Justin D. Blasberg

Onconase mediated NFKβ downregulation in malignant pleural mesothelioma

Treatment of malignant pleural mesothelioma (MPM) with Ranpirnase (Onconase) results in disruption of protein translation and cell apoptosis. We hypothesize that Onconase exerts an effect via downregulation of nuclear factor kappa B (NFKβ) by specific microRNAs (miRNAs) and that interference of this pathway could have implications for MPM resistance to chemotherapy. Three immortalized MPM cell lines (H2959, H2373 and H2591) were exposed to Onconase at 0–20 μg/ml. Cell counts were measured at 48 and 72 h. Gene expression in miRNA-enriched RNA was validated by reverse transcription–PCR (RT–PCR). The functional implications of miRNA expression were evaluated by transfecting miRNA mimics or inhibitors into MPM cell lines, and performing Matrigel invasion, cell proliferation, soft agar colony formation and scratch closure assays. Effects on NFKβ expression and downstream targets including ABC transporters, BCL-xl and IAP were assessed by RT–PCR and western blotting. Treatment with 20 μg/ml of Onconase significantly decreased cell count and invasion. Hsa-miR-17* was significantly upregulated and hsa-miR-30c was significantly downregulated by Onconase treatment in all cell lines. Forced expression of hsa-miR-17* mimic and hsa-miR-30c inhibitor each significantly decreased functional activity of Onconase in all assays. NFKB1 (p50) expression and downstream targets were also decreased with Onconase treatment, as well as with forced expression of miRNA mimic and inhibitors. Onconase treatment caused a significant decrease in cell proliferation, invasion and in expression of certain miRNAs. Recapitulation of the resultant miRNA expression pattern with hsa-miR-17* mimic and hsa-miR-30c inhibitor resulted in downregulation of NFKB1 and reduced malignant behavior in functional assays. Thus, Onconase likely exerts its antitumor effect through these miRNAs.

Functional Heterogeneity of Osteopontin Isoforms in Non-small Cell Lung Cancer

Introduction: Osteopontin (OPN) is a multifunctional protein with an important but poorly understood role in non-small cell lung cancer (NSCLC) pathogenesis. Moreover, the role of the three known mRNA isoforms (OPNa, OPNb, and OPNc) has not been reported. We hypothesize that OPN isoforms play different roles in determining the metastatic potential of NSCLC. Methods: We amplified mRNA for each OPN isoform in NSCLC tumors and matched normal lung. The functional impact of each isoform was evaluated by transfecting cDNA plasmids specific to each isoform into NSCLC cell lines and comparing behavior to empty vector controls in scratch closure, cell proliferation, soft-agar colony formation, and Matrigel invasion assays. Gene array was used to evaluate differences in downstream targets and was compared with a panel of markers for epithelial-mesenchymal transition (EMT). Results: OPNa expression was increased in 91% of NSCLC tumors compared with matched lung. OPNa overexpression significantly increased activity in scratch closure, proliferation, soft-agar colony formation, and Matrigel invasion assays compared with controls in all cell lines. OPNb overexpression produced a less significant modulation of function. OPNc overexpression significantly decreased activity in proliferation, colony formation, and invasion assays compared with controls. Expression arrays revealed an increase in EMT with OPNa overexpression but not OPNc. Differences were validated by quantitative reverse transcriptase-polymerase chain reaction. Conclusions: Overexpression of the individual OPN isoforms in NSCLC results in divergent functional phenotypes. OPNa produced an aggressive phenotype, whereas OPNc produced a more indolent phenotype. Exon 4, which is transcribed in OPNa but absent in OPNc, may be central to this phenomenon and could serve as a target for isoform-specific inhibition of OPN in NSCLC.

