Cisplatin, gemcitabine, and paclitaxel in locally advanced or metastatic non-small-cell lung cancer: a phase I-II study. Southern Italy Cooperative Oncology Group.

PURPOSE: Because both cisplatin-paclitaxel and cisplatin-gemcitabine combinations are generally considered to be among the most active regimens in non-small-cell lung cancer (NSCLC) patients, this study aimed to determine the maximum-tolerated dose (MTD) of paclitaxel when combined with fixed doses of cisplatin and gemcitabine in advanced NSCLC patients and aimed to define the therapeutic activity of this new regimen. PATIENTS AND METHODS: From October 1996 to September 1998, 75 patients with stage IIIB-IV NSCLC, who were either chemotherapy-naive (65 patients) or who had been pretreated (10 patients), received fixed doses of cisplatin (50 mg/m(2)) and gemcitabine (1,000 mg/m(2)) and escalating doses of paclitaxel in a 1-hour infusion, all on days 1 and 8, every 3 weeks. RESULTS: Five different paclitaxel doses were tested, for a total of 275 cycles delivered. The escalation was stopped at the paclitaxel dose of 75 mg/m(2) in pretreated patients, whereas it continued to 150 mg/m(2) in chemotherapy-naive patients. A total of 65 chemotherapy-naive patients were treated. A paclitaxel dose of 125 mg/m(2) was recommended for phase II, and a total of 39 patients were treated at this level, for a total of 158 cycles delivered. No treatment-related deaths occurred. Five patients were hospitalized because of sepsis, and packed RBC transfusion was required in 13 patients. Grade 4 neutropenia and thrombocytopenia occurred in 23 (31%) and eight (11%) patients, respectively. Overall, 74 of the 75 patients were assessable for response. Four complete (CR) and 38 partial (PR) responses were recorded, for an overall response rate (ORR) of 57%. Three of the ten pretreated patients achieved a PR, compared with four CRs and 35 PRs in the 64 chemotherapy-naive patients (ORR, 61%). Thirty-eight of 39 patients included in phase II were assessable for response and quality of life (QOL) (one patient's disease was not measurable). Two CRs and 24 PRs were recorded in this group, for an ORR of 68% (95% confidence interval, 51% to 82%). The QOL score improved in 27 of 38 (71%) patients. The median survival time was 15 months in the 65 chemotherapy-naive patients, but it had not yet been reached in the 39 patients included in phase II, for whom the 1-year projected survival was 70%. CONCLUSION: The cisplatin-gemcitabine-paclitaxel combination is a feasible and well-tolerated approach in advanced NSCLC patients. Both a major response and a QOL improvement can be obtained in a high proportion of patients, with a median survival time exceeding 1 year. A phase III trial comparing this combination with other effective regimens is under way.

Relationships betxween Fas expression, activation molecule CD25, and functional activity of tumor-associated lymphomonocytes from neoplastic effusions.

Fas ligand (FasL), a cell surface molecule belonging to the tumor necrosis factor family, binds to its receptor Fas, thus inducing apoptosis of Fas bearing cells. In the present study we assessed the expression of Fas, activation molecule interleukin (IL)-2 receptor alpha chain (CD25) and an index of functional activity such as thymidine uptake under mitogen stimulation of tumor associated lymphomonocytes (TALM) from 7 neoplastic effusions of advanced cancer patients. The same parameters were studied in peripheral blood mononuclear cells (PBMC) of 7 patients with cancer of different sites and in 7 normal subjects. The proliferative response to phytohemagglutinin (PHA), measured as [3H]-thymidine uptake, of TALM was significantly lower than that of PBMC of cancer patients. The expression of CD25 on unstimulated fresh TALM was slightly higher than that of PBMC from normal subjects: after 24 h of PHA stimulation the CD25 was expressed both on TALM and PBMC from normal subjects. The expression of Fas was assessed on unstimulated TALM, PBMC from cancer patients and normal subjects immediately after (by 2 h, t0) the cell separation, and at different times (24 h and 48 h) thereafter, and on PHA-stimulated TALM, PBMC from cancer patients and normal subjects after 24 h and 48 h of culture (in RPMI 1640). At all times (t0, 24 h and 48 h) the Fas expression by unstimulated TALM was significantly higher than that of PBMC from normal subjects: the Fas expression by PBMC from cancer patients was roughly in the same range as PBMC from normal subjects. At 24 h the Fas expression by PHA-stimulated TALM was significantly higher than that of PBMC from normal subjects, whereas at 48 h the difference was not significant. The TALM studied by us showed to be functionally defective and expressing relatively high levels of Fas showing the characteristics to be considered as a target for FasL expressing tumor cells, which in this way may escape immune control.

