STereotactic Ablative RadioTherapy in NEWly Diagnosed and Recurrent Locally Advanced Non-Small Cell Lung Cancer Patients Unfit for ConcurrEnt RAdio-Chemotherapy: Early Analysis of the START-NEW-ERA Non-Randomised Phase II Trial.

PURPOSE: This is a single arm phase 2 trial (Clinical trials.gov NCT05291780) to assess local control (LC) and safety of SAbR in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) unfit for concurrent chemo-radiation therapy (ChT-RT). METHODS: Neoadjuvant ChT was prescribed in fit patients. The tumor volume included primary tumor and any regionally positive node/s. The coprimary study endpoints were LC and safety. RESULTS: Between December 31, 2015, and December 31, 2020, 50 patients with LA-NSCLC were enrolled. Histology was squamous cell carcinoma and adenocarcinoma (ADC) in 52% and 48%, respectively. Forty (80%) patients had ultracentral tumor. Twenty-seven (54%) received neoadjuvant ChT and 7 (14%) adjuvant durvalumab. Median prescribed dose was 45 Gy (range, 35-55) and 40 Gy (35-45) in 5 daily fractions to tumor and node/s, respectively. After a median follow-up of 38 months (range, 12-80), 19 (38%) patients had experienced local recurrence (LR) at a median time of 13 months (range, 7-34). The median LR-free survival (FS) was not reached (95% confidence interval [CI], 28 to not reached). The 1-, 2-, and 3-year LR-FS rates were 86% ± 5%, 66% ± 7%, and 56% ± 8%, respectively. At last follow-up, 33 (66%) patients were alive. Median overall survival (OS) was 55 months (95% CI, 43-55 months). The 1-, 2-, and 3-year OS rates were 94% ± 3%, 79% ± 6%, and 72% ± 7%, respectively. No patients developed ≥ grade (G) 3 toxicity. ADC (hazard ratio [HR], 3.61; 95% CI, 1.15-11.35) was a significant predictor of better LC, while OS was significantly conditioned by smaller planning target volumes (HR, 1.004; 95% CI, 1.001-1.010) and tumor, node, and metastasis stage (HR, 4.8; 95% CI, 1.34-17). CONCLUSIONS: Patients with LA-NSCLC treated with SABR had optimal LC and promising OS in absence of ≥G3 toxicity. Our early outcomes would suggest the feasibility of using this approach in patients with LA-NSCLC unfit for concurrent ChT-RT.

Pulmonary Hamartoma Associated With Lung Cancer (PHALC Study): Results of a Multicenter Study.

PURPOSE: Pulmonary hamartoma is the most common benign tumor of the lung. We analyzed a 20-year historical series of patients with pulmonary hamartoma undergoing surgical resection, aiming to evaluate the characteristics, the outcomes, and the association between hamartoma and lung cancer. METHODS: It was a retrospective multicenter study including the data of all consecutive patients with pulmonary hamartoma undergoing surgical resection. The end-points were to evaluate: (i) the characteristics of hamartoma, (ii) outcomes, and (iii) whether hamartoma was a predictive factor for lung cancer development RESULTS: Our study population included 540 patients. Upfront surgical or endoscopic resection was performed in 385 (71%) cases while in the remaining 155 (29%) cases, the lesions were resected 20 ± 3.5 months later due to increase in size. In most cases, lung sparing resection was carried out including enucleation (n = 259; 48%) and wedge resection (n = 230; 43%) while 5 (1%) patients underwent endoscopic resection. Only two patients (0, 2%) had major complications. One patient (0.23%) had recurrence after endoscopic resection, while no cases of malignant degeneration were seen (mean follow-up:103.3 ± 93 months). Seventy-six patients (14%) had associated lung cancer, synchronous in 9 (12%) and metachronous in 67 (88%). Only age > 70-year-old (p = 0.0059) and smokers > 20 cigarettes/day (p < 0.0001) were the significant risk factors for lung cancer. CONCLUSION: PH was a benign tumor, with no evidence of recurrence and/or of malignant degeneration after resection. The association between hamartoma and lung cancer was a spurious phenomenon due to common risk factors.

