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Introduction: The immune checkpoint inhibitors (ICPIs) agents anti-T lymphocytes-associated antigen 4 (CTLA-4) and anti-programmed cell death protein-1 (PD-1) and its ligands (PD-L1/PD-L2) have opened a new scenario in the treatment of cancer. These agents can induce immuno-related adverse events (irAEs), which may affect the endocrine system. Purpose: The aim of this study was to analyze the occurrence and the course of endocrine irAEs in cancer patients treated with anti-PD-1 immunotherapy. Methods: This was a retrospective, multicentre study, involving cancer patients treated with the PD-1 inhibitors nivolumab or pembrolizumab at reference Oncology Centres. One hundred and seventy-nine consecutive patients with different types of cancer (mostly non-small cell lung cancer, melanoma, kidney cancer) were included in the study. Patients had received nivolumab (70.9%) or pembrolizumab (29.1%) for 2–33 months. The study evaluated clinical data records until the established date of July 15, 2018. The primary end point was the assessment of endocrine toxicity and possible predictive factors. Results: Endocrine toxicity occurred in 54 out of 179 patients (30.2%) and was related to thyroid dysfunction, with the exception of one case of diabetes mellitus. Thyroid toxicity occurred mostly within 2 months from the initiation of immunotherapy (83% of cases). A pre-existing thyroid dysfunction was a significant predictor of disease flare. Conclusions: Thyroid alterations are frequently associated with anti PD-1 treatment in cancer patients. Regular thyroid assessment should be performed, particularly in the first months of treatment and in patients with a pre-existing thyroid disease.

Background Bronchioloalveolar carcinoma (BAC) is a histological subtype of non-small cell lung cancer (NSCLC), particularly of adenocarcinoma. Given its multifocality and the poor activity of chemotherapy, there is no established treatment for BAC, although promising results have been achieved with inhibitors of the epidermal growth factor receptor (EGFR). No tumor marker has been validated in the diagnosis and follow-up of lung cancer, in particular to predict the outcome of treatment with EGFR inhibitors.Purpose As CA 15–3 antigen serum levels are reported to be pathologically abnormal in adenocarcinoma of the lung, we chose this tumor marker to monitor treatment with EGFR inhibitors of patients affected by adenocarcinoma with BAC features or pure BAC.Patients and methods We collected data from 26 consecutive Caucasian patients with BAC, mostly women and never smokers, who received EGFR inhibitors.Results We noticed that all patients with normal CA 15–3 serum levels at baseline (15/26, 57.7%) showed a response to EGFR inhibitors, whereas all patients with abnormal CA 15–3 serum levels (11/26, 42.3%) did not.Conclusion Our data suggest that CA 15–3 levels might be a predictive factor for the response to EGFR inhibitors in patients with BAC.

To evaluate time trends of the spectrum of AIDS-defining diseases in Italy, 1982-1996.

Summary A direct antiglobulin test (DAT) was performed in 70 patients with anti-HIV antibodies (group A: seropositive patients without or with minimal disease and group B: AIDS patients with or without malignancies). A positive DAT was found in 24 of 70 patients (34%, significantly higher compared to 0.1% in healthy controls) and a higher prevalence of positive DAT was observed in group B than in group A patients (55% versus 21% p<0.01). When comparing DAT-positive and negative patients within the same clinical group, no significant difference is seen in haemoglobin levels. There is no difference in serum bilirubin, haptoglobin or reticulocyte count between DAT-positive and negative patients altogether or in the same clinical group. AZT therapy seems to exert no significant influence on the onset of a positive DAT. The results confirm a high prevalence of positive DAT in patients with HIV antibodies, mainly in worse clinical conditions, and suggest that a positive DAT might be a prognostic factor in the clinical course of the disease.

