Stefano Margaritora

Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: definitive results of a phase III randomized trial

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.

α7-Nicotinic Acetylcholine Receptors Affect Growth Regulation of Human Mesothelioma Cells Role of Mitogen-Activated Protein Kinase Pathway

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 α-7 nicotinic acethlycholine receptors, evaluated by α-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 [45Ca2+] uptake, and consequently activation of mitogen-activated protein kinase pathway (extracellular signal-regulated kinase and p90RSK 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-κB complexes and phosphorylation of Bad at Ser112; curare proapoptotic via G0-G1 arrest p21waf-1 dependent but p53 independent). The involvement of the nonneuronal cholinergic system in mesothelioma appears reasonable and open up new therapeutic strategies.

Pulmonary metastases: can accurate radiological evaluation avoid thoracotomic approach?

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.

Phase I Trial of Weekly Gemcitabine and Concurrent Radiotherapy in Patients With Inoperable Non–Small-Cell Lung Cancer

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.

Thirty-Five–Year Follow-Up Analysis of Clinical and Pathologic Outcomes of Thymoma Surgery

BACKGROUND The impact of myasthenia gravis on patients with thymoma is still controversial when perioperative and long-term outcomes are analyzed. With the unique opportunity of a 35-year follow-up in a single institution, thymomatous myasthenia gravis cohort, we investigated the influence of early and long-term clinical predictors. METHODS We reviewed a surgical series of 317 (1972 to 2007) patients with thymoma: clinical and pathologic features were analyzed as prognostic factors matched against the short- and long-term survival and recurrence rates. RESULTS Male to female ratio was 153:164; median age, 49 years. Myasthenia gravis coexisted in 276 patients (87.1%). Thymomas were classified according to the Masaoka (42.0% stage I, 32.2% stage II, 21.5% stage III, and 4.4% stage IV) and the World Health Organization (3.5% type A, 9.5% type AB, 19.2% type B1, 57.7% type B2, 8.2% type B3, and 1.9% thymic carcinoma) staging systems. The resection was complete in 295 patients (93.1%). Operative mortality and morbidity were respectively 1.6% and 7.6%. No differences were recorded in postoperative outcome stratifying for myasthenia gravis or comorbidities. Mean follow-up was 144.7 +/- 104.4 months. The overall 5-, 10-, 20-, and 30-year survival rates were 89.9%, 84.1%, 73%, and 58.6%, respectively. The completeness of resection (p < 0.001), the Masaoka staging (p = 0.010), and the World Health Organization classification (p < 0.001) all significantly influenced the long-term survival (univariate analysis). Only completeness of resection was significantly correlated with a better prognosis (p < 0.001) in multivariate analysis. Masaoka staging (p < 0.001) and World Health Organization classification (p < 0.001) significantly correlated with the disease-free survival in the univariate and multivariate analyses as significant prognostic factors (Masaoka, p < 0.001; World Health Organization, p = 0.011). Myasthenia gravis patients showed a better prognosis in terms of long-term survival (p = 0.046) and disease-free survival (p = 0.012) in the univariate analysis. CONCLUSIONS We confirm the evidence that the clinical staging and the histologic classification influence long-term survival. The presence of myasthenia gravis was not significantly related to operative outcome, but prolongs both long-term survival and disease-free survival.

Gene expression signature for angiogenic and nonangiogenic non-small-cell lung cancer

Angiogenesis is regarded as essential for tumour growth. However, we have demonstrated that some other aggressive non-small-cell lung carcinomas (n-SCLC) do not have angiogenesis. In this study, using cDNA microarray analysis, we demonstrate that angiogenic and nonangiogenic tumour types can be distinguished by their gene expression profiles. Tissue samples from 42 n-SCLC patients were obtained with consent. In all, 12 tumours were nonangiogenic and 30 angiogenic. The two groups were matched by age, sex, smoking and tumour stage. Total RNAs were extracted followed by microarray hybridization and image scan procedure. Data were analysed using GeneSpring 5.1 software. A total of 62 genes were found to be able to separate angiogenic from nonangiogenic tumours. Nonangiogenic tumours have higher levels of genes concerned with mitochondrial metabolism, mRNA transcription, protein synthesis and the cell cycle. Angiogenic tumours have higher levels of genes coding for membrane vesicles, integrins, remodelling, angiogenesis and apoptosis. These results further support our first finding that nonangiogenic lung tumours are fast-growing tumours filling the alveoli in the absence of vascular remodelling. We raise the hypothesis that in nonangiogenic tumours, hypoxia leads to a higher activation of the mitochondrial respiratory chain, which allows tumour growth without triggering angiogenesis.