Biliothoracic Fistula after Microwave Ablation of Liver Metastasis : Literature Review.

Microwave ablation is a safe and effective interventional approach, widely used in the treatment of unresectable primary or metastatic hepatic lesions. Thoracobiliary fistula is a rare postablation complication that can be treated with a conservative or surgical approach. We reviewed aetiology, pathogenesis, clinical picture, diagnostic possibilities, and therapeutic options for biliothoracic fistula developed after microwave ablation of liver metastasis. Furthermore, we reported our experience of successful conservative management of a nonhealing thoracobiliary fistula occurred after percutaneous thermal ablation of colorectal cancer liver metastasis. Our case supports a conservative approach based on percutaneous biliary system decompression and synthetic glue embolization for the treatment of combined biliopleural and biliobronchial fistula.

Classification Model to Estimate MIB-1 (Ki 67) Proliferation Index in NSCLC Patients Evaluated With 18F-FDG-PET/CT.

BACKGROUND/AIM: Proliferation biomarkers such as MIB-1 are strong predictors of clinical outcome and response to therapy in patients with non-small-cell lung cancer, but they require histological examination. In this work, we present a classification model to predict MIB-1 expression based on clinical parameters from positron emission tomography. PATIENTS AND METHODS: We retrospectively evaluated 78 patients with histology-proven non-small-cell lung cancer (NSCLC) who underwent 18F-FDG-PET/CT for clinical examination. We stratified the population into a low and high proliferation group using MIB-1=25% as cut-off value. We built a predictive model based on binary classification trees to estimate the group label from the maximum standardized uptake value (SUVmax) and lesion diameter. RESULTS: The proposed model showed ability to predict the correct proliferation group with overall accuracy >82% (78% and 86% for the low- and high-proliferation group, respectively). CONCLUSION: Our results indicate that radiotracer activity evaluated via SUVmax and lesion diameter are correlated with tumour proliferation index MIB-1.

Prognostic factors of lung cancer in lymphoma survivors (the LuCiLyS study).

BACKGROUND: Second cancer is the leading cause of death in lymphoma survivors, with lung cancer representing the most common solid tumor. Limited information exists about the treatment and prognosis of second lung cancer following lymphoma. Herein, we evaluated the outcome and prognostic factors of Lung Cancer in Lymphoma Survivors (the LuCiLyS study) to improve the patient selection for lung cancer treatment. METHODS: This is a retrospective multicentre study including consecutive patients treated for lymphoma disease that subsequently developed non-small cell lung cancer (NSCLC). Data regarding lymphoma including age, symptoms, histology, disease stage, treatment received and lymphoma status at the time of lung cancer diagnosis, and data on lung carcinoma as age, smoking history, latency from lymphoma, symptoms, histology, disease stage, treatment received, and survival were evaluated to identify the significant prognostic factors for overall survival. RESULTS: Our study population included 164 patients, 145 of which underwent lung cancer resection. The median overall survival was 63 (range, 58-85) months, and the 5-year survival rate 54%. At univariable analysis no-active lymphoma (HR: 2.19; P=0.0152); early lymphoma stage (HR: 1.95; P=0.01); adenocarcinoma histology (HR: 0.59; P=0.0421); early lung cancer stage (HR: 3.18; P<0.0001); incidental diagnosis of lung cancer (HR: 1.71; P<0.0001); and lung cancer resection (HR: 2.79; P<0.0001) were favorable prognostic factors. At multivariable analysis, no-active lymphoma (HR: 2.68; P=0.004); early lung cancer stage (HR: 2.37; P<0.0001); incidental diagnosis of lung cancer (HR: 2.00; P<0.0001); and lung cancer resection (HR: 2.07; P<0.0001) remained favorable prognostic factors. Patients with non-active lymphoma (n=146) versus those with active lymphoma (n=18) at lung cancer diagnosis presented better median survival (64 vs. 37 months; HR: 2.4; P=0.02), but median lung cancer specific survival showed no significant difference (27 vs. 19 months; HR: 0.3; P=0.17). CONCLUSIONS: The presence and/or a history of lymphoma should not be a contraindication to resection of lung cancer. Inclusion of lymphoma survivors in a lung cancer-screening program may lead to early detection of lung cancer, and improve the survival.

