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This study presents data suggesting that both human mesothelioma (cell lines and human mesothelioma biopsies) and human normal mesothelial cells express receptors for acetylcholine and that stimulation of these receptors by nicotine prompted cell growth via activation of nicotinic cholinergic receptors. Thus, these data demonstrate that: (a) human mesothelioma cells and human biopsies of mesothelioma as well as of normal pleural mesothelial cells express functionally alpha-7 nicotinic acethlycholine receptors, evaluated by alpha-bungarotoxin-FITC binding, receptor binding assay, Western blot, and reverse transcription-PCR; (b) choline acetyltransferase immunostaining is present in mesothelioma cells; (c) mesothelioma cell growth is modulated by the cholinergic system in which agonists (i.e., nicotine) has a proliferative effect, and antagonists (i.e., curare) has an inhibitory effect, evaluated by cell cloning, DNA synthesis and cell cycle; (d) nicotine induces Ca(+2) influx, evaluated by [(45)Ca(2+)] uptake, and consequently activation of mitogen-activated protein kinase pathway (extracellular signal-regulated kinase and p90(RSK) phosphorylation), evaluated by Western blot; and (e) apoptosis mechanisms in mesothelioma cells are under the control of the cholinergic system (nicotine antiapoptotic via induction of nuclear factor-kappaB complexes and phosphorylation of Bad at Ser(112); curare proapoptotic via G(0)-G(1) arrest p21(waf-1) dependent but p53 independent). The involvement of the nonneuronal cholinergic system in mesothelioma appears reasonable and open up new therapeutic strategies.

Background: Stage IIIb (T4/N3) non-small-cell lung cancer (NSCLC) is considered an inoperable disease and treatment is an enduring challenge. Surgery after induction therapy seems to improve locoregional control. We report the results of a phase II prospective trimodality trial (chemotherapy and concomitant radiotherapy plus surgery) in patients with stage IIIb NSCLC., Methods: From November 1992 to June 2000, 39 patients (37 men and 2 women, mean age 65 years) with clinical stage IIIb (34 T4N0 to 2, 4 T2 to 3N3, 1 T4N3, excluding T4 for malignant pleural effusion) entered the study. They received intravenous infusions of cisplatin 20 mg/m(2) and 5-fluorouracil 1,000 mg/m(2) (days 1 to 4 and 25 to 28) combined with a total dose of 50.4 Gy radiotherapy delivered over 4 weeks (1.8 Gy daily). Upon clinical restaging responders underwent surgery., Results: All patients were available for clinical restaging. No complete response was observed. Twenty-one patients had partial response (53.8%), 16 had stable disease (41%), and 2 had progressive disease (5.2%). Hematologic toxicity was moderate. Twenty-two patients (56.4%), 21 with partial response and 1 with stable disease, underwent surgery with no perioperative death. A radical resection was possible in 21 cases. Nine lobectomies, 3 bilobectomies, and 9 pneumonectomies were performed. Complications occurred in 5 patients (23.6%). Fourteen of the patients who underwent surgery (66.6%) showed a pathologic downstaging. A complete pathologic response was obtained in 9 cases (49%). Overall 5-year survival (Kaplan-Meier) was 23%. Resected versus non-resected patients showed a significant difference: 38% versus 5.6% (p = 0.028, log rank)., Conclusions: This trimodal approach for stage IIIb NSCLC appears safe and effective. It provides good therapeutic results with acceptable morbidity in surgical cases.

Post-pneumonectomy spontaneous pneumothorax is fortunately a very rare condition. We describe herein a late spontaneous right pneumothorax case occurring in a post-pneumonectomy patient and treated by thoracotomic bullectomy.

