Guglielmo Nasti

Concomitant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy plus highly active antiretroviral therapy in patients with human immunodeficiency virus‐related, non‐Hodgkin lymphoma

The feasibility and efficacy of concomitant chemotherapy and highly active antiretroviral therapy (HAART) is still unknown in patients with human immunodeficiency virus (HIV)‐related malignancies. To evaluate the impact of chemotherapy plus HAART on the clinical course of patients with HIV‐related, systemic, non‐Hodgkin lymphoma (HIV‐NHL), the authors compared retrospectively a group of 24 patients with HIV‐NHL who were treated with the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy regimen plus HAART with a group of 80 patients who were treated with CHOP chemotherapy or a CHOP‐like regimen (i.e., cyclophosphamide, doxorubicin, teniposide, and prednisone with vincristine plus bleomycin) without receiving antiretroviral therapy.

Overexpression of Both CXC Chemokine Receptor 4 and Vascular Endothelial Growth Factor Proteins Predicts Early Distant Relapse in Stage II-III Colorectal Cancer Patients

Purpose: CXC chemokine receptor 4 (CXCR4) and vascular endothelial growth factor (VEGF) are implicated in the metastatic process of malignant tumors. However, no data are currently available on the biological relationship between these molecules in colorectal cancer. We studied whether CXCR4 and VEGF expression could predict relapse and evaluated in vitro the contribution of CXCR4 in promoting clonogenic growth, VEGF secretion, and intercellular adhesion molecule-1 (ICAM-1) expression of colorectal cancer cells. Experimental Design: CXCR4 and VEGF were studied in colorectal cancer tissues and in Lovo, HT29, and SW620 colorectal cancer cell lines by immunohistochemistry. Correlations with baseline characteristics of patients and tumors were analyzed by χ2 test. VEGF secretion induced by CXCL12 was measured by ELISA. The effect of CXCL12 on ICAM-1 expression was evaluated by flow cytometry. Clonogenic growth induced by CXCL12 was determined by clonogenic assays. Functional effects induced by CXCL12 were prevented by the administration in vitro of AMD3100, a bicyclam noncompetitive antagonist of CXCR4. Results: Seventy-two patients, seen between January 2003 and January 2004, were studied. CXCR4 was absent in 16 tumors (22.2%); it was expressed in ≤50% of cells in 25 (34.7%) tumors and in >50% of cells in 31 (43.0%) tumors. VEGF was absent in 17 (23.6%) tumors; it was expressed in ≤50% of cells in 16 (22.2%) tumors and in >50% of cells in 39 (54.2%) tumors. There was a significant association between CXCR4 expression and lymph nodal status (P = 0.0393). There were significant associations between VEGF and tumor invasion (P = 0.0386) and lymph nodal involvement (P = 0.0044). American Joint Committee on Cancer stage (P = 0.0016), VEGF expression (P = 0.0450), CXCR4 expression (P = 0.0428), and VEGF/CXCR4 expression (P = 0.0004) had a significant prognostic value for disease-free survival with univariate analysis. The predictive ability of the American Joint Committee on Cancer stage and of the concomitant and high expression of VEGF and CXCR4 was confirmed by multivariate analysis. Prognosis is particularly unfavorable for patients whose primary tumors express CXCR4 and VEGF in >50% of cells (median disease-free survival in relapsed patients, 5.8 months; hazard ratio of relapse, 8.23; 95% confidence interval, 7.24-14.29). In clonogenic assays, CXCL12 (20 ng/mL/d) significantly increased the number of clones in SW620, HT29, and Lovo cells at 7 and 14 days. Again, CXCL12 was able to stimulate VEGF secretion in SW620, HT29, and Lovo cells as well as up-regulated ICAM-1. These effects were prevented by the administration of AMD3100 (1 μmol/L). Conclusions: We have shown that concomitant and high expression of CXCR4 and VEGF is a strong and independent predictor of early distant relapse in colorectal cancer. CXCR4 triggers a plethora of phenomena, including stimulation of clonogenic growth, induction of VEGF release, and ICAM-1 up-regulation. These data support the inhibition of CXCR4 to prevent the development of colorectal cancer metastasis.

