaining Italian population.

Development and specificities of anti-interferon neutralizing antibodies in patients with chronic hepatitis C treated with pegylated interferon-α.

Only limited data are available on the development of neutralizing antibodies (NAB) in patients with chronic hepatitis C (CHC) treated with pegylated interferon-α (PEG-IFN-α). The aim of this study was to evaluate the immunogenicity of PEG-IFN-α when administered to CHC patients who had or had not previously received standard IFN-α therapy. In addition, the specificities of NAB, together with the ability of leucocyte (LE) -IFN-α to re-establish therapeutic responsiveness in NAB-positive patients, were evaluated. NAB were assessed using a quantitative, standardized, virus-induced cytopathic effect assay. The seroconversion rate to PEG-IFN-α was higher in patients who had received previous standard IFN-α treatment than in those treated exclusively with PEG-IFN-α. Also, NAB produced during PEG-IFN-α therapy were unable to neutralize LE-IFN-α entirely, even though they can neutralize several IFN-α subtypes. In addition, the results indicate that a change to LE-IFN-α therapy can be associated with restoration of clinical responses in NAB-positive patients who had become resistant after showing an initial response to PEG-IFN-α treatment. This study emphasizes the importance of evaluating NAB development in CHC patients who become resistant to PEG-IFN-α treatment, and suggests management alternatives for patients who develop NAB.

Immigration and hepatitis B virus: epidemiological, clinical and therapeutic aspects.

This study in Italy aimed to evaluate the epidemiological, clinical and therapeutic aspects of hepatitis B virus (HBV) infection in a population of recent (< 6 months) immigrants. Between February 2003 and December 2004, 83 (9.3%) out of 890 immigrants tested positive for hepatitis B surface antigen. All were men and 62.6% came-from Africa, 21.6% from Asia and 16.8% from Eastern Europe. About half (54.3%) of the patients had elevated alanine aminotransferase levels and detectable serum HBV DNA. Genotype distribution was as follows: E (20 cases), D (14 cases) and A (11 cases). Our study underscores the potential of migratory flow to introduce genotype non-D hepatitis B virus into our country.

Combined effect of Neridronate and specific antibiotic therapy in a case of tuberculous spondylodiscitis.

Because of the increased incidence of tuberculosis (TB) in recent years, infective spondylitis is still a major problem in the world. In skeletal TB the spine is the most often involved and lumbosacral spine involvement is rare. Nowadays early diagnosis and new medical treatment can reduce the incidence of the serious skeletal sequelae and the number of surgery procedures in spinal TB. We present a case of TB spondylodiscitis characterized by a rapid and progressive clinical and radiological improvement after treatment with Neridronate and chemotherapic drugs. Our data suggest that in the treatment of the TB spondylodiscitis the combined use of these drugs is a good alternative to stimulate bone reparative process to the chemotherapy alone. To our knowledge this is first case of a patient with TB discitis treated with Neridronate. Further studies are necessary to confirm the effectiveness of Neridronate treatment added to antiTB drugs in spondylodiscitis.

Immigration and hepatitis B virus: epidemiological, clinical and therapeutic aspects

This study in Italy aimed to evaluate the epidemiological, clinical and therapeutic aspects of hepatitis B virus [HBV] infection in a population of recent [< 6 months] immigrants. Between February 2003 and December 2004, 83 [9.3%] out of 890 immigrants tested positive for hepatitis B surface antigen. All were men and 62.6% came from Africa, 21.6% from Asia and 16.8% from Eastern Europe. About half [54.3%] of the patients had elevated alanine aminotransferase levels and detectable serum HBV DNA. Genotype distribution was as follows: E [20 cases], D [14 cases] and A [11 cases]. Our study underscores the potential of migratory flow to introduce genotype non-D hepatitis B virus into our country

HIV-1 biological phenotype and predicted coreceptor usage based on V3 loop sequence in paired PBMC and plasma samples.

