Ernesto Pozzi

Prognostic significance of Ki67 labelling in resected non small cell lung cancer.

One hundred and eleven tissue samples of primary non small cell lung cancer obtained from patients undergoing radical surgery for resectable disease were investigated for the presence and distribution of Ki67 related antigen using an immunohistochemical technique, as a marker of the proliferative activity of the tumour. No correlation was seen between Ki67 expression and clinico-pathological variables (sex, age, histology, grading and pTNM stage) but disease-free survival was significantly lower in patients with higher Ki67 score (> 25% positive cells) at diagnosis (P < 0.03). Growth fraction evaluated by Ki67 labelling may provide a complementary prognostic parameter in non small cell lung cancer.

Primary human mesothelioma cells express class II MHC, ICAM-1 and B7-2 and can present recall antigens to autologous blood lymphocytes.

Mesothelioma cells (MMc) are considered to be weakly immunogenic and the experimental approaches attempting to induce an immune response against these cells have been disappointing. Our aim was to investigate whether MMc possess the surface accessory molecules involved in antigen presentation and whether these cells are capable of presenting recall antigens to autologous blood lymphocytes. Four primary MMc cultures were generated from malignant effusions and examined to assess whether the accessory molecules required for antigen presentation were present on their surfaces. Intercellular adhesion molecule‐1 (ICAM‐1; CD54); class I and class II major histocompatibility complex‐DR (MHCI and MHCII‐DR); B7–1 (CD80.3); and B7–2 (CD86) expression by MMc was studied by immunocytochemical and/or FACScan analysis. MMc were pulsed with purified protein derivative (PPD), Tetanus toxoid (TT) and Candida albicans (CA) bodies, and incubated with autologous lymphocytes. Lymphocyte proliferation was estimated by radionucleotide incorporation. Phenotypic analysis showed the presence of MHCII‐DR, ICAM‐1 and B7–2 on primary MMc cultures, whereas the phenotypic evaluation of 2 established MMc lines did not show the presence of the B7–1 and B7–2 molecules. In addition, MHCII‐DR was detectable only after interferon gamma (IFN‐γ) stimulation. Primary MMc cultures acquired the capability to induce lymphocyte proliferation after pulse with the recall antigens. To achieve characterization of these lymphocytes, we generated a PPD‐specific CD4+ T‐cell clone. PPD‐pulsed MMc were shown to specifically induce T‐cell clone proliferation through a MHCII‐DR‐mediated process. We conclude that primary MMc possess the surface molecules required for antigen presentation and can present recall antigens to CD4+ lymphocytes. Int. J. Cancer 78:740–749, 1998.

Phase I:II dose finding study of paclitaxel and carboplatin in advanced non-small cell lung cancer

INTRODUCTIONnThis phase I study was designed to establish the maximum tolerated dose (MTD) of the carboplatin paclitaxel combination, given without routine growth factor support to previously untreated patients with stage IIIB and IV non-small cell lung cancer.nnnPATIENTS AND METHODSnFifty patients (one stage IIIa, 31 stage IIIb and 18 stage IV) were sequentially assigned to one of 14 treatment groups in which paclitaxel and carboplatin were administered in doses ranging from 130 to 235 mg/m2 and from 230 to 375 mg/m2 , respectively. Paclitaxel was administered as a 3-h intravenous infusion using non-polyvinylchloride tubing and connectors. The carboplatin infusion, over 30 min, was administered at the completion of the paclitaxel infusion.nnnRESULTSnThe MTD for the combination has been reached at 235 mg/m2 of paclitaxel and at 375 mg/m2 of carboplatin. The combination shows a good safety profile with very few and brief episodes of neutropenia without any infectious episodes. At the doses tested thrombocytopenia did not occur at all. Among 47 assessable patients there was one complete response and 17 partial responses for an overall response rate of 38%. There has been a tendency to a dose-response relationship for the combination with only six partial responses (27%) reported in 22 patients who received paclitaxel at doses < or = 195 mg/m2 and carboplatin at doses < 350 mg/m2 and 12 partial responses in 25 patients (48%) receiving paclitaxel > 195 mg/m2 and carboplatin > or = 350 mg/m2, respectively. The median event-free survival time is 33 weeks (range, 4-156 +). With a minimum follow up duration of 57 weeks the median overall survival time is 51.81 weeks (range, 7-162 +) and the 1-year survival rate is 49%.nnnCONCLUSIONnIn advanced NSCLC the carboplatin-paclitaxel combination can be safely administered at the doses of 375 and 225 mg/m2 every 4 weeks, it appears to be active and well tolerated.