EGFR-targeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation.

The two essential requirements for pathologic specimens in the era of personalized therapies for non-small cell lung carcinoma (NSCLC) are accurate subtyping as adenocarcinoma (ADC) versus squamous cell carcinoma (SqCC) and suitability for EGFR molecular testing, as well as for testing of other oncogenes such as EML4-ALK and KRAS. Actually, the value of EGFR expressed in patients with NSCLC in predicting a benefit in terms of survival from treatment with an epidermal growth factor receptor targeted therapy is still in debate, while there is a convincing evidence on the predictive role of the EGFR mutational status with regard to the response to tyrosine kinase inhibitors (TKIs). This is a literature overview on the state-of-the-art of EGFR oncogenic mutation in NSCLC. It is designed to highlight the preclinical rationale driving the molecular footprint assessment, the progressive development of a specific pharmacological treatment and the best method to identify those NSCLC who would most likely benefit from treatment with EGFR-targeted therapy. This is supported by the belief that a rationale for the prioritization of specific regimens based on patient-tailored therapy could be closer than commonly expected.

Esophageal diverticula. Physiopathological basis for surgical management.

From 1980 to 1990, 31 patients were treated surgically in our department for esophageal diverticula: 12 Zenkers 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.

Malignant solitary fibrous tumors of the pleura: retrospective review of a multicenter series.

Introduction: Available data on the malignant solitary fibrous tumor of the pleura (mSFTP), a very rare neoplasm with unpredictable prognosis, are scarce. The aim of this study is to collectively analyze the aggregated data from the largest series in the English literature to date, a multicenter, 10-year study of 50-cases. Methods: We retrospectively reviewed the clinical records of patients who underwent surgical resection for mSFTP in the period between January 2000 to July 2010. Long-term survival (LTS) and 5-year disease-free survival were analyzed in detail. Results: There were 24 men and 26 women (median age, 66 years; age range, 44–83 years). Thirty-two patients (64%) were symptomatic. A malignant pleural effusion was diagnosed in 12 cases. Surgical resection included isolated mass excision in 13 patients and extended resection in 35. In the remaining two cases only biopsies were undertaken. The resection was complete in 46 cases (92%). Adjuvant treatment was administered to 15 patients. Median follow-up was 116 months (range, 18–311 months). Overall LTS and disease-free survival were 81.1% and 72.1%, respectively. Fifteen patients (30%) experienced a relapse of the disease. Complete resection yielded much better LTS than partial resection (87.1% versus 0%; p < 0.001). At the Cox regression analysis, incomplete resection (hazards ratio [HR]: 39.02; 95% confidence interval [CI]:4.04–380.36; p = 0.002) and malignant pleural effusion (HR: 3.44; 95%CI: 0.98–12.05; p = 0.053) were demonstrated to be risk factors for earlier death. At multivariate analysis, chest-wall invasion and malignant pleural effusion increased the risk of recurrence (HR: 4.34; 95%CI: 1.5%–12.6%; p = 0.007 and HR: 3.48; 95%CI: 1.1%–11.0%; p = 0.038, respectively). Conclusions: Surgical resection remains the treatment of choice for mSFTP. Relapse is common (approximately 30%). Incomplete resection and malignant pleural effusion at diagnosis impact LTS negatively.

Enduring challenge in the treatment of nonsmall cell lung cancer with clinical stage IIIB: results of a trimodality approach

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.