Paired PBMCs and plasma samples from 34 HIV-infected patients were studied to verify the relationship between coreceptor use based on genotyping of V3 region of HIV-1 envelope gp120 and biological phenotype with virus isolation and subsequent correlation to clinical characteristics. The "11/25" rule, geno2pheno and PSSM were compared. All SI patients were HIV-1 subtype B (p=0.04) and had a lower CD4 count than NSI patients (p=0.01), while no differences were observed in mean HIV-RNA (log) (p=0.6). SI phenotype was not associated with AIDS-defining events (p=0.1) or with concurrent antiretroviral therapy (p=0.4). With geno2pheno, which shows the highest sensibility (83%), an X4 or X4/R5 genotype in PBMC DNA was also associated to B-subtype and lower CD4 count (p=0.01) compared to R5 isolates. Based on plasma RNA sequences, the predicted coreceptor usage agreed with PBMC DNA in 79% of cases with the "11/25" rule, 82% with geno2pheno, and 82% with PSSM. A X4 virus in plasma (but not in PBMCs) was significantly associated with HAART in all three methods (p=0.01 for "11/25" rule, p=0.01 for geno2pheno and p=0.03 for PSSM). Due to viral mixtures and/or difficulties in genotype interpretation, current V3 sequence-based methods cannot accurately predict HIV-1 coreceptor use.

Risk factors and outcome among a large patient cohort with community-acquired acute hepatitis C in Italy.

BACKGROUND: The epidemiology of acute hepatitis C has changed during the past decade in Western countries. Acute HCV infection has a high rate of chronicity, but it is unclear when patients with acute infection should be treated. METHODS: To evaluate current sources of hepatitis C virus (HCV) transmission in Italy and to assess the rate of and factors associated with chronic infection, we enrolled 214 consecutive patients with newly acquired hepatitis C during 1999-2004. The patients were from 12 health care centers throughout the country, and they were followed up for a mean (+/- SD) period of 14+/-15.8 months. Biochemical liver tests were performed, and HCV RNA levels were monitored. RESULTS: A total of 146 patients (68%) had symptomatic disease. The most common risk factors for acquiring hepatitis C that were reported were intravenous drug use and medical procedures. The proportion of subjects with spontaneous resolution of infection was 36%. The average timespan from disease onset to HCV RNA clearance was 71 days (range, 27-173 days). In fact, 58 (80%) of 73 patients with self-limiting hepatitis experienced HCV RNA clearance within 3 months of disease onset. Multiple logistic regression analyses showed that none of the variables considered (including asymptomatic disease) were associated with increased risk of developing chronic hepatitis C. CONCLUSIONS: These findings underscore the importance of medical procedures as risk factors in the current spread of HCV infection in Italy. Because nearly all patients with acute, self-limiting hepatitis C--both symptomatic and asymptomatic--have spontaneous viral clearance within 3 months of disease onset, it seems reasonable to start treatment after this time period ends to avoid costly and useless treatment.

Extended lamivudine treatment in patients affected by chronic active anti-Hbe positive hepatitis.

The aim of the study was to evaluate the biochemical and virological response and the histological changes in 34 chronic hepatitis B anti-Hbe-positive patients treated with lamivudine at 100 mg/day orally for five years. Liver biopsies were performed in all patients at least 6 months before starting therapy and 3 months after the stop of treatment. After 12 months of therapy, 70.6% of patients showed evidence of HBV DNA clearance and normal ALT levels; 64.7% and 55.8% of patients maintained a complete response after two and three years of therapy, respectively, 47% after four years and 44.1% after five years. The histological activity index improved in 13%, remained unchanged in 61% and worsened in 26% of patients with tyrosine-methionine-aspartate-aspartate (YMDD) variants compared to 63, 27 and 0% without variants, respectively. The authors conclude that the clinical benefit of lamivudine is greatest for patients without YMDD variants after 5 years of extended treatment.

Cryoglobulinemia in subjects with HCV infection alone, HIV infection and HCV/HIV coinfection.

OBJECTIVES: To assess the prevalence of cryoglobulinemia in three groups of patients: HCV-positive/HIV-negative, HCV/HIV co-infected and HIV mono-infected. METHODS: From September 2002 to December 2003, 58 patients with documented HCV infection, 70 subjects with HIV/HCV co-infection, and 48 subjects with HIV infection alone were enrolled. Serum samples were tested for detectable cryoglobulins, liver enzymes, HCV viral load and HCV genotypes. Plasma HIV-RNA levels and CD4+ cell count were also evaluated in HIV-positive subjects. RESULTS: Cryoglobulinemia was detected in 24.1% HCV mono-infected, 14.2% HCV/HIV co-infected and 6% HIV mono-infected patients. A significant statistical correlation was found between the presence of cryoglobulins and HCV infection (P = 0.03), while cryoglobulins were unrelated to HIV mono-infection (P = 0.16) and HCV/HIV co-infection (P=0.7). No significant correlation was observed between the presence of cryoglobulinemia and alanine transaminase (ALT) levels, HCV viremia and duration of HCV infection. Circulating cryoglobulins in HIV patients were not correlated with plasma HIV viral load, CD4+ cell count or duration of HIV infection. Only two HCV mono-infected patients complained of arthralgia. CONCLUSION: A similar rate of cryoglobulinemia prevalence was detected in the patient groups with an HCV-related infection. HIV infection does not appear to play a significant role in cryoglobulin production.

