A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer.

BACKGROUND: Continuation or 'switch' maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC. PATIENTS AND METHODS: The primary end point of this open-label, randomized phase II study was progression-free survival (PFS). Patients with non-progressive, advanced NSCLC after platinum-based doublet (first-line) chemotherapy (with or without bevacizumab), any histology, with Eastern Cooperative Oncology Group performance status 0-1 were eligible. Randomization was 2 : 1 in favor of imetelstat, administered at 9.4 mg/kg on days 1 and 8 of a 21-day cycle, or observation. Telomere length (TL) biomarker exploratory analysis was carried out in tumor tissue by quantitative PCR (qPCR) and telomerase fluorescence in situ hybridization. RESULTS: Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54-1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41-1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14-1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11-1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39-1.88; and HR = 0.51; 95% CI 0.2-1.28; P = 0.145). CONCLUSIONS: Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat.

COPD treatment: real life and experimental effects on peripheral NK cells, their receptors expression and their IFN-γ secretion.

A role in pulmonary immunity has been ascribed to Natural Killer (NK) cells and several in vitro studies have shown a corticosteroid-induced inhibition of NK cells mediated cytotoxicity. Several clinical trials on chronic obstructive pulmonary disease (COPD) have suggested a relationship between COPD treatment and occurrence of respiratory infections. Aims of our study were to investigate if real life COPD treatment affects peripheral blood NK cells total count and their receptors expression and to assess if different doses of formoterol and budesonide, administered alone or in combination, are able to modulate the surface expression of activating (NKp30, NKp44, NKp46 and NKG2D) and inhibitory (KIR2DL2/L3, KIR3DL1 and NKG2A) receptors on peripheral blood NK cells of COPD patients. Moreover, we evaluated the potential effect of treatment with budesonide and/or formoterol on IFN-γ secretion in vitro. NK cells were isolated from peripheral blood of 7 healthy volunteers, 9 chronic bronchitis (CB) and 11 COPD patients. Total NK cells count and activating and inhibitory receptors expression were evaluated. NK cells were cultured for 20h in 96-well plates with IL-2 (100IU/ml)+IL-12 (2.5ng/ml), with or without budesonide (Bud; 1 and 0.01µM) and formoterol (For; 30 and 0.3nM) alone or in combination. Cells were analyzed by flow cytometry and IFN-γ was measured in cell supernatants by ELISA test. No difference between real life treated COPD, CB and healthy subjects was found concerning NK total count and NK cell receptors expression. When cells were stimulated over night with cytokines and treated with drugs, only NKG2D receptor was modulated. Its expression was significantly downregulated by budesonide alone and in combination with formoterol in COPD patients. IFN-γ production induced by stimulation with IL-2+IL-12 was decreased in a highly significant way (p<0.01) by all treatments in all groups. Even if in vitro experiments with budesonide, alone or in combination with formoterol, showed a modulation of NKG2D receptor expression and IFN-γ production, our ex vivo results show that real life LABA and ICS treatment does not influence peripheral NK cells count and their receptors phenotype.

Omalizumab modulates bronchial reticular basement membrane thickness and eosinophil infiltration in severe persistent allergic asthma patients.

Severe persistent asthma causes a substantial morbidity and mortality burden and is frequently not well controlled, despite intensive guideline-based therapy. The unique monoclonal antibody approved for patients with severe allergic asthma is omalizumab: a recombinant humanised murine against IgE antibodies. The aim of the present study is to investigate the effect of long-term anti-IgE on the thickening of the reticular basement membrane (RBM) and eosinophil infiltration in bronchial biopsies from patients with severe persistent allergic asthma. Biopsies were obtained from 11 patients with severe persistent allergic asthma before and after (12 months) treatment with omalizumab. RBM thickness and eosinophils were measured by using light microscope image analysis. A significant mean reduction in RBM thickness and eosinophil infiltration were measured after one-year omalizumab treatment. No correlation between eosinophil reduction and RBM thickness reduction was found. No correlation between each of the previous two parameters and clinical parameters was detected. In conclusion, our study showed that a substantial proportion of severe asthmatics reduced the original bronchial RBM thickness and eosinophil infiltration after one-year treatment with anti-IgE, thus emphasizing the possible role of omalizumab in affecting airway remodeling in severe persistent allergic asthma.