Fifty cases of Hodgkin's disease in intravenous drug users (IVDU) have been collected by the Italian Cooperative Group on AIDS-Related Tumors (G.I.C.A.T.). Ninety-two per cent of the patients were males; the median age was 26 years. Persistent generalized lymphadenopathy (PGL) at onset was present in 54% of patients, AIDS in 9%, ARC in 9% while 28% were simply HIV-positive. The initial median absolute number of CD4 lymphocytes was 264/mmc. Opportunistic infections were diagnosed in 20% of patients. In most patients the histological pattern was that of mixed cellularity and lymphocytic depletion (76%). In almost half the initial symptom was a persistent lymph node enlargement due to PGL. In the majority of patients (58%) only a clinical staging and bone marrow biopsy could be performed due to the presence of opportunistic infections, rapid disease progression or refusal of pathologic staging procedures. One patient presented with a Waldeyer's ring involvement, but no other unusual presentations were observed. After MOPP alternated or followed by ABVD or MOPP alone, 15/29 CR (52%) and 14/29 PR (48%) were observed. The median duration of CR was 14 months, while the median survival of CR has not been reached; the median survival of patients treated with chemotherapy with CD4 values at presentation {geq}400/mmc was significantly superior to that in those with CD4 < 400/mmc. The overall median survival was 16 months. Twenty-eight per cent of patients receiving chemotherapy + radiotherapy developed opportunistic as well as non-opportunistic infections (21%). Lethal hepatic toxicity was observed in 2 patients.In conclusion, Hodgkin's disease in IVDU was not found to be associated with unusual presentations, as previously reported for homosexuals. Complete remissions could be achieved in over 50% of patients, but in IVDU non-opportunistic infections in addition to opportunistic infections may also limit treatment administration. The presence of parenchymal functional impairment due to drug abuse, or drug abuse-related infections, such as pneumonia, endocarditis and hepatitis, should lead to the choice of antitumour agents with no or only minor potential liver, lung and cardiac toxicity.

In order to assess modes of human immunodeficiency virus (HIVV) transmission from heterosexual intravenous drug users (IVDUs) to their partners, condom use and sexual habits with both steady and occasional partners were investigated. A total of 349 heterosexual IVDUs (247 men and 102 women) who ignored, at the time of interview, their HIV serostatus were interviewed. Respondents were asked for information on condom use and sexual habits for the three year period prior to the interview. Nearly 40% of IVDUs reported sexual intercourse with both steady partners and occasional partners. Fifty-four percent of their steady partners and 48% of their occasional partners were individuals who did not belong to groups at risk for HIV infection. Anal intercourse with steady partners was reported by 29% of IVDUs and 24% of IVDUs with occasional partners. Condom use during vaginal intercourse was seldom reported: 83% of IVDUs never used a condom with steady partners and 75% did not use one with occasional partners. IVDUs who were 1) unmarried, 2) enrolled in the study after 1986, 3) partners of not at-risk individuals, 4) partners of a foreigner and, 5) aware of their partners HIV seropositivity showed significantly higher, albeit still low, frequencies of condom use with steady partners. Conversely, all these factors seemed to have little impact on condom use with occasional partners. Condom use and sexual habits were similarly reported by HIV-positive and HIV-negative IVDUs. The present study shows that high-risk sexual behaviours among IVDUs are very widespread and it stresses the need for intensive counselling to promote condom use among IVDUs.

Hodgkin's disease (HD) has been described in patients with HTV infection in association with unfavourable prognostic factors. Similarly, HD in the older general population has a poorer prognosis than in younger patients.

Ninety-two cases of Hodgkin's disease (HD) in patients with HIV infection have been collected by the Italian Cooperative Group on AIDS and Tumors (G.I.C.A.T.). In accordance with the epidemiology of HIV infection in Italy, 82% were intravenous drug users (IVDU), 8% homosexual men, 5% IVDU + homosexuals and 5% heterosexuals. At diagnosis of HD, 16% had AIDS, 20% AIDS related complex (ARC), 33% persistent generalized lymphadenopathy (PGL) and 31% were asymptomatic. Fifty-three percent of the patients had stage IV disease and 70% mixed cellularity and lymphocytic depletion. Forty-six patients were treated with MOPP or MOPP ≃ ABVD ± radiotherapy (zidovudine was not given) with complete remission (CR) in 54% and partial remission (PR) in 467percnt; of the patients. Fifty-six percent of these patients developed opportunistic infections (OI) during therapy or follow-up. Sixteen patients were treated with epirubicin, bleomycin and vinblastine (EBV) and concomitant zidovudine, with CR in 44% and PR in 38%. However, only one of these patients developed OI during therapy or follow-up. The clinico-pathological features and natural history of HD in HIV setting are peculiar and quite distinct from those observed in HD in the general population. Better combined chemotherapy and antiretroviral therapy is needed in order to ameliorate the CR rate and decrease the OI in patients with HIV infection and HD.

in an Italian cooperative study on AIDS and cancer a diagnosis of Hodgkin's disease was established in 36 HIV-positive patients. the series was characterized by a high proportion of drug abusers, a high proportion of mixed cellularity and lymphocytic depletion subtypes and short survival. It is still unclear if HIV infection promotes the development of Hodghn's disease or only modifies the course of the disease. According to the authors, however, patients who are HIV seropositive and have biopsyproven Hodgkin's disease should be considered as fulfilling the criteria for AIDS.