Impact of unreported HIV-1 reverse transcriptase mutations on phenotypic resistance to nucleoside and non-nucleoside inhibitors.

An extended spectrum of HIV-1 reverse-transcriptase (RT) mutations in HAART-treated patients has been recently described. To verify the possible association of previously unreported RT mutations with a decrease of phenotypic susceptibility to nucleoside (NRTIs) and non-nucleoside (NNRTIs) RT inhibitors, the RT sequence of 328 HIV-1-positive patients (102 naïve and 226 treated with HAART participating in either the PhenGen or Genpherex study) was analyzed. All treated patients were tested at the time of therapeutic failure with both phenotypic (Antivirogram, Virco) and genotypic analyses (VircoGen); the frequency of RT substitutions (positions 1-240) with respect to consensus B was compared to that of naïve patients using a Chi-square test. Amino acid changes at 13 positions not included in the IAS list of resistance-associated mutations were detected more frequently in treated than in naïve subjects. The mutations involving 10 of these positions were associated with a reduced susceptibility to antiretroviral drugs; K20R, T39A, K43EQN, E203KD, H208Y, and D218E were correlated with NRTI resistance while mutations K101EQP, H221Y, K223EQ, L228HR were associated to NNRTI resistance. A correlation was found between K20R and lamivudine resistance (P = 0.006) while T39A (P = 0.005), K43EQN (<0.001), E203KD (P = 0.010), and H208Y (P = < 0.001) seemed to be associated with a previous use of zidovudine and stavudine and with the development of thymidine analog resistance. For H208Y, an association with use/resistance to abacavir (P = 0.004) was also noted. D218E showed a weak association to didanosine resistance (P = 0.013). The data confirm that previously unreported mutations are associated with antiretroviral drug experience and, more importantly, with a reduced susceptibility to NRTIs and NNRTIs.

Access to HAART in HIV-infected immigrants: a retrospective multicenter Italian study.

Since 1996, AIDS has declined in the Italian population, but cases in foreign patients, including both recent immigrants and long-term residents, have increased from 3.9% in 1995-1996 to 15.4% in 2001-2002. This increase can only be partly explained by a higher migratory flow and might reflect a delayed access to health facilities and to antiretroviral therapy in migrants. We performed a survey for the year 2003 of HIV-infected immigrants to Italy from countries outside the European Union to verify which factors might influence a lack of access to highly active antiretroviral therapy (HAART). Italian centers of infectious diseases were requested to send sociodemographic and clinical data of HIV-infected immigrant patients. A total of 553 HIV-infected immigrants (49.9% women) were evaluated, representing 6.5% of all HIV-infected patients from these centers. The mean duration of residency in Italy was 6.6 +/- 5.0 years. The country of origin was Africa (64.5%), North and South America (24.2%), Eastern Europe (7.0%), and Asia (3.8%). A total of 407 of 553 patients (73.6%) were taking antiretroviral drugs at the time of screening. Females presented a younger age (p = 0.001), a lower frequency of Centers for Disease Control (CDC) stage B/C (p = 0.008) and a more frequent heterosexual exposure to HIV (p < 0.001), while no differences were observed for time of first positive serology (p = 0.7). CD4 cell count (p = 0.9) and log plasma HIV-RNA (p = 0.1). Characteristics of HAART patients were compared to those of nontreated patients, despite a CD4 cell count less than 350 cells/mm(3). No significant difference was found for gender, country of origin, risk factor, and years of Italian residence, while legal immigrants (p = 0.018) and registered in the National Health Service (p = 0.014) were significantly more likely to receive HAART compared to illegal immigrants.

[Epidemiologic multicenter study of the prevalence of hepatitis in hospitalised immigrants in Italy in the year 2002]. / Studio epidemiologico multicentrico sulla prevalenza di epatiti virali in immigrati ospedalizzati in Italia nel 2002.

