Domenico Galetta

Long-term results of endoscopic thoracic sympathectomy for upper limb hyperhidrosis

BACKGROUND Immediate results of endoscopic thoracic sympathectomy (ETS) for hyperhidrosis are good. Adverse effects are well known but are supposed to decrease with time. We report the long-term results of ETS with regard to efficacy, side effects and patient satisfaction. METHODS From 1993 to 1998, 382 patients suffering from hyperhidrosis of the upper limbs were operated on by means of bilateral ETS. One hundred twenty-five could be reached. There were 91 females and 34 males with a mean age of 28 years. The mean follow-up was 3.8 years (range: 24 to 84 months). Patients answered a detailed questionnaire from an independent observer addressing the following issues: stability of the initial result, outcome of side effects, degree of satisfaction. RESULTS The global recurrence rate was 8.8%: 6.6% for palmar hyperhidrosis and 65% for axillary hyperhidrosis. Compensatory sweating was observed in 86.4% of the patients. It was considered as minor by 61% of them, as embarrassing by 31.5%, and as disabling by 7.5%. Other reported side effects were: Horners syndrome in 3 patients (2.4%), healing in 2 of them; chronic rhinitis in 3 (2.4%); gustatory sweating in 9 (7.2%); and hand dryness in 42%. Sixty-five percent of the patients were fully satisfied, 28.7% were globally satisfied, and 6.3% regretted the operation. Ninety-two percent of the patients claimed they would ask for the operation if it were to be redone. CONCLUSIONS This study confirms that results of ETS are good and stable for palmar hyperhidrosis but deteriorate for axillary hyperhidrosis. Compensatory sweating does not improve with time and is the main cause of dissatisfaction. Recommendations drawn from these results are the following: (1) patients suffering from isolated axillary hyperhidrosis should rather be treated by local therapy; (2) patients should be better informed of adverse effects.

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.

Four-arm robotic lobectomy for the treatment of early-stage lung cancer

OBJECTIVES We investigated the feasibility and safety of four-arm robotic lung lobectomy in patients with lung cancer and described the robotic lobectomy technique with mediastinal lymph node dissection. METHODS Over 21 months, 54 patients underwent robotic lobectomy for early-stage lung cancer at our institute. We used a da Vinci Robotic System (Intuitive Surgical, Inc, Mountain View, Calif) with three ports plus one utility incision to isolate hilum elements and perform vascular and bronchial resection using standard endoscopic staplers. Standard mediastinal lymph node dissection was performed subsequently. Surgical outcomes were compared with those in 54 patients who underwent open surgery over the same period and were matched to the robotic group using propensity scores for a series of preoperative variables. RESULTS Conversion to open surgery was necessary in 7 (13%) cases. Postoperative complications (11/54, 20%, in each group) and median number of lymph nodes removed (17.5 robotic vs 17 open) were similar in the 2 groups. Median robotic operating time decreased by 43 minutes (P = .02) from first tertile (18 patients) to the second-plus-third tertile (36 patients). Median postoperative hospitalization was significantly shorter after robotic (excluding first tertile) than after open operations (4.5 days vs 6 days; P = .002). CONCLUSIONS Robotic lobectomy with lymph node dissection is practicable, safe, and associated with shorter postoperative hospitalization than open surgery. From the number of lymph nodes removed it also appears oncologically acceptable for early lung cancer. Benefits in terms of postoperative pain, respiratory function, and quality of life still require evaluation. We expect that technologic developments will further simplify the robotic procedure.

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.

Review Article: Pulmonary Sarcomatoid Carcinomas: A Practical Overview

Pulmonary sarcomatoid carcinomas (PSCs) are currently defined as poorly differentiated non-small-cell carcinomas containing a component with sarcoma or sarcoma-like (spindle and/or giant cell) features. They consist of 5 major histological variants, namely pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma. The segregation of PSCs into a distinct clinicopathologic entity seems justified on the basis of morphologic, behavioral, and genotypic/phenotypic attributes. As a group, PSCs generally run an aggressive clinical course and may cause major difficulties in the differential diagnosis with other primary and secondary malignancies of the lung. At present, PSCs are believed to represent a family of carcinomas “in transition,” in which diverse pathways of clonal evolution account for histological differences of a common ancestor lesion. The sarcomatous or sarcomatoid component of these tumors is thought to derive from carcinoma cells during the progression of carcinogenesis through the activation of an epithelial—mesenchymal transition program leading to sarcomatous transformation or metaplasia (conversion paradigm). Conceivably, targeting the epithelial—mesenchymal transition program could become a valid therapeutic strategy for these life-threatening tumors, whose sensitivity to current medical manipulation is disappointing.

