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Introduction: Homologous recombination repair (HRR) is a critical pathway for the repair of DNA damage caused by cisplatin or poly-ADP ribose polymerase (PARP) inhibitors. HRR may be impaired by multiple mechanisms in cancer, which complicates assessing the functional HRR status in cells. Here, we monitored the ability of non-small-cell lung cancer (NSCLC) cells to form subnuclear foci of DNA repair proteins as a surrogate of HRR proficiency., Methods: We assessed clonogenic survival of 16 NSCLC cell lines in response to cisplatin, mitomycin C (MMC), and the PARP inhibitor olaparib. Thirteen tumor explants from patients with NSCLC were subjected to cisplatin ex vivo. Cells were assayed for foci of repair-associated proteins such as BRCA1, FANCD2, RAD51, and γ-H2AX., Results: Four cell lines (25%) showed an impaired RAD51 foci-forming ability in response to cisplatin. Impaired foci formation correlated with cellular sensitivity to cisplatin, MMC and olaparib. Foci responses complemented or superseded genomic information suggesting alterations in the ATM/ATR and FA/BRCA pathways. Because baseline foci in untreated cells did not predict drug sensitivity, we adapted an ex vivo biomarker assay to monitor damage-induced RAD51 foci in NSCLC explants from patients. Ex vivo cisplatin treatment of explants identified two tumors (15%) exhibiting compromised RAD51 foci induction., Conclusions: A fraction of NSCLC harbors HRR defects that may sensitize the affected tumors to DNA-damaging agents including PARP inhibitors. We propose that foci-based functional biomarker assays represent a powerful tool for prospective determination of treatment sensitivity, but will require ex vivo techniques for induction of DNA damage to unmask the underlying HRR defect.

Objective(s): Recommendations for surveillance after stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) are not well defined. Prospective studies evaluating the efficacy of SBRT have used interval posttreatment imaging with computed tomography (CT). We set out to determine whether positron emission tomography (PET) combined with diagnostic chest CT (PET/d-chest) can enhance detection of potentially salvageable recurrence after SBRT., Methods: We performed a retrospective analysis of posttreatment imaging for 35 patients consecutively treated with SBRT for biopsy-proven early-stage NSCLC. PET/d-chest was generally performed every 3 months after treatment. A board-certified radiologist who did not have access to the PET results retrospectively interpreted the CT scans. CT results were reported according to response criteria used in Radiation Therapy Oncology Group 0236 and compared with PET/d-chest readings. Local and regional recurrence-free survival was compared using the Mantle-Cox (log-rank) test., Results: Median follow-up was 12.8 months. Twenty-four patients had stage IA, 7 stage IB, 3 stage IIA, and 1 stage IIB biopsy-proven NSCLC. Two-year overall survival was 62%. CT scans indicated no regional recurrences. PET/d-chest indicated 10 regional recurrences. The 1-year rate of regional recurrence-free survival as evaluated by CT and PET/d-chest was 100% and 69.4%, respectively (P = .0045). Four of 10 patients with a diagnosis of regional recurrence underwent salvage treatment with definitive chemoradiotherapy., Conclusions: PET/d-chest enhances the detection of regional progression of NSCLC after SBRT over currently recommended practices. In patients who are fit for salvage treatment, where early detection of recurrence can increase the likelihood of successful treatment, PET/d-chest appears critical for follow-up., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: Electromagnetic (EM) navigation is increasingly used to assist with bronchoscopic interventions such as biopsy or fiducial placement. Electromagnetic navigation can also be a useful adjunct to computed tomography (CT)-guided thermal ablation and biopsy of lung tumors. This study compares procedures carried out using an EM navigation system (Veran Medical Technologies Inc, St Louis, MO) with procedures using CT fluoroscopy only., Methods: Over a 23-month period, 17 patients scheduled for thermal ablation were prospectively enrolled in this study. The mean age was 72 years (range, 60-84 years). Seven patients were women. Patients were randomized to EM navigation (n = 7) or CT fluoroscopy alone (n = 10). In some cases, additional ablation or biopsies were performed with or without EM navigation depending on the randomization arm. All procedures were performed under general anesthesia either by a thoracic surgeon or a radiologist., Results: A total of 23 procedures were performed in 17 patients: 20 were ablation procedures and 3 were biopsies. Fourteen were performed for non-small cell lung cancer, and 9 for pulmonary metastases from other organs. Despite randomization, patients receiving EM navigation had a trend for smaller tumors (mean diameter, 1.45 vs 2.90 cm; P = 0.06). For thermal ablation procedures, the time to complete intervention was significantly less when EM navigation was used (mean, 7.6 vs 19 minutes; P = 0.022). Although not statistically significant, there were fewer skin punctures (mean, 1 vs 1.25; P = 0.082), fewer adjustments (mean, 5.6 vs 11.8; P = 0.203), less CT fluoroscopy time (mean, 21.3 vs 34.3 seconds; P = 0.345), and fewer CT scans (mean, 7 vs 15; P = 0.204) whenever EM navigation was used., Conclusions: Electromagnetic navigation reduces the time to successfully place an ablation probe in a target tumor. Further study is required to determine whether EM navigation may also reduce the number of adjustments, skin punctures, and CT scans as well as decrease CT fluoroscopy time.

