Concomitant high gene copy number and protein overexpression of IGF1R and EGFR negatively affect disease-free survival of surgically resected non-small-cell-lung cancer patients.

BACKGROUND: Insulin-like growth factor 1 receptor (IGF1R) represents a novel molecular target in non-small-cell-lung cancer (NSCLC). IGF1R and epidermal growth factor receptor (EGFR) activation are essential to mediate tumor cell survival, proliferation, and invasion. This study investigates the prognostic role of IGF1R and EGFR in surgically resected NSCLC. MATERIALS AND METHODS: IGF1R and EGFR copy number gain (CNG) were tested by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry (IHC) in 125 stage I-II-IIIA NSCLC patients. RESULTS: Fourty-six tumors (40.3%) were IGF1R FISH-positive (FISH+), and 76 (67.2%) were EGFR FISH+. Tumors with concomitant IGF1R/EGFR FISH+ were observed in 34 cases (30.1%). IGF1R and EGFR FISH+ were associated with SCC histology (p = 0.01 and p = 0.04, respectively). IGF1R and EGFR protein over-expression (IHC+) were detected in 45 (36.0%) and 69 (55.2%) cases, respectively. Tumors with concomitant IGF1R/EGFR IHC+ were detected in 31 (24.8%) patients. IGF1R/EGFR FISH+ and IGF1R/EGFR IHC+ were significantly associated (χ(2) = 4.02, p = 0.04). Patients with IGF1R/EGFR FISH+ and IGF1R/EGFR IHC+ were associated with shorter disease-free survival (DFS) (p = 0.05 and p = 0.05, respectively). Patients with concomitant IGF1R/EGFR FISH+/IHC+ had a worse DFS and overall survival (p = 0.005 and p = 0.01, respectively). The multivariate model confirmed that IGF1R/EGFR FISH+/IHC+ (hazard ratio (HR), 4.08; p = 0.01) and tumor stage (II-III vs I) (HR, 4.77; p = 0.003) were significantly associated with worse DFS. CONCLUSIONS: IGF1R/EGFR FISH+ correlates with IGF1R/EGFR IHC+. IGF1R/EGFR FISH+/IHC+ is an independent negative prognostic factor for DFS in early NSCLC. These features may have important implications for future anti-IGF1R therapeutic approaches.

[Surgical treatment of well differentiated neuroendocrine tumours of the lung]. / Terapia chirurgica dei tumori neuroendocrini ben differenziati del polmone.

The bronchial tree represents the most frequent site of origin of carcinoids (around 25% of the total). The spectrum of differentiation of lung neuroendocrine tumors ranges from low-malignancy (carcinoids) to highly aggressive forms (small cell lung carcinoma) Diagnostic and therapeutic strategies therefore vary greatly. In well differentiated tumors (carcinoids) signs and symptoms are related to the airways obstruction in central forms, while peripheral forms are mostly discovered accidentally if asymptomatic. Clinical or subclinical paraneoplastic syndromes are associated in a minority of cases. Diagnostic work-up includes CT multislice, bronchial endoscopy and Octreoscan with chest Single Photon Emission Computed Tomography (SPECT). Further contribute may be added by the (68), Ga-DOTA-D-Phe(1)-Tyr(3)-ocreotide (DOTATOC) and 5-hydroxytryptophan (5-HTP) PET-CT, at present available only in a few centres, and by endobronchial ultrasound (EBUS), fluorescence bronchoscopy and virtual bronchoscopy. Surgery is the treatment of choice, while medical therapy is useful to treat the hypersecretion in paraneoplastic syndromes and to control tumor proliferation in metastatic or/and inoperable disease.

[Lymphectomy in differentiated thyroid cancers: our experience]. / La linfectomia nelle neoplasie differenziate della tiroide: nostra esperienza.