Aims: A case-control study was performed to investigate the relationship between cervical cancer and TP53 polymorphism at codon 72 in young black African women from The Gambia., Materials and Methods: The TP53 polymorphism at codon 72 was examined by PCR amplification and SSCP analysis in 40 patients with primary cervical cancer and in 20 healthy women of the same age and from the same geographical area. The occurrence of TP53 polymorphism in combination with the HPV-16 E6 genotype (assayed by PCR) was evaluated., Results: The distribution of TP53 genotypes in cervical cancer patients and in the control group was not statistically different (p = 0.45) and homozygosity for argine at residue 72 was not associated with cervical cancer (odds ratio: 1.24; 95% confidence interval 0.21-9.16). Similarly, a different genotype distribution, cervical cancer and presence of HPV-16 E6 were not observed., Conclusions: These results cannot rule out an association between TP53 polymorphism at codon 72, HPV infection and the etiology of cervical cancer in this population sample.

rHuTNF potentiates CPT-cytotoxicity in human ovarian A2780 cells. In this study, we examined the role of NF-kappaB in this potentiation. A pulse-labelled DNA study indicated that the combination CPT+TNF had little effect on the rate of DNA elongation at 6 h after drug removal, whereas CPT alone produced a complete inhibition for at least 6 h after drug removal. Flow cytometry analyses showed that CPT+TNF arrested cells in the G2-M phase, whereas CPT blocked cells in S phase. Looking at the persistence of the NF-kappaB complexes in cells, it appeared that they were still present at 24 h in TNF-treated cells. In contrast, in CPT-treated cells they persisted for 6 h. In CPT+TNF-treated cells, the NF-kappaB complexes disappeared quickly and became undetectable at 6 h. The induction of apoptosis was detected only in the CPT+TNF treated cells (using flow cytometry, a filter binding assay and ApopTag staining). These findings show that TNF, in combination with CPT, reduces the time that NF-kappaB complexes persist in cells likely resulting in the induction of apoptosis.

Oncogenic Ras proteins have been seen as an important target for novel anticancer drugs. Due to the functional role of Ras farnesylation, fanesyltransferase (FTase) inhibition was thought to be a strategy for interfering with Ras-dependent transformation. When farnesylation is blocked, the function of Ras protein is severely impaired because of the inability of the nonfarnesylated protein to anchor to the membrane. Although it has been clearly demonstrated that FTase inhibitors (FTIs) inhibit Ras farnesylation, it is uncertain whether the antiproliferative effects of these compounds result exclusively from the effects on Ras. Moreover, no consensus has been reached as to the relevant targets(s) of FTIs that can explain their mosaic pharmacology. In searching for downstream targets for FTIs effects, CENP-E and CENP-F/mitosin were identified. Different studies showed that the inhibition of farnesylation interferes with CENP-E-microtubule association. In the presence of FTIs, chromosome alignment to the metaphase plate is delayed, suggesting that farnesylated proteins are involved in a step critical to bipolar spindle formation and chromosome alignment. An important question is whether these biological effects might contribute to the chemotherapeutic effects of the FTIs. However, FTIs, triggering the spindle checkpoint, might elevate the rate of cellular missegregation to levels that are incompatible with cell viability, as well as have a reduced (but still significant?) effect on checkpoint-proficient normal cells. As an example, RPR-115135 induced micronuclei (MN) increase in cancer cells displaying high chromosome instability (CIN) levels, whereas in normal cells it is devoid of activity. Cancer cells showing high CIN level might represent an ideal target for the activity of some FTIs.