Objective: This study examined the impact of neoadjuvant chemotherapy and concurrent high-dose radiation therapy on survival in patients with node-negative T3 and T4 non-small cell lung cancer., Methods: A total of 110 consecutive patients underwent surgical resection for invasive T3N0M0 (94 patients) and T4N0M0 (16 patients) non-small cell lung cancer between 1979 and 2008. Forty-seven patients received neoadjuvant chemotherapy and concurrent high-dose (5940 cGy) radiation therapy before resection (Chemo-RT group). Sixty-three patients underwent surgical resection without receiving induction chemoradiotherapy (Surg group), of whom 21 received neoadjuvant radiation, 19 received adjuvant radiation, 17 received surgery alone, 2 received adjuvant chemotherapy, 2 received adjuvant chemoradiotherapy, and 2 received brachytherapy. Survival of the Chemo-RT and Surg groups was compared using both crude and adjusted Cox proportional hazards models., Results: The 5-year, 10-year, and median survivals were 61%, 50%, and 90 months, respectively, in the Chemo-RT group versus 22%, 14%, and 22 months, respectively, in the Surg group. Subjects in the Surg group had an increased risk of death (hazard ratio, 2.60; 95% confidence interval, 1.62-4.18; P = .0001) compared with the Chemo-RT group. After adjustment for potential confounding variables of age, sex, tumor size, tumor location, type of operation, and decade of care, subjects in the Surg group remained at increased risk of death (hazard ratio, 2.81; 95% confidence interval, 1.45-5.44, P = .002) compared with the Chemo-RT group., Conclusions: Aggressive treatment of node-negative invasive T3 and T4 NSCLC with induction chemoradiotherapy may significantly prolong survival. This approach should be evaluated in a prospective multicenter national trial., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

David Palma and colleagues report on the impact of stereotactic body radiation therapy (SBRT) on treatment patterns of elderly patients in the Netherlands. This study, published recently in the Journal of Clinical Oncology, is a retrospective review of data collected by the Amsterdam Cancer Registry. This study highlights many of the difficulties encountered when comparing the effectiveness of surgical resection and SBRT., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Currently, lobectomy is the preferred treatment for early-stage, non-small cell lung cancer primarily because of the increased local recurrence rate that has been reported with sublobar resection. Sublobar resection is typically used for high-risk, but still operable, patients with lung cancer. Several recent studies have demonstrated comparable recurrence and survival rates between lobectomy and sublobar resection for small, stage I lung cancers. In particular, attention to technical details such as performing a segmentectomy or a wide wedge resection (rather than a simple wedge resection), or the addition of brachytherapy, can result in improved outcomes. Also, the potential for better preservation of pulmonary function with sublobar resection has fueled the debate arguing for sublobar resections even for patients who are considered to be "good risk" and able to tolerate a lobectomy. This article reviews the current status of sublobar resection for early-stage lung cancer, with particular attention to issues such as tumor size, type of sublobar resection, use of adjuvant brachytherapy, and preservation of pulmonary function.

