Carbon monoxide, cigarettes and family doctors.

AIMS AND BACKGROUND: General practitioners could play a key role in preventive programs against tobacco-related diseases. However, they seldom take action in the office even with minimal advice counselling. Such behaviour might reflect the lack of academic teaching and the lack of practice with motivational and dependence questionnaires, considered basic tools to help smokers to quit successfully. The study was aimed to investigate the awareness of a sample of Italian family doctors as regards tobacco epidemiology and smoking cessation strategies. METHODS: A total of 428 family doctors were administered a questionnaire with a set of questions on their personal smoking habits and on personal initiatives in the office towards smokers. Another set of questions regarded their knowledge on tobacco issues, with special attention to carbon monoxide, which is widely perceived as a very dangerous poison and works as a motivational tool on smokers and adolescents. Carbon monoxide measurement was carried out on all participants to obtain objective data on smoking and to show the feasibility of the test. RESULTS: The percentage of self-reported current smokers among general practitioners was 24%, with a high prevalence of ex-smokers (46%), and 29% of never smokers. Family doctors were more keen to counsel adolescents than adults about tobacco, and they were very interested in continuing medical education on the issue. The doctors who took part in our study showed a surprising limited knowledge of all the issues associated with smoking cessation and prevention such as epidemiology, cigarette characteristics, success rate of smoking cessation programs, Fagerström's tolerance questionnaire, safety of nicotine replacement therapy and the knowledge of carbon monoxide as a product of cigarette smoke. CONCLUSIONS: The scenario depicted by our survey underscores the necessity to improve the knowledge and performance of primary care physicians on tobacco-related issues in order to implement primary and secondary prevention in clinical practice.

Intensification of 111In-DTPA-octreotide scintigraphy by means of pretreatment with cold octreotide in small cell lung cancer.

Small cell lung cancer (SCLC) expresses somatostatin receptors that can be traced with 111In-DTPA-octreotide scintigraphy. Although this technique is currently employed for staging and follow-up of neuroendocrine tumors of the gastrointestinal tract, its role in the clinical work-up of SCLC is at present under discussion. A better imaging contrast is desirable and recent reports suggest that this aim could be achieved by pretreatment with cold octreotide. Here we report on the results of 111In-DTPA-octreotide scintigraphy in 12 SCLC patients carried out before and after octreotide treatment. The patients were treated for 7 days with octreotide 200 micrograms three times a day s.c. Uptake was studied at 5 h with whole body planar and SPET imagings. In all cases studied, pretreatment with octreotide was followed by enhancement of tumor imaging. In one patient a better contrast of the lesions was found at the parenchymal and mediastinal levels as well as at brain level, allowing a clear definition of otherwise questionable metastases. After octreotide treatment, a decrease in background uptake in the subdiaphragmatic area was observed in most cases, allowing a better imaging of liver metastases. The enhancement effect was confirmed by semiquantitative analysis of scintigraphic uptake. Taken together, our results seem to indicate that cold octreotide enhancement can improve 111In-DTPA-octreotide imaging and optimize its clinical role in SCLC.

Refractory pulmonary aspergillosis: compassionate trial with terbinafine.

The frequency of bronchopulmonary aspergillosis is increasing due to the growing number of patients requiring steroids or other immunosuppressive therapies. Conventional treatments are ineffective in some patients and side-effects are an important issue. The aim of this work was to evaluate the effectiveness and safety of terbinafine, a new allylamine antimycotic drug, in three immunocompetent patients affected by lower respiratory tract aspergillosis [one chronic empyema due to Aspergillus fumigatus (AF) and two chronic necrotising aspergillosis] not responsive to the usual antimycotic therapies. In in vitro and animal model systems, terbinafine is as active as amphotericin B and itraconazole. Patients received terbinafine at doses ranging from 5 to 15 mg/kg per day, according to clinical status, for 3-5 months, depending on the clinical course of the disease and compliance. In patient 1 a negative anti-AF precipitin was obtained together with eradication of AF from the pleural cavity, which allowed a successful intrathoracic myo-omento-mammoplasty. In patients 2 and 3, AF was eradicated, anti-AF immunoprecipitins decreased, and clinical and radiological findings significantly improved. On the basis of the effectiveness of terbinafine demonstrated in this preliminary work, large studies to evaluate the use of terbinafine in bronchopulmonary aspergillosis are warranted. Moreover, the drug is not associated with resistance or significant side-effects.

