Francesco Puma

BRCA1: a novel prognostic factor in resected non-small-cell lung cancer.

Background Although early-stage non-small-cell lung cancer (NSCLC) is considered a potentially curable disease following complete resection, patients have a wide spectrum of survival according to stage (IB, II, IIIA). Within each stage, gene expression profiles can identify patients with a higher risk of recurrence. We hypothesized that altered mRNA expression in nine genes could help to predict disease outcome: excision repair cross-complementing 1 (ERCC1), myeloid zinc finger 1 (MZF1) and Twist1 (which regulate N-cadherin expression), ribonucleotide reductase subunit M1 (RRM1), thioredoxin-1 (TRX1), tyrosyl-DNA phosphodiesterase (Tdp1), nuclear factor of activated T cells (NFAT), BRCA1, and the human homolog of yeast budding uninhibited by benzimidazole (BubR1). Methodology and Principal Findings We performed real-time quantitative polymerase chain reaction (RT-QPCR) in frozen lung cancer tissue specimens from 126 chemonaive NSCLC patients who had undergone surgical resection and evaluated the association between gene expression levels and survival. For validation, we used paraffin-embedded specimens from 58 other NSCLC patients. A strong inter-gene correlation was observed between expression levels of all genes except NFAT. A Cox proportional hazards model indicated that along with disease stage, BRCA1 mRNA expression significantly correlated with overall survival (hazard ratio [HR], 1.98 [95% confidence interval (CI), 1.11-6]; P = 0.02). In the independent cohort of 58 patients, BRCA1 mRNA expression also significantly correlated with survival (HR, 2.4 [95%CI, 1.01-5.92]; P = 0.04). Conclusions Overexpression of BRCA1 mRNA was strongly associated with poor survival in NSCLC patients, and the validation of this finding in an independent data set further strengthened this association. Since BRCA1 mRNA expression has previously been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 mRNA expression may provide additional information for customizing adjuvant antimicrotubule-based chemotherapy, especially in stage IB, where the role of adjuvant chemotherapy has not been clearly demonstrated.

The prognostic value of pre-operative and post-operative B-type natriuretic peptides in patients undergoing noncardiac surgery: B-type natriuretic peptide and N-terminal fragment of pro-B-type natriuretic peptide: A systematic review and individual patient data meta-analysis

OBJECTIVES The objective of this study was to determine whether measuring post-operative B-type natriuretic peptides (NPs) (i.e., B-type natriuretic peptide [BNP] and N-terminal fragment of proBNP [NT-proBNP]) enhances risk stratification in adult patients undergoing noncardiac surgery, in whom a pre-operative NP has been measured. BACKGROUND Pre-operative NP concentrations are powerful independent predictors of perioperative cardiovascular complications, but recent studies have reported that elevated post-operative NP concentrations are independently associated with these complications. It is not clear whether there is value in measuring post-operative NP when a pre-operative measurement has been done. METHODS We conducted a systematic review and individual patient data meta-analysis to determine whether the addition of post-operative NP levels enhanced the prediction of the composite of death and nonfatal myocardial infarction at 30 and ≥180 days after surgery. RESULTS Eighteen eligible studies provided individual patient data (n = 2,179). Adding post-operative NP to a risk prediction model containing pre-operative NP improved model fit and risk classification at both 30 days (corrected quasi-likelihood under the independence model criterion: 1,280 to 1,204; net reclassification index: 20%; p < 0.001) and ≥180 days (corrected quasi-likelihood under the independence model criterion: 1,320 to 1,300; net reclassification index: 11%; p = 0.003). Elevated post-operative NP was the strongest independent predictor of the primary outcome at 30 days (odds ratio: 3.7; 95% confidence interval: 2.2 to 6.2; p < 0.001) and ≥180 days (odds ratio: 2.2; 95% confidence interval: 1.9 to 2.7; p < 0.001) after surgery. CONCLUSIONS Additional post-operative NP measurement enhanced risk stratification for the composite outcomes of death or nonfatal myocardial infarction at 30 days and ≥180 days after noncardiac surgery compared with a pre-operative NP measurement alone.

XPG mRNA Expression Levels Modulate Prognosis in Resected Non–Small-Cell Lung Cancer in Conjunction with BRCA1 and ERCC1 Expression

BACKGROUND Molecular markers can help identify patients with early-stage non-small-cell lung cancer (NSCLC) with a high risk of relapse. Excision repair cross-complementing 1 (ERCC1), Xeroderma pigmentosum group G (XPG), and breast cancer 1 (BRCA1) are involved in DNA damage repair, whereas ribonucleotide reductase M1 (RRM1) is implicated in DNA synthesis. Expression levels of these molecules might therefore have a prognostic role in lung cancer. PATIENTS AND METHODS We examined ERCC1, RRM1, XPG, and BRCA1 mRNA levels by real-time quantitative polymerase chain reaction in 54 patients with stage IB-IIB resected NSCLC. A strong correlation was observed between the 4 genes. RESULTS For patients with low BRCA1, regardless of XPG mRNA expression levels, disease-free survival (DFS) was not reached. For patients with intermediate/high BRCA1 and high XPG, DFS was 50.7 months. However, for patients with intermediate/high BRCA1 and low/intermediate XPG, DFS decreased to 16.3 months (P = .002). Similar differences were observed in overall survival, with median survival not reached for patients with low BRCA1, regardless of XPG levels, or for patients with intermediate/high BRCA1 and high XPG. Conversely, for patients with intermediate/high BRCA1 levels and low/intermediate XPG levels, median survival dropped to 25.5 months (P = .007). CONCLUSION BRCA1 and XPG were identified as independent prognostic factors for both median survival and DFS. High BRCA1 mRNA expression confers poor prognosis in early NSCLC, and the combination of high BRCA1 and low XPG expression still further increases the risk of shorter survival. These findings can help optimize the customization of adjuvant chemotherapy.