In this multicenter, retrospective study of 160 brain biopsies in the assessment of HIV-related focal brain lesions, diagnostic sensitivity was acceptable (87), but the procedure carried considerable morbidity (7.5) and mortality (3.1). Moreover, it is not always possible to initiate the changes in therapy indicated by the results, and overall survival remains poor, with a median of 2 months. Criteria for brain biopsy for the diagnosis of focal brain lesions should be redefined to include selected patients for whom a less invasive approach does not yield a definitive diagnosis.

ObjectiveThe optimal therapeutic opproach for pts with HD-HIV is unknown, In an attempt to improve the results that we obtained in a previous prospective study with EBY without G-CSF (Cancer, 73: 437–44, 1994). in January 1993 we started a second trial consisting of CT, concomitant antiretroviral therapy (AZT or DDI), and G-CSF.

The incidence of cervical intraepithelial neoplasias has increased in HIV - infected women, and invasive cervical ca is currently considered an AIDS defining condition. However the natural history of HIV - related cervical ca is still unknown. To better characterize cervical ca in HIV - infected women we evaluated 54 cases, including 35 (65%) carcinoma in situ (Cis) and 19 (35%) invasive ca, collected by the GICAT between January 1986 and June 1995. The median age was 28 years (range 19–38). The majority (70%) of patients (pts) were intravenous drug users and an history of sexual promiscuity and anogertital HPV-disease was reported by 55% and 88% of pts, respectively.At the diagnosis of cervical ca, 59% of pts had asymptomatic HIV - disease or PGL (category A), while 20% had sympotmatic HIV disease for diagnostic for AIDS (category B) and 15% had already a diagosis of AIDS (category C). Overall the mean CD4 cell count was 360 (± 230.8 SD), however the mean CD4 cell count was significantly lower in the Cis group than in the invasive ca group (279±221.7 vs 455±270.4, p=0.03). All pts had squamous cell neoplasia. Among pts with invasive Ca, 63% had stage I acording to FIGO, 21% stage II and 16% stage III-IV. Pts with Cis received cone biopsy (85%) and cryotherapy or laser therapy (15%), whereas pts with invasive ca were treated with major surgery (S) (53%), radiotherapy (24%) or combination therapy (S-chemotherapy) (23%). Complete remission (CR) occurred in 97% of Cis pts and in 81% of invasive ca pts (p=0.09); the recurrence rate was similar in the two groups (13% vs 20%, respectively), as well is the incidence of AIDS-associated infections during follow up (52% vs 57%, respectively). Median survival was 66 me for Cis pts and 101mo for invasive ca pts (p=NS). In conclusion, invasive cervical ca is still occurring in at low rate in pts with HIV-infection in Italy, usually with a relatively good immune function. On the other hand there is a higher prevalence of Cis (65%) emphasizing the importance of integrating gynecological care into medical service for HIV-infected women. Supported by ISS grants.