Terbinafine in the treatment of non-immunocompromised compassionate cases of bronchopulmonary aspergillosis.

Conventional treatments of broncho-pulmonary aspergillosis are often ineffective and result in associated side-effects. Terbinafine (a new allylamine derivative), although as active against Aspergillus in vitro as amphotericin B and itraconazole, is less effective in rodent models because of a rapid hepatic first-pass effect. As terbinafine is metabolized differently in humans, the aim of this work was to evaluate this drug, for the first time, in the treatment of seven immunocompetent patients with lower respiratory tract mycotic infections unresponsive to the usual antimycotic drugs. Diagnosis was based on identification of fungal isolates, worsening of respiratory function tests, chest radiographs and computerized tomographic (CT) scan changes, positive skin test, aspergillin precipitins and clinical history. Terbinafine was administered at doses ranging from 5 to 15 mg kg-1 day-1 depending on the clinical severity of the disease, and was given for 90-270 days depending on clinical progress and compliance. In three patients A. fumigatus was suppressed with resolution of signs and symptoms; four patients showed transitory A. fumigatus suppression with marked clinical and radiological improvement. During relapses no resistance to terbinafine was observed. No significant side-effects were detected. Terbinafine appeared to be as effective as amphotericin B and itraconazole in the treatment of bronchopulmonary aspergillosis in nonimmunocompromised patients. These preliminary results suggest that controlled studies are warranted.

111In-DTPA-D-Phe-1-octreotide scintigraphy of small cell lung cancer.

Twenty-one patients with small cell lung cancer (SCLC) were investigated with 111in-octreotide (111-In-OCT) scintigraphs, 5 hours after the i.v. injection of 111 MBq of the radiotracer. Whole-body and planar scintigraphy as well as SPECT of the thorax were required. The scintigraphic results were compared to those of other conventional diagnostic procedures used for the staging and follow-up of SCLC patients. 111In-OCT detected 86% (48/56) of the lesions already known at the time of scintigraphy, being positive for all 20 SCLC lesions and negative for one lung adenocarcinoma. 111In-OCT showed a high sensitivity for mediastinal metastases (94%) and good sensitivity for bone (75%) and abdominal lymph node metastases (71%). It did not detect 2 liver metastases but revealed 5 unknown lesions which were then confirmed by other diagnostic examinations. 111In-OCT was also effective in patients with low levels of NSE. Three patients received cold octreotide for seven days to investigate whether this treatment might affect SCLC imaging. Scans were performed before and after treatment. The 111In-OCT uptake increased in the cancer lesions while the fixation in normal tissues decreased, demonstrating enhancement of SCLC imaging following cold octreotide administration.

Indium-111-DTPA-octreotide scintigraphy modulation by treatment with unlabelled somatostatin analogue in small-cell lung cancer.

AIMS AND BACKGROUND: Small-cell lung cancer (SCLC) tissue expresses somatostatin receptors and can be visualized by means of the indium-111-labelled somatostatin analogue DTPA-D-Pheoctreotide. The aim of the study was to investigate whether treatment with a cold somatostatin analogue can affect the imaging of somatostatin receptor scintigraphy. METHODS: Three patients with SCLC were treated with 200 micrograms of cold octreotide three times a day subcutaneously for 7 days. Whole body and planar scintigraphy was performed before and after the treatment. RESULTS: 111In-DTPA-octreotide uptake was increased in cancer lesions, whereas fixation in normal tissues (liver, spleen, kidneys) decreased. CONCLUSIONS: This is the first demonstration of an enhancement of SCLC imaging following unlabelled somatostatin analogue administration. Similar results have been described by other authors in a limited number of carcinoid tumors.

Somatostatin receptor imaging of small cell lung cancer (SCLC) by means of 111In-DTPA octreotide scintigraphy.