Tumorlets, Multicentric Carcinoids, Lymph-Nodal Metastases, and Long-Term Behavior in Bronchial Carcinoids

Background: The clinical significance of lymph-node metastases, multicentric forms, and tumorlets in bronchial carcinoids is still a matter of debate. Aim of this study was to analyze their prevalence and clinical significance in a series of 123 bronchial carcinoids. Patients and Methods: Nodal dissection and serial sections of resected lung parenchima for research of multicentric forms and tumorlets were performed in most patients. Survival curve was produced using the Kaplan-Meyer method and multivariate analysis by the Cox proportional hazard model. Results: Lymph-node involvement was present in 14% of typical (14 of 100) and 13.04% of atypical carcinoids (3 of 23). Multicentric forms (syncronous carcinoids or tumorlets) were found in 11.3% of the total with a negative impact on survival (p = 0.021). Multiple tumorlets were found in 7.3% of all cases at the standard pathologic examination, but whenever accurate palpation and serial sections of the surgical specimen were performed, the percentage reached 24% of the cases. Overall survival was 98.2%, 95.8%, and 83.9% for typical and 71.6%, 57.3%, and 24% for atypical carcinoid respectively at 5, 10, and 15 years. Time from surgery was significantly directly correlated with recurrences (p < 0.0001) and disease related death (p = 0.0002). Conclusions: A high prevalence of tumorlets, multiple carcinoids, and lymph-nodal involvement was found in our series. On the basis of these observations bronchial carcinoids always require major surgical procedures with systematic nodal dissection, and a careful search for multifocal lesions should always be performed. Follow-up should always be accurate and protracted, due to the frequency of very long-term relapses (often more than 10 years after surgery).

Long-term safety and tolerance of silicone and self-expandable airway stents: an experimental study

BACKGROUND A variety of respiratory stents are currently available, but the ideal airway prosthesis seems far from being recognized. The objective of this study was to verify safety and long-term effect on the bronchial wall of three different types of airway stents. METHODS Twelve healthy adult sheep were divided in three groups, scheduled to receive: (1) bare self-expandable metallic stents (Gianturco); (2) silicone stents (Dumon); and (3) covered self-expandable synthetic stents (Polyflex). Insertions were performed through a rigid bronchoscope under general anesthesia. Chest roentgenogram was performed 1 and 6 months after surgery, and flexible bronchoscopy after 6 months. Twelve months postoperatively, the animals were killed and a postmortem examination was carried out. RESULTS All Polyflex stents migrated during the observation period; one late migration was observed in the Dumon group. Microscopic study showed: (1) Gianturco stents: full-thickness perforation of the bronchial wall covered by a thick layer of a chronic inflammatory infiltrate. Infection by Candida at the bottom of some ulcerations; (2) Dumon stents: mild bronchial inflammation (squamous metaplasia, submucosal inflammatory infiltrates; granuloma-like infiltrates). In case of displacement, no significant changes of the previously stented bronchus occurred; and (3) Polyflex stents: no changes of the previously stented bronchi. CONCLUSIONS Gianturco stents proved unsafe in the long term, owing to the risk of severe airway wall damage. The Polyflex stent is well tolerated but presents a high migration rate. Silicone stents show several limitations but appear to be well tolerated by the host mucosa.

Resection With Curative Intent After Endoscopic Treatment of Airway Obstruction

BACKGROUND Endoscopic treatment of malignant central airway obstructions usually is done for palliation. The exact role of such a procedure as preparatory to operation remains controversial. METHODS From 1987 through 1996, 24 patients at our institution underwent tracheobronchial pulmonary resection after preliminary endoscopic treatment. During the same period, 304 patients underwent 449 operative rigid bronchoscopies for airway obstructions, most involving the use of a neodymium:yttrium-aluminum-garnet laser. The indications for operation were squamous cell carcinoma in 14 patients, bronchial gland tumors in 8 patients, and papillary thyroid cancer infiltrating the trachea in 2 patients. The total resection rate was 9.5% (5% for squamous cell carcinoma, 75% for low-grade malignant bronchial tumors, and 75% for papillary thyroid cancer). The median period between operative rigid bronchoscopy and operation was 18 days. RESULTS No complications were observed after endoscopic treatment. There were two perioperative deaths (adult respiratory distress syndrome after carinal resection and pulmonary embolism after pneumonectomy) and one major complication (poor postoperative pulmonary function after pneumonectomy). No anastomotic complications were observed in the tracheobronchoplastic procedures. Follow-up was possible in every patient but 1: 6 patients died at a median of 30.5 months after operation (range, 3 to 46 months), 2 patients are alive with disease, and the rest are alive without evidence of disease at a median of 21 months (range, 2 to 61 months). CONCLUSIONS Most patients who require endoscopic therapy for malignant airway obstructions are not candidates for operative resection. Preliminary endoscopic relief of obstruction can increase operability and improve surgical results in a highly selected group of patients.