Lobectomy with angioplasty: which is the best technique for pulmonary artery reconstruction?

Lobectomies with bronchial and/or vascular reconstruction are conservative procedures aimed at managing locally advanced lung cancer, avoiding a pneumonectomy. Considering morbidity, mortality and the functional consequences of a pneumonectomy, such procedures must be in the technical armamentarium of every thoracic surgeon. Vascular reconstruction of the pulmonary artery (PA) is seldom performed with or without the bronchial sleeve resection. Both functional and oncologic outcomes have been reported to be better than after a pneumonectomy. Different technical options are now available but some aspects and technical details are not standardized. Indications, possible complications, planning and even definitions need to be more solid to allow for definitive improvement in such procedures. This analysis is aimed at assessing the acquired technical data with special emphasis on the PA reconstruction with autologous tissues.

Stent placement versus surgical palliation for adults with malignant gastric outlet obstruction.

BACKGROUND: Malignant gastric outlet obstruction is the clinical and pathological consequence of cancerous disease causing a mechanical obstruction to gastric emptying. It usually occurs when malignancy is at an advanced stage; therefore, people have a limited life expectancy. It is of paramount importance to restore oral intake to improve quality of life for the person in a manner that has a minimal risk of complications and a short recovery period. OBJECTIVES: To assess the benefits and harms of endoscopic stent placement versus surgical palliation for people with symptomatic malignant gastric outlet obstruction. SEARCH METHODS: In May 2018 we searched the Cochrane Central Register of Controlled Trials, Ovid MEDLINE, Ovid Embase and Ovid CINAHL. We screened reference lists from included studies and review articles. SELECTION CRITERIA: We included randomised controlled trials comparing stent placement with surgical palliation for people with gastric outlet obstruction secondary to malignant disease. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted study data. We calculated the risk ratio (RR) with 95% confidence intervals (CI) for binary outcomes, mean difference (MD) or standardised mean difference (SMD) with 95% CI for continuous outcomes and the hazard ratio (HR) for time-to-event outcomes. We performed meta-analyses where meaningful. We assessed the quality of evidence using GRADE criteria. MAIN RESULTS: We identified three randomised controlled trials with 84 participants. Forty-one participants underwent surgical palliation and 43 participants underwent duodenal stent placement. There may have been little or no difference in the technical success of the procedure (RR 0.98, 95% CI 0.88 to 1.09; low-quality evidence), or whether the time to resumption of oral intake was quicker for participants who had undergone duodenal stent placement (MD -3.07 days, 95% CI -4.76 to -1.39; low-quality evidence).Due to very low-quality evidence, we were uncertain whether surgical palliation improved all-cause mortality and median survival postintervention.The time to recurrence of obstructive symptoms may have increased slightly following duodenal stenting (RR 5.08, 95% CI 0.96 to 26.74; moderate-quality evidence).Due to very low-quality evidence, we were uncertain whether surgical palliation improved serious and minor adverse events. The heterogeneity for adverse events was moderately high (serious adverse events: Chi² = 1.71; minor adverse events: Chi² = 3.08), reflecting the differences in definitions used and therefore, may have impacted the outcomes. The need for reintervention may have increased following duodenal stenting (RR 4.71, 95% CI 1.36 to 16.30; very low-quality evidence).The length of hospital stay may have been shorter (by approximately 4 to 10 days) following stenting (MD -6.70 days, 95% CI -9.41 to -3.98; moderate-quality evidence). AUTHORS' CONCLUSIONS: The use of duodenal stent placement in malignant gastric outlet obstruction has the benefits of a quicker resumption of oral intake and a reduced inpatient hospital stay; however, this is balanced by an increase in the recurrence of symptoms and the need for further intervention.It is impossible to draw further conclusions on these and the other measured outcomes, primarily due to the low number of eligible studies and small number of participants which resulted in low-quality evidence. It was not possible to analyse the impact on quality of life each intervention had for these participants.

