Diagnostic Accuracy of Endobronchial Optical Coherence Tomography for the Microscopic Diagnosis of Usual Interstitial Pneumonia.

Rationale: Early, accurate diagnosis of interstitial lung disease (ILD) informs prognosis and therapy, especially in idiopathic pulmonary fibrosis (IPF). Current diagnostic methods are imperfect. High-resolution computed tomography has limited resolution, and surgical lung biopsy (SLB) carries risks of morbidity and mortality. Endobronchial optical coherence tomography (EB-OCT) is a low-risk, bronchoscope-compatible modality that images large lung volumes in vivo with microscopic resolution, including subpleural lung, and has the potential to improve the diagnostic accuracy of bronchoscopy for ILD diagnosis. Objectives: We performed a prospective diagnostic accuracy study of EB-OCT in patients with ILD with a low-confidence diagnosis undergoing SLB. The primary endpoints were EB-OCT sensitivity/specificity for diagnosis of the histopathologic pattern of usual interstitial pneumonia (UIP) and clinical IPF. The secondary endpoint was agreement between EB-OCT and SLB for diagnosis of the ILD fibrosis pattern. Methods: EB-OCT was performed immediately before SLB. The resulting EB-OCT images and histopathology were interpreted by blinded, independent pathologists. Clinical diagnosis was obtained from the treating pulmonologists after SLB, blinded to EB-OCT. Measurements and Main Results: We enrolled 31 patients, and 4 were excluded because of inconclusive histopathology or lack of EB-OCT data. Twenty-seven patients were included in the analysis (16 men, average age: 65.0 yr): 12 were diagnosed with UIP and 15 with non-UIP ILD. Average FVC and DlCO were 75.3% (SD, 18.5) and 53.5% (SD, 16.4), respectively. Sensitivity and specificity of EB-OCT was 100% (95% confidence interval, 75.8-100.0%) and 100% (79.6-100%), respectively, for both histopathologic UIP and clinical diagnosis of IPF. There was high agreement between EB-OCT and histopathology for diagnosis of ILD fibrosis pattern (weighted κ: 0.87 [0.72-1.0]). Conclusions: EB-OCT is a safe, accurate method for microscopic ILD diagnosis, as a complement to high-resolution computed tomography and an alternative to SLB.

Modified En Bloc Spondylectomy for Tumors of the Thoracic and Lumbar Spine: Surgical Technique and Outcomes.

BACKGROUND: Total en bloc spondylectomy (TES) for the treatment of spinal tumors decreases local recurrence and improves survival compared with intralesional resection. TES approaches vary in both the number of stages to complete the procedure and instruments with which osteotomies are performed. METHODS: We describe a 2-stage technique that employs the use of threadwire saws. We performed a retrospective review of cases of primary tumors and solitary metastases involving the thoracic or lumbar spine treated with use of our modified technique at our institution between 2010 and 2016, identifying eligible patients by searching for specific phrases in operative reports found in our oncologic database. Clinical notes, operative notes, imaging reports, and pathology reports were reviewed for all patients. RESULTS: Thirty-three patients underwent our modified technique, in which we pass a threadwire saw between the vertebral body and the thecal sac. The most common tumor type was chordoma (64%), and tumors were most commonly located in the lumbar spine (61%). There were no intraoperative injuries to the spinal cord or great vessels. One patient experienced a dural tear secondary to the passage of a saw. Seventeen (52%) of the patients had perioperative complications, with 1 death. Seven (22%) of the patients had complications occurring within 90 days after discharge, and 8 (25%) had complications occurring >90 days after discharge. Instrumentation failure was observed in 8 cases (25%). Negative margins were obtained in 94% of the cases. Local recurrence was observed in 2 cases (6%). The majority of patients had normal motor function at the time of the most recent follow-up. CONCLUSIONS: Our modified en bloc spondylectomy represents an effective technique for the resection of spinal tumors in selected patients, allowing for visualization of vessels anterior to the spine and the avoidance of spinal cord injury. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Outcomes With Open and Minimally Invasive Ivor Lewis Esophagectomy After Neoadjuvant Therapy.

