Giuliano Daddi

High coexpression of both insulin-like growth factor receptor-1 (IGFR-1) and epidermal growth factor receptor (EGFR) is associated with shorter disease-free survival in resected non-small-cell lung cancer patients

BACKGROUND Insulin-like growth factor receptor-1 (IGFR-1) represents a novel molecular target in non-small-cell lung cancer (NSCLC). IGFR-1 and epidermal growth factor receptor (EGFR) activation is essential to mediate tumor cell survival, proliferation and invasion. We explored the correlation between IGFR-1 and EGFR, their relationship with clinicopathological parameters and their impact on outcome in resected stage I-III NSCLC patients. PATIENTS AND METHODS Tumors from 125 surgical NSCLC patients were evaluated for IGFR-1 and EGFR expression by immunohistochemistry. Kaplan-Meier estimates of survival and time to recurrence were calculated for clinical variables and biologic markers using the Cox model for multivariate analysis. RESULTS IGFR-1 protein overexpression was detected in 36.0% of NSCLC patients and was associated with larger tumor size (P = 0.04) but not with other clinical or biological characteristics. EGFR protein overexpression was observed in 55.2% of NSCLC, more frequently in squamous cell carcinoma (SCC) than non-SCC (63.7% versus 36.3%, chi(2) = 9.8, P = 0.001). IGFR-1 protein expression was associated with EGFR protein expression (P = 0.03). At the multivariate analysis, high coexpression of both IGFR-1 and EGFR was a significant prognostic factor of worse disease-free survival (DFS) (hazard ratio 2.51, P = 0.01). CONCLUSION A statistically significant association was observed between high coexpression of both IGFR-1 and EGFR and worse DFS in early NSCLC patients.

Preservation of the inferior mesenteric artery in colorectal resection for complicated diverticular disease

BACKGROUND Preservation of the inferior mesenteric artery (IMA) and consequential blood flow to the rectum would reduce the risk of leakage of a colorectal anastomosis. METHODS One hundred and sixty-three patients undergoing left colectomy for complicated diverticular disease of the colon were randomly placed into two groups: A, n = 86; and B, n = 77. In group A, the integrity of the IMA was preserved by artery skeletization (IMAS); in group B, the IMA was divided at its origin. Variables recorded included duration of the surgical procedure, need for blood transfusion, length of hospital stay, operative mortality and morbidity, staple-ring disruption, and radiologic and clinical leakage. Anastomotic stenosis and recurrence of diverticular disease were noted. RESULTS Surgical time was superior in the IMAS group. Radiologic and clinical leakages were significantly higher in group B (P = 0.02, P = 0.03, respectively). In group A a significant lower number of staple-ring disruptions was observed, evolving into clinical dehiscence. CONCLUSION Preserving the natural blood supply to the rectum and the ensuing use of a healthy well-nourished rectal stump are suggested as the main aspects of IMAS in preventing and healing leakage of colorectal anastomosis.

Plasma DNA, microsatellite alterations, and p53 tumor mutations are associated with disease-free survival in radically resected non-small cell lung cancer patients: a study of the perugia multidisciplinary team for thoracic oncology.

