Partitioning of bronchopulmonary carcinoids in two different prognostic categories by Ki-67 score

Introduction: Histological distinction between typical and atypical bronchopulmonary car- cinoids is based on mitotic activity and necrosis. Regardless of these two parameters, outcome after surgery is often unpredictable. In this study the prognostic value of different clinico-pathological factors was retrospectively analyzed in a large series of patients with bronchopulmonary carcinoid. Materials and Methods: The long-term post-surgical out- come of 106 radically treated patients affected by bronchopulmonary carcinoid from two Italian centers was correlated with tumor characteristics assessed by combining conven- tional histology with a panel of immunohistochemical markers of neuroendocrine differen- tiation (chromogranin-A, NSE) and proliferation activity (Ki-67 score). Results: Carcinoids were assessed as typical (TC = 75; 70.8%) and atypical (AC = 31; 29.2%). Mean follow-up was 8.3 years (range: 0-20; median: 8.0). All cases expressed neuroendocrine markers. At univariate analysis, tumor recurrence [14/75 TC (18.7%), 15/31 AC (48.4%)] correlated with carcinoid histotype (P = 0.003), tumor size (P = 0.012), mitotic index (P = 0.044), Ki-67 score (P < 0.0001), and synchronous node metastasis (P = 0.037). Of these, Cox multivari- ate analysis confirmed only Ki-67 score as independent predictor of disease recurrence (P = 0.009). The best cut-off for Ki-67 score (calculated by ROC curves) discriminating recurrent vs non-recurrent disease was 4% (sensitivity 79.3%; specificity 83.8%; area under the curve 0.85). By stratifying patients according to this cut-off, a significantly dif- ferent disease-free survival was found (log-rank test P < 0.0001). Conclusion: Ki-67 score accurately separates bronchopulmonary carcinoids in two well-distinct histo-prognostic categories. Ki-67 score predicts the patients outcome better than mitotic count, histotype, and tumor stage and it is therefore helpful in establishing the appropriate follow-up. © 2011 Grimaldi, Muser, Beltrami, Machin, Morelli, Pizzolitto, Talmassons, Marciello, Colao, Monaco, Monaco and Faggiano

Isoniazid and its hydrazine metabolite in patients with tuberculosis

Objective: The serum profiles of isoniazid and its hydrazine metabolite were investigated in patients with tuberculosis in steady-state conditions in the hope of identifying a pharmacokinetic approach that could be useful in the clinical assessment of other patients with the same disease state. Patients and Study Design: Isoniazid was coadministered with the other drugs included in the antitubercular regimen (rifampicin, ethambutol, streptomycin, morinamide). Concentrations of isoniazid and its hydrazine metabolite were measured in the collected serum samples by high performance liquid chromato-graphy. The pharmacokinetic parameters of isoniazid were estimated by WINNONLIN. Since an isoniazid serum concentration of 1.5 mg/L 3 hours after (C3) the administration of the dose (D) was demonstrated to be therapeutically efficacious with minimal neurotoxic adverse effects, the theoretical dosage adjustment (D(a)) required to achieve this optimal concentration in all our patients was calculated according to the inactivator index (I3) method proposed by Vivien et al. [I3 = (C) + 0.6)/D]; [D(a) = 2.1/I3]. Results: A large interindividual pharmacokinetic variability was observed [especially for maximum concentration (C(max)), trough levels, area under the curve (AUC), and hydrazine metabolite production] not only according to the acetylator status as expected, but inside each group as well. The mean D(a) was significantly lower than the mean D in the slow acetylators (2.32 \ub1 0.78 vs 4.75 \ub1 0.47 mg/kg; p < 0.00001), while no statistically significant difference was found in the rapid acetylators (4.16 \ub1 3.07 vs 4.68 \ub1 0.81 mg/kg; p = 0.53). Conclusion: Our findings suggest that slow acetylators show a mean daily isoniazid exposure (AUC) two-fold higher than rapid acetylators (36.42 \ub1 11.53 vs 16.50 \ub1 7.02 mg/L\ub7h; p < 0.0001) when nearly equal isoniazid daily doses are administered (4.75 \ub1 0.47 vs 4.68 \ub1 0.81 mg/kg; p = 0.81) and no peculiar pathophysiological conditions affecting isoniazid disposition are present. It might be speculated that slow acetylators may often benefit from reduced doses (< 5 mg/kg), since this strategy could either guarantee efficacy and reach the desired C(max) and C3 levels, or minimise potential toxicity risks lowering isoniazid daily exposure and fluctuations of hydrazine metabolite serum concentrations. However, care should be exercised and therapeutic drug monitoring needs to be performed in all patients, especially when peculiar pathophysiological conditions such its malabsorption - could affect the drug's pharmacokinetics

Pharmacokinetic aspects of levofloxacin 500 mg once daily during sequential intravenous/oral therapy in patients with respiratory tract infections