Objective: to report the surgical facts of unresectable patients with locally advanced non-small cell lung cancer (NSCLC) treated in a phase I trial with concurrent weekly gemcitabine and radiotherapy who achieved a clinical downstaging so as to re-enter resectability., Materials and Methods: from 3/99 to 11/00, 30 patients (ten stage IIIa, 16 IIIb and four IV) with histologically proven, unresectable NSCLC, were enrolled in this phase I trial. Gemcitabine was given weekly for 5 consecutive weeks as a 30-min intravenous infusion, at least 4 h before radiotherapy. Starting dose: 100 mg/m(2). Maximum tolerated dose (MTD): 350 mg/m(2). Radiotherapy total dose: 50.4 Gy (1.8 Gy/day) on primitive tumour and involved lymph nodes., Results: 27 out of 30 patients (90%) were evaluable for clinical restaging (three patients who decided to continue their treatment elsewhere have been excluded). A major clinical response (partial+complete response) was observed in 17 out of 27 cases (62.9%). Clinical complete response rate was 3.7% (1/27) while partial response rate was 59.2% (16/27). Nine patients (33.4%) showed a clinical stable disease and one a disease progression (3.7%). Fourteen patients re-entered resectability and were operated upon: seven lobectomies; four bilobectomies; two pneumonectomies and one explorative thoracotomy. Mean operation duration time was 112 min; mean blood loss was 390 cc. Thirty-day morbidity and mortality were nil. Mean post-operative hospital stay was 6.8 days. A slight increase in operational technical difficulty was encountered. Definitive histology showed a pathologic downstaging of 71.4% (10/14). In four patients, only microscopic neoplastic remnants were found., Conclusions: combined treatment with weekly gemcitabine and concurrent radiotherapy is feasible. In patients with advanced NSCLC who achieved a good clinical response and therefore were judged to be resectable, surgery was possible without any increase in thirty-day morbidity and mortality. Satisfactory pathologic results were obtained.

Objectives: To evaluate the effectiveness of radiological assessment (high-resolution CT (HRCT), helical CT (HCT) scan) of lung metastases and to verify if a complete manual exploration by thoracotomy is necessary., Materials and Methods: From 1/96 to 1/00, 166 consecutive patients presenting with lung metastases were treated. Preoperative CT scan (HRCT in 78 patients, group A; HCT in 88 patients, group B) to assess the number, size and location of the lesions (slice thickness 5 mm; reconstruction interval 3-5 mm) was always performed. All patients underwent axillary thoracotomy (staged when lesions were bilateral); accurate palpation of the lung parenchyma was always performed to identify any undetected lesion. Non-metastatic lesions were excluded., Results: We performed 356 wedge resections in 161 patients (113 monolateral, 70.2%; 48 bilateral, 29.8%) and five lobectomies. In group A, primary neoplasm was epithelial in 44 patients, sarcoma in 26 and germ cell in eight, and in group B, epithelial in 61 patients, sarcoma in 20 and germ cell in seven. Three hundred and sixty-one histologically proven metastases were resected (188 in group A and 173 in group B). HRCT correctly identified 142/188 lesions (sensitivity 75%); HCT revealed 142/173 metastases (sensitivity 82.1%). Sensitivity for lesions less than 6 mm in maximum diameter was 48% (30/58 false negative) in group A and 61.5% (20/52 false negative) in group B., Conclusions: The sensitivity of HCT exceeds that of HRCT. However, complete manual exploration by thoracotomy remains the procedure of choice for patients undergoing pulmonary metastasectomy, because of limitation in preoperative radiological assessment of lung lesions smaller than 6 mm.

Primary pulmonary meningioma is an uncommon, usually benign, soft tissue tumour which has rarely been reported. We report an additional case of primary pulmonary meningioma occurring in an asymptomatic 56-year-old man whose diagnosis was only established after resection. The features of this lesion together with a review of the previous literature are described.