Background: Thermal ablation is increasingly used to treat pulmonary tumors in medically inoperable patients. Most procedures are performed with sedation in the radiology suite. Ideally, the ablation should encompass the entire tumor volume with a surrounding margin of necrosis; however, ablation may not be as effective in the normal aerated lung surrounding a denser tumor. Inducing atelectasis of the lung may potentially increase ablation volumes and increase local cancer control. This study examines the effect of single-lung ventilation on ablation size using a microwave system., Methods: Twenty microwave ablation procedures were performed in the lungs of 10 swine. Bilateral thoracotomy using a clamshell approach was used. In one lung, ablation was performed with continuous ventilation. In the contralateral lung, single-lung ventilation was achieved by clamping the bronchus before ablation. The ablated lobes were resected and sent for pathologic analysis. Routine and supravital staining was performed., Results: The ablation zone was clearly demarcated on gross examination, and in all cases 100% ablation occurred, without skip areas of viability. The ablation zones were elliptical with the long axis parallel to the axis of the ablation probes (active tip, 3.7 cm). Ablation diameters and volume were compared between the ventilated and nonventilated lungs. Ablation volume was superior in nonventilated lungs (10.74 cm(3) versus 7.35 cm(3); p = 0.039) primarily because of differences in the short axis of the ablation zone., Conclusions: Microwave energy can effectively ablate normal pulmonary parenchyma without skip areas of viable tissue within the gross ablation field. The volume of necrosis is increased in nonventilated lungs, suggesting that ablation results can be improved in patients by using general anesthesia with single-lung ventilation. Future studies will be required to confirm this hypothesis., (Copyright © 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: We evaluated an electromagnetic (EM) navigation system (Veran Medical Technologies Inc, St. Louis, MO) to determine its potential to reduce the number of skin punctures and instrument adjustments during computed tomographic-guided percutaneous ablation and biopsy of lung nodules., Description: Ten patients undergoing lung percutaneous ablation were prospectively enrolled. The mean age was 70 years. Positioning of the needle device was verified with computed tomographic fluoroscopy prior to the execution of any biopsy or ablation. Each EM navigation-guided procedure was defined as an EM-intervention., Evaluation: Nineteen EM interventions were performed. When an EM-guided biopsy was performed, the intervention was done immediately prior to ablation. For all 19 EM interventions, only one skin-puncture was required. The mean number of instrument adjustments required was 1.2 (range, 0 to 2). The mean time for each EM intervention was 5.2 minutes (range, 1 to 20 minutes). Pneumothorax occurred in 5 patients (50%). Only the number of instrument adjustments was significantly related to the pneumothorax rate (p = 0.005)., Conclusions: The EM navigation is feasible and seems to be a useful aid for image-guided procedures. Early experience suggests a low number of skin-puncture and instrument adjustments using the EM navigation system. Instrument adjustments were a key factor in pneumothorax development., (2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Epidermal growth factor receptor (EGFR) has gained importance in non-small cell lung cancer given impressive responses to agents targeting this molecule, particularly in bronchioloalveolar carcinoma (BAC) and adenocarcinomas, mixed subtype, with BAC components (adeno/BAC). This study assesses EGFR signaling in these tumors., Methods: One hundred fifty tumors were classified as BAC or adeno/BAC. Tumor marker expression was determined by immunohistochemistry. Correlations with expression were examined for all tumors (BAC and adeno/BAC), and by BAC and adeno/BAC subset analyses., Results: Positive immunophenotype was observed in 40.6% of tumors for EGFR, 51.3% for p-AKT, 58.7% for p-ERK, and 28.0% for PTEN, with increased overexpression of EGFR (p = 0.025) and p-AKT (p < 0.0001) in adeno/BAC. Epidermal growth factor receptor immunophenotype was greater in never-smokers (p = 0.008) and correlated with improved overall survival (p = 0.018). On subset analysis, EGFR correlated with improved overall survival (p = 0.05) and disease-free interval (p = 0.044) only in adeno/BAC. Epidermal growth factor receptor independently predicted improved disease-free interval in adeno/BAC (p = 0.03; hazard ratio, 0.47; 95% confidence interval, 0.23 to 0.94)., Conclusions: Overexpression of EGFR in lung adenocarcinomas with components of BAC histology correlate with never-smoker status and improved overall survival and disease-free interval. Epidermal growth factor receptor immunophenotype may be a useful predictor of clinical outcomes in this tumor subset.

