Luca Tavecchio

The contribution of salvage surgery to the management of childhood osteosarcoma.

Between January 1970 and December 1988, 174 consecutive patients under the age of 20 years with curatively resected primary osteosarcoma were treated at our institute; 72 in the years of 1970 to 1981 and 102 in the years 1982 to 1988. In the latter period, adjuvant chemotherapy was replaced by neoadjuvant programs, and new criteria were adopted for the management of lung metastases, consisting in early bilateral surgical staging and lung resection through median sternotomy for all patients with purely intrathoracic relapse. Follow-up was updated in December 1989. During the last period, the overall 5-year survival improved significantly from 35% to 58% (P less than .001). The disease-free survival rose from 38% to 45% at 5 years, with median values of 15 months versus 33 months, while the frequency of isolated lung metastases dropped from 58% to the actuarial 48%. The proportion of patients who underwent complete resections of their pulmonary metastases rose from 17% (seven of 42) to 55% (27 of 49), without operative mortality. Due to such a high proportion of patients eligible for salvage surgery, the overall survival from detection of lung metastases improved from 0% to 28% at 5 years (P less than .001). Contralateral occult metastases were resected in three of 15 subjects with monolateral clinical lesions, and five patients underwent subsequent lung resections. These data indicate that systematic bilateral pulmonary resection plays an important role in improving the final cure rate of childhood osteosarcoma, beyond the benefit resulting from neoadjuvant chemotherapy.

Prognostic value of TP53, KRAS and EGFR mutations in nonsmall cell lung cancer: The EUELC cohort

Nonsmall cell lung cancer samples from the European Early Lung Cancer biobank were analysed to assess the prognostic significance of mutations in the TP53, KRAS and EGFR genes. The series included 11 never-smokers, 86 former smokers, 152 current smokers and one patient without informed smoking status. There were 110 squamous cell carcinomas (SCCs), 133 adenocarcinomas (ADCs) and seven large cell carcinomas or mixed histologies. Expression of p53 was analysed by immunohistochemistry. DNA was extracted from frozen tumour tissues. TP53 mutations were detected in 48.8% of cases and were more frequent among SCCs than ADCs (p<0.0001). TP53 mutation status was not associated with prognosis. G to T transversions, known to be associated with smoking, were marginally more common among patients who developed a second primary lung cancer or recurrence/metastasis (progressive disease). EGFR mutations were almost exclusively found in never-smoking females (p=0.0067). KRAS mutations were detected in 18.5% of cases, mainly ADC (p<0.0001), and showed a tendency toward association with progressive disease status. These results suggest that mutations are good markers of different aetiologies and histopathological forms of lung cancers but have little prognostic value, with the exception of KRAS mutation, which may have a prognostic value in ADC.

Median sternotomy and multiple lung resections for metastatic sarcomas.

In the attempt to apply salvage surgery to the majority of patients with pulmonary tumour relapse, we have adopted a new treatment plan consisting of early bilateral lung exploration and resection through median sternotomy in all cases of sarcoma with resectable lung metastases, including synchronous or previously resected ones. The present paper summarizes the early results achieved with this technique in 56 consecutive patients treated between 1985 and 1988. Perioperative mortality was zero, and morbidity negligible. Occult contralateral metastases were resected in about one third of subjects with monolateral clinical lesions. Overall actuarial survival from first pulmonary resection is 51% at 2 years and 35% at 3 years. A slightly more favourable trend is evident for solitary lesions but the difference is not statistically significant. No difference in survival is observed in relation to the initial disease-free interval or to the histological type. The majority of relapses occurred within 6 months of sternotomy (23/35) and were confined to the lungs (21/35). Ten of these 21 patients with pulmonary relapse have undergone further resection and 5 of them are alive, with a median survival of 28 months. Present results are encouraging as far as resectability and early recurrence rate are concerned. Median sternotomy appears a most valuable therapeutic approach to pulmonary metastases from sarcomas, being safe and effective in local control of disease, and compatible with further surgical management of pulmonary recurrences.