Somatostatin receptors have been described on the membrane of neoplastic cells derived from the APUD system and their expression has also been demonstrated on small cell lung cancer (SCLC) in vitro and in vivo. 21 patients with SCLC were studied using 111In-octreotide (111In-OCT) scintigraphy. Scintigraphic examinations were performed following intravenous (i.v.) injection of 111 MBq 111In-OCT with whole-body scintigraphy and planar scintigraphy of the thorax as well as the SPET technique. No short-term side effects were described following 111In-OCT administration. We studied the 111In-OCT biodistribution in 3 patients with serial scintigraphies at 1, 5 and 24 h. We used the 5 h as standard scanning time for the following 18 patients. The scintigraphic results were compared with those of other conventional diagnostic procedures. 111In-OCT detected 86% (48/56) of the lesions already known at the time of scintigraphy. It was positive in all 20 SCLC patients and negative in one lung adenocarcinoma. 111In-OCT showed high sensitivity for mediastinal metastases (94%) and good sensitivity for bone metastases (75%) and abdominal lymph node metastases (71%). 111In-OCT did not detect two liver metastases. 111In-OCT detected five unknown lesions which were confirmed by other diagnostic examinations. 111In-OCT was also effective in cancer patients with low levels of NSE. Our study shows that 111In-OCT scintigraphy is a reliable, non-invasive technique to detect primary SLCL and its locoregional or distant metastases. The clinical utility of receptor status characterisation obtained with 111In-OCT scintigraphy should be evaluated by means of an appropriate prospective study.

111In-octreotide uptake in granulomatous and tumor lesions in a patient with small-cell lung cancer.

A case of a patient with small cell lung cancer and right submandibular node enlargement due to granulomatous lymphadenitis is presented. Diagnostic procedures included: biopsy of the cervical node, transmission computed tomography of the chest, bronchoscopic examination and biopsy of the pulmonary lesion. The patient underwent 111In-octreotide scintigraphy (whole body and single photon emission tomography) which revealed both lesions. We conclude that granulomatous lesions are to be considered as a possible cause of false positive results, when octreotide scintigraphy is used to evaluate distant metastases in patients with known cancer.

Effect of octreotide on neuroenolase levels in patients with small cell lung cancer.

AIMS AND BACKGROUND: The somatostatin analog octreotide has an antiproliferative effect on small cell lung cancer lines in vitro and in experimental xenograft transplantation systems in vivo. Thus it is worth investigating octreotide activity in the clinical setting. METHODS: We studied the effect of octreotide (200 micrograms three times a day subcutaneously for seven days) on serum levels of the tumor marker neuroenolase in 13 patients with small cell lung cancer. RESULTS: A decrease in neuroenolase levels was observed at day 7 during octreotide treatment, with a mean +/- SD of 32.6 +/- 42.0 ng/ml compared to basal values of 44.4 +/- 57.7 ng/ml and to washout values of 50.3 +/- 65.7 ng/ml (P < 0.03). CONCLUSIONS: Our results indicate that octreotide is effective in reducing neuroenolase levels in small cell lung cancer patients. These data suggest a possible role for octreotide in the treatment of this kind of tumor.

Evaluation of neuron-specific enolase, tissue polypeptide antigen, and carcinoembryonic antigen as markers for staging and monitoring response to therapy of lung cancer.

Serum neuron-specific enolase (NSE), tissue polypeptide antigen (TPA), and carcinoembryonic antigen (CEA) were measured in 60 patients with small-cell lung carcinoma (SCLC) and in 94 patients with advanced non-small-cell lung carcinoma (NSCLC) at diagnosis, during induction chemotherapy, and at restaging. At diagnosis, the positivity rates of NSE, TPA, and CEA were 88, 52, and 43% in SCLC, and 20, 62, and 53% in NSCLC, respectively. Serum NSE and TPA levels were significantly higher in extensive than in limited SCLC. TPA and CEA levels were significantly correlated with the extent of NSCLC. NSE and TPA were significantly concordant with the clinical response to initial combination chemotherapy, the former in SCLC, the latter in both SCLC and NSCLC. By discriminant analysis, the presentation levels of the markers were not predictive of response to induction chemotherapy, whereas changes in NSE and TPA levels after the first cycle of chemotherapy were.

Adjuvant treatment of stage I lung cancer with high-dose vitamin A.