Salbutamol: how does it enter smooth muscle cells?

Polyspecific organic cation transporters (OCTs) in human cell membranes are involved in the uptake, distribution and excretion of cationic compounds. Although their relevance to drug disposition in the liver, small intestine and kidney has been investigated previously, less is known about the influence of these transporters on the pharmacokinetics and pharmacodynamics of inhaled drugs. Drugs that are commonly administered by inhalation for the treatment of respiratory diseases, such as glucocorticoids and cationic ß(2)-agonists, might interact with several of these transporters, which are strongly expressed on the surfaces of airway epithelial cells. We evaluated the expression of OCT3 and measured the in vitro uptake of the short-acting ß(2)-agonist salbutamol (SALB), alone or in combination with corticosterone (CS) and beclomethasone dipropionate (BDP), by bronchial smooth muscle cells. Our results showed that these cells express the OCT3 transporter and that SALB enters the cell in a transporter-independent fashion. Moreover, CS and BDP have different activities on SALB transport inside the cell. CS increases SALB transport and BDP decreases SALB transport, although neither of these effects are statistically significant. A better understanding of these mechanisms might lead to the improved treatment of airway diseases.

A phase I trial of pan-Bcl-2 antagonist obatoclax administered as a 3-h or a 24-h infusion in combination with carboplatin and etoposide in patients with extensive-stage small cell lung cancer.

BACKGROUND: Bcl-2 family genes are frequently amplified in small cell lung cancer (SCLC). A phase I trial was conducted to evaluate the safety of obatoclax, a Bcl-2 family inhibitor, given in combination with standard chemotherapy. METHODS: Eligible patients (3-6 per cohort) had extensive-stage SCLC, measurable disease, ≤ 1 before therapy, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients were treated with escalating doses of obatoclax, either as a 3- or 24-h infusion, on days 1-3 of a 21-day cycle, in combination with carboplatin (area under the curve 5, day 1 only) and etoposide (100 mg m(-2), days 1-3). The primary endpoint was to determine the maximum tolerated dose of obatoclax. RESULTS: Twenty-five patients (56% male; median age 66 years) were enrolled in three dose cohorts for each schedule. Maximum tolerated dose was established with the 3-h infusion at 30 mg per day and was not reached with the 24-h infusion. Compared with the 24-h cohorts, the 3-h cohorts had higher incidence of central nervous system (CNS) adverse events (AEs); dose-limiting toxicities were somnolence, euphoria, and disorientation. These CNS AEs were transient, resolving shortly after the end of infusion, and without sequelae. The response rate was 81% in the 3-h and 44% in the 24-h infusion cohorts. CONCLUSION: Although associated with a higher incidence of transient CNS AEs than the 24-h infusion, 3-h obatoclax infusion combined with carboplatin-etoposide was generally well tolerated at doses of 30 mg per day. Though patient numbers were small, there was a suggestion of improved efficacy in the 3-h infusion group. Obatoclax 30 mg infused intravenously over 3 h on 3 consecutive days will be utilised in future SCLC studies.

Thyrotropin receptor autoantibody measurement following radiometabolic treatment of hyperthyroidism: comparison between different methods.

BACKGROUND: TSH receptor antibodies (TRAb) play a crucial role in the pathogenesis of Graves' disease (GD). The use of human recombinant TSH-receptor far improved the analytical performance of TRAb assays (2nd-generation assays). The 3rd-generation assay is based on the inhibition of binding of a human biotin-labeled monoclonal thyroid- stimulating antibody (M22) to TSH-receptor by the autoantibodies present in the serum. AIM: We aimed to assess the ability of the 2nd- and 3rd-generation assays to detect serum TRAb following radioiodine therapy for hyperthyroidism. METHODS: Sera from 47 hyperthyroid (25 autoimmune, 22 non-autoimmune) patients were tested using the two different assays before and at different time intervals after radioiodine therapy. The modifications of TRAb were evaluated, as well as the correlation between the two methods. RESULTS: The results obtained by the two methods proved to be closely correlated. A rise in TRAb was invariably observed in GD patients following radioiodine, with a median peak at 6 months, irrespective of their initial clinical status, presence of ophthalmopathy, smoking habits or other variables. Such a rise was nearly superimposable using both methods. No TRAb appearance was observed in patients with non-autoimmune hyperthyroidism. CONCLUSIONS: The use of methods of higher sensitivity with respect to that formerly used indicate that nearly all GD patients develop TRAb following radioiodine, and that this phenomenon is transient and not related to baseline conditions and clinical outcome/efficacy of treatment.

Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker.

BACKGROUND: Histone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA. METHODS: This phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin. RESULTS: In total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day(-1) on days 1-3, followed by doxorubicin (20 mg m(-2)) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day(-1) of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day(-1). Non-dose-limiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for > or =8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression. CONCLUSION: These findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day(-1). The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting.

Cardiac toxicity: old and new issues in anti-cancer drugs.

Although rare, cardiotoxicity is a significant complication of cancer treatment. The incidence and severity of cardiovascular side effects are dependent on the type of drugs used, dose and schedule employed, and age of patients, as well as the presence of coexisting cardiac diseases and previous mediastinal irradiation. Classically, anthracyclines are among one of the most active agents in oncology, but their use is often hampered by their cumulative dose-limiting cardiotoxicity. In the past decade, combination therapy with new drugs such as taxanes or anti- EGFR, and Her-2 therapy as a single agent have also resulted in unexpected cardiotoxicity. Cardiac damage can be secondary to an alteration of cardiac rhythm, changes in blood pressure and ischaemia, and can also alter the ability of the heart to contract and/or relax. The clinical spectrum of these toxicities can range from subclinical abnormalities to being catastrophic, life-threatening and sometimes fatal. Knowledge of this toxicity can aid clinicians to choose the optimal and least toxic regimen suitable for an individual patient. In this work we present an exhaustive review of the cardiovascular side effects associated to new anticancer drugs, from new formulations of anthracyclines to tyrosine kinase inhibitors and monoclonal antibodies.

Prevalence of post-partum thyroiditis in Liguria (Italy): an observational study.

BACKGROUND: Post-partum thyroiditis (PPT) is an autoimmune disorder occurring within the first year following delivery. A variable prevalence has been reported in different surveys. We prospectively evaluated PPT prevalence and outcome in a cohort of pregnant women living in a well-defined geographic area. AIM: A subset from a group of healthy women consecutively evaluated for thyroid function and thyroid autoimmunity during pregnancy, referring to the same obstetric unit, were followed up at 4-6 months and 1 yr after delivery. MATERIALS/SUBJECTS AND METHODS: Follow-up for PPT was performed in 258 pregnant women. Control data were obtained in a comparable group of healthy non-pregnant women. Free T3 (fT3), free T4 (fT4), TSH thyroglobulin/thyroid peroxidase autoantibodies (TgAb/TPOAb), and urinary iodine excretion were measured. RESULTS: Autoantibody positivity was observed in 9.3% of pregnant, similar to control women. Forty-three out of 59 autoantibody-positive women were followed up; 23 showed PPT at the first control, 18 had hypothyroidism at 1 yr (5 had not shown PPT at the first control). Among 215 out of 584 autoantibody-negative women followed up, 27 developed PPT (15 of them without thyroid autoantibodies); 16 developed thyroid autoantibodies without PPT. After 1 yr, 9 women had hypothyroidism: only 1 of them was autoantibody-negative at the former control. Urinary iodine was increased in several pregnant women. CONCLUSIONS: An overall PPT prevalence of about 18% may be estimated. PPT was also observed in autoantibody- negative women. Differences with other surveys may be related to both study protocol and characteristics of the population studied.

Prevalence and prognostic significance of neuroendocrine cells in esophageal adenocarcinoma.