BACKGROUND: Neoadjuvant therapy is integral in the treatment of locally advanced esophageal cancer. Despite increasing acceptance of minimally invasive approaches to esophagectomy, there remain concerns about the safety and oncologic soundness after neoadjuvant therapy. We examined outcomes in patients undergoing open and minimally invasive (MIE) Ivor Lewis esophagectomy after neoadjuvant therapy. METHODS: This was a retrospective series of 130 consecutive patients with esophageal cancer undergoing Ivor Lewis esophagectomy with curative intention after neoadjuvant therapy at a tertiary academic center (2008 to 2012). RESULTS: An open procedure was performed in 74 patients (56.9%), and 56 (43.1%) underwent MIE after neoadjuvant therapy. MIE patients had shorter median intensive care unit (p = 0.002) and hospital lengths of stay (p < 0.0001). The incidence of postoperative complications was similar (open: 54.8% vs MIE: 41.1%, p = 0.155). However, observed respiratory complications were significantly reduced after MIE (8.9%) compared with open (29.7%; p = 0.004). Anastomotic leak rates were similar (open: 1.4% vs. MIE: 0%, p = 1.00). Mortality at 30 and 90 days was comparable (open: 2.7% and 4.1% vs MIE: 0% and 1.8%, p = 0.506 and p = 0.634, respectively). Complete resection rates and the number of collected lymph nodes was similar. Overall survival rates at 5 years were similar (open: 61% vs MIE: 50%, p = 0.933). MIE was not a significant predictor of overall survival (hazard ratio, 1.07; 95% confidence interval, 0.61 to 1.87; p = 0.810). CONCLUSIONS: MIE proves its safety after neoadjuvant therapy because it leads to faster progression during the early postoperative period while reducing pulmonary complications. Open and MIE approaches appear equivalent with regards to perioperative oncologic outcomes after neoadjuvant therapy. Long-term outcomes need further validation.

Idiopathic Subglottic Stenosis: Factors Affecting Outcome After Single-Stage Repair.

BACKGROUND: Idiopathic subglottic stenosis is a rare inflammatory condition affecting the subglottic larynx. We have treated 263 patients (only 2 were male) with this condition. The purpose of this study is to determine factors affecting outcome and predisposing to complications. METHODS: Information was gathered from chart reviews, surveys, and a prospective database. RESULTS: Median time from diagnosis to surgery was 24 months. Antinuclear antibodies when measured were positive in 76 patients (47%). Prior tracheal procedures were done in 58 patients (22%), and 184 patients (70%) had prior endoscopic procedures. Resection of the posterior cricoid mucosa with tracheal membranous wall flap was done in 150 patients (57%). Tailored cricoplasty was performed in 105 patients (40%). Extubation in the operating room was achieved in 247 patients (94%). Steroid therapy for edema was required in 63 patients (24%). Anastomotic complications occurred in 30 patients, 17 granulations and 7 subcutaneous air. Twenty-three patients (8.7%) have recurrence (14 mild, 9 recalcitrant) requiring dilation. Risk factors for anastomotic complications and recurrence were edema requiring steroids, use of mitomycin C, and prior tracheostomy, stents, and vocal cord involvement. Follow-up was available for 227 patients. Follow-up survey of 180 patients revealed, on a 10-point scale, effectiveness 9.4, satisfaction 9.4, and symptom improvement 9.4. A normal voice was present in 82 patients (45%); 96 patients (54%) had change in voice; and 121 patients (67%) had difficulty projecting their voice. CONCLUSIONS: Single-stage reconstructive surgery resulted in 96% good-to-excellent results. Recalcitrant stenosis developed in 4% of patients. Stents, postoperative edema, mitomycin use, and vocal cord involvement are risks for recurrence. Recurrence was related to reactivation of disease in 14 patients and to technical problems in 6 patients.

Lymph Node Assessment and Impact on Survival in Video-Assisted Thoracoscopic Lobectomy or Segmentectomy.