Purpose: To report the evidence of a phase I trial planned to determine the maximum-tolerated dose (MTD) and related toxicity of weekly gemcitabine (GEM) and concurrent radiotherapy in patients with non--small-cell lung cancer (NSCLC). In addition, the response to treatment was evaluated and reported., Patients and Methods: Thirty-six patients with histologically confirmed NSCLC deemed unresectable because of advanced stage were observed and treated according to a combined chemoradiation protocol with GEM as chemotherapeutic agent. GEM was given weekly for 5 consecutive weeks as a 30-minute intravenous infusion concurrent with radiotherapy (1.8 Gy/d; total dose, 50.4 Gy). The initial dose was 100 mg/m(2). Pulmonary, esophageal, cardiac, hematologic, and skin toxicities were assessed. The dose of GEM was increased by 50 mg/m(2) up to a dose of 250 mg/m(2); an additional increase by 25 mg/m(2) up to the MTD was planned and realized. Three patients were enrolled for each dose level., Results: Dose-limiting toxicity was identified for the 375-mg/m(2) level with two episodes of grade 2 esophagitis and two of grade 3 pulmonary actinic interstitial disease. The weekly dose of GEM 350 mg/m(2) was well tolerated., Conclusion: A weekly GEM dose of 350 mg/m(2) concurrent with radiotherapy was well tolerated. Promising results regarding response to treatment were observed and reported.

Background and Purpose: To evaluate the benefits and the drawbacks of post-operative radiotherapy in completely resected Stage I (a and b) non-small cell lung cancer (NSCLC)., Materials and Methods: Patients with pathological Stages Ia and Ib NSCLC have been randomized into two groups: Group 1 (G1) received adjuvant radiotherapy, Group 0 (G0) the control group did not receive any adjuvant therapy. Local control, toxicity and survival have been evaluated., Results: Between July 1989 and June 1997, 104 patients with pathological stage I NSCLC have been enrolled in this study. Fifty-one patients were randomized to G1 and 53 to G0. Six patients have been excluded from the study due to incomplete follow-up data. Regarding local control, one patient in the G1 group had a local recurrence (2.2%) while in the G0 12 local recurrences have been observed (23%). Seventy-one percent of patients are disease-free at 5 years in G1 and 60% in G0 (P=0.039). Overall 5-year survival (Kaplan-Meier) showed a positive trend in the treated group: 67 versus 58% (P=0.048). Regarding toxicity in G1, six patients experienced a grade 1 acute toxicity. Radiological evidence of long-term lung toxicity, with no significant impairment of the respiratory function, has been detected in 18 of the 19 patients who have been diagnosed as having a post-radiation lung fibrosis., Conclusions: Adjuvant radiotherapy gave good results in terms of local control in patients with completely resected NSCLC with pathological Stage I. Overall 5-year survival and disease-free survival showed a promising trend. Treatment-related toxicity is acceptable.

Objective: To verify if in our experience with 'induction therapy' in non-small cell lung cancer (NSCLC) the clinical re-staging is really predictive of pathological staging., Materials and Methods: From January 1990 to February 2000, 136 patients with locally advanced NSCLC underwent a protocol of induction therapy according to three different treatment plans: Carboplatin + radiotherapy--study A; Cisplatin + 5-Fluorouracil + radiotherapy--study B; Gemcitabine + radiotherapy--study C., Results: Clinical re-staging showed in the patients enrolled in study A a clinical Complete Response rate (cCR) of 2.3%; a clinical Partial Response rate (cPR) of 50%; a clinical Stable Disease (cSD) rate of 44.3%; a clinical Disease Progression (cDP) rate of 3.4%. In study B, cCR was 0%; cPR: 71.4%; cSD 10.7%; cDP: 17.9%. In study C, cCR was 0%; cPR: 23.5%; cSD: 11.8%; cDP: 64.7%. After clinical re-staging, 76 patients (47 group A; 23 group B; 6 group C) were judged to be resectable and underwent a surgical operation. Pathological staging showed no tumour in eight patients (10.5%; 8/76) (three in study A, four in study B, one in study C) and microscopic neoplastic remnants in seven (9.2%; 7/76). Thirty-nine patients were pN0. Overall downstaging rate in the operated patients was 51%. No precise correlation was found among clinical re-staging and pathological staging. We had two cCRs and eight pCRs, and all of these pCRs had been re-staged as cPR except in one case (cSD). In seven cases, where only microscopic remnants have been found, six had been clinically restaged as cPR and one as cSD., Conclusions: Our experience confirmed how often the clinical re-staging data are unreal. Accordingly surgery should be indicated in any case where an induction therapy has been administered, if it is reasonably possible.