Neuroendocrine differentiation is common in adenocarcinomas of the stomach and colon and may be associated with a slightly better prognosis in gastric adenocarcinoma. We studied neuroendocrine differentiation in esophageal adenocarcinomas and associated Barrett's esophagus (BE) to determine association with patient outcome. Fifty-eight cases of esophageal adenocarcinoma (15 biopsies, 43 resections) from 52 patients were stained with a monoclonal antibody to chromogranin (CG). Medical records were reviewed for tumor stage, response to therapy, and patient survival. Thirty-two patients received radiation and chemotherapy, and four received radiation. Twelve of 58 (20.7%) esophageal adenocarcinomas contained scattered CG-positive cells. Tumors with CG-positive cells were moderately to poorly differentiated, and many consisted of large cribriform glands, similar to intestinal-type adenocarcinomas. One case of small cell carcinoma of the esophagus was weakly CG positive; another was negative. Neuroendocrine differentiation was retained in lymph node metastases in two cases but lost in three other cases. In 10 CG-negative primary tumors, lymph node metastases were also negative. For five of six patients with paired biopsy/resection specimens, no CG-positive cells were seen in either specimen; one patient had CG-positive cells only in the resection. There was no difference in tumor stage at surgery or survival time between CG-positive and CG-negative tumors. BE was present in 34 cases and contained CG-positive cells in 21 of 34 (61.8%). Low-grade dysplasia contained CG-positive cells in 11 of 14 cases (78.6%) and high-grade dysplasia in 3 of 6 cases. Fourteen of 21 (66.7%) adenocarcinomas associated with CG-positive BE were negative for CG. In summary, neuroendocrine differentiation is common in BE and is retained in low- and high-grade dysplasia but is usually lost in esophageal adenocarcinoma. The presence of scattered neuroendocrine cells does not affect patient outcome.

Expression of beta-catenin, alpha-catenin, and E-cadherin in Barrett's esophagus and esophageal adenocarcinomas.

Loss of expression and function of the E-cadherin/catenin membrane complex can result in loss of cell adhesion and contribute to invasive or metastatic potential in carcinomas. The aim of this study was to examine the expression of alpha- and beta-catenin and E-cadherin in Barrett's esophagus with and without dysplasia and in esophageal adenocarcinomas and to identify any relationship with tumor growth pattern and clinical outcome. Immunoperoxidase staining for alpha- and beta-catenin and E-cadherin was performed on specimens of Barrett's esophagus with and without dysplasia and on 54 esophageal adenocarcinoma specimens. Membranous staining for all of the components was seen in normal gastric and esophageal mucosa. Abnormal expression of beta-catenin, alpha-catenin, and E-cadherin was significantly associated with higher degrees of dysplasia in Barrett's esophagus. Fourteen of 16 cases of high grade dysplasia and 7 of 7 cases of intramucosal carcinoma showed abnormal expression of beta-catenin, compared with 3 of 6 cases indefinite for dysplasia and 11 of 17 cases with low grade dysplasia (P = 0.022). Similar results were seen for expression of alpha-catenin (P < .01) and E-cadherin (P = .049). In esophageal adenocarcinomas, preserved expression of these proteins occurred more frequently in well-differentiated tumors; abnormal expression was more common in diffusely infiltrative poorly differentiated tumors that did not form glands. Focal nuclear staining for beta-catenin was present in two high-grade dysplasias, two intramucosal carcinomas, and five adenocarcinomas. No survival advantage was demonstrated for patients whose tumors retained expression of these cell adhesion components. In conclusion, abnormal expression of the E-cadherin/catenin membrane complex is common in esophageal adenocarcinoma and occurs early in the dysplasia/carcinoma sequence in Barrett's esophagus, indicating that disturbances in this cell adhesion complex might be important in tumorigenesis and tumor progression in this disorder.

New Agents in the Management of Non-Small Cell Lung Cancer.

BACKGROUND: Non-small-cell carcinoma of the lung has long been considered a chemotherapeutically resistant neoplasm. Newer agents and combinations are being tested. METHODS: The authors have reviewed data on recent and active phase I and phase II trials of several new agents and combinations. RESULTS: New drugs that affect both response rates and survival include vinorelbine, paclitaxel, docetaxel, gemcitabine, topotecan, and irinotecan. CONCLUSIONS: The advent of several relatively well-tolerated agents that alone have beneficial effects in advanced non-small-cell lung cancer provides reasonable hope that more effective drug combinations will soon be available for this disease.

[Adhesive peritonitis caused by a foreign body. A case report]. / Peritoniti plastiche da corpo estraneo. Caso clinico.

After investigation of the international literature on this subject, the authors describe a case report of adhesive-stenotic and retractile peritonitis, very likely caused bt a foreign body reaction (surgical stitches, gloves, rice powder, etc.?). This case-report is interesting both to remember the existence of this pathology and to limit its iatrogenic development. In conclusion, it is advisable to wash surgical gloves with sterile solutions and to limit enlarged bowel resections mostly in young people.