Factorial phase III randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study

BACKGROUND The addition of cyclo-oxygenase-2 (COX-2) inhibitors and prolonged constant infusion (PCI) of gemcitabine to treatment for advanced non-small-cell lung cancer (NSCLC) might improve treatment efficacy. We aimed to assess whether the addition of rofecoxib or PCI gemcitabine could improve overall survival compared with first-line treatment with cisplatin plus gemcitabine given by standard infusion. METHODS Patients with stage IV or IIIb (with supraclavicular nodes or pleural effusion) NSCLC who were under 70 years of age and who had performance status 0 or 1 were eligible for this multicentre, prospective, open-label, randomised phase III trial with 2 x 2 factorial design. Patients were randomly assigned to one of four treatment groups: group A, gemcitabine 1200 mg/m(2) in a 30-min intravenous infusion on days 1 and 8 and intravenous cisplatin 80 mg/m(2) on day 1, every 21 days for six cycles; group B, the same treatments as group A plus oral rofecoxib 50 mg/day until disease progression; group C, intravenous PCI gemcitabine 1200 mg/m(2) in a 120-min infusion on days 1 and 8 and intravenous cisplatin 80 mg/m(2) on day 1, every 21 days for six cycles; group D, the same drugs as group C plus oral rofecoxib 50 mg/day until disease progression. The primary endpoint was overall survival; secondary endpoints were progression-free survival, response rate, quality of life, and toxicity. Analyses were intention-to-treat. This trial is registered on the clinical trials site of the US National Institutes of Health website http://clinicaltrials.gov/ct/show/NCT00385606. FINDINGS Between Jan 30, 2003, and May 3, 2005, 400 patients were enrolled. Median age was 60 years (range 29-71). PCI gemcitabine did not improve overall survival (median 47 weeks [95% CI 40-55] vs 44 [36-52], with standard gemcitabine infusion, hazard ratio (HR) of death 0.93 [0.74-1.17], p=0.41), progression-free survival, nor any other secondary endpoint. Vomiting and fatigue were significantly worse with PCI gemcitabine. The two rofecoxib groups were closed early (on Oct 1, 2004) due to withdrawal of the drug because of safety issues. With intention-to-treat statistical analyses limited to 240 patients (ie, those randomised before July 1, 2004) who had at least 3 months of treatment, rofecoxib did not prolong overall survival (median 44 weeks [CI 36-55] vs 44 [40-54] without rofecoxib, and HR of death 1.00 [0.75-1.34], p=0.85), or progression-free survival, but did improve response rate (41%vs 26%, p=0.02), global quality of life, physical, emotional and role functioning, fatigue, and sleeping. Rofecoxib significantly increased the incidence of diarrhoea and decreased constipation, fatigue, fever, weight loss, and pain, and analgesic consumption. Severe cardiac ischaemia was more frequent with rofecoxib than without; however, the difference was not statistically significant in the primary analysis (p=0.06) and became significant when patients who were randomised between July 1, 2004, and Sept 30, 2004, were included in the analysis (p=0.03). INTERPRETATION Neither PCI gemcitabine nor rofecoxib prolonged survival in the patients in this study. Rofecoxib improved response rate and several quality-of-life items, including pain-related items and global quality of life. Further studies with less cardiotoxic COX-2 inhibitors are needed in NSCLC.

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.

A 10-Year Single-Center Experience on 708 Lung Metastasectomies: The Evidence of the “International Registry of Lung Metastases”

Introduction: The International Registry of Lung Metastases defined a new staging system based on identified prognostic factors for long-term survival after metastasectomy. The aim of our study was to confirm the validity of the International Registry of Lung Metastases classification system in patients who underwent curative lung metastasectomy in a single center. Methods: We retrospectively reviewed 575 patients who underwent 708 lung metastasectomies from January 1998 to October 2008. Complete curative pulmonary resections were performed in 490 cases (85%). Three hundred seventy-two patients developed lung metastases from epithelial tumors, 80 from sarcomas, 27 from melanomas, and 11 from germ cell tumors. The mean disease-free interval (DFI) was 46.6 months. Open surgical resection was performed in 479 patients. One hundred eighty-five patients had a single-lung metastasis. Lymph node dissection was performed in 353 cases. Results: After a mean follow-up of 34 months, 247 patients (43%) had died. Multivariate analysis disclosed that completeness of resection (p < 0.0001), patients with germ cell tumors (p = 0.04), and DFI ≥36 months (p = 0.01) were also associated with a better prognosis. The actuarial survival after complete metastasectomy was 74% at 2 years and 46% at 5 years. Conclusions: We confirmed completeness of surgery, histology, and DFI ≥36 months as independent prognostic factors. Number of metastases, presence of lymph node metastases, surgical approach, and number of metastasectomies did not statistically influence long-term survival.