In the last decade, several neoadjuvant trials for NSCLC patients with mediastinal lymph node involvement (N2) have been scheduled. The uniform plan is based on clinical staging, therapy, clinical re-staging, surgery (when is possible) and, finally, pathological staging. The precise classification of tumor during the three different staging procedures is mandatory. Considering clinical re-staging and pathological staging, nowadays surgery could be considered correct for most of the patients enrolled in the neoadjuvant protocols including cases where a major clinical response has not been achieved. Several experiences demonstrated how often the clinical restaging overesteems neoplastic tissue by fibrosis and scar and could judge as unresectable patients with a minimal residual disease.

Objective: We describe our experience with the staged axillary thoracotomy (SAT), for the treatment of bilateral lung metastases., Materials and Methods: Between January 1995 and June 1998, 75 lung metastasectomies were carried out in our institution, 49 (65%) monolateral, and 26 (35%) bilateral. In the latter group of patients we adopted a staged axillary thoracotomy., Results: All wedge resections and two lobectomies (1 LUL and 1 RLL) were performed through this approach. Resection has been complete in all patients. Histology was epithelial in 15 (57%), sarcoma in nine (35%) and germ cell in two (8%). Two to three metastases have been resected in 10 patients (38%); four to 10 in 12 patients (46%) and over 10 in four patients (15%). The radiological pre-operative assessment was accurate in 15 patients (57%), underestimated in nine (35%) and overestimated in two (8%). The average interval between the two procedures has been 24 +/- 6 days. The average operation duration time was 50 min (range 36-67). We do not report any post-operative death or major complication. The average hospitalization was 3.2 days (range 2-6) for each single procedure and 6.2 days (range 4-10) for both procedures., Conclusion: This technique is adequate, fast and safe and did not affect the shoulder girdle motion at all providing an excellent cosmetic outcome. The operative trauma is limited and a minor post-operative pain is present. A shortening of the interval between the two operations is allowed.

Background: Non Small Cell Lung Carcinomas (NSCLC) comprise 90% of all lung carcinomas. Studies have demonstrated a preferential central (bronchus-derived) localization for squamous cells, whereas adenocarcinomas are frequently peripheral (bronchiolo-alveolus derived). It has been suggested that exposure to carcinogenic insults including cigarette smoke, may induce different types of tumors in different locations., Materials and Methods: Forty one NSCLC patients staged according to WHO and TNM were considered for localization and biological parameters (p53 expression, cell ploidy and S-phase)., Results: p53 overexpression was found more frequently in central than in peripheral tumors (69% vs 39%) (p = 0.074). Central tumors were more aneuploid (69%) than peripheral ones (46%) (p = 0.03) No difference in smoking habit was observed in the two groups., Conclusions: Our results suggest that there is no apparent biological difference between these two groups of NSCLCs, and that the smoking does not play a role in either histotype determination or biological behavior.

Surgery for pulmonary tubercolosis (PTB) is now the second place treatment. Among the surgical indications the most debated is the multi-drug resistance of a focal pulmonary tuberculous disease. Other indications are: bronchiectasis, hemoptysis and the presence of a broncho-pleural fistula. Pulmonary Aspergilloma is a frequent indication for surgery; it is commonly a PTB sequela and causes severe complications. The presence of an unknown pulmonary mass or nodule is a surgical criterion because it might signal a cancer. Surgery therefore now constitutes a valid option for the treatment of clinical patterns of PTB unresponsive to medical treatment in severe, potentially fatal clinical conditions.