HIV-NHL represent an heterogeneous group of diseases, characterised by the presence of distinct molecular-pathological entities, but overall considered associated with a poor outcome, Few extensive studies on clinico-pathological correlations have been conducted. In this study we examined the relationship between pathological and clinical data obtained from a monoistitutional series of 120 pts with HIV-NHL, diagnosed and treated with chemotherapy from September 1987 to July 1995. The most common histologic type was small non-cleaved cell lymphoma (J group) (33%), followed by miscellaneous NHL (M group) (23%), large cell immunoblastic (H group) (19%), large non-cleaved lymphoma(G group) (15%) and by Ki-1+ anaplastic large cell lymphoma (Ki-1 + ALC) (11%). The clinical presentation of the J group was found significantly different compared with that of diffuse large cell lymphoma (DLCL) group (G, H, Ki-1+ ALC), as follows: better immune function (vs H group, p=0.02), poorer performance status (PS) (vs G group, p=0.01), higher abnormal serum LDH level (vs G group, p=0.02), more disseminated disease (vs H group, p=0.01), higher involvement of peripheral lymphnodes (vs H group, P=0.02), bone marrow involvment (vs H group, p=0.001 and vs G group, p=0.04), and lesser Waldeyer ring involvement (vs H, G, Ki-1 ALC group, p=0.001 group, p=0.03, p=0.04, respectively). Within the DLCL group the distribution of cases with respect to presenting clinical features showed male predominance, poorer PS and higher degree of immunodeficiency in Ki-1 + ALC than in G group (p=0.03, p=0.02, p=0.05, respectively). As far as the outcome a better survival was found only in G group (median 16.4mo) than in H group (median 6.6mo) (p=0.01). These findings suggest that G NHL should not be included with H in the same category of DLCL (Harris et al, 1994) since H is associated with poor outcome. Supported by ISS and AIRC grants.

PurposeTo evaluate the feasibility and activity of a second line chemotherapy regimen consisting of VP16, mitoxantrone and prednimustine (VMP) in patients with relapsed or resistant HIV related non-Hodgkin's lymphoma (HIV-NHL).

Prevalence and determinants of HIV infection were assessed in 313 parenteral drug addicts admitted to five Centers for Drug-Addict Assistance and two prisons located in the northeast of Italy (Friuli Venezia-Giulia), an area some distance from the major Italian cities first reached by the AIDS epidemic. The overall prevalence of HIV positivity was also rather high in this area, ie 30% with 24–36% confidence interval. The most important risk factors (besides syringe sharing applicable to all drug addicts), turned out to be of a geographical nature, ie living in Pordenone province (where a US military base is located) or coming from other endemic areas and having travelled long distances in the past three years. Prostitution also seemed to increase the risk of infection, but duration of drug addiction had little effect. In addition to persistent generalized lymphadenopathy (closely linked to HIV infection), reversal of helper:suppressor T-cell ratio was found in 67% of HIV positive individuals, but also in 31% of HIV negative ones. Clinical signs and symptoms strongly linked with HIV positivity were fatigue, weight loss, splenomegaly, fever and nocturnal sweats.

In patients with HIV-NHL several prognostic factors have already been identified to correlate with survival: low CD4 count, prior history of AIDS and poor performance status (PS). The role of other prognostic factors, such as age, LDH, stage and multiple extranodal sites, that have been identified in intermediate-high grade NHL of the general population is presently unclear in HIV setting. We have investigated HIV-related and standard prognostic factor in 96 pts with HIV-NHL diagnosed and treated with combination chemotherapy (CT) at our Institute between September 1987 and December 1993. Cinical findings and laboratory data were evaluated by univariate and multivariate analyses to investigate prognostic factors potentially influencing survival. Eighty-three pts were males, 13 female, median age was 32 yean (range 23–79), intravenous drug users were 48 (50%), in accordance to the overall epidemiology in Italy. Prior AIDS was diagnosed in 25% of pts, median CD4 count was 116/mm3 (range 1–2429) at the diagnosis of HIV-NHL. All pts had intermediate or high grade HIV-NHL according to the WF, 73% of pts had Stages III-IV, multiple extranodal sites were detected in 53% pts, PS 2 in 48% and increased LDH values in 54% pts. Eighty-seven per cent of pts were included in prospective studies with combination CT: CR occured in 48% pts, while overall median survival was 7 months. Among the classical and the HIV-related prognoatic factors, the following had statistically significant influence on survival: PS ≥ 2. elevated LDH level, age 40 years and CD4 cell count < 1000/mm3, active opportunistic infections at diagnosis of NHL and B symptoms multivariate analyses revealed that only age, serum LDH level, and CD4 cell count were independent predictors of shortened survival. The increased hazard for patients with age 40 years (95% Confidence Interval [CI] 1.2 – 2.3), for patients with increased LDH it was 1.8 (95% CI 1.01 – 3.1) and for patients with CD4 cell < 100/mm3 it was 1.7 (95% CI 1.01 – 2.9).In conclusion this study shows that in addition to a HIV-related prognostic factor, i.e. CD4 count< 100/mm3, also standard prognostic factors, such as age and LDH, are independent unfavourable prognostic factors and should be included in the design of future clinical trials of HIV-NHL.