INTRODUCTION: At present we are still debating on which is the most adequate therapeutic strategy concerning the size of the thyroidectomy and the extension of the lymphectomy in differentiated thyroid tumors. PATIENTS AND METHODS: From January 2000 to December 2005, 334 operations for thyroid neoplasms have been performed; 304 (91%) for differentiated tumors. In 124 cases (37%) the latero-cervical and/or the central compartment lymphectomy have been associated with thyroidectomy: 79 monolateral and central compartment lymphectomies (ML and CCL) (64%), 11 bilateral and central compartment lymphectomies (BL and CCL) (8%), and 34 central compartment lymphectomies (CCL) (28%) have been performed. RESULTS: Out of the 124 lymphectomies, in 44 cases (35.5%) we found the presence of metastasis in the lymph nodes of latero-cervical and central compartments, in 10 cases (8%) absence of metastasis in the lymph nodes of the latero-cervical and central compartments, in 25 cases (20%) presence of metastasis in the latero-cervical lymph nodes and absence of metastasis in the lymph nodes of the central compartment. In 11 cases of bilateral and central compartment lymphectomies, 5 of them (4%) had positive lymph nodes of the latero-cervical and central compartments, while the other, only 6 (5%), had positive latero-cervical lymph nodes on the same side as the neoplasia. In 34 central compartment lymphectomies there was absence of metastasis. Mortality rate was zero. There was one case (0.8%) of recurrent laryngeal nerve temporary bilateral palsy (RTBP); 4 cases (3.2%) of recurrent temporary monolateral palsy (RTMP); 2 cases (1.6%) of definitive monolateral palsy (DMP); 29 cases (23.5%) of temporary hypoparathyroidism (TH); 7 cases (5.5%) of definitive hypoparathyroidism (DH). CONCLUSIONS: Latero-cervical lymphectomy should be performed by necessity when clinical tests or pre-diagnostic exams show suspect lymph nodes, whereas central compartment lymphectomy should be performed in any case of thyroid neoplasia.

Efficient naked plasmid cotransfection of lung grafts by extended lung/plasmid exposure time.

BACKGROUND: Multiple gene cotransfection may be an effective strategy to modulate concurrent pathologic events after lung transplantation. We investigated in vivo naked plasmid lung cotransfection during cold preservation and the role of lung parenchyma/naked plasmid exposure time. METHODS: F344 rats underwent left main bronchus instillation of pCF1-CAT (chloramphenicol acetyl transferase) (130 microg) +/- pCF1-beta-Gal (beta-galactosidase) (130 microg) in saline. Part Ia: 4 degrees C preservation versus cotransfection. Lung isografts (4 groups, n = 8) were stored after transfection for 1 (2 groups: one received only pCF1-CAT), 6, and 18 hours. Recipient sacrifice was after 48 hours. Part Ib: 4 degrees C preservation versus transgene expression. Rats were sacrificed 48 hours after transfection in a nontransplant setting (2 groups, n = 8; one received only pCF1-CAT). In a third group (n = 8) lungs were harvested 24 hours after transfection, stored for 18 hours, and recipients were sacrificed after 24 hours. The CAT and beta-Gal enzymatic-linked immunosorbent assays were performed. Part II: Lung/plasmid exposure time. In three groups (n = 6) after pCF1-CAT transfection the left main bronchus was not clamped, clamped for 10 minutes, or clamped for 1 hour. Sacrifice was after 48 hours. RESULTS: Part Ia: Lung CAT protein was (in picograms per 100 microg of total protein): median, 42 (range, 25 to 95) after 1 hour (only CAT); 67 (19 to 296) after 1 hour, 32 (6 to 157) after 6 hours; and 9 (5 to 243) after 18 hours. Lung beta-Gal protein was (in picograms per 100 microg of total protein): median, 20 (range, 5 to 353) after 1 hour; 17 (6 to 157) after 6 hours; 4 (1 to 74) after 18 hours (1 hour versus 18 hours, p = 0.04 for both proteins). CAT and beta-Gal production were significantly correlated (p = 0.0001, r = 0.924). Part Ib: Lung CAT protein was (in picograms per 100 microg of total protein): median, 2 (range, 0.6 to 10) no transplant, only CAT; 7 (0.3 to 13) no transplant; 3 (0.9 to 14) transplant. Part II: Left lung CAT protein was (in picograms per 100 microg of total protein): median, 31 (range, 6 to 83) no clamp; 74 (25 to 430) 10 minutes of clamp; 111 (30 to 263) 1 hour of clamp. Right lung CAT protein was (in picograms per 100 microg of total protein): median, 0.06 (range, 0 to 0.9) no clamp; 1 (0 to 6) 10 minutes of clamp; 1 (0 to 18) 1 hour of clamp. CONCLUSIONS: Efficient lung isograft endobronchial cotransfection results from using naked plasmid. Cold preservation affects transfection efficiency but not transgene expression. Lung parenchyma/naked plasmid exposure time determines transfection efficiency.

Recipient intramuscular gene transfer of active transforming growth factor-beta1 attenuates acute lung rejection.