Since January 1987, in a consecutive series of 56 resections of the chest-wall for cancer, the wall defect was repaired by a prosthetic implant on 14 occasions (10 silastic sheeting, 4 goretex soft tissue patch). Indications for thoracic wall resection were: T3 primary lung cancers (7 cases), local recurrences after breast cancer surgery (5 cases), primary and metastatic neoplasms arising in the chest-wall (2 cases). No rejection was reported nor episodes of flail chest or respiratory disorders. No major complications occurred in patients who underwent postoperative radiotherapy; only 1 case of persistent seroma was observed. Followup ranges from 3 to 37 months. In no case was a local recurrence of tumor observed. Cosmetic results were considered from acceptable to good in all patients. In every case a total control of pain symptoms was achieved. There were 6 deaths at a mean interval of 22 months from operation (4 lung cancers, 1 breast cancer, 1 osteosarcoma), all due to metastatic spread of the disease.

From 1980 to 1990, 31 patients were treated surgically in our department for esophageal diverticula: 12 Zenker's diverticula (ZD); 11 mid-thoracic diverticula (MTD); 8 epiphrenic diverticula (ED). Cricopharyngeal dysfunction was detectable in 8 of 12 ZD patients (66.6%). Cricopharyngeal myotomy with diverticulectomy was performed in all cases. There were no deaths. Relief of dysphagia was obtained in all cases. No recurrences of dysphagia or diverticulum were observed at a mean follow-up of 3 years. A motility disorder was observed in 10 of 11 MTD (90.9%). An extended esophageal myotomy with diverticulectomy was performed in 3 cases, an extended myotomy alone in 3 cases, a diverticulectomy alone in 5 cases; an anti-reflux procedure was added in 6 cases. One patient died on the 7th postoperative day. All remaining patients were free of symptoms at a mean follow-up of 3.2 years. A motor dysfunction was detected in all 8 ED patients (100%). No diverticulectomy was performed. Six patients underwent Heller-Dor myotomy and 2 underwent Nissen fundoplication. There were no deaths. Relief of symptoms was obtained in all patients, at a mean follow-up of 3.1 years. Myotomy with diverticulectomy represents the treatment of choice in ZD. As regards MTD and ED, the treatment of the underlying motor disorder is the main therapeutic goal, whereas diverticulectomy is reserved to selected patients.

Primary tumors of lung and breast represent the most frequent cause of neoplastic involvement of the thoracic wall, being primary parietal neoplasms extremely rare; metastatic lesions of the thoracic wall are not an infrequent finding, but represent just an occasional indication for surgery. Prosthetic reconstruction after a resection that includes the bony structures of the thoracic cage is dependent upon the extension of the parietal excision. We report a personal experience with 11 cases of prosthetic reconstruction of the thoracic wall out of a total of 54 extended resections accomplished between 1979 and 1990. We did not find prosthetic reconstruction indicated for thoracic wall defects smaller than 5 cm in diameter, wherever located. As regards larger parietal defects, a reconstructive procedure appeared always necessary for anterior or lateral regions of the thorax, while we never used prosthetic implants for posterior defects, regardless of their size. In all cases we used a Silastic sheet, 1.016 mm thick, reinforced by Dacron mesh, whose margins were molded on the form of the thoracic defect and secured by 2/0 Prolene suture. Follow up ranged from 6 to 36 months. No case of rejection has been observed up to date and no interference with radiation treatment or chemotherapy has been reported.

From January 1983 to October 1989, 221 bronchogenic carcinomas were surgically treated at our Department. Different stapling techniques were employed in 153 cases: 138 stapled sutures of main and lobar bronchi, 33 stapled parenchymal sutures and 21 stapled sutures of the pulmonary artery. Stapling-related complications were observed in 3 patients: 1 bronchopleural post-pneumonectomy fistula (0.72%); 2 persisting air leakages following stapled parenchymal suture (6%). The use of vascular staplers, though, has never been associated with complications. The advantages related to the use of stapling devices are represented by lower air leakage and bleeding rates, with a reduced operative trauma; on the other hand, disadvantages seem to be more theoretical than realistic. At our Department stapling devices nowadays represent the choice in thoracic surgery either for main and lobar bronchi or parenchymal sutures.