BACKGROUND: The objective of this study was to evaluate the influence of total number of resected lymph nodes, lymph node ratio, and the number of lymph node stations sampled on prognosis in patients with early stage non-small cell lung cancer (NSCLC) treated with video-assisted thoracoscopic surgery (VATS). METHODS: Five hundred and fifty patients who underwent VATS lobectomy or segmentectomy for early clinical stage NSCLC were retrospectively analyzed from 2006 to 2012. Disease-free survival (DFS) and overall survival (OS) were compared for cutoff values of total number of resected lymph nodes (RNs) and lymph node stations (LNS) using Kaplan-Meier methods and Cox proportional hazard models. RESULTS: Lobectomy was performed in 493 (90%) patients with a median follow-up of 2.7 years. Median age was 68 (range, 29 to 92 years) and 342 (62%) were female. Pathologic stage I, II, and III was observed in 434 (79%), 80 (14.5%) and 36 (6.5%) patients, respectively. The N0, N1, and N2 pathologic nodal status was observed in 485 (88%), 38 (7%), and 27 (5%) patients, respectively. Nodal upstaging was observed in 11.3% (59 of 550) in the total cohort and 15% (49 of 332) in patients who underwent LNS greater than 3 compared with 5% (10 of 218) in patients with LNS 3 or less (p < 0.01). Multivariate analysis identified LNS greater than 3 as a negative independent predictor for DFS (hazard ratio 2.36, p = 0.003) and OS (hazard ratio 1.77, p = 0.046). CONCLUSIONS: Sampling greater than 3 LNS and greater than 10 RNs was associated with an increase in nodal upstaging. Only LNS greater than 3 was found to be an independent predictor of mortality in VATS lobectomy and segmentectomy in clinical early-stage NSCLC.

Whole-miRNome profiling identifies prognostic serum miRNAs in esophageal adenocarcinoma: the influence of Helicobacter pylori infection status.

Cell free circulating microRNAs (cfmiRNAs) have been recognized as robust and stable biomarkers of cancers. However, little is known about the prognostic significance of cfmiRNAs in esophageal adenocarcinoma (EA). In this study, we explored whether specific cfmiRNA profiles could predict EA prognosis and whether Helicobacter pylori (HP) infection status could influence the association between cfmiRNAs and EA survival outcome. We profiled 1075 miRNAs in pooled serum samples from 30 EA patients and 30 healthy controls. The most relevant cfmiRNAs were then assessed for their associations with EA survival in an independent cohort of 82 patients, using Log-rank test and multivariate Cox regression models. Quantitative real-time PCR (qRT-PCR) was used for cfmiRNA profiling. HP infection status was determined by immunoblotting assay. We identified a panel of 18 cfmiRNAs that could distinguish EA patients from healthy subjects (P = 3.0E-12). In overall analysis and in HP-positive subtype patients, no cfmiRNA was significantly associated with EA prognosis. In HP-negative patients, however, 15 cfmiRNAs were significantly associated with overall survival (OS) (all P < 0.05). A combined 2-cfmiRNA (low miR-3935 and high miR-4286) risk score was constructed; that showed greater risk for worse OS (HR = 2.22, P = 0.0019) than individual cfmiRNA alone. Patients with high-risk score had >10-fold increased risk of death than patients with low risk score (P = 0.0302; HR = 10.91; P = 0.0094). Our findings suggest that dysregulated cfmiRNAs may contribute to EA survival outcome and HP infection status may modify the association between cfmiRNAs and EA survival.

Invasive adenocarcinoma of the lung is associated with the upper lung regions.

OBJECTIVES: We postulated that ventilation-perfusion (V/Q) relationships within the lung might influence where lung cancer occurs. To address this hypothesis we evaluated the location of lung adenocarcinoma, by both tumor lobe and superior-inferior regional distribution, and associated variables such as emphysema. MATERIALS AND METHODS: One hundred fifty-nine cases of invasive adenocarcinoma and adenocarcinoma with lepidic features were visually evaluated to identify lobar or regional tumor location. Regions were determined by automated division of the lungs into three equal volumes: (upper region, middle region, or lower region). Automated densitometry was used to measure radiographic emphysema. RESULTS: The majority of invasive adenocarcinomas occurred in the upper lobes (69%), with 94% of upper lobe adenocarcinomas occurring in the upper region of the lung. The distribution of adenocarcinoma, when classified as upper or lower lobe, was not different between invasive adenocarcinoma and adenocarcinoma with lepidic features (formerly bronchioloalveolar cell carcinoma, P = 0.08). Regional distribution of tumor was significantly different between invasive adenocarcinoma and adenocarcinoma with lepidic features (P = 0.001). Logistic regression analysis with the outcome of invasive adenocarcinoma histology was used to adjust for confounders. Tumor region continued to be a significant predictor (OR 8.5, P = 0.008, compared to lower region), whereas lobar location of tumor was not (P = 0.09). In stratified analysis, smoking was not associated with region of invasive adenocarcinoma occurrence (P = 0.089). There was no difference in total emphysema scores between invasive adenocarcinoma cases occurring in each of the three regions (P = 0.155). There was also no difference in the distribution of region of adenocarcinoma occurrence between quartiles of emphysema (P = 0.217). CONCLUSION: Invasive adenocarcinoma of the lung is highly associated with the upper lung regions. This association is not related to smoking, history of COPD, or total emphysema. The regional distribution of invasive adenocarcinoma may be due to V/Q relationships or other local factors.

