HHV-8 and EBV are not commonly found in idiopathic pulmonary fibrosis

BACKGROUND AND AIM OF THE WORK: Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia (IPF/UIP) is a diffuse and progressive lung disease whose pathogenesis is incompletely understood. Recently, the presence of Herpesvirus-specific DNA was detected in the large majority of cases of a series of IPF/UIP and other lung interstitial diseases. We have therefore tested our own IPF/UIP series for the presence of HHV-8 and EBV proteins. METHODS: We used a variety of sensitive technologies including immunohistochemistry with NCL-HHV8-LNA and EBV-LMP1 antibodies, as well as of EBV RNA (EBER) by in-situ hybridisation; the presence of HHV-8 and EBV DNA was also investigated by means of PCR and subsequent analysis using a microfluidic apparatus. RESULTS: Despite the good sample quality, immunohistochemical, in-situ hybridisation and PCR results were negative for both EBV and HHV-8. CONCLUSIONS: We conclude that EBV and HHV-8 are not involved in the pathogenesis of IPF/UIP.     

Long-term clinical outcome of AIDS-related Kaposi's sarcoma during highly active antiretroviral therapy

The long-term impact of highly active antiretroviral therapy (HAART) in AIDS patients with Kaposi's sarcoma (KS) was evaluated in 22 consecutive, HAART-na?ve KS patients attending a single Italian referral centre for HIV/AIDS. Clinical, virologic and immunologic responses to HAART were assessed at baseline and every three months during the follow-up. Peripheral blood mononuclear cell (PBMC)-associated human herpesvirus 8 (HHV-8) load was also evaluated by real-time PCR in 13 patients with durable clinical KS complete response (CR). In a median follow-up of 40 months (range 17-78), the KS overall clinical response rate was 91%: 18 complete and 2 partial responses were achieved, and two patients experienced disease progression. CR persisted in all 18 patients, including the 5 poor-risk KS patients in whom CR lasted for > 60 months, and was significantly linked to an increase in CD4+ cell counts and a drop in HIV-1-RNA copies. Compared to baseline levels, a decrease in PBMC HHV-8 load was observed at CR, and a significant further reduction was found at the end of follow-up. In this monocentric study, AIDS-KS patients treated with HAART showed high clinical response rate. Patients with CR showed a prolonged remission, lasting more than 5 years in a group of poor-risk patients, and a persistent reduction in circulating HHV-8-infected cells. These findings highlight that HAART deeply modifies the natural history of this tumour in AIDS patients, and that this long-lasting approach may be considered a first-line treatment for the majority of HIV-1-infected patients developing KS.     

A pilot study on the effect of acetyl-L-carnitine in paclitaxel- and cisplatin-induced peripheral neuropathy

AIMS AND BACKGROUND: In addition to bone marrow suppression and renal toxicity, neurotoxicity is a commonly occurring side effect of widely used chemotherapeutic agents like taxanes, cisplatin and vinca alkaloids. Neurotoxicity can cause antitumor therapy discontinuation or dose regimen modification. The aim of the present exploratory study was to investigate the activity of acetyl-L-carnitine in reversing peripheral neuropathy in patients with chemotherapy-induced peripheral neuropathy. METHODS AND STUDY DESIGN: Twenty-seven patients (16 males and 11 females) with paclitaxel and/or cisplatin-induced neuropathy (according to WHO recommendations for the grading of acute and subacute toxic effects) were enrolled. Patients received at least one cisplatin- (n = 5) or one paclitaxel- (n = 11) based regimen, or a combination of both (n = 11). Patients with chemotherapy-induced peripheral neuropathy were treated with acetyl-L-carnitine 1 g/die i.v. infusion over 1-2 h for at least 10 days. RESULTS: Twenty-six patients were evaluated for response having completed at least 10 days of acetyl-L-carnitine therapy (median, 14 days; range, 10-20). At least one WHO grade improvement in the peripheral neuropathy severity was shown in 73% of the patients. A case of insomnia related to ALC treatment was reported in one patient. Acetyl-L-carnitine seems to be an effective and well-tolerated agent for the treatment of chemotherapy-induced peripheral neuropathy. CONCLUSIONS: Our preliminary results should be confirmed in double-blind, placebo controlled studies.     