The Surgical Apgar Score in esophagectomy

OBJECTIVE The Surgical Apgar Score is a validated prognostic tool that is based on select intraoperative variables (heart rate, mean arterial pressure, and blood loss). It has been shown to be a strong predictor of morbidity and mortality in a variety of surgical populations. Esophagectomy for malignancy represents a unique subset of patients at high risk for postoperative complications. This study assessed the ability of a modified esophagectomy Surgical Apgar Score (eSAS) to predict 30-day major morbidity. METHODS A retrospective review included 168 patients who underwent elective esophagectomy for malignant disease at the University of Wisconsin from January 2009 through July 2013. Preoperative patient characteristics, intraoperative details, and short-term outcomes were recorded. Primary outcome was 30-day major morbidity. Univariate and multivariate analyses were performed to determine associations between predictive variables, eSAS, and major morbidity. RESULTS Major morbidity occurred in 35% of cases. Univariate analysis showed that eSAS of 6 or less was strongly associated with major morbidity (unadjusted odds ratio, 2.55; 95% confidence interval, 1.32-4.91; P = .005). Other risk factors included transhiatal technique, body mass index less than 20 or greater than 35 kg/m(2), and history of diabetes mellitus. In multivariate analysis, eSAS of 6 or less remained a strong predictor of postoperative complications (adjusted odds ratio, 3.75; 95% confidence interval, 1.70-8.26; P = .001). CONCLUSIONS The eSAS was strongly associated with 30-day major morbidity after esophagectomy. Prospective studies are needed to determine whether improved outcomes can be achieved with the eSAS for risk-stratified triage and postoperative care modification.

Association of Delayed Adjuvant Chemotherapy With Survival After Lung Cancer Surgery.

Importance Adjuvant chemotherapy offers a survival benefit to a number of staging scenarios in non–small-cell lung cancer. Variable recovery from lung cancer surgery may delay a patient’s ability to tolerate adjuvant chemotherapy, yet the urgency of chemotherapy initiation is unclear. Objective To assess differences in survival according to the time interval between non–small-cell lung cancer resection and the initiation of postoperative chemotherapy to determine the association between adjuvant treatment timing and efficacy. Design, Setting, and Participants This retrospective observational study examined treatment-naive patients with completely resected non–small-cell lung cancer who received postoperative multiagent chemotherapy between 18 and 127 days after resection between January 2004 and December 2012. The study population was limited to patients with lymph node metastases, tumors 4 cm or larger, or local extension. Patients were identified from the National Cancer Database, a hospital-based tumor registry that captures more than 70% of incident lung cancer cases in the United States. The association between time to initiation of adjuvant chemotherapy and survival was evaluated using Cox models with restricted cubic splines. Exposures Adjuvant chemotherapy administered at different time points after surgery. Main Outcomes and Measures Effectiveness of adjuvant chemotherapy according to time to initiation after surgery. Results A total of 12 473 patients (median [interquartile range] age, 64 [57-70] years) were identified: 3073 patients (25%) with stage I disease; 5981 patients (48%), stage II; and 3419 patients (27%), stage III. A Cox model with restricted cubic splines identified the lowest mortality risk when chemotherapy was started 50 days postoperatively (95% CI, 39-56 days). Initiation of chemotherapy after this interval (57-127 days; ie, the later cohort) did not increase mortality (hazard ratio [HR], 1.037; 95% CI, 0.972-1.105; P = .27). Furthermore, in a Cox model of 3976 propensity-matched pairs, patients who received chemotherapy during the later interval had a lower mortality risk than those treated with surgery only (HR, 0.664; 95% CI, 0.623-0.707; P < .001). Conclusions and Relevance In the National Cancer Database, adjuvant chemotherapy remained efficacious when started 7 to 18 weeks after non–small-cell lung cancer resection. Patients who recover slowly from non–small-cell lung cancer surgery may still benefit from delayed adjuvant chemotherapy started up to 4 months after surgery.