AIDS-Related Kaposi’s Sarcoma: Evaluation of Potential New Prognostic Factors and Assessment of the AIDS Clinical Trial Group Staging System in the Haart Era—the Italian Cooperative Group on AIDS and Tumors and the Italian Cohort of Patients Naïve From Antiretrovirals

PURPOSE To assess potential new prognostic factors and to validate the AIDS Clinical Trials Group (ACTG) for AIDS-related Kaposis sarcoma (AIDS-KS) staging system in the highly active antiretroviral therapy (HAART) era. PATIENTS AND METHODS We collected epidemiologic, clinical, staging, and survival data from 211 patients with AIDS-KS enrolled in two prospective Italian human immunodeficiency virus (HIV) cohort studies. We included in the analysis all patients with the diagnosis of KS made from January 1996, the time at which HAART became available in Italy. RESULTS In the univariate analysis, survival was not influenced by sex, age, level of HIV viremia at KS diagnosis, HAART at KS diagnosis (HAART-naïve v HAART-experienced), or type of HAART combination. Regarding ACTG classification, the 3-year survival rate was 85% for T0 patients and 69% for T1 patients (P =.007), 83% for S0 patients and 63% for S1 patients (P =.003), and 83% for I0 patients and 71% for I1 patients (P =.06). In the multivariate analysis, only the combination of poor tumor stage (T1) and poor systemic disease (S1) risk identified patients with unfavorable prognosis. The 3-year survival rate of patients with T1S1 was 53%, which was significantly lower compared with the 3-year survival rates of patients with T0S0, T1S0, and T0S1, which were 88%, 80%, and 81%, respectively (P =.0001). CONCLUSION In the era of HAART, a refinement of the original ACTG staging system is needed. CD4 level does not seem to provide prognostic information. Two different risk categories are identified: a good risk (T0S0, T1S0, T0S1) and a poor risk (T1S1).

Impact of highly active antiretroviral therapy on the presenting features and outcome of patients with acquired immunodeficiency syndrome–related Kaposi sarcoma†‡§

The objective of the current study was to evaluate the impact of highly active antiretroviral therapy (HAART) on clinical characteristics of presentation and the natural history of Kaposi sarcoma (KS) in patients already receiving HAART at the time of KS diagnosis.

Improvement of Systemic Human Immunodeficiency Virus-Related Non-Hodgkin Lymphoma Outcome in the Era of Highly Active Antiretroviral Therapy

To assess the impact of highly active antiretroviral therapy (HAART) on the outcome of systemic human immunodeficiency virus-related non-Hodgkin lymphoma (HIV-NHL), we retrospectively analyzed 235 patients in whom HIV-NHL was diagnosed from April 1988 through December 1999. A multivariate Cox proportional hazards model was used to estimate prognostic factors for overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS). Complete remission occurred in 49% of patients, and the 3-year rates of OS, PFS, and DFS were 19%, 49%, and 73%, respectively. The greatest risk for shortened OS, PFS, and DFS was associated with no HAART use (compared with long-term HAART use); hazard ratios were 17.42 (95% confidence interval [CI], 17.42-40.25), 9.11 (95% CI, 3.71-22.32), and 8.54 (95% CI, 1.19-61.11), respectively. Our study suggests that the long-term use of HAART may favorably change the outcome for patients with systemic HIV-NHL.

Chronic hepatitis C in HIV infection: feasibility and sustained efficacy of therapy with interferon alfa-2b and tribavirin.