Induction chemotherapy followed by alternating chemo-radiotherapy in non-endemic undifferentiated carcinoma of the nasopharynx: optimal compliance and promising 4-year results

Concomitant chemo-radiotherapy is the standard treatment for advanced nasopharyngeal carcinoma (NPC). Induction chemotherapy may improve the results further by enhancing both loco-regional and distant control. Fifty patients with untreated, stage IV (UICC 1992) undifferentiated NPC were initially treated with three courses of epidoxorubicin, 90 mg/m(2), day 1 and cisplatin, 40 mg/m(2), days 1 and 2, every three weeks and then underwent three courses of cisplatin, 20 mg/m(2)/day, days 1-4 and fluorouracil, 200mg/m(2)/day, days 1-4 (weeks 1, 4, 7), alternated to three splits of radiation (week 2-3, 5-6, 8-9-10) up to 70 Gy. All patients but one received 3 cycles of induction chemotherapy. Toxicities from induction chemotherapy were grade III or IV mucositis (2%), grade III or IV nausea/vomiting (22%), grade III or IV hematological toxicity (6%). At the end of induction phase 12% of CRs, 84% of PRs were recorded. Toxicities from alternating chemo-radiotherapy were grade III or IV mucositis (30%), grade III or IV nausea/vomiting (8%), grade III or IV hematological toxicity (24%). Overall, 86% of CRs and 14% of PRs were observed. Four-year progression free survival and overall survival rates are 71% and 81%, respectively. In a small number of patients studied, no correlation between the level of EGFR overexpression and outcomes was detected. In locally advanced UNPC our combined program including induction chemotherapy followed by alternating chemo-radiotherapy is active and gives promising long-term outcomes with acceptable toxicity and optimal patients' compliance. This program merits to be tested in a phase III trial.     

Cis-acting genomic elements of the Pas1 locus control Kras mutability in lung tumors

The Pas1 locus is the major tumor modifier of lung tumorigenesis in mouse inbred strains. Of six genes contained in a conserved haplotype, three (Casc1, Kras and Ifltd1) have been proposed as Pas1 candidates, but mechanistic evidence is sparse. Herein, we examined urethane-induced lung tumorigenesis in a new mouse model developed by replacing the Kras gene with an Hras gene in the susceptible A/J-type Pas1 locus and crossing these mice with either C57BL/6J or A/J mice. Heterozygous mice carrying the Hras-replacement gene were more susceptible than wild-type mice to lung carcinogenesis, indicating that Hras replacement not only compensates for Kras functions, but is more active. Indeed, most lung tumors carried a Gln61Leu mutation in the Hras-replacement gene, whereas no mutations were observed in the endogenous Hras gene. Thus, the context of the Kras locus determined mutability of ras genes. In mice carrying the Hras-replacement gene, the mutation frequency affecting the wild-type Kras gene was much higher when this gene was located in the A/J type than in the C57BL/6J-type Pas1 locus (12 versus 0%, -log P=5.0). These findings identify cis-acting elements in the Pas1 locus as the functional components controlling genetic susceptibility to lung tumorigenesis by modulating mutability of the Kras gene.     