Surgical therapy of pulmonary aspergillomas: a 30-year North American experience.

BACKGROUND: Pulmonary aspergilloma is resected to control life-threatening complications such as massive hemoptysis. The role of prophylactic resection in asymptomatic patients is unclear. METHODS: A retrospective review was conducted of 60 patients treated at a tertiary center from 1980 to 2010. RESULTS: The mean age in 34 (56.7%) men and 26 (43.3%) women was 51 years. Immunosuppression, most commonly from chronic steroid use, was present in 17 (28.3%) patients, and preexisting lung disease was present in 47 (78.3%) patients. Hemoptysis occurred in 33 (55%) patients, whereas 9 (15.0%) patients were asymptomatic. Aspergilloma was simple in 13 (21.7%) patients and complex in 47 (78.3%) patients. Surgical approach was by thoracotomy (n=51 [85.0%]), video-assisted thoracoscopic surgery (n=7 [11.7%]), or a cavernostomy (n=2 [3.3%]). Sublobar resections (n=28 [46.7%]) were most common, followed by lobectomy (n=27 [45%]) and pneumonectomy (n=3 [5%]). Postoperative morbidity occurred in 18 (30%) patients, with prolonged air leak the most frequent complication (n=9 [15%]). Two (3.3%) patients experienced empyema, and 4 (6.7%) patients had bronchopleural fistulas (BPFs). Two patients died within 30 days (3.3%). During a mean follow-up of 54.1±62.2 months, 3 patients had recurrent aspergillomas (5.0%). Actuarial 10-year survival was 62.5% for simple and 68.5% for complex aspergillomas (p=0.858). Comorbid conditions (human immunodeficiency virus [HIV] positivity, malignancy) and male sex were associated with lower survival. CONCLUSIONS: Selective surgical treatment favoring lesser pulmonary resection results in fungal eradication and control in most patients. Overall survival is similar after surgical management of simple and complex aspergillomas.

The impact of coexisting COPD on survival of patients with early-stage non-small cell lung cancer undergoing surgical resection.

BACKGROUND: COPD is a recognized risk factor for lung cancer, but studies of coexisting COPD in relation to lung cancer outcomes are limited. We assessed the impact of COPD on overall survival (OS) and progression-free survival (PFS) in patients with early-stage non-small cell lung cancer (NSCLC). METHODS: Patients (N = 902) with early-stage (stage IA-IIB) NSCLC treated with surgical resection were retrospectively analyzed. The association of self-reported, physician-diagnosed COPD with survivals of NSCLC was assessed using the log-rank and Cox regression models, adjusting for age, sex, BMI, smoking, stages, and performance status. RESULTS: Among this cohort of patients with NSCLC, 330 cases had physician-diagnosed COPD, and 572 did not have COPD. The 5-year OS in patients with COPD (54.4%) was significantly lower (P = .0002) than that in patients without COPD (69.0%). The 5-year PFS rates for patients with COPD and without COPD were 50.1% and 60.6%, respectively (P = .007). Compared with patients without COPD, patients with COPD had increased risk of worse OS (adjusted hazard ratio [HRadj] = 1.41, P = .002) and PFS (HRadj = 1.67, P = .003). The associations between COPD and worse survival outcomes were stronger in men and in squamous cell carcinoma (SCC). CONCLUSIONS: Coexisting COPD is associated with worse survival outcomes in patients with early-stage NSCLC, particularly for men and for SCC.