Background: Overexpression of squamous cell carcinoma-related oncogene (SCCRO) is associated with invasive progression and poor outcomes in non-small cell lung cancer. We assessed the role of SCCRO as a tumor marker in bronchioloalveolar carcinoma (BAC), a subtype of adenocarcinoma exhibiting evidence of histologic tumor progression. We hypothesized that SCCRO expression would correlate with invasive tumor phenotypes and worse survival in BAC., Methods: We classified 150 tumors as pure BAC, BAC with focal invasion, or adenocarcinoma with BAC features. A tissue microarray was constructed from areas of benign lung, BAC, and invasive adenocarcinoma in these tumors. Squamous cell carcinoma-related oncogene expression was graded by immunohistochemistry from 0 to 3 (absent, low, moderate, or high), with positive SCCRO phenotype defined as grade 3. Squamous cell carcinoma-related oncogene specificity was determined by Wilcoxon rank test and area under the receiver-operator curve, survival by the Kaplan-Meier method, and correlation with prognostic factors by log-rank test., Results: Of the 86.0% (129 of 150) of specimens suitable for analysis, positive SCCRO phenotype was seen in 16.3% (21 of 129) and was 100.0% specific for tumor versus benign tissue (area under receiver-operator curve, 0.92). Positive SCCRO phenotype was greater in tumors with increasing degrees of invasive histologic type (7.0% pure BAC, 13.6% BAC with focal invasion, and 28.6% adenocarcinoma with BAC features; p = 0.02). Low-level SCCRO expression was present in 83.9% (99 of 118) of benign tissues and correlated with tobacco use and poor survival (p = 0.05)., Conclusions: Squamous cell carcinoma-related oncogene is a marker of invasive tumor progression in BAC. Low-level expression in adjacent benign lung predicts worse survival, and may represent field cancerization or host-tumor effects.

Background: The histologic criteria defining bronchioloalveolar carcinoma (BAC) were recently revised, but it is unclear whether these criteria predict clinical behavior. This study determined the outcome of resected BAC in relationship to clinical and radiologic disease pattern, and pathologic features., Methods: Between 1989 and 2000, 100 consecutive surgically treated patients with adenocarcinomas exhibiting various degrees of BAC features were retrospectively studied. Histology was reviewed; tumors were classified as pure BAC, BAC with focal invasion, and adenocarcinoma with BAC features. Clinical and radiologic pattern were classified as unifocal, multifocal, or pneumonic. Demographic data, tumor stage, and outcome were recorded. Survival was analyzed by the Kaplan-Meier method, and prognostic factors were determined by the log-rank test., Results: Patient median age was 65, and 74% of the patients were female. Pure BAC, BAC with focal invasion, and adenocarcinoma with BAC features occurred in 47, 21, and 32 patients, respectively. Unifocal disease occurred in 64 patients, multifocal in 29, and pneumonic in 7. Seventy-one patients had stage I/II tumors, 22 had stage III/IV, and 7 patients had Stage X tumors. Overall 5-year survival was 74%. There was no significant difference in survival among the three histologic subtypes. The pneumonic pattern had significantly worse survival compared with unifocal and multifocal patterns. Pathologic stage predicted survival, with 5-year survivals for I/II and III/IV of 83.7% and 59.6%, respectively., Conclusions: Clinical pattern and pathologic stage, but not the degree of invasion on histologic examination predict survival. Multifocal disease is associated with excellent long-term survival after resection. The favorable survival of stage III/IV BAC indicates that the current staging system does not fully describe this disease in patients undergoing resection because of its distinct tumor behavior.