AIM: To retrospectively evaluate the prevalence of hepatitis in immigrant patients hospitalised in 48 Italian Operative Unit of Infectious Diseases during 2002. METHODS AND PATIENTS: in our study we included the clinical data of 2255 immigrated patients hospitalised, during the period between 01/01/2002-31/12/2002, in ordinary admission or in Day Hospital in Infectious Diseases O.U. and we have evaluated the prevalence of hepatitis in this population. RESULTS: 282 patients affected by hepatitis has been evidenced (12.5% of total hospitalised patients). The prevalent form was HBV-related (41.6% in chronic forms and 48.4% in acute), while the rate for HCV were less (37.5% in chronic and 3% in acute). The most part of patient were men (59.6%), with a mean age of 34.2 years and come from east-European countries (34.39%). CONCLUSION: Viral hepatitis are the third infectious diseases evidenced in immigrated population. HBV-chronic hepatitis is the prevalent form in immigrated patients, as expression of absence of vaccine prophylaxis in many countries. HCV-form was less frequent and it is particularly presents in east-European patients, probably as expression of endogenous drug abuse.

Simit epidemiological multicentric study on hospitalized immigrants in Italy during 2002.

The aim of this article is to retrospectively evaluate the patient characteristics and the most common infectious diseases in immigrant patients hospitalized in 46 Italian infectious disease clinics during 2002. The main Italian infectious disease clinics were invited to fill in a questionnaire that regarded the number and type of hospital admissions, the country of origin, and demographic features (age, sex, and resident state) of immigrants. A total of 46 clinics including 2255 patients participated in the study. Most patients were men (63%) with an age between 16 and 40 years (63.4%) covered by the National Health Service (71%) and coming from Africa (44.3%). The main infectious diseases observed were: 378 (16.76%) cases of HIV infection, 303 (13.43%) cases of tuberculosis diseases, 282 (12.5%) cases of various forms of viral hepatitis, 177 (7.84%) cases of respiratory diseases, and 196 (8.69%) gastrointestinal diseases. Tropical diseases found were 134 (5.94%) including 95 cases of malaria (70.9%). In conclusion, a broad range of diseases was noted in immigrants which were directly correlated with conditions of poverty. Only a few tropical diseases were diagnosed and therefore the immigrant should not be considered as an infectious disease carrier.

Peginterferon alfa-2b treatment for patients affected by acute hepatitis C: presentation of six case reports.

Acute hepatitis C often progresses to chronic infection (70%). In this clinical study, we evaluated if early treatment with peginterferon alfa-2b can prevent acute hepatitis C from developing into a chronic disease. Six patients with acute hepatitis C, based on a well-documented hepatitis C virus (HCV) seroconversion with high alanine aminotransferase (ALT) levels (> 10 x ULN) and persistent HCV RNA titers after 3 months from disease onset, were consecutively treated with peginterferon alfa-2b at 1.5 microg/kg/weekly/sc for 24 weeks. The viral load was quantified by PCR assay. Response was defined as undetectable HCV RNA and normal ALT levels at the end of therapy and after a 6-month follow-up. All patients completed therapy; at the end of therapy, 5/6 patients (83%) responded and no relapses were observed during follow-up. No correlation was found between treatment response and pretreatment viral load, viral genotype, and interval between acute infection diagnosis and start of therapy.

Prevalence of HIV infections in hospitalised immigrants in Clinics of Infectious Diseases in Italy: a multicentric survey.

Our aim was to evaluate the prevalence of HIV infection in immigrants hospitalised in infectious disease settings in Italy during 2002. Each participating centre filled in a CRF which regarded the number of immigrants hospitalised in ordinary regime or in day-hospital during 2002 and, for HIV-positive patients only, some demographic (age, sex, origin) and clinical features (only HIV positivity or AIDS, new diagnosis or not, diagnosis of opportunistic infections). A total of 46 Infectious Diseases Units participated in the study and a total number of 2255 patients were tested for anti-HIV, irrespective of the cause of hospitalization, with 378 (16%) cases of positivity. Women accounted for 47.9%; the mean age of the population was 34.5 years. African patients showed a higher prevalence of HIV infections than subjects from other geographical areas (61.9% of all cases). Most HIV-infected patients were unaware of their positivity. In conclusion, HIV infection represents one of the main health problems among immigrants, particularly of African origin.