BACKGROUND: Gene transfer into the donor graft has been demonstrated to be feasible in reducing ischemia-reperfusion injury and rejection in lung transplantation. This study was undertaken to determine whether intramuscular gene transfer into the recipient can also reduce subsequent lung graft rejection. METHODS: Brown Norway rats served as donors and F344 rats as recipients. Recipient animals were injected with 10(10) plaque-forming units of adenovirus encoding active transforming growth factor beta1 (group I, n = 6), beta-galactosidase as adenoviral controls (group II, n = 6), or normal saline without adenovirus (group III, n = 6) into both gluteus muscles 2 days before transplantation. Gene expression was confirmed by enzyme-linked immunosorbent assay. Graft function was assessed on postoperative day 5. RESULTS: Successful gene transfection and expression were confirmed by the presence of active transforming growth factor beta1 protein in muscle and plasma. Oxygenation was significantly improved in group I (group I vs II and III, 353.6 +/- 63.0 mm Hg vs 165.7 +/- 39.9 and 119.1 +/- 41.5 mm Hg; p = 0.02 and 0.004). The muscle transfected with the transforming growth factor beta1 showed granulation tissue with fibroblast accumulation. CONCLUSIONS: Intramuscular adenovirus-mediated gene transfer of active transforming growth factor beta1 into the recipients attenuates acute lung rejection as manifested by significantly improved oxygenation in transplanted lung allografts. This intramuscular transfection approach as a cytokine therapy is feasible in transplantation and may be useful in reducing rejection as well as reperfusion injury.

Iliac crest biopsy versus rib segment resection for the detection of bone marrow isolated tumor cells from lung and esophageal cancer.

OBJECTIVE: The presence of isolated tumor cells in the bone marrow affects the prognosis of both esophageal cancer and non-small cell lung cancer (NSCLC). Therefore, preoperative assessment of isolated tumor cells may be useful to plan multimodality treatment. Rib segment resection at surgery provides adequate amounts of bone marrow for the detection of isolated tumor cells while bone marrow aspirate from the iliac crest does not. The iliac crest biopsy according to the Jamshidi technique procures a core of tissue apt for histology and not simply for cytology. The aim of this study was to compare the accuracy of iliac crest biopsy versus rib segment resection in the diagnosis of isolated tumor cells in order to obtain a useful preoperative approach. MATERIAL AND METHODS: Twenty-one consecutive patients (18 NSCLC, three esophageal cancer) were evaluated. None had chemotherapy prior to evaluation. Bone marrow was obtained preoperatively by iliac crest biopsy using the Jamshidi needle and at surgery by rib segment resection. Positive cytokeratin neoplastic cells were searched by immunohistochemistry on tissue sections from the iliac crest biopsies and by flow cytometry on cell suspensions from the rib segments. RESULTS: Isolated tumor cells were detected in the rib segments of ten patients. In all cases the Jamshidi needle biopsy was not diagnostic. CONCLUSION: Our results suggest that, if the diagnosis of bone marrow isolated tumor cells has clinical relevance, the preoperative assessment should be performed by rib segment resection or methods other than iliac crest aspirate or biopsy. Further investigation is needed to determine whether isolated tumor cells have a preferential spread to chest bones other than distant bone sites.

The role of silicone stents in the treatment of cicatricial tracheal stenoses.

OBJECTIVE: Tracheal stenting for cicatricial stenoses is reserved for patients whose lesions are deemed inoperable for local or general reasons. The aim of our study was to verify the long-term results of silicone tracheal stents in such a clinical setting. METHODS: Clinical data of 45 patients treated by tracheal silicone stents, between 1987 and 1999, were reviewed. All patients had highly symptomatic cicatricial stenoses; they were selected for stenting rather than for surgery because of local and general conditions. This series has been divided in two groups according to the purpose of stenting: bridge to surgery or definitive treatment. Follow-up ranged between 12 and 83 months. Twenty-seven patients received a Montgomery T tube (Hood Laboratories, Pembroke, Mass), 16 a Dumon stent (Novatech, Plan de Gras, France), and 2 a Dynamic stent (Rusch, Kernen, Germany). RESULTS: No procedure-related mortality was observed. Nine patients underwent curative resection and reconstruction after a variable stenting period; one had a recurrent stenosis and was treated for palliation with a T tube. Tracheal stenting was performed for palliation as a definitive treatment in 37 patients. Among this group, 11 patients died of unrelated causes at a median of 10 months after the endoscopic treatment. The stent was permanently removed in 10 after a median interval of 32 months (range 9-70 months); in 4 others, symptomatic recurrence of the stenosis was observed within 6 weeks of stent removal. None of the patients successfully decannulated had a completely normal tracheal lumen but all remained asymptomatic because the residual stenosis was mild or well tolerated for concomitant limitation of physical activity. CONCLUSIONS: Long-term treatment with a silicone stent was safe and well tolerated in cicatricial tracheal stenoses. This procedure can be considered as a bridge to curative surgery or as a definitive treatment. The latter, generally performed for palliation, may provide satisfactory therapeutic results in selected patients, even in the presence of severe circumferential stenoses.

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.