Immunhistochemistry by Means of Widely Agreed-Upon Markers (Cytokeratins 5/6 and 7, p63, Thyroid Transcription Factor-1, and Vimentin) on Small Biopsies of Non-small Cell Lung Cancer Effectively Parallels the Corresponding Profiling and Eventual Diagnoses on Surgical Specimens

Introduction: More detailed typing of non-small cell lung cancer on small biopsy specimens is increasingly required, albeit sometimes demanding with morphology alone. Little, however, is known about the likelihood of immunohistochemistry (IHC)-assessed small biopsies to effectively parallel profiling and, hence, eventual diagnoses of surgical specimens. Methods: Sixty-three preoperative biopsies and the corresponding surgical specimens from 30 consecutive squamous cell carcinomas, 22 adenocarcinomas, 2 adenosquamous carcinomas, eight sarcomatoid carcinomas, and one yolk sac tumor were jointly evaluated semiquantitatively for cytokeratins 5/6 and 7, p63, thyroid transcription factor-1, and vimentin immunoreactivity. Surgical specimens were the gold standard for morphology and IHC. Results: Hierarchic clustering analysis of both surgical specimens and biopsies showed a nonrandom and overlapping distribution of the relevant markers, which closely correlated with each other and the diverse tumor categories, as confirmed by mosaic plot analysis. There were no differences in area under the curve-receiver operating characteristic curves for each marker between any two samples, with the exception of p63 that paralleled more effectively squamous cell carcinoma on biopsies than surgical specimens. Fifty-nine of 63 (94%) lesions were correctly classified by IHC on biopsy compared with 53 of 63 (84%) by revised morphology, with the predictive positive value being 97% for squamous cell carcinoma, 88% for adenocarcinoma, and 100% for sarcomatoid and adenosquamous carcinoma. Yolk sac tumor and three of eight sarcomatoid carcinomas, however, failed any diagnostic recognition. Conclusions: Diverse cell differentiation lineages of non-small cell lung cancer may be consistently detected by IHC in small biopsies, making the eventual typing of tumors effective in most cases.

Validation of a Proliferation-based Expression Signature as Prognostic Marker in Early Stage Lung Adenocarcinoma

Purpose: New prognostic markers to guide treatment decisions in early stage non–small cell lung cancer are necessary to improve patient outcomes. In this report, we assess the utility of a predefined mRNA expression signature of cell-cycle progression genes (CCP score) to define 5-year risk of lung cancer–related death in patients with early stage lung adenocarcinoma. Experimental Design: A CCP score was calculated from the mRNA expression levels of 31 proliferation genes in stage I and stage II tumor samples from two public microarray datasets [Directors Consortium (DC) and GSE31210]. The same gene set was tested by quantitative PCR in 381 formalin-fixed paraffin-embedded (FFPE) primary tumors. Association of the CCP score with outcome was assessed by Cox proportional hazards analysis. Results: In univariate analysis, the CCP score was a strong predictor of cancer-specific survival in both the Directors Consortium cohort (P = 0.00014; HR = 2.08; 95% CI, 1.43–3.02) and GSE31210 (P = 0.0010; HR = 2.25; 95% CI, 1.42–3.56). In multivariate analysis, the CCP score remained the dominant prognostic marker in the presence of clinical variables (P = 0.0022; HR = 2.02; 95% CI, 1.29–3.17 in Directors Consortium, P = 0.0026; HR = 2.16; 95% CI, 1.32–3.53 in GSE31210). On a quantitative PCR platform, the CCP score maintained highly significant prognostic value in FFPE-derived mRNA from clinical samples in both univariate (P = 0.00033; HR = 2.10; 95% CI, 1.39–3.17) and multivariate analyses (P = 0.0071; HR = 1.92; 95% CI, 1.18–3.10). Conclusions: The CCP score is a significant predictor of lung cancer death in early stage lung adenocarcinoma treated with surgery and may be a valuable tool in selecting patients for adjuvant treatment. Clin Cancer Res; 19(22); 6261–71. ©2013 AACR.