PURPOSE: Vitamin A and retinoids are strong inhibitors of epithelial cancer promotion and progression in experimental carcinogenesis. This study examined whether they may prevent the occurrence of upper aerodigestive cancer in subjects heavily exposed to tobacco smoking, such as patients already cured of an early-stage lung cancer. PATIENTS AND METHODS: The adjuvant effect of high-dose vitamin A was tested on 307 patients with stage I non-small-cell lung cancer. After curative surgery, patients were randomly assigned to either a group prescribed retinol palmitate administration (orally 300,000 IU daily for 12 months) or a control group prescribed no treatment. RESULTS: After a median follow-up of 46 months, the number of patients with either recurrence or new primary tumors was 56 (37%) in the treated arm and 75 (48%) in the control arm. Eighteen patients in the treated group developed a second primary tumor, and 29 patients in the control group developed 33 second primary tumors. A statistically significant difference in favor of treatment was observed concerning time to new primary tumors in the field of prevention (P = .045, log-rank test). The treatment difference in terms of disease-free interval was close to statistical significance (P = .054, log-rank test) and just significant when adjusted for primary tumor classification (P = .038, Cox regression model). CONCLUSION: Daily oral administration of high-dose vitamin A is effective in reducing the number of new primary tumors related to tobacco consumption and may improve the disease-free interval in patients curatively resected for stage I lung cancer. The impact of such a treatment on survival needs to be further explored.

Influence of glutathione administration on the disposition of free and total platinum in patients after administration of cisplatin.

The kinetics of platinum (Pt) was studied in 12 patients suffering from non-small-cell lung cancer or pleural mesothelioma. Each subject received an infusion of cisplatin (CDDP, 80 mg/m2), and six patients were pretreated with glutathione (GSH, 2.5 g given i.v.) at 15 min prior to the cisplatin infusion. After a 3- to 4-week interval, all patients were given a second course of treatment on the same schedule. A biexponential model was fitted to plasma concentrations of total and ultrafilterable Pt. The excretion of Pt in urine was evaluated during the first 48 h after the CDDP infusion. Following the administration of CDDP alone or with GSH pretreatment, the pharmacokinetic parameters of Pt did not significantly differ between the treatments. Also, the unbound fraction determined at each sampling time did not vary significantly between the treatments. However, it is noteworthy that the mean values obtained for the terminal half-life, the volume of distribution, the renal clearance, the percentage of the dose excreted in the urine, and the mean residence time of total Pt were higher in patients who had been pretreated with GSH, suggesting that GSH might increase both the rate of Pt elimination and the extent of Pt distribution and, as a consequence of the latter, might prolong the residence time of Pt in the body. In addition, the unbound fraction of Pt from the 4th to the 48th was higher following the first dose of CDDP+GSH than after treatment with CDDP alone. Because of the rather high variability in the values of the parameters obtained, further work is planned using a larger number of patients.

Activity of doxorubicin and cisplatin combination chemotherapy in patients with diffuse malignant pleural mesothelioma. An Italian Lung Cancer Task Force (FONICAP) Phase II study.

Twenty-six symptomatic patients with diffuse malignant pleural mesothelioma (DMPM) were enrolled in a Phase II Italian Lung Cancer Task Force (FONICAP) study to assess the activity and toxicity of doxorubicin and cisplatin combination chemotherapy. The drug schedule was as follows; 60 mg/m2 of doxorubicin and 60 mg/m2 of cisplatin both given intravenously (IV) on day 1 every 3 to 4 weeks. Of the 24 evaluable patients, 6 objective partial responses (25%; 95% confidence limits, 9.77% to 46.71%) were observed. Twelve of 24 patients (50%), including 6 with no radiologic evidence of response, had a clinical improvement as demonstrated by an objective reduction of symptom or performance status scores along treatment. The overall median survival time was 10 months. Toxicity was mild and dose reductions or suspensions were not required. The combination of doxorubicin and cisplatin is effective and well tolerated. It might be considered for palliation of symptomatic patients with DMPM.

Combination chemotherapy and interferon alpha 2b in the treatment of advanced non-small-cell lung cancer. The Italian Lung Cancer Task Force (FONICAP).