Membrane-bound and soluble IL-2 receptors (p55 and p75 chains) on peripheral blood mononuclear cells from patients with solid malignancies.

The aim of the investigation was to study directly the IL-2 receptor (IL-2R) and its subunits, p55 and p75 chains, either membrane-bound or soluble, on PBMC of patients with solid malignancies and, indirectly, the same patients' PBMC ability to produce IL-2. Fifty-eight cancer patients, 29 men and 29 women, were studied: their mean age was 57.3 yr, range 35-79. Twenty-two healthy age-sex-matched subjects served as controls. The tumors were the most common and the most representative among human cancers, i.e., breast, lung, head and neck, digestive tract and liver, prostate and gynecologic cancers: they were generally in advanced stages and in 23 cases metastatic. The PBMC proliferative response to PHA, PHA plus IL-2, and IL-2 was evaluated along with the response to PHA in the presence of anti-p55, anti-p75 monoclonal antibodies, or both. Moreover, membrane-bound IL-2R (p55 and p75 chains) on PHA-stimulated PBMC was detected, along with soluble IL-2R in the serum and in the culture supernatants. The conclusions suggest that in solid malignancies: the membrane-bound IL-2Rs, both p55 and p75 chains, are expressed normally, there is an high serum level of soluble IL-2R, there is a normal release of soluble IL-2R in culture, and there is an indirect evidence of a lack of IL-2 production. Therefore, no primary impairment of IL-2R was found in solid tumors. Moreover, in our study we have found no difference in any parameter studied between patients with and patients without metastases.

Role of interleukin-2 (IL-2) in cancer-related immune deficiency: in vitro response to IL-2, production of IL-2, and IL-2 receptor expression in patients with advanced cancer.

The aims of the investigation were 1) to determine if there are defects in interleukin-2 (IL-2) regulation on either phytohemagglutinin (PHA)-activated or non-PHA-activated peripheral blood mononuclear cells (PBMC) in cancer patients to ascertain the role of IL-2 in this disease; 2) to carry out preliminary experiments for a direct quantitative evaluation of endogenous IL-2 production by PBMC cultures; and 3) to evaluate the IL-2 receptor expression by PBMC of cancer patients. An assessment of lymphocyte subsets was also performed with monoclonal antibodies in a selected group of patients. A total of 170 patients entered the study. Cancer sites were larynx (48), breast (44), lung (30), colorectal(23), and gynecologic (25). Staging showed in the former three cancer sites predominantly localized or only locally advanced disease and in the latter two sites disseminated disease. PBMC cultures were performed with microtiter plate technique and 3H-thymidine uptake evaluation using polyclonal mitogens, IL-2, and a monoclonal antibody against IL-2 receptor. Our results provided evidence that the cancer patients exhibit a T-cell functional immunodepression, which, to some extent, progresses during tumor growth so that the localized disease shows a low-grade defect and advanced disease a high-grade defect. Our data also clearly suggest that IL-2 deficiency is the primary factor involved in this functional immune impairment. We found no significant defect in the IL-2 receptor expression by PBMC of cancer patients. Our data also seem to support the in vivo therapeutic administration of IL-2 and lymphokine-activated killer cells to cancer patients.

Interleukin 2 (IL 2) relationships with the cancer-related immunodeficiency: in vitro response to exogenous IL 2 by PHA-activated and non PHA-activated peripheral blood mononuclear cells from cancer patients.

The aims of the investigation were: 1) to determine if there are defects in interleukin 2 (IL 2) regulation either on phytohemagluttinin (PHA)-activated or non PHA-activated peripheral blood mononuclear cells (PBMC) in cancer patients, in order to ascertain the role of IL 2 in this disease, and 2) to carry out preliminary experiments for a direct quantitative evaluation of endogenous IL 2 production by PBMC cultures of cancer patients. An assessment of lymphocytes subsets was also performed with monoclonal antibodies in a selected group of patients. A total of 159 patients entered the study. Cancer sites were: larynx, 49; breast, 42; lung (NSC), 25; colorectal, 18; and gynecologic, 25. In the former 3 cancer sites, staging showed localized or only locally advanced disease and in the later 2 sites it showed disseminated disease. Our results provided evidence that the cancer patients exhibit a T cell functional immunodepression, which progresses during tumor growth, so that the localized disease shows a low-grade defect and advanced disease shows a high-grade defect. Our data also clearly suggested that the factor involved with a primary role in this functional immune impairment is the IL 2 deficiency. In our study we have not found a substantial difference of activity between recombinant and nonrecombinant IL 2, although the comparison of the relative activities of the two types of IL 2 is not easy to make, since they are expressed in different ways; however the recombinant one appeared to be slightly more active, probably for the higher purity. Our data also seem to support the perspective of the in vivo therapeutic administration of IL 2 in cancer patients.