Fragile Histidine Triad gene inactivation in lung cancer: the European Early Lung Cancer Project

RATIONALE Fragile histidine triad (FHIT) is a tumor suppressor gene involved in the pathogenesis of lung cancer. OBJECTIVES The purpose of this study was to investigate the different molecular alterations leading to the inactivation of FHIT gene function and to validate their use as biomarkers of risk for progression of the disease in patients belonging to the multicentric European study for the Early detection of Lung Cancer (EUELC) who were resected for early-stage lung tumors. METHODS FHIT immunostaining was performed on 305 tumor samples. The methylation status of FHIT promoter was assessed by nested methylation-specific polymerase chain reaction (MSP-PCR) in 232 tumor and 225 normal lung samples of which a subset of 187 patients had available normal/tumor DNA pairs. Loss of heterozygosity (LOH) at the FHIT locus was analyzed in 202 informative cases by D3S1300 and D3S1234 microsatellite markers. MEASUREMENTS AND MAIN RESULTS Lost or reduced FHIT expression was found in 36.7 and 75.7% of the tumor samples, respectively. Methylation of the FHIT promoter was found in 36.7% of tumor and 32.7% of normal lung samples, whereas LOH was detected in 61.9% of the tumors. A strong association with complete loss of FHIT expression was present when methylation and LOH were analyzed together (P = 0.0064). Loss of FHIT protein expression was significantly more frequent in squamous cell carcinoma histotype (P < 0.0001) and in smokers (P = 0.008). FHIT methylation in normal lung was associated with an increased risk of progressive disease (OR, 2.27; P = 0.0415). CONCLUSIONS Our results indicate that different molecular mechanisms interplay to inactivate FHIT expression and support the proposition that FHIT methylation in normal lung tissue could represent a prognostic marker for progressive disease.

Reduced FEZ1/LZTS1 Expression and Outcome Prediction in Lung Cancer

Chromosomal deletions are often observed in lung cancers suggesting that inactivation of tumor suppressor genes plays an important role in the development of this neoplasm. The region around chromosome 8p22 is a frequent and early target of these deletions and has therefore been investigated for the presence of candidate genes. The FEZ1/LZTS1 gene, located at 8p22, is inactivated in many cancers with 8p deletions, including prostate, esophageal, gastric, bladder, and breast cancer and the Fez1 protein has been shown to suppress growth of cancer cells and to regulate mitosis. To elucidate the role of FEZ1 in lung cancer, we have analyzed its expression by immunohistochemistry in 103 primary lung cancer specimens including 98 non-small cell lung cancers (57 adenocarcinomas, 32 squamous cell carcinomas, 7 large cell carcinomas, and 2 others) and five small cell carcinomas. Absence of Fez1 protein expression was observed in 27 cases (26%) and additional 43 cases (42%) showed strong reduction in immunoreactivity. There was a positive association between loss of FEZ1 expression and tumor grading (P = 0.0345) and a tendency toward a reduction in the mortality rate in subjects with strong FEZ1 expression. Overall, these data indicate an important role for FEZ1 in lung cancer and suggest the possibility that it may serve as a novel prognostic indicator.

Prolonged venous infusion of cisplatin and concurrent radiation therapy for lung carcinoma. A feasibility study

Fifty patients with non resectable and/or inoperable bronchogenic carcinoma were entered into a feasibility study of cisplatin (CDDP) given in continuous infusion with concurrent radiation therapy. The radiation therapy regimen consisted of 2 Gy given 5 days a week in the first 3 and last 2 weeks of a 7‐week split course (50 Gy of total dose). The CDDP (daily dose of 4 to 6 mg/m2) was administered to cover the days of radiation treatment by means of a central venous catheter and a portable pump. Less than 1% of predicted duration of infusion was lost due to complications related to venous access and pump. Toxicity was moderate. The overall probability of a locoregional major response (complete + partial) within 1 month after treatment completion was 86%. Twenty‐three patients underwent resection. The 1‐year actuarial probability of survival was 64%. The high response and survival rates warrant further studies on concurrent CDDP continuous infusion and radiation therapy in inoperable lung carcinoma.

Lung resection as salvage treatment for metastatic osteosarcoma.