Introduction: This prospective study examined association between circulating plasma DNA, microsatellite alterations (MA), p53 mutations with time to relapse and survival in surgically treated non-small cell lung cancer (NSCLC) patients (pts). Methods: Plasma samples, adjacent lung tissue, and lung tumor tissue specimens were collected from consecutive patients with stage I–III NSCLC. Blood samples of 66 matched healthy donors with positive smoking history were collected as controls. The plasma DNA amount was determined by real-time PCR. The analysis of MA at loci D3S1300, D3S1289, D3S1266, and D3S2338 on chromosome 3p was performed by radiolabeled PCR. p53 Mutations (exons 5, 6, 7, and 8) were detected by PCR-single-strand conformational polymorphism assay. Results: There were 76 patients, 65 men; median age was 68 years (range, 42–86), 20 had stage I, 40 stage II, and 16 stage III, the majority of pts (48.7%) had squamous-cell histology. Sixty-nine (91%) were smokers and most had good Eastern Cooperative Oncology Group performance status (0/1:72/4). Mean circulating DNA of all pts was 60 ng/ml versus 5 ng/ml in smoker-matched controls (p < 0.0001). In pts without recurrence, mean circulating DNA was 48.5 ng/ml at baseline, 32.8 ng/ml at 3rd month, and 20.6 ng/ml at 12th month after surgery. In pts with recurrence, mean circulating DNA at baseline was 97.1 ng/ml. At 3rd month after surgery, mean DNA concentration was significantly lower in disease-free pts than in patients with recurrent disease (32.8 versus 292.7 ng/ml; p = 0.0016). MA in at least one locus was found in 39.5% of NSCLC tumors. p53 Genomic mutations were observed in 54.0% of tumor samples. Statistically significant associations were observed between MA and squamous-cell histotype (p = 0.007) and between p53 mutations and lymph node involvement (p = 0.012). MA and p53 mutations were found to be significantly associated with recurrence of disease (p = 0.033 and 0.026, respectively). Conclusion: Our results suggest that MA and p53 mutations in tumor DNA have a potential prognostic role for disease recurrence in NSCLC patients, and elevated levels of plasma circulating DNA identify patients with possible systemic disease at diagnosis. This might be proposed as an early detection test of disease recurrence.

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.

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.

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.

Laparoscopic omental flap for the treatment of major sternal wound infection after cardiac surgery

BACKGROUND The ideal reconstructive procedure after sternal debridement is still a matter of debate. The omentum might be theoretically preferable for its favorable properties, but it is seldom used because it entails the added trauma of a laparotomy. METHODS Three female patients with severe osteomyelitis after myocardial revascularization underwent sternal debridement and filling of the defect with a laparoscopically prepared omental flap. Sternal wound closure was achieved as a single-stage procedure in 2 patients. The third patient had a poststernotomy septicemia and required a 2-stage procedure. The abdominal procedures were conducted through 3 operating 5-mm ports. Omental flaps were developed by complete separation from the transverse colon and lengthening by division of some anastomosing arteries between gastroepiploic vessels and Barkows arcade. Thoracic transposition of the omentum was achieved through a 5-cm diaphragmatic incision. The flaps were able to reach the base of the neck and fill the sternal defect in all patients. RESULTS A smooth postoperative course was observed. Oral intake was started from day 2; sole oral nutrition was maintained from day 3 or 4. Optimal wound healing was observed with minimal or absent local discomfort. Minor transient paradoxical movements of the anterior chest wall disappeared within 1 month. Postoperative hospital stay was 9, 14, and 14 days, respectively. CONCLUSIONS Laparoscopic omentoplasty, compared with the open procedure, entails several advantages for the treatment of sternal osteomyelitis. The introduction of minimally invasive techniques may widen the indications for the use of the omentum in the treatment of major sternal wound infections.

Epidemiology of non-gastroenteropancreatic (neuro)endocrine tumours.

The widespread availability and reliability of immunohistochemical techniques in the last three decades have allowed researchers to identify cells with common neuroendocrine markers in virtually every organ. As a whole, these neuroendocrine cells form the so‐called diffuse neuroendocrine system. Tumours arising from the cells of the diffuse neuroendocrine system are defined as (neuro)endocrine tumours (NETs). NETs have been increasingly described in recent years. However, despite the increase in the number of published papers focused on NET, we still lack adequate epidemiological data, particularly for non‐gastroenteropancreatic (GEP) NETs. Furthermore, the real incidence of neuroendocrine differentiation for most sites is not completely known and is probably underestimated. As a consequence, data on the clinical features of many NET subgroups are not well known or confusing. For all of these reasons, we have attempted to evaluate the epidemiology of non‐GEP NETs, reviewing the limited data available in the literature.