Levofloxacin is considered an effective antibiotic in the treatment of community-acquired lower respiratory tract infections (LRTIs). A study was carried out on 17 in-patients to assess the pharmacokinetics of a 500 mg once-daily switch intravenous (iv)/oral regimen of levofloxacin in the treatment of LRTI patients. Blood samples were collected under steady-state conditions at appropriate intervals. Levofloxacin plasma concentrations were analysed by means of HPLC and pharmacokinetic parameters were estimated using the WinNonlin pharmacokinetic software package. A lower clearance of levofloxacin (&lt;2 mL/min/kg), conditioning both a longer elimination half-life (∼9 h) and a larger AUCO0-τ (∼80 mg/Lh), was observed for both routes in our patients than in healthy volunteers. These differences may be explained considering that levofloxacin is excreted mainly as unchanged drug by the renal route, and most of our patients (71%) were very elderly subjects whose renal function physiologically declines with age. The almost complete (≥99%) absolute oral bioavailability suggests that a comparable exposure to the iv regimen may be achieved after oral administration. The overall clinical success rate was 94.1%

Non-small cell lung carcinoma: morphology and DNA content

Objective: To correlate stage-related and histologic features of non-small cell lung cancer (NSCLC) with DNA flow cytometric parameters. Study design: The clinicopathologic features, DNA flow cytometric parameters (ploidy type, S-phase fraction and DNA index [DI]) of 72 surgically resected NSCLC were reviewed. Results: NSCLC were classified on the basis of their DI in diploid, peridiploid, hypotriploid, triploid, hypertriploid, tetraploid, hypertetraploid and multiploid tumors. DI was significantly related to pleural infiltration, pT, histologic type and evidence of necrosis. Tumors infiltrating the pleura were mostly triploid or hypertriploid; high pT stages were also hypertetraploid. Adenocarcinomas showed a wide DI distribution, squamous carcinomas were mostly diploid, triploid or hypertriploid and large cell carcinomas were mostly triploid, hypertriploid and hypertetraploid. The best combination of features able to predict disease relapse was pT plus pN plus grading and divergent differentiation. Conclusion: Many stage-related and histologic features are associated with particular DI classes, which vary in relation to the feature itself and, in some cases, regardless of classical methods of grading and histologic typing. DNA content analysis highlights greater biologic heterogeneity in NSCLC than evidenced morphologically

Partitioning of bronchopulmonary carcinoids in twodifferent prognostic categories by Ki-67 score

Introduction: Histological distinction between typical and atypical bronchopulmonary carcinoids is based on mitotic activity and necrosis. Regardless of these two parameters, outcome after surgery is often unpredictable. In this study the prognostic value of different clinico-pathological factors was retrospectively analyzed in a large series of patients with bronchopulmonary carcinoid. Patients and Methods:The long-term post-surgical outcome of 106 radically treated patients affected by bronchopulmonary carcinoid from two Italian centers was correlated with tumor characteristics assessed by combining conventional histology with a panel of immunohistochemical markers of neuroendocrine differentiation (chromogranin-A, NSE) and proliferation activity (Ki-67 score). Results: Carcinoids were assessed as typical (TC=75; 70.8%) and atypical (AC=31; 29.2%). Mean follow-up was 8.3 years (range: 0–20; median: 8.0). All cases expressed neuroendocrine markers. At univariate analysis, tumor recurrence [14/75 TC (18.7%), 15/31 AC (48.4%)] correlated with carcinoid histotype (P =0.003), tumor size (P =0.012), mitotic index (P =0.044), Ki-67 score (P <0.0001), and synchronous node metastasis (P =0.037). Of these, Cox multivariate analysis confirmed only Ki-67 score as independent predictor of disease recurrence (P =0.009).The best cut-off for Ki-67 score (calculated by ROC curves) discriminating recurrent vs non-recurrent diseasewas 4% (sensitivity 79.3%; specificity 83.8%; area under the curve 0.85). By stratifying patients according to this cut-off, a significantly different diseasefree survival was found (log-rank test P <0.0001). Conclusion: Ki-67 score accurately separates bronchopulmonary carcinoids in two well-distinct histo-prognostic categories. Ki-67 score predicts the patients outcome better than mitotic count, histotype, and tumor stage and it is therefore helpful in establishing the appropriate follow-up

Sequential chemotherapy with Paclitaxel plus Cisplatin, followed by Vinorelbine, followed by Gemcitabine in advanced non-small cell lung cancer: an Alpe Adria Thoracic Oncology Multidisciplinary group study (ATOM 001)

Aim of this study was to determine the activity and toxicity of a sequential chemotherapy regimen in advanced non-small cell lung cancer (NSCLC). Fifty-one previously untreated stage IIIB/IV NSCLC patients were enrolled to receive two cycles of cisplatin plus paclitaxel (80/175 mg/m2 every 21 days), followed by two cycles of vinorelbine (30 mg/m2 on days 1 and 8 every 21 days), followed by two cycles of gemcitabine (1000 mg/m 2 on days 1, 8, and 15 every 28 days). Forty-one patients (82%) completed the planned six cycles. Grade 3-4 neutropenia was the major toxicity (41% of patients) and it was mainly associated with vinorelbine administration. Response rate after cisplatin plus paclitaxel was 18%; this percentage increased to 41% after vinorelbine, and it reached 43% upon completion of the entire six cycle treatment program. Median survival time was 14.4 months, 1-year survival rate was 53%, and 2-year survival rate was 18%. Median time to disease progression was 6.8 months. This sequential chemotherapy regimen is feasible and active in patients with advanced NSCLC. This pilot experience provides the basis for an ongoing randomized phase III trial comparing our sequential regimen versus cisplatin plus gemcitabin