Surgical Considerations in Tracheal and Carinal Resection

Surgical resection of the trachea and carina requires a highly specialized team of thoracic surgeons, anesthesiologists, and operative support staff because of the complex nature of these procedures. Improvements in the design and application of low-pressure cuffed endotracheal tubes and extensive experience in tracheal reconstruction have reduced ventilation associated airway injury and facilitated new techniques for repair. Even with these improvements, tracheal surgery for stenosis is still commonplace, as is the need for resection in cases of benign and malignant lesions of the airway. Surgical consideration of malignant lesions involving the carina remains a challenge for localized cancer and more commonly for tumors arising from the lung with radial involvement of the main bronchus and carina. These patients often require pneumonectomy during carinal resection with complicated reconstructive efforts to establish airway continuity. Careful patient selection, operative planning, and execution by both the thoracic surgery and anesthesia teams are required for optimal results.

Defining outcomes of patients with clinical stage I small cell lung cancer upstaged at surgery

BACKGROUND A proportion of patients with clinical stage I small cell lung cancer (SCLC) will be upstaged following surgical resection. The existing data regarding the management of upstaged SCLC patients and guidelines for their treatment remains sparse. The primary objective was to describe the impact of pathologic upstaging following surgical resection. METHODS The National Cancer Database was queried for patients with clinical stage I SCLC (cT1-2a,N0,M0) who underwent resection with curative intent followed by adjuvant therapy, excluding patients who underwent surgery alone. Clinical and pathologic T, N, and M staging were compared to identify patients that were upstaged. RESULTS Four-hundred and seventy-seven patients were identified with clinical stage I SCLC. Pathologic upstaging occurred in 25% (117). Of those upstaged, 30% (35) were due to a higher pathologic T descriptor and 81% (95) were due to the presence of nodal disease. Overall 5-year survival was significantly worse for upstaged patients compared with those patients who remained a pathologically stage I (36% vs 52%, p<0.001). Among patients with positive lymph node involvement, adjuvant chemotherapy and radiation therapy was associated a significantly improved 5-year survival compared to adjuvant chemotherapy alone (20% vs 55%, respectively, p<0.01). The use of adjuvant chemotherapy and radiation therapy in patients with nodal disease after surgical resection was an independent predictor of improved survival (HR 0.36, 95% CI 0.18-0.73, p<0.01). CONCLUSIONS Pathologic upstaging is common after surgical resection of stage I SCLC, and is associated with significantly inferior survival. These data provide evidence that recommend the use of adjuvant chemotherapy and radiation therapy in the setting of nodal upstaging after resection of clinical stage I SCLC patients.

Management of Early Stage Non–Small Cell Lung Cancer in High-Risk Patients

The preferred treatment of stage I non-small cell lung cancer (NSCLC) is anatomic resection with systematic mediastinal lymph node evaluation. However, 20% of patients with operable lung cancer are not candidates for this type of resection. Recent advancements in radiology-guided technologies have expanded the treatment options for high-risk patients with early-stage NSCLC. There has simultaneously been resurgence in interest and refinement of indications and techniques for sublobar resection in this population. While these treatments appear to have decreased peri-procedural morbidity and mortality, their oncologic efficacy compared to that of lobectomy remains to be determined.

Timing of Surgery after Neoadjuvant Chemoradiation in Locally Advanced Non–Small Cell Lung Cancer

Introduction: A subset of patients with potentially resectable clinical stage IIIA NSCLC are managed with trimodality therapy. However, little data exist to guide the timing of surgery after neoadjuvant therapy. This study examined whether the time interval between neoadjuvant chemoradiation (NCRT) and surgical resection affects overall survival. Methods: Patients with clinical stage IIIA disease (T1–3 N2) NSCLC who underwent NCRT were identified in the National Cancer Data Base (NCDB) between 2004 and 2012 and categorized on the basis of the interval between chemoradiation and surgery (0 to ≤3, >3 to ≤6, >6 to ≤9, and >9 to ≤12 weeks). Other clinical stages were excluded. The Kaplan‐Meier method and log‐rank tests were used to compare overall survival rates, and a bootstrapped Cox proportional hazards model was used to determine significant contributors to overall survival. Results: Of the 1623 patients identified, 7.9% underwent an operation 0 to 3 weeks or less after NCRT, 50.5% underwent an operation greater than 3 and less than or equal to 6 weeks after NCRT, 31.9% underwent an operation greater than 6 and less than or equal to 9 weeks after NCRT, and 9.6% underwent an operation greater than 9 and less than or equal to 12 weeks after NCRT. Multivariate survival analysis demonstrated no significant difference in survival in those who underwent an operation within 6 weeks of NCRT. However, significant drops in overall survival were observed in those who had an operation greater than 6 and less than or equal to 9 weeks after NCRT (hazard ratio = 1.33, 95% confidence interval: 1.01–1.76, p = 0.043) and greater than 9 and less than or equal to 12 weeks after NCRT (hazard ratio = 1.44, 95% confidence interval: 1.04–2.01, p = 0.030). Conclusions: The findings from this retrospective study suggest that overall survival may be significantly lower in patients with clinical stage IIIA N2 NSCLC who undergo an operation later than 6 weeks after NCRT. These results discourage unnecessary delays in surgery.