Short and long-term outcomes after esophagectomy for cancer in elderly patients.

BACKGROUND: As worldwide life expectancy rises, the number of candidates for surgical treatment of esophageal cancer over 70 years will increase. This study aims to examine outcomes after esophagectomy in elderly patients. METHODS: This study is a retrospective review of 474 patients undergoing esophagectomy for cancer during 2002 to 2011. A total of 334 (70.5%) patients were less than 70 years old (group A), 124 (26.2%) 70 to 79 years (group B), and 16 (3.4%) 80 years or greater (group C). We analyzed the effect of age on outcome variables including overall and disease specific survival. RESULTS: Major morbidity was observed to occur in 115 (35.6%) patients of group A, 58 (47.9%) of group B, and 10 (62.5%) of group C (p = 0.010). Mortality, both 30-day and 90-day was observed in 2 (0.6%) and 7 (2.2%) of group A, 4 (3.2%) and 7 (6.1%) of group B, and 1 (6.3%) and 2 (14.3%) of group C, respectively (p = 0.032 and p = 0.013). Anastomotic leak was observed in 16 (4.8%) patients of group A, 6 (4.8%) of group B, and 0 (0%) of group C (p = 0.685). Anastomotic stricture (defined by the need for ≥ 2 dilations) was observed in 76 (22.8%) of group A, 13 (10.5%) of group B, and 1 (6.3%) of group C (p = 0.005). Five-year overall and disease specific survival was 64.8% and 72.4% for group A, 41.7% and 53.4% for group B, 49.2% and 49.2% for group C patients (p = 0.0006), respectively. CONCLUSIONS: Esophagectomy should be carefully considered in patients 70 to 79 years old and can be justified with low mortality. Outcomes in octogenarians are worse suggesting esophagectomy be considered on a case by case basis. Stricture rate is inversely associated to age.

Surgical treatment of nonmalignant tracheoesophageal fistula: a thirty-five year experience.

BACKGROUND: Acquired nonmalignant tracheoesophageal fistula in the adult patient develops in a variety of conditions. We have applied surgical closure with success for 35 years. METHODS: From 1975 to 1991, 38 patients underwent surgical repair of a tracheoesophageal fistula. A retrospective study of 36 additional patients undergoing surgical repair from 1992 to 2010 was conducted. RESULTS: The most common causes were postintubation injury (n=17, 47%), trauma (n=6, 17%), prior laryngectomy (n=6, 17%), and prior esophagectomy (n=4, 11%). Four patients presented after failing fistula control with an endoluminal stent. The tracheal defect was closed with resection and reconstruction (n=17, 41%), laryngotracheal resection (n=5, 12%), membranous tracheal repair (n=17, 41%), or repair over a tracheal T tube (n=2, 5%), while esophageal repair consisted of 2-layer closure (n=31, 78%), 1-layer closure (n=6, 15%), esophagostomy (n=1, 3%), end-to-end esophageal anastomosis (n=1, 3%), or full thickness skin graft reconstruction (n=1, 3%). The esophageal and tracheal repairs were buttressed by interposing pedicled muscle or omental flaps in all patients. There was 1 postoperative death (3%). Recurrence after repair developed only in fistulas arising after esophagectomy or laryngectomy (n=4, 11%). Fistula closure was ultimately successful in 34 patients (94%). Twenty-nine patients (83%) resumed oral intake and 25 patients (71%) were breathing without a tracheal appliance. CONCLUSIONS: Successful closure of benign tracheoesophageal fistula is achieved with several surgical techniques based on buttressed repair and restoration of normal breathing and swallowing. Closure of complex postsurgical fistula may fail. Endoluminal stenting was not found useful.

Risk factor analysis for the recurrence of resected solitary fibrous tumours of the pleura: a 33-year experience and proposal for a scoring system.