BackgroundThe role combination therapy with interferon alfa-2b and tribavirin (US: ribavirin) plays in producing sustained virological responses in patients with HIV and chronic hepatitis C (HCV) infection is still unknown. ObjectivesTo determine the feasibility and sustained response of interferon alfa-2b and tribavirin combination therapy. DesignPhase II study. MethodsSeventeen patients were enrolled at the National Cancer Institute, Aviano, Italy and received combination therapy with interferon alfa-2b 3 MIU subcutaneously three times a week plus tribavirin 1000–1200 mg/day for 24 weeks. Antiretroviral therapy was concomitantly given in all but one patient. ResultsAt the end of treatment, five (31%) patients achieved clearance of HCV RNA and 11 (69%) showed normalized liver function enzyme levels. In three patients, serum HCV RNA concentration was still undetectable 24 weeks after treatment, with an overall sustained virological response rate of 19% The serum liver enzymes were still normal in 10 patients 24 weeks after treatment, the overall sustained biochemical response rate being 62% All patients with HCV RNA clearance at the end of treatment and 24 weeks after treatment had a concomitant biochemical response. Overall the combination treatment was well tolerated. ConclusionsOur data confirm that the combination of interferon alfa-2b and tribavirin is well tolerated and feasible in patients with HIV–HCV co-infection and it can be associated safely with highly active antiretroviral therapy. The sustained response achieved with the drug combination does not seem to be any better than that achieved with 12 months of monotherapy with interferon alfa-2b.

Vinorelbine Is an Effective and Safe Drug for AIDS-Related Kaposi’s Sarcoma: Results of a Phase II Study

PURPOSE To assess the safety and efficacy of vinorelbine in patients with AIDS-related Kaposis sarcoma (KS). PATIENTS AND METHODS From December 1994 to May 1997, within the Italian Cooperative Group on AIDS and Tumors, we enrolled 36 patients with AIDS-related KS who experienced disease progression after one or more regimens of systemic chemotherapy. Patients were treated with vinorelbine 30 mg/m(2) every 2 weeks by intravenous bolus. RESULTS Of 35 assessable patients, three (9%) had a clinical complete response and 12 (34%) had a partial remission, for an overall objective response rate of 43% (95% confidence interval, 26% to 61%). For the 15 patients with objective responses, the median duration of response from the beginning of therapy until the development of progression was 176 days, whereas the median progression-free survival and the median survival durations for 35 assessable patients were 151 days and 216 days, respectively. Vinorelbine also induced responses in patients who had become resistant to regimens that included other vinca alkaloids. Overall, vinorelbine was well tolerated. Toxicity, including neurologic toxicity, was mild and reversible. Neutropenia was the most frequent dose-limiting toxicity. CONCLUSION Vinorelbine is safe and effective in the treatment of patients with advanced KS who have been previously treated with one or more chemotherapy regimens.

Metronomic administration of zoledronic acid and taxotere combination in castration resistant prostate cancer patients: phase I ZANTE trial.

Background. Docetaxel (DTX) and zoledronic acid (ZOL) are effective in patients with hormone resistant prostate cancer (HRPC) with bone metastases. A phase I clinical trial of metronomic administration of Zoledronic Acid ANd TaxoterE combination (ZANTE trial) in 2 different sequences was conducted in HRPC. Patients and methods. Twenty-two patients enrolled into the study (median age: 73 years; range: 43-80) received one of three escalated doses of DTX (30, 40 and 50mg/m2) in combination with a fixed dose of ZOL (2mg), both administered every 14 days in two different sequences: DTX at the day 1 followed by ZOL at the day 2 (sequence A) or the reverse (sequence B). Patients were evaluated for adverse events and serum IL-8, MMP-2 and MMP-9 were evaluated prior and after therapy with the two sequences of administration of DTX and ZOL. Results. The maximum tolerated dose was not achieved with sequence A. Two patients at third level of sequence B developed dose limiting toxicity. A disease control was obtained in six out of nine patients treated with sequence A, where a decrease of biological markers and PSA were also observed. No evidence of anti-tumor activity was observed in patients treated with sequence B. Conclusions. The bi-weekly combination of DTX (50mg/m2) followed by ZOL was feasible and show promising anti-tumor activity.

Human immunodeficiency virus-related non-Hodgkin lymphoma: Activity of infusional cyclophosphamide, doxorubicin, and etoposide as second-line chemotherapy in 40 patients

The prognosis of patients with human immunodeficiency virus (HIV)‐related non‐Hodgkin lymphoma (NHL) is poor. In fact, despite a high complete response (CR) rate, approximately 50% of these patients die from progressive lymphoma.

Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild‐type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti‐BIL study)

Biliary tract cancer (BTC) is a rare and lethal disease with few therapeutic options. Preclinical data suggest that the epidermal growth factor receptor (EGFR) pathway could be involved in its progression.