Biological prognostic factors in non-small cell lung cancer

The results of conventional treatments for lung cancer remain poor and long-term survival rates have changed little over the last 10 years. In the same period of time there has been an explosion in the knowledge on the processes of cellular transformation, tumour progression, invasion and metastasis. The major categories of biological events implicated in non-small cell lung cancer include growth factor receptors expression (epidermal growth receptor, p185c-neu), autocrine growth factor production (transforming growth factor alpha), dominant oncogenes activation (ras genes) and deletion of tumour suppressor genes (p53 gene, retinoblastoma gene) and these are some of the abnormalities associated with specific histological types and with poor prognosis. Additional prognostic information can be obtained from the evaluation of the ploidy and proliferative activity of the tumours, carbohydrate antigens expression, presence of neuroendocrine differentiation and the evaluation of markers of the sequential steps involved in the process of tumour dissemination.

Lymphocyte subpopulations analysis in pleural fluid and peripheral blood in patients with lymphocytic pleural effusions.

Lymphocyte subpopulations analysis by an 11-monoclonal antibody (MoAb) panel was carried out in pleural fluid and in peripheral blood in 30 patients affected by newly diagnosed, untreated pleural effusion of different etiology determinated with bacteriological, cytological or histological criteria. Lymphocytes were the predominant cell type, in pleural fluid, in neoplastic pleural effusions as well as in congestive heart failure pleural effusions and, especially, in tuberculous pleural effusions. Lymphocyte analysis in pleural fluid and in peripheral blood suggests the involvement of different mechanisms for the lymphocyte accumulation in the pleural space according to different etiologies. Tuberculous pleural effusions showed an evident CD4+ and TEC T5.9+ lymphocyte accumulation from peripheral blood. In these patients, cutaneous skin test response to purified protein derivative was strongly related to this situation. In neoplastic pleural effusions there was a lower percentage of CD4+ lymphocytes, reflecting circulating lymphocyte pool; however, in neoplastic pleural effusions, various lymphocyte patterns may be sometimes observed depending on different histologies. Passive lymphocyte accumulation seems to be the most important mechanism in congestive-heart-failure pleural effusions.

Studies of MR 889, a new synthetic proteinase inhibitor.

We investigated the proteinase inhibitory activity of MR 889, a thiolactic acid derivative. It is able to in vitro inhibit at low concentration (10(-5),10(-6)M) the activity of porcine pancreatic elastase, human neutrophil elastase and bovine chymotrypsin. In addition, MR 889 is able to inhibit the residual activity of alpha 2-macroglobulin-trapped human neutrophil elastase, paralleling the efficacy of phenylmethylsufonylfluoride. Finally, MR 889 has been shown to in vitro reduce the burden of elastase- and chymotrypsin-like activity found in sputum sol-phases of patients admitted for chronic bronchitis exacerbation.