OBJECTIVES: Surveillance after resection of solitary fibrous tumours of the pleura (SFTP) remains undefined. This study reviews our experience with surgical treatment of SFTP to determine the specific risk factors to predict recurrence. METHODS: A retrospective review of 59 patients surgically treated for SFTP during the years 1977-2010 was conducted. Clinico-pathological factors for recurrence were analysed by Kaplan-Meier and Cox proportional hazard methods. RESULTS: The mean age was 57 ± 14 years. There were 32 (54%) men. Among 32 (54%) symptomatic patients, chest pain (22%), cough (19%) and dyspnoea (17%) were most frequent. The mean tumour size was 7.3 ± 6.7 cm, and 14 patients had SFTPs larger than 10 cm. An SFTP was pedunculated in 38 (67%) cases and had a visceral origin in 40 (68%). Paraneoplastic syndromes were observed in 3 (5%) patients. On histopathologic analysis, 4 (7%) presented ≥ 4 mitosis/10 high-power fields (HPFs), 8 (15%) atypia, 14 (24%) hypercellularity and 6 (10%) necrosis. After a mean follow-up of 8.8 ± 7.0 years, we observed 8 (14%) recurrences; median time to recurrence was 6 years (range 2-16 years). Two (3%) patients received adjuvant therapy. We constructed a predictive score for recurrence by assigning one point to each of the six variables: parietal (vs visceral) pleural origin, sessile (vs pedunculated) morphology, size >10 cm (vs <10 cm), the presence of hypercellularity, necrosis and mitotic activity ≥ 4/HPF (vs <4). A score of ≥ 3 best predicted recurrence (sensitivity: 100%, specificity: 92%, area under receiver operating characteristic curve = 0.966, P < 0.0001). With a score of ≥ 3, recurrence-free survival was 80%, 69, 23 and 23% at 3, 5, 10 and 15 years, whereas a score of <3 was 100% up to 15 years. Our scoring system was superior in predicting malignant behaviour and recurrence compared with England's criteria or de Perrot staging. CONCLUSIONS: The proposed scoring system is simple, easily obtained from existing pathological description and reliably predicts recurrence in this patient population harbouring SFTP. The SFTP score may stratify patient risk and guide postoperative surveillance. We recommend validation in additional clinical series.

Aortic homograft reconstruction of partial laryngectomy defects: a new technique.

OBJECTIVES: Wide-field transcervical partial laryngectomy often precludes tracheotomy decannulation. It is done infrequently today, primarily because of the popularity of chemotherapy-radiotherapy treatment regimens and limited enthusiasm for using transcervical partial laryngectomy after failed radiotherapy. We sought to identify a new reconstructive technique that would provide an alternative to total laryngectomy in as many patients as possible. METHODS: We performed a retrospective examination of 15 patients who underwent single-stage wide-field transcervical partial laryngectomy with cryopreserved aortic homograft reconstruction. Eight of the 15 patients had previously undergone failed radiotherapy. At least 40% of the cricoid circumference was resected in 8 patients. RESULTS: All 15 patients had their tracheotomy tube removed and have laryngeal phonation, and 14 of the 15 resumed oral intake. There were no major surgical complications. CONCLUSIONS: Use of aortic homografts is a new, reliable, and versatile reconstructive option for performing conservation laryngeal cancer surgery that allows for airway, swallowing, and voice preservation.

Comparison of perioperative outcomes following open versus minimally invasive Ivor Lewis oesophagectomy at a single, high-volume centre.

OBJECTIVES: With the increasing popularity of minimally invasive oesophageal resections, equivalence, if not superiority, to open techniques must be demonstrated. Here we compare our open and minimally invasive Ivor Lewis oesophagectomy (MIE) experience. METHODS: A prospective database of all oesophagectomies performed at Massachusetts General Hospital in Boston, MA between November 2007 and January 2011 was analysed. A total of 38 MIE and 76 open Ivor Lewis (OIE) oesophagectomies were performed for oesophageal carcinoma. Sixty-day surgical, oncological and postoperative outcomes were examined between the two groups. RESULTS: Groups had similar demographics in terms of age, gender, tumour histology, clinical stage, preoperative comorbidities and neoadjuvant therapy. No difference was found with respect to adequacy of oncological resections. The median number of lymph nodes retrieved (OIE: 21, inter-quartile range (IQR): (16, 27) versus MIE: 19, IQR: (15, 28)), resection margins (OIE: 6.6% positive versus MIE: no positive margins) and 60-day mortality (OIE: 2.6% versus MIE: no deaths) were comparable. However, rates of pulmonary complications were significantly lower in the MIE group (OIE: 43.4 versus MIE: 2.6%, P < 0.001). Additionally, the median length of ICU and hospital stay, intraoperative blood loss and amount of intravenous fluids infused intraoperatively were also significantly decreased with MIE, while median operative times and the requirement for intraoperative blood transfusion were not significantly different between the two groups. Multivariate logistic regression analysis identified MIE as the only variable associated with a significant reduction in the rate of pulmonary complications in our study, while pre-existing pulmonary comborbidity was associated with an increased risk of pulmonary complications. CONCLUSIONS: Open and MIE appear equivalent with regard to early oncological outcomes. A minimally invasive approach, however, appears to lead to a significant reduction in the rate of postoperative pulmonary complications. Length of ICU and hospital stay, as well as intraoperative blood loss and intravenous fluid requirements are also reduced in the setting of MIE. Long-term survival data will need to be followed closely. A large, multi-centred, randomized, controlled trial is warranted to confirm these results.

Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers.

Most anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancers (NSCLCs) are highly responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). However, patients with these cancers invariably relapse, typically within 1 year, because of the development of drug resistance. Herein, we report findings from a series of lung cancer patients (n = 18) with acquired resistance to the ALK TKI crizotinib. In about one-fourth of patients, we identified a diverse array of secondary mutations distributed throughout the ALK TK domain, including new resistance mutations located in the solvent-exposed region of the adenosine triphosphate-binding pocket, as well as amplification of the ALK fusion gene. Next-generation ALK inhibitors, developed to overcome crizotinib resistance, had differing potencies against specific resistance mutations. In addition to secondary ALK mutations and ALK gene amplification, we also identified aberrant activation of other kinases including marked amplification of KIT and increased autophosphorylation of epidermal growth factor receptor in drug-resistant tumors from patients. In a subset of patients, we found evidence of multiple resistance mechanisms developing simultaneously. These results highlight the unique features of TKI resistance in ALK-positive NSCLCs and provide the rationale for pursuing combinatorial therapeutics that are tailored to the precise resistance mechanisms identified in patients who relapse on crizotinib treatment.

Interactions between environmental factors and polymorphisms in angiogenesis pathway genes in esophageal adenocarcinoma risk: a case-only study.

BACKGROUND: Gastroesophageal reflux disease (GERD), higher body mass index (BMI), smoking, and genetic variants in angiogenic pathway genes have been individually associated with increased risk of esophageal adenocarcinoma. However, how angiogenic gene polymorphisms and environmental factors jointly affect esophageal adenocarcinoma development remains unclear. METHODS: By using a case-only design (n = 335), the authors examined interactions between 141 functional/tagging angiogenic single nucleotide polymorphisms (SNPs) and environmental factors (GERD, BMI, smoking) in modulating esophageal adenocarcinoma risk. Gene-environment interactions were assessed by a 2-step approach. First, the authors applied random forest to screen for important SNPs that had either main or interaction effects. Second, they used case-only logistic regression to assess the effects of gene-environment interactions on esophageal adenocarcinoma risk, adjusting for covariates and false-discovery rate. RESULTS: Random forest analyses identified 3 sets of SNPs (17 SNPs-GERD, 26 SNPs-smoking, and 34 SNPs-BMI) that had the highest importance scores. In subsequent logistic regression analyses, interactions between 2 SNPs (rs2295778 of HIF1AN, rs13337626 of TSC2) and GERD, 2 SNPs (rs2295778 of HIF1AN, rs2296188 of VEGFR1) and smoking, and 7 SNPs (rs2114039 of PDGRFA, rs2296188 of VEGFR1, rs11941492 of VEGFR1, rs17708574 of PDGFRB, rs7324547 of VEGFR1, rs17619601 of VEGFR1, and rs17625898 of VEGFR1) and BMI were significantly associated with esophageal adenocarcinoma development (all false-discovery rates ≤0.10). Moreover, these interactions tended to have SNP dose-response effects for increased esophageal adenocarcinoma risk with increasing number of combined risk genotypes. CONCLUSIONS: These findings suggest that genetic variations in angiogenic genes may modify esophageal adenocarcinoma susceptibility through interactions with environmental factors in an SNP dose-response manner.