Isolated cardiophrenic angle node metastasis from ovarian primary. report of two cases

Ovarian cancer is the most lethal gynaecologic malignancy. It usually spreads out of the abdomen involving thoraco-abdominal organs and serosal surface. This disease is poorly curable and surgery, at early stage, is supposed to achieve the best survival outcome. In systemic dissemination, chemiotherapy is indicated, sometimes with neoadjuvant aim. The most common clinical expressions of advanced ovarian carcinoma are multiple adenopathy, neoplastic pleuritis, peritoneal seeding and distant metastasis, mainly hepatic and pulmonary. Isolated adenopathy of the mediastinum is rare and isolated bilateral have never been described before. We report two cases of isolated bilateral cardiophrenic angle lymphnode metastasis from ovarian carcinoma, without peritoneal and pleural involvement. Both patients were successfully resected through minimally invasive thoracic surgery. About the role of surgery, few data are available but survival seems to be longer after resection thus, more investigation is required to make the indication to surgery more appropriate in advanced cases.

Chest wall stabilization with synthetic reabsorbable material.

Experimental results and preliminary clinical experience with synthetic reabsorbable materials in chest wall reconstruction are reported. Six beagle dogs underwent chest wall resection involving three or four consecutive ribs. Reparative procedure was performed by construction of a polydioxanone-band grid, anchored to the adjacent undamaged ribs. A mild wound infection developed in 1 animal but resolved without rejection of the prosthesis. The experimental material has shown favorable properties, both mechanical and biological. Subsequently, 11 patients, with different indications, underwent reconstructive procedures of the chest wall with reabsorbable prostheses. No complications have occurred. Long-term stability was excellent in all patients, with a mean follow-up longer than 6 months. The advantages of reabsorbable compounds are pointed out along with the possible applications for chest wall reconstruction after chest wall resection.

Clinical outcome with platinum-based chemotherapy in patients with advanced nonsquamous EGFR wild-type non-small-cell lung cancer segregated according to KRAS mutation status.

BACKGROUND We hypothesized that KRAS mutations function as a marker of poor sensitivity to first-line platinum-based chemotherapy in patients with advanced nonsquamous EGFR wild-type (WT) non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Consecutive advanced nonsquamous EGFR WT NSCLCs treated at the Medical Oncology of Perugia with simultaneous assessment of KRAS mutation status were eligible. Anaplastic lymphoma kinase (ALK) gene status was known in roughly half of the patients who had KRAS WT. RESULTS Two hundred four patients were included. Among them, the 77 individuals carrying a KRAS-mutant phenotype experienced a significantly inferior outcome in terms of response rate (P = .04), disease control rate (P = .05), and progression-free survival (PFS) (P = .05) compared with the EGFR WT/KRAS WT population. The association between KRAS mutation and shorter PFS remained statistically significant at multivariate analysis (hazard ratio [HR], 1.45). In addition, patients with KRAS mutations reported a significantly shorter overall survival (OS) compared with patients with EGFR WT/KRAS WT/ALK negativity (n = 64) (P = .02). Among patients with KRAS mutations, those harboring a mutation at codon 13 (n = 12) performed worse than those with a mutation at codon 12 (n = 62) in terms of both PFS and OS (P = .09 for both). CONCLUSION KRAS mutation appears to negatively affect sensitivity to first-line platinum-based chemotherapy in patients with advanced nonsquamous EGFR WT NSCLC. Studies on larger case series are needed to address differences in clinical outcome according to the type of mutation.

Bone heterograft for chest wall reconstruction after sternal resection

BACKGROUND Experimental and clinical results of chest-wall reconstruction with bone heterograft after sternectomy are reported. METHODS Seven dogs underwent subtotal or total sternectomy and reconstruction by implantation of a cortico-spongy bone heterograft sandwiched between two layers of a reabsorbable mesh. RESULTS No major postoperative complications were observed. The implant has shown favorable mechanical and biological properties. Six and 9 months after operation all animals were sacrificed and pathologic examination showed good incorporation of the implanted bone with only partial resorption of its spongiosa. Subsequently, 2 patients underwent sternal resection with different indications and reconstruction was achieved by the technique developed experimentally. No complications were observed. Excellent immediate chest-wall stabilization was obtained, persisting for a follow-up period longer than 6 months. CONCLUSIONS In comparison with autologous bone, sterile bone heterograft seems to offer the same mechanical properties with a significantly reduced surgical trauma.