Grading the neuroendocrine tumors of the lung: an evidence-based proposal.

Lung neuroendocrine tumors are catalogued in four categories by the World Health Organization (WHO 2004) classification. Its reproducibility and prognostic efficacy was disputed. The WHO 2010 classification of digestive neuroendocrine neoplasms is based on Ki67 proliferation assessment and proved prognostically effective. This study aims at comparing these two classifications and at defining a prognostic grading system for lung neuroendocrine tumors. The study included 399 patients who underwent surgery and with at least 1 year follow-up between 1989 and 2011. Data on 21 variables were collected, and performance of grading systems and their components was compared by Cox regression and multivariable analyses. All statistical tests were two-sided. At Cox analysis, WHO 2004 stratified patients into three major groups with statistically significant survival difference (typical carcinoid vs atypical carcinoid (AC), P=0.021; AC vs large-cell/small-cell lung neuroendocrine carcinomas, P<0.001). Optimal discrimination in three groups was observed by Ki67% (Ki67% cutoffs: G1 <4, G2 4-<25, G3 ≥25; G1 vs G2, P=0.021; and G2 vs G3, P≤0.001), mitotic count (G1 ≤2, G2 >2-47, G3 >47; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001), and presence of necrosis (G1 absent, G2 <10% of sample, G3 >10% of sample; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001) at uni and multivariable analyses. The combination of these three variables resulted in a simple and effective grading system. A three-tiers grading system based on Ki67 index, mitotic count, and necrosis with cutoffs specifically generated for lung neuroendocrine tumors is prognostically effective and accurate.

Detection by denaturant gradient gel electrophoresis of tumor-specific mutations in biopsies and relative bronchoalveolar lavage fluid from resectable non-small cell lung cancer.

A PCR-denaturant gradient gel electrophoresis (DGGE) method was developed for the detection of p53 and K-ras mutations in primary operable tumors and paired BAL samples of non-small cell lung cancer. Among 36 patients, 9 showed p53 exon V mutations in biopsies and in three paired bronchoalveolar lavage (BAL) specimens with a 33% concordance. Five patients presented p53 exon VI mutations in biopsies and in two paired BALs with a 40% concordance. No mutations were found in p53 exon VII either in biopsies or in paired BAL samples with 100% concordance. Exon VIII mutations were found in six primary tumors and in two BALs with a 33% concordance. Of 36 patients, we detected 7 (19.4%) with K-ras exon I mutations on tumor samples. DGGE analysis of DNA from BAL samples revealed three mutations distributed on K-ras exon I with a 42% overall concordance with respect to tumor tissue. Molecular screening by DGGE of p53-amplified DNA from BAL had cumulative 46.6% sensitivity, 100% specificity, and 77.7% accuracy. DGGE K-ras detection showed 43% sensitivity, 100% specificity, and 88.8% test accuracy. The method proposed demonstrated to be specific, accurate, and at relatively low cost but limited by low sensitivity in detecting the presence of neoplastic cells in patients with resectable non-small cell lung cancer.

Induction therapy in non-small-cell lung cancer: a comparison of clinical and post-surgical staging.

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.

Tailored surgery for esophageal body diverticula.

OBJECTIVE: The aim of our study was to identify the presence of associated functional disorders (dysmotility or gastro-esophageal reflux, GER), to select patients who need surgery and to plan a tailored surgical treatment in patients affected by esophageal body diverticula. METHODS: We report on 51 consecutive patients with esophageal body diverticula, observed at our department, who underwent a thorough functional evaluation by means of radiology, endoscopy and manometry; 24 h pH-monitoring was performed in 11 patients who complained of symptoms of GER. The treatment of choice was planned in each patient on the basis of the following elements: the need of diverticulum excision and correction of esophageal body dismotility, LES dysfunction or GER. RESULTS: An esophageal motor dysfunction was detected in 73% (37 patients) of our total cases with an impaired LES function in 53% (27 patients); GER was identified in nine out the 11 patients submitted for 24 h pH-monitoring. On the overall series, we observed dysmotility or GER in 49/51 patients (96%). Sixteen patients did not require surgical treatment and eight patients refused it; 27 patients underwent tailored surgery. The overall complication rate was 11% (two esophageal fistulae, one acute coronary disease) with 7% mortality rate (one septic shock from esophageal leakage and one myocardial infarction). At follow up (average 47 months; range 6-103 months) 92% satisfactory results (Visick I and II) and only 8% of poor results were observed in our series. None of 13 patients who underwent conservative management had major complications at mean follow-up of 64 months. CONCLUSIONS: Based upon our experience, we believe that any case of diverticulum of the esophageal body deserves a complete physiopathological evaluation because an underlying functional disorder is associated in most cases. The evidence that the diverticulum per se can be considered as the ultimate phenomenon of an underlying functional disease determined the need for a tailored surgery, planning treatment of the functional disorder as the primary goal, not necessarily associated with a diverticulectomy. In our experience a tailored surgical treatment provided best results.

[Stapling techniques in exeresis surgery of bronchogenic carcinoma]. / Tecniche di stapling nella chirurgia di exeresi del carcinoma broncogeno.

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.