Cost analysis of pulmonary lobectomy procedure: comparison of stapler versus precision dissection and sealant.

OBJECTIVE: We aimed to evaluate the direct costs of pulmonary lobectomy hospitalization, comparing surgical techniques for the division of interlobar fissures: stapler (ST) versus electrocautery and hemostatic sealant patch (ES). METHODS: The cost comparison analysis was based on the clinical pathway and drawn up by collecting the information available from the Thoracic Surgery Division medical team at Mantova Hospital. Direct resource consumption was derived from a previous randomized controlled trial including 40 patients. Use and maintenance of technology, equipment and operating room; administrative plus general costs; and 30-day use of postsurgery hospital resources were considered. The analysis was conducted from the hospital perspective. RESULTS: On the average, a patient submitted to pulmonary lobectomy costs €9,744.29. This sum could vary from €9,027 (using ES) to €10,460 (using ST). The overall lower incidence (50% vs 95%, P=0.0001) and duration of air leakage (1.7 days vs 4.5 days, P=0.0001) in the ES group significantly affects the mean time of hospital stay (11.0 days vs 14.3 days) and costs. Cost saving in the ES group was also driven by the lower incidence of complications. The main key cost driver was staff employment (42%), then consumables (34%) and operating room costs (12%). CONCLUSION: There is an overall saving of around €1,432.90 when using ES patch for each pulmonary lobectomy. Among patients undergoing this surgical procedure, ES can significantly reduce air leakage incidence and duration, as well as decrease hospitalization rates. However, further multicenter research should be developed considering different clinical and managerial settings.

Totally submuscular implantation of subcutaneous implantable cardioverter defibrillator: a safe and effective solution for obese or oversized patients.

The subcutaneous implantable cardioverter-defibrillator (S-ICD) is a safe alternative to transvenous ICD. We describe a submuscular S-ICD placement technique in a severely obese with an oversized chest. Submuscular configuration allows optimal system positioning and impendence values warranting a safe and effective shock transmission. This technique is safe and improves patients comfort.

Ex vivo pulmonary nodule detection with miniaturized ultrasound convex probes.

BACKGROUND: The intraoperative localization of small and deep pulmonary nodules is often difficult during minimally invasive thoracic surgery. We compared the performance of three miniaturized ultrasound (US) convex probes, one of which is currently used for thoracic endoscopic diagnostic procedures, for the detection of lung nodules in an ex vivo lung perfusion model. METHODS: Three porcine cardiopulmonary blocks were perfused, preserved at 4°C for 6 h and reconditioned. Lungs were randomly seeded with different patterns of echogenicity target nodules (9 water balls, 10 fat, and 11 muscles; total n = 30). Three micro-convex US probes were assessed in an open setting on the pleural surface: PROBE 1, endobronchial US 5-10 MHz; PROBE 2, laparoscopic 4-13 MHz; PROBE 3, fingertip micro-convex probe 5-10 MHz. US probes were evaluated regarding the number of nodules localized/not localized, the correlation between US and open specimen measurements, and imaging quality. RESULTS: For detecting target nodules, the sensitivity was 100% for PROBE 1, 86.6% for PROBE 2, and 78.1% for PROBE 3. A closer correlation between US and open specimen measurements of target diameter (r = 0.87; P = 0.0001) and intrapulmonary depth (r = 0.97; P = 0.0001) was calculated for PROBE 1 than for PROBES 2 and 3. The imaging quality was significantly higher for PROBE 1 than for PROBES 2 and 3 (P < 0.04). CONCLUSIONS: US examination with micro-convex probes to detect pulmonary nodules is feasible in an ex vivo lung perfusion model. PROBE 1 achieved the best performance. Clinical research with the endobronchial US micro-convex probe during minimally invasive thoracic surgery is advisable.

Sublobar resection versus lobectomy for stage I non-small cell lung cancer: an appropriate choice in elderly patients?