Resection of pulmonary metastases has achieved a central role in the overall management of osteosarcoma, since a number of studies have demonstrated that salvage surgery is able to cure 20 to 40% of all relapsing patients. This paper presents the results of surgical management of 27 consecutive cases of pulmonary metastases from osteosarcoma, who underwent complete resection at the Istituto Nazionale Tumori of Milan between 1975 and 1986. In the present series, overall actuarial survival at 3 years from the first thoracotomy was 47%, with a median survival of 28 months and no operative mortality. Better results were observed in patients with single lesions (68% survival) or when the interval to lung metastases exceeded 12 months (60% survival). These data support the concept of pulmonary metastasectomy as effective salvage therapy for metastatic osteosarcomas whose distant spread is confined in the lungs.

Superior vena cava resection in thoracic malignancies: does prosthetic replacement pose a higher risk?

BACKGROUND After superior vena cava (SVC) resection, the need for reconstruction varies among tangential resection, pericardial patch repair and prosthetic replacement. Patients undergoing complete prosthetic replacement often require a different surgical approach, intra-operative SVC cross-clamping and anticoagulation when polytetrafluoroethylene (PTFE) prosthesis is used. This study tested the hypothesis that PTFE replacement may interfere with perioperative outcome. MATERIALS AND METHODS Clinical records from a series of 72 consecutive SVC resections performed between 1998 and 2008 were reviewed. Complications were classed into five categories: surgical, respiratory, cardiac, SVC system thrombosis and nerve damage. Each category of postoperative complications was considered as an outcome variable in a univariate analysis testing 12 covariates as risk factors. Covariates considered clinically relevant or statistically significant were included in the multivariate model. RESULTS During the considered period, 28 patients underwent total SVC resection with PTFE prosthetic replacement and 44 patients underwent SVC repair by the use of direct running suture (nine patients), stapling (30 patients) or autologous pericardial patch (five patients). Two patients died postoperatively (2.8%). Major complications were mainly due to respiratory failure, which occurred in nine cases (acute respiratory failure in five cases, recurrent atelectasis in three cases, acute respiratory distress syndrome (ARDS) in one case). In terms of overall mortality and morbidity, univariate analysis did not confirm a detrimental effect of SVC replacement as compared with SVC repair, as major postoperative complications occurred in similar proportion in both groups (respectively, 6/28, 21.4% vs 7/44, 15.9%, p=0.54). No other risk factor was identified by univariate analysis. CONCLUSIONS Complete prosthetic replacement does not increase overall postoperative morbidity in patients undergoing SVC resection and can be safely performed when other reconstruction techniques preclude sufficient tumour-free resection margin or compromise adequate blood flow.

Safety of absorbable suture for sternal closure after pulmonary or mediastinal resection

The reliability of polyglyconate monofilament (Maxon) suture for sternal closure was tested on 216 consecutive sternotomies, performed on 208 patients in our department from January 1986 to December 1990. The reason of sternotomy was primary lung cancer in 34 cases (16%), lung metastases in 127 (59%), and disorders of the thymus in 55 (25%). Mean age was 38 years (range 3 to 78 years); multiple lung resections were performed in 102 patients (average 7 lesions, range 2 to 30); maximum extent of the operation was pneumonectomy in 2 cases, lobectomy in 53, segmentectomy in 27, and wedge resection in 74. Prior chemotherapy had been administered in 75 cases (35%). A second sternotomy was performed in 8 cases. No cases of sternal dehiscence, sternal infection, or empyema were observed, after a median follow-up of 27 months. Overall perioperative mortality was 0.9% (2/216). Our series demonstrates the safety of polyglyconate monofilament (Maxon) suture for sternal closure. Absorbable sutures appear to be a safe alternative to steel wire closure in patients undergoing extended pulmonary or mediastinal resection.

Extrapericardial solitary fibrous tumour of the pericardium

Solitary fibrous tumour (SFT) occurs most commonly in the pleura and is extremely rare in the pericardium. The authors report a case of a 60-year-old man in whom a large mediastinal mass was accidentally discovered. Computed tomography showed involvement of the left anterosuperior mediastinum with displacement of the trachea, large vessels and oesophagus; histopathological findings after complete resection of the neoplasia demonstrated an SFT of the pericardium, the first reported case with extrapericardial pattern of growth. A review of the literature on SFTs of the pericardium is provided.