[Aspects and behavior of x-ray computed tomographic studies in subacute sclerosing panencephalitis]. / Aspetti e comportamento dell'indagine tomodensitometrica nella panencefalite sclerosante subacuta.

The authors reports cerebral Computerized Axial Tomography findings examined, in association with other diagnostic tests, in 5 cases of Subacute Sclerosing Panencephalitis in the acute phase and repeated in 2 of these patients later, during the state and terminal phases of the disease. Hypodensity of the white matter was the main sign of initial cerebral parenchymal involvement and an atrophic aspect was most indicative of the terminal phase. Moreover, it has been shown that associated with clinical symptomatology, immunologic data and EEG signs, cerebral Computerized Axial Tomography may offer the possibility for evaluating the nature and the evolutive stage of the disease and facilitate differential diagnosis from other degenerative encephalopathies.

[Opsoclonic encephalopathy in childhood (Kinsbourne syndrome)]. / L'encefalopatia opsoclonica nell'infanzia (sindrome di Kinsbourne).

Kinsbourne's syndrome (ataxia--opsoclonus--myoclonus) is described. The characteristics of this syndrome are: infections of the upper respiratory tract and enteric system and behavioural disturbances leading to the typical symptomatological triad. Various tests were carried out to determine the presence of neuroblastoma which is often associated (46%) to this syndrome. These tests resulted negative. Differential diagnosis was considered in relation to other conditions which present a characteristic symptomatology similar to Kinsbourne's syndrome. Synthetic ACTH (Synacthen) treatment produced a regression of the clinical symptoms. Based on the examinations carried out, which always resulted negative even after 36 months, and on the drug dependence, the present case was diagnosed as primitive opsoclonus.

[Cutaneous, radiologic and endocrinologic aspects of adrenoleukodystrophy]. / Su alcuni aspetti cutanei, radiologici ed endocrinologici della adrenoleucodistrofia.

A case of adrenoleucodistrophy in a 9 year old boy is reported. At onset, strabismo, skin hyperpigmentation, difficulty in deambulation and retarded writing and language capability were seen. The child's condition rapidly worsened. Normal hemochrome, urine tests, azotemia, blood calcium levels, alkaline phosphate, aminoaciduria and lipidogram values were found. EEG showed diffused slow activity mainly bilaterally at the anterior deviations. TAC revealed hypodense grey matter, especially in the parietal zone, a typical finding in leucodystrophy (Cattarossi e coll., 1981). Cellular biopsy showed modifications of the fibrocells, considered indicative of this condition. The study of the hypothalamic hypophyseal - adrenal - gonadal axis showed a significant increase of LH and RH after stimulation, increased testosterone and androstenedione and reduced basal plasma cortisol, and after stimulation, levels. These findings suggest that hyposurrenalism may be secondary to 21 - hydroxylase deficiency.

[Psychological aspects of the epileptic child and his relationship to his family environment]. / Aspetti psicologici del bambino epilettico e suoi rapporti con l'ambiente familiare.

Intellectual development and psychic problems were examined in thirty children, suffering from center - encephalic and focal epilepsy. Two parameters were taken into consideration: social insertion and family adaptation. Intellectual development was evaluated with the Terman-Merril test. At the same time, correlations between the epileptic form, the age of the onset of the seizures and their frequency, the precocity of therapeutic treatment were considered. The intellectual development and the personality were good in 23,7%, when the subjects were enclosed in valid familiar environment and when clinic disappearance of seizures was rapid; these aspects were compromised in 76,3%, when emotively valid family substractum was deficient and therapy was tardily started and barely efficient. On the basis of these data Authors affirm the importance of the precocity of therapy and the emotively valid substratum for preventing the behaviour disturbances in epileptic patients.