PURPOSES: The aim of this study was to evaluate whether sublobar resection could achieve recurrence and survival rates equivalent to lobectomy in high-risk elderly patients. METHODS: We conducted a retrospective multicenter study that including all consecutive patients (aged >75 years) who underwent operation for clinical stage I non-small cell lung cancer (NSCLC). The clinicopathological data, postoperative morbidity and mortality, recurrence rate and vital status were retrieved. The overall survival, cancer-specific survival and disease-free survival were also assessed. RESULTS: Two hundred and thirty-nine patients (median age 78 years) were enrolled. Lobectomies were performed in 149 (62.3 %) patients and sublobar resections in 90 (39 segmentectomies, 51 wedge resections). There were no differences in the recurrence rates following lobar versus sublobar resections (19 versus 23 %, respectively; p = 0.5) or the overall survival (p = 0.1), cancer-specific survival (p = 0.3) or disease-free survival (p = 0.1). After adjusting for 1:1 propensity score matching and a matched pair analysis, the results remained unchanged. A tumor size >2 cm and pN2 disease were independent negative prognostic factors in unmatched (p = 0.01 and p = 0.0003, respectively) and matched (p = 0.02 and p = 0.005, respectively) analyses. CONCLUSIONS: High-risk elderly patients may benefit from sublobar resection, which provides an equivalent long-term survival compared to lobectomy.

Experimental left pneumonectomy in pigs: procedure and management.

BACKGROUND: Because there is no detailed description of procedures and perioperative management of major pulmonary resections in swine, we reviewed our experience to delineate the most effective practice in performing left pneumonectomy. MATERIALS AND METHODS: Analysis of 11 consecutive left pneumonectomies. Animal data, operative reports, anesthesia records, and perioperative facts were evaluated. Follow-up information until postoperative day 60, methods of care-taking, therapy administration, and all the stabling aspects were systematically assessed. The investigation was aimed at highlighting those procedural steps or details which make the difference in optimizing the available resources (animals, instruments, and personnel). No statistical analysis was performed considering data characteristics and the descriptive nature of information. RESULTS: Surgery requires a median time of 2 h and 16 min; two operators and one anesthesiologist represent the basic team. Circulators' number depends on goals to accomplish. The most straightforward procedure requires careful dissection of the pulmonary ligament (limited view), pulmonary veins (low variability), pulmonary artery (delicate), and finally bronchus (no variability observed). The key factors for good anesthesia management have been identified: sedation by caregivers, preoxygenation before induction of general anesthesia, high respiratory rates with low tidal volume after pneumonectomy, and noninvasive ventilation after extubation. Antibiotic prophylaxis has been performed. Postoperative care must be continuous until animals are able to stand up, afterward "preventive noncurative," and always animal friendly. Ideas for minimally stressful therapy administration are helpful. CONCLUSIONS: After the delineation of this methodology, the compliance to a routine practice allowed us to reduce time, stress, and cost; quality and quantity of possible research increased.

Minimally invasive thoracoscopic technique for cardiac resynchronization therapy.

Outcome of surgical left ventricular (LV) lead placement is not well defined in patients with failed percutaneous cardiac resynchronization therapy. An extended experience with epicardial LV lead placement is here reported, describing the minimally invasive procedure performed at our institution using a thoracoscopic surgical approach.

MYC and human telomerase gene (TERC) copy number gain in early-stage non-small cell lung cancer.

OBJECTIVES: We investigated the frequency of MYC and TERC increased gene copy number (GCN) in early-stage non-small cell lung cancer (NSCLC) and evaluated the correlation of these genomic imbalances with clinicopathologic parameters and outcome. MATERIALS AND METHODS: Tumor tissues were obtained from 113 resected NSCLCs. MYC and TERC GCNs were tested by fluorescence in situ hybridization (FISH) according to the University of Colorado Cancer Center (UCCC) criteria and based on the receiver operating characteristic (ROC) classification. RESULTS: When UCCC criteria were applied, 41 (36%) cases for MYC and 41 (36%) cases for TERC were considered FISH-positive. MYC and TERC concurrent FISH-positive was observed in 12 cases (11%): 2 (17%) cases with gene amplification and 10 (83%) with high polysomy. By using the ROC analysis, high MYC (mean ≥ 2.83 copies/cell) and TERC (mean ≥ 2.65 copies/cell) GCNs were observed in 60 (53.1%) cases and 58 (51.3%) cases, respectively. High TERC GCN was associated with squamous cell carcinoma (SCC) histology (P=0.001). In univariate analysis, increased MYC GCN was associated with shorter overall survival (P=0.032 [UCCC criteria] or P=0.02 [ROC classification]), whereas high TERC GCN showed no association. In multivariate analysis including stage and age, high MYC GCN remained significantly associated with worse overall survival using both the UCCC criteria (P=0.02) and the ROC classification (P=0.008). CONCLUSIONS: Our results confirm MYC as frequently amplified in early-stage NSCLC and increased MYC GCN as a strong predictor of worse survival. Increased TERC GCN does not have prognostic impact but has strong association with squamous histology.