Perspectives on salvage therapy for non-small-cell lung cancer

Platinum-based chemotherapy offers a modest survival advantage over best supportive care in chemotherapy-naive patients with a good performance status and advanced/metastatic non-small-cell lung cancer (NSCLC). Despite the survival benefit associated with first-line chemotherapy, the majority of patients will experience relapse or disease progression. In clinicalpractice, an increasing number of patients maintain a good performance status after first-line treatment and are eligible for further treatments. Docetaxel (Taxotere) at 75 mg/m2 given once every 3 weeks has been the standard of care for second-line chemotherapy since the year 2000. Pemetrexed (Alimta) is a novel multitargeted antifolate agent with single-agent activity in first- and second-line treatment of NSCLC. A large phase 111 study comparing docetaxel to pemetrexed in second-line therapy demonstrated that pemetrexed is equally active and less toxic than docetaxel. Based on these results, pemetrexed is a reasonable second-line chemotherapy option for patients with recurrent, advanced NSCLC. Progress made in the field of molecular biology has led to the identification of drugs active against specific cellular targets. Gefitinib (Iressa) and erlotinib (Tarceva) are both orally active tyrosine kinase inhibitors of the epidermal growth factor receptor. Phase II and III trials have demonstrated that these agents are active particularly in a subgroup of patients with specific biologic characteristics. Both drugs have been approved for the treatment of pretreated NSCLC. Other drugs, such as cetuximab (Erbitux) and bevacizumab (Avastin) have shown promising activity in NSCLC and are currently being tested in clinical trials.     

Analysis of inflammatory and immune response biomarkers in sputum and exhaled breath condensate by a multi-parametric biochip array in cystic fibrosis

Cystic Fibrosis (CF) lung disease is characterized by high levels of cytokines and chemokines in the airways, producing chronic inflammation. Non-invasive biomarkers, which are also specific for the inflammatory and immune responses, are urgently needed to identify exacerbations and evaluate therapeutic efficacy. The aim of this study is to evaluate the association of sputum and exhaled breath condensate (EBC) biomarker changes with clinical exacerbation and response to therapy. We studied the simultaneous presence and concentration of twelve cytokines and growth factors (EGF, IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-gamma, MCP-1, TNF-alpha and VEGF) by a multi-parametric biochip array in sputum and EBC of 24 CF patients before, after 6 and 15 days of therapy, and 15 days after the end of treatment for an acute exacerbation. Correlations with functional respiratory tests (FEV1, FVC) and the systemic marker C-reactive protein (CRP) were looked for. In sputum, before therapy, VEGF and IL-1beta levels positively correlated with the respiratory function and CRP. Sputum IL-1alpha, IL-1beta IL-4, IL-10, TNF-alpha, and VEGF significantly decreased, while EGF increased, during therapy. IL-8 and IL-4 levels negatively correlated with the respiratory function at 15 and 30 days from the start of therapy, respectively. IL-4, IL-6, IL-10 and TNF-alpha positively correlated with CRP during therapy. Although some EBC biomarkers correlated with respiratory function and CRP, no significant associations with these clinical parameters were found. Sputum IL-1beta and VEGF might be considered biomarkers of an acute exacerbation in CF patients. A panel of sputum cytokines and growth factors may better describe the response to intravenous antibiotic treatment of CF than one single systemic marker.     

Docetaxel and epirubicin compared with docetaxel and prednisone in advanced castrate-resistant prostate cancer: a randomised phase II study

Background:

This randomised phase II study compared the activity and safety of the combination docetaxel (D)/epirubicin (EPI) with the conventional treatment D/prednisone (P) in advanced castrate-resistant prostate cancer (CRPC) patients.

Materials and methods:

Patients were randomly assigned to D 30 mg m⁻² as intravenous infusion (i.v.) and EPI 30 mg m⁻² i.v. every week (D/EPI arm), or D 70 mg m⁻² i.v. every 3 weeks and oral P 5 mg twice daily (D/P arm). Chemotherapy was administered until disease progression or unacceptable toxicity.

Results:

A total of 72 patients were enrolled in the study and randomly assigned to treatment: 37 to D/EPI and 35 to D/P. The median progression-free survival (PFS) was 11.1 months (95% CI 9.2–12.6 months) in the D/EPI arm and 7.7 months (95% CI 5.7–9.4 months) in the D/P arm (P=0.0002). The median survival was 27.3 months (95% CI 22.1–30.8 months) in the D/EPI arm and 19.8 months (95% CI 14.4–24.8 months) in the D/P arm (P=0.003). Both regimens were generally well tolerated.

Conclusion:

The treatment of advanced CRPC with weekly D combined with weekly EPI was feasible and tolerable, and led to superior PFS than the treatment with 3-weekly D and oral P.