Tachykinin activation of human monocytes from patients with interstitial lung disease, healthy smokers or healthy volunteers

Three types of tachykinin receptors, NK(1), NK(2)and NK(3), have been described to preferentially interact with substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) respectively. Experimental evidence indicates that SP and NKA modulate the activity of inflammatory and immune cells, including mononuclear ones, and points to their involvement in lung pathophysiology. We previously reported that NK(1)and NK(2)receptors are present on monocytes (MO) isolated from healthy donors or rheumatoid patients - a greater sensitivity to NK(2)receptor stimulation was observed in the latter condition. This study evaluated the effects of SP and NKA, as well as NK(1)and NK(2)selective agonists and antagonists, on MO obtained from healthy volunteers, healthy smokers or patients with interstitial lung diseases (e.g. sarcoidosis and idiopathic pulmonary fibrosis). Superoxide anion (O(2)(-)) production was chosen as a parameter of cell activation. SP and NKA dose-dependently evoked O(2)(-)production from MO in all the conditions evaluated, their effects being competitively antagonized by selective antagonists (CP 96 345 and MEN 10 627, respectively). When selective NK(1)and NK(2)agonists were used, [Sar(9)Met(O(2))(11)]SP, a selective NK(1)agonist, induced a more than doubled O(2)production in MO obtained from patients with interstitial lung diseases as compared to healthy volunteers, whereas MO isolated from healthy volunteers were more sensitive to NK(2)receptor stimulation.

Phase II study of high-dose paclitaxel and carboplatin in previously untreated, unresectable non-small cell lung cancer.

INTRODUCTIONnThis phase II study was designed to assess the activity and tolerability of the carboplatin-paclitaxel combination, given without routine growth factor support to previously untreated patients with stage IIIB and IV non-small cell lung cancer.nnnPATIENTS AND METHODSnSixty patients (15 stage IIIb and 45 stage IV) received paclitaxel 225 mg/ml on day 1, followed by carboplatin AUC 6 mg/ml per minute (Calvert formula) every 3 weeks. Paclitaxel was administered as a 3-h intravenous infusion followed by carboplatin over 30 min, on completion of paclitaxel administration.nnnRESULTSnThe combination showed a good safety profile with Grade 4 neutropenia occurring in 31% of patients without any serious infectious episodes requiring hospitalization. Moderate to severe anemia and thrombocytopenia seldom occurred. Sensorimotor peripheral neuropathy (Grade 2-3) and myalgia (Grade 3-4) were documented in 34 and 20% of the patients, respectively. Among 59 evaluable patients, there was one complete response and 26 partial responses for an overall response rate of 46% (95% C.I.: 34-59%). With a minimum follow-up duration of 16.5 months, the median overall survival time is 52 weeks and the 1-year survival rate is 50%. Median duration of response is 20 weeks (range: 4-52) and progression-free survival is 22 weeks (range: 5-77).nnnCONCLUSIONnIn advanced NSCLC, the combination carboplatin-paclitaxel at doses of AUC 6 mg/ml per minute and 225 mg/ml every 3 weeks, is both active and relatively well-tolerated.

Lomefloxacin versus amoxicillin in the treatment of acute exacerbations of chronic bronchitis : an italian multicenter study

Nine centers in Italy participated in a worldwide, multicenter study comparing the effectiveness and safety of lomefloxacin and amoxicillin in patients with acute exacerbations of chronic bronchitis caused mainly by gram-negative pathogens. The 157 enrolled patients received either 400 mg lomefloxacin once daily (n = 78) or 500 mg amoxicillin every 8 hours (n = 79) for 7-10 days. A total of 131 patients were evaluable for bacteriologic efficacy and 154 for clinical efficacy. At 2-4 days after the conclusion of treatment, the bacterial eradication rate was 84.8% for lomefloxacin-treated patients and 64.6% for amoxicillin-treated patients (p = 0.0065); the clinical success rate (cure plus improvement) for lomefloxacin was 94.7% and for amoxicillin was 83.3% (p = 0.0212). The reinfection rate was lower in the lomefloxacin group than in the amoxicillin group (3.0% vs 13.8%, p = 0.0382). Both drug regimens were well tolerated. Once-a-day treatment with 400 mg lomefloxacin was more effective than 500 mg amoxicillin three times daily for the treatment of acute exacerbations of chronic bronchitis caused by gram-negative pathogens.