Incidence, Risk Factors, and Analysis of Survival of Unexpected N2 Disease in Stage I Non-Small Cell Lung Cancer.

BACKGROUND: To evaluate the incidence, predictors, and survival of unexpected pN2 disease in patients with clinical stage I non-small cell lung cancer. METHODS: This is a retrospective observational multicenter study on all consecutive patients operated for clinical stage I non-small cell lung cancer from January 2006 to December 2012. Medical records were reviewed to investigate the incidence and risk factors for unexpected pN2 disease. Then, the survival of patients with unexpected pN2 disease was statistically compared with that of patients with clinical N2 disease operated after induction therapy in the same period. RESULTS: Our study population counted 901 patients. An incidence of 12% (108/901) unexpected pN2 disease was found. Among 3,389 lymph nodes sampled, 124 distinct metastases were found. Of the 108 patients, 92 (85%) had metastases in single N2 station and 16 (15%) patients had disease in multiple N2 stations; 47 (44%) had pN2 disease without pN1 involvement (skip metastases) and 61/108 (56%) had also pN1 metastases. Factors associated with unexpected pN2 disease were central tumor location (p < 0.003), cT2a (p < 0.0001) and pT2a stage (p < 0.0001), pN1 disease (p = 0.004), and a standard uptake value > 4.0 (0.007). Patients with pN2 disease compared with patients with cN2 disease presented a better median overall survival (56 versus 20 months; p = 0.001) and disease-free survival (46 versus 11 months; p < 0.0001). CONCLUSIONS: The preoperative effort to discover unexpected pN2 disease in patients with clinical stage I non-small cell lung cancer is not justified, considering their good survival. Thus, preoperative invasive mediastinal procedures in such cases are not indicated.

B-type natriuretic peptide following thoracic surgery: a predictor of postoperative cardiopulmonary complications.

OBJECTIVES: B-type natriuretic peptides (BNPs) are secreted by the human heart in response to ventricular wall stretch or myocardial ischaemia, and predict adverse cardiovascular events and death in the general population. Following non-cardiac surgical procedures, there is growing evidence supporting BNP measurement as a powerful independent predictor of death and perioperative complications. However, the clinical implication of elevated BNP measurements after pulmonary resection has not been completely defined. This study aimed to evaluate the role of BNP in predicting adverse cardiopulmonary events after thoracic surgery. METHODS: A prospective, short-term, observational cohort study was conducted in a tertiary care hospital, including consecutive patients undergoing scheduled pulmonary resection between April 2012 and October 2013. Baseline clinical details were obtained; serum BNP levels were measured at baseline and on postoperative days 1 and 4. RESULTS: We enrolled 294 consecutive patients, median age 66 [interquartile range (IQR): 57-73], 67% male. There were 2 perioperative deaths, and 52 patients experienced one or more cardiopulmonary complications. The baseline median BNP value was normal (29.5 pg/ml, IQR: 16-57.2), and showed significant postoperative increase, peaking on day 1. Patients who developed postoperative complications had a significantly greater BNP increase (P < 0.0001) when compared with those without complications. A postoperative day 1 BNP measurement of ≥118.5 [receiver operating characteristic area: 0.654; 95% confidence interval (CI): 0.57-0.74; P = 0.001] was associated with a 3-fold risk of developing postoperative cardiopulmonary complications [odds ratio (OR): 2.94; 95% CI: 1.32-6.57; P = 0.008]. Logistic regression analysis showed major pulmonary resections (lobectomies or pneumonectomies), BNP ≥ 118.5 and age ≥ 65 to be the only independent predictive variables. In the subset of patients undergoing lobectomy or pneumonectomy (n = 226), BNP was the strongest independent predictor of complications (OR: 3.49; 95% CI: 1.51-8.04). CONCLUSIONS: Our results show that BNP elevation, measured in the first days after thoracic surgery, is independently associated with postoperative adverse events. In patients undergoing major pulmonary resections, a postoperative BNP elevation is the strongest independent predictor of cardiopulmonary complications.