Thirty-four patients with previously untreated advanced non-small-cell lung cancer were treated with a combination of polychemotherapy and recombinant interferon. Chemotherapy consisted of cyclophosphamide, 400 mg/m2, epidoxorubicin, 50 mg/m2, and cisplatin, 40 mg/m2 (CAP) i.v. on day 4; recombinant alpha 2b interferon (r alpha 2b IFN) was given i.m. daily at the dose of 3-5 MU from days 1 to 7. The treatment was repeated every 4 weeks. In the 32 eligible patients the overall response rate was 19.3% (95% C.L. 7.4-37.4%). Non-hematologic toxicity consisted formerly in flulike symptoms and fatigue complained of by 37.5% and 31.2% of patients, respectively, and vomiting reported in 68.7% of patients; grade III-IV myelotoxicity was observed in 12.5% of cases. In no case was the toxicity life threatening. The median overall actuarial survival and progression-free survival were 37 and 20 weeks, respectively. This study indicates that the combination of CAP chemotherapy and r alpha IFN is feasible and active in the treatment of advanced non-small-cell lung cancer.

Safety of high-dose vitamin A. Randomized trial on lung cancer chemoprevention.

The paper reports on the efficacy and side effects of high-dose vitamin A, administered as adjuvant treatment for resected stage I lung cancer in a randomized clinical trial. After a median follow-up of 28 months, 283 patients were evaluable: 138 allocated to treatment with retinol palmitate (300,000 IU daily for at least 12 months) and 145 to standard observation. The clinical results available to date do well justify a continuation of the study. Skin dryness and desquamation were the most frequent symptoms, affecting 60% of all treated patients. Other symptoms such as dyspepsia, headache, nosebleeds and mild hair loss occurred in less than 10% of patients, and were self-terminating. Only in 4 patients (3%) was the treatment interrupted because of symptoms potentially related to vitamin A administration. As for laboratory tests, gamma-GT levels were abnormally elevated in 69% of treated patients vs. 39% of controls at 24 months (mean 149 vs. 58 IU/l; p less than 0.05). Serum triglyceride concentrations over 150 mg/dl were seen in 74% of treated patients vs. 43% of controls at 12 months (mean 283 vs. 179 mg/dl; p less than 0.05). There were no other laboratory signs of toxicity attributable to vitamin A. In our experience, high-dose retinoyl palmitate administration was a well-tolerated and safe treatment. The long-term impact on lipid metabolism still remains to be determined.

Disseminated tuberculosis of the central nervous system responsive to rifabutin.

Multiple cerebral tuberculomas are now very rare. We report the case of a young man with an 8-month history of headache, febricula and abscess of the left tibiotarsal joint, which was found to contain mycobacterium tuberculosis. Chest X-rays revealed miliariform dissemination to both lungs while CT and MR brain scans revealed numerous small nodules, especially in the posterior cranial fossa. Despite anti-tuberculosis therapy the patient developed a right pyramidal hemisyndrome and intracranial hypertension. The inclusion of rifabutin in the treatment schedule was followed by rapid improvement and a year later the patient was in good health and free from cerebral and pulmonary lesions. The interest of the case lies in the multiplicity of sites of the TB process in a non immunodepressed patient, the dissemination to the CNS without meningeal involvement, the resistance to standard antimycobacterials and the swift response to rifabutin.

In vivo and in vitro growth of SCLC cells derived from biopsies.

In order to increase the availability of SCLC cells derived from biopsies, in vivo and in vitro growth methods were investigated. The cells grown in both conditions were periodically monitored for reactivity with 2 monoclonal antibodies (MAbs): MLuC1 directed against SCLC cells and IM1 which recognizes the class II antigen on activated lymphocytes and macrophages. About 50% of the 28 analyzed SCLC specimens were found to proliferate in one or both systems. The in vitro-grown cells exhibited the same heterogeneity found in the original cell suspensions and moreover, in some cases only normal cells were recovered after several in vitro passages. From the subcutaneous transplanted tumors a large number of MLuC1-positive tumor cells could easily be recovered, thus indicating the validity of the in vivo methodology. The MBr1 MAb, directed against an epithelial antigen, was found to react with about 50% of the 26 tested tumors, mainly those which demonstrated in vivo and/or in vitro growth capacity. These data suggest that only some tumors, presumably with peculiar biological characteristics, can efficiently grow in these artificial systems.