Hospital Volume and Outcomes of Robot-Assisted Lobectomies

Background: The positive impact of hospital operative volume on outcomes following video‐assisted thoracoscopic surgery has been established. The goal of this study was to determine whether or not this volume/outcome relationship translates to robot‐assisted thoracoscopic surgery (RobATS) lobectomy. Methods: Patients who underwent RobATS lobectomy were identified between 2008 and 2013 in the Healthcare Cost and Utilization Project National Inpatient Sample database. Hospital volume, as well as demographic, clinical, and health‐care system‐related factors were selected as potential predictors of outcomes. Outcome variables included length of stay (LOS), inpatient mortality, and complications. Hospitals were designated by quartiles according to annual case volume, with very low‐volume defined as the first quartile and high‐volume defined as the fourth quartile. Regression analyses were used to identify independent predictors of the outcomes of interest. Results: A total of 8,253 RobATS lobectomies were identified. Compared with very low‐volume centers, patients at high‐volume hospitals had a shorter mean LOS (5.8 vs 6.5 days; P = .001) and decreased mortality rate (0.5% vs 1.9%; P < .001) but more complications (28.1% vs 27.6%; P = .025). In multivariable analysis, high hospital volume was prognostic for decreased mortality (OR, 0.134; P< .001) and shorter LOS (0.2 days; SE, 0.05; P<.001). Hospital volume was not prognostic for any complications, including pulmonary, cardiovascular, intraoperative, or infectious complications. Conclusions: Undergoing lobectomy at high‐volume RobATS centers confers favorable mortality and LOS outcomes compared with very low‐volume centers. In this relatively early phase of adoption of RobATS, the long‐term clinical impact of differences in LOS as well as the lack of clinical impact on the incidence of complications remain to be determined more definitively. However, the beneficial effect of volume on mortality suggests a need for the careful adoption of this promising technology.

Anesthesia for nonintubated video-assisted thoracic surgery.

Purpose of review This review focuses primarily on nonintubated video-assisted thoracic surgery (NIVATS), and discusses advantages, indications, anesthetic techniques, and approaches to intraoperative crisis management. Recent findings Advancements in endoscopic, endovascular, and robotic techniques have expanded the range of surgical procedures that can be performed in a minimally invasive fashion. For thoracic operations in particular, video-assisted thoracic surgery (VATS) has largely replaced traditional thoracotomy, and continued technical development has made surgical access into the pleural space even less disruptive. As a consequence, the need for general anesthesia and endotracheal intubation has been re-examined, such that regional or epidural analgesia may be sufficient for cases where lung collapse can be accomplished with spontaneous ventilation and an open hemithorax. This concept of NIVATS has gained popularity, and in some centers has now expanded to include procedures involving placement of multiple ports. Although still relatively uncommon at present, a small number of randomized trials and meta-analyses have indicated some advantages, suggesting that NIVATS may be a desirable alternative to general anesthesia with endotracheal intubation for specific indications. Summary Although anesthesia for NIVATS is associated with some of the same risks as general anesthesia with endotracheal intubation, NIVATS can be successfully performed in carefully selected patients.