Impact of epidermal growth factor receptor and KRAS mutations on clinical outcome in resected non-small cell lung cancer patients.

OBJECTIVES: Surgery yields best results for non-small cell lung cancer (NSCLC) patients. Epidermal growth factor receptor (EGFR) and its downstream factor Kirsten rat sarcoma viral oncogene homolog (KRAS) are variably mutated in NSCLC. Such mutations predict clinical response to tyrosine kinase inhibitors. This study evaluated incidence and correlation of EGFR and KRAS mutations with clinicopathologic parameters and outcome in resected stage I to III NSCLC. METHODS: We analyzed the clinical characteristics and outcome data for 230 patients who underwent resection at our institution for stage I to III NSCLC. The tumors were assessed for both EGFR (exons 18 to 21) and KRAS (exons 2 and 3) mutations by nested polymerase chain reaction and sequenced in both sense and antisense direction. Kaplan-Meier estimates of overall survival and disease-free survival were calculated for clinical and biological variables using Cox model. RESULTS: EGFR and KRAS mutations were detected in 22 (9.6%) and 39 (16.9%) patients, respectively. In the whole population, both EGFR and KRAS mutations were significantly correlated with adenocarcinoma (ADC). Overall, EGFR mutations were more frequent in women (P<0.0001) and in nonsmokers (P<0.0001). In the ADC/BAC group, KRAS mutations were more frequent in man (P<0.02) and EGFR mutations (exon 19 deletion and L858R) demonstrated a tendency towards worse disease-free survival (P=0.056). No difference in outcome was seen between patients harboring KRAS mutations compared with KRAS wild type. CONCLUSIONS: EGFR and KRAS mutations are frequent in ADCs and are not prognostic factors for survival. EGFR mutations could be used to identify patients suitable for adjuvant treatment with targeted therapy resulting in potentially improved outcomes.

Co-expression of receptors of the HER family correlates with clinical outcome in non-small cell lung cancer (NSCLC).

HER family receptors play a critical role in lung carcinogenesis. There is a growing body of evidence showing that cooperation between them contributes to a more aggressive tumor phenotype and impacts on their response to targeted therapy. We explored immunohistochemical co-expression of HER family receptors (HER1, HER2, HER3, HER4) and its potential role as prognostic factor in resected non-small cell lung cancer (NSCLC). Expression of HER family receptors was assessed by immunohistochemistry on 125 surgically resected NSCLC. Kaplan-Meier estimates of overall survival (OS), disease-free survival (DFS), and time to recurrence were calculated for clinical variables and HER expression, using the Cox model for multivariate analysis. HER1 and HER3 expression was detected more frequently in squamous cell carcinoma (p = 0.002 and p = <0.001, respectively). HER4 was more often expressed in patients older than 60 years (p = 0.02) and in tumors of low histological grade (p = 0.04). Cases which expressed only HER1 had a worse DFS (p = 0.01) and OS (p = 0.01) compared to cases expressing HER1 and one or more of the other family members and to cases which did not express HER1 but one of the other HERs. By multivariate analysis, stage was an independent prognostic factor for DFS and OS. Furthermore, different patterns of co-expression of HER family receptors showed a statistically significant correlation with a shorter DFS (p = 0.03) and OS (p = 0.02). Our findings suggest that expression of HER1 only is correlated with worse DFS and OS. A better understanding of the functional relationships between these receptors may lead to a useful predictive indicator of response to targeted therapy.