Publications by authors named "Gaetano Rocco"

308 Publications

Contrast-enhanced computed tomography prior to percutaneous transthoracic needle biopsy reduces the incidence of hemorrhage.

Ann Transl Med 2021 Feb;9(4):288

Department of Respiratory Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, China.

Background: Hemorrhage is the second most common complication of percutaneous transthoracic needle biopsy (PTNB), and at present, there is no effective prevention strategy. Contrast-enhanced computed tomography (CECT) has the advantage of clearly visualizing blood supply within the lesion and aiding in the imaging of blood vessels, which can reduce hemorrhage complicating PTNB. As no large-sample studies were evaluating whether CECT could reduce hemorrhage, we conducted the present retrospective study.

Methods: From November 2011 to February 2016, 1,282 biopsies at Jinling Hospital were retrospectively reviewed; 555 underwent CECT, and 727 underwent non-contrast computed tomography (CT). Factors associated with hemorrhage were defined, and hemorrhage rates were compared between the 2 groups.

Results: We found that pre-biopsy CECT was associated with a reduced incidence of biopsy-related hemorrhage compared to non-contrast CT (16.4% 23.1%, P=0.003). Propensity score matching (PSM) analysis also showed that the incidence of hemorrhage in the CECT group was lower than that of the non-contrast CT group at a ratio of 1:1 (P=0.039), 1:2 (P=0.028), or 1:3 (P=0.013). In the multivariate analysis, CECT before PTNB was found to be significantly associated with a reduced risk of hemorrhage [odds ratio (OR): 0.671, 95% confidence interval (CI): 0.499-0.902, P=0.008]. Puncture position, lesion size, depth of needle tract, and the number of punctures were also found to be associated with hemorrhage (all P<0.05).

Conclusions: Compared with non-contrast CT, CECT significantly reduced the risk of post-biopsy pulmonary hemorrhage, which suggests that CECT should be performed before PTNB.
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http://dx.doi.org/10.21037/atm-20-4384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944326PMC
February 2021

Canyons and Volcanoes: The Effects of Radiation on the Chest Wall.

Ann Thorac Surg 2021 Mar 6. Epub 2021 Mar 6.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Tumors involving the sternum often require complete removal of the bony structure to achieve cure and prevent recurrence. The type and extent of reconstruction must be carefully selected. Full-thickness sternal defects often necessitate semirigid or rigid biocompatible prostheses and carefully transposed myocutaneous flaps. Superimposed infection on radiation-induced cancer or osteoradionecrosis involving the sternum is also observed, and optimal treatment relies on an experienced multidisciplinary team. We report the successful management of two cases of sternal involvement after radiation: a canyon-like lesion and a volcano-like lesion.
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http://dx.doi.org/10.1016/j.athoracsur.2021.03.003DOI Listing
March 2021

The American College of Surgeons Surgical Risk Calculator performs well for pulmonary resection: A validation study.

J Thorac Cardiovasc Surg 2021 Jan 21. Epub 2021 Jan 21.

Thoracic Service, Department of Thoracic Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Objective: The American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator (NSQIP SRC) was developed to estimate the risk of postoperative morbidity and mortality within 30 days of an operation. We sought to externally evaluate the performance of the NSQIP SRC for patients undergoing pulmonary resection.

Methods: Patients undergoing pulmonary resection at our center between January 2016 and December 2018 were included. Using data from our institution's prospectively maintained Society of Thoracic Surgeons General Thoracic Database, we identified 2514 patients. We entered requisite patient demographic information, preoperative risk factors, and procedural details into the online calculator. Predicted performance of the calculator versus observed outcomes was assessed by discrimination (concordance index [C-index]) and calibration.

Results: The observed and predicted probabilities of any complication were 8.3% and 9.9%, respectively, and of serious complications were 7.4% and 9.2%, respectively. Observed and predicted 30-day mortality were 0.5% and 0.9%, respectively. The C-index for readmission was 0.644; the C-indices corresponding to all other outcomes in the NSQIP SRC ranged from 0.703 to 0.821. Calibration curves indicated excellent calibration for all binary end points, with the exception of renal failure (predicted underestimated observed probabilities), discharge to a nursing or rehabilitation facility (overestimated), and sepsis (overestimated). Correlation between predicted and observed length of stay was moderate (Spearman coefficient, 0.562), and calibration was good.

Conclusions: Except for readmission, renal failure, discharge to a location other than home, and sepsis, the NSQIP SRC can be used to reasonably predict postoperative complications in patients undergoing pulmonary resection.
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http://dx.doi.org/10.1016/j.jtcvs.2021.01.036DOI Listing
January 2021

Mutation Is Associated with Increased Risk of Recurrence in Surgically Resected Lung Adenocarcinoma.

Clin Cancer Res 2021 Feb 16. Epub 2021 Feb 16.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: is the most common mutation in primary lung adenocarcinoma. Phase I clinical trials have demonstrated encouraging clinical activity of inhibitors in the metastatic setting. We investigated disease-free survival (DFS) and tumor genomic features in patients with surgically resected -mutant lung adenocarcinoma.

Experimental Design: Patients who underwent resection of stage I-III lung adenocarcinoma and next-generation sequencing (NGS) were evaluated. Exclusion criteria were receipt of induction therapy, incomplete resection, and low-quality NGS. Mutations were classified as wild-type (), G12C (), or non-G12C (). DFS was compared between groups using the log-rank test; factors associated with DFS were assessed using Cox regression. Mutual exclusivity and cooccurrence, tumor clonality, and mutational signatures were assessed.

Results: In total, 604 patients were included: 374 (62%), 95 (16%), and 135 (22%). Three-year DFS was not different between -mutant and tumors. However, 3-year DFS was worse in patients with than tumors (log-rank = 0.029). tumors had more lymphovascular invasion (51% vs. 37%; = 0.032) and higher tumor mutation burden [median (interquartile range), 7.0 (5.3-10.8) vs. 6.1 (3.5-9.7); = 0.021], compared with tumors. mutation was independently associated with worse DFS on multivariable analysis. Our DFS findings were externally validated in an independent The Cancer Genome Atlas cohort.

Conclusions: mutations are associated with worse DFS after complete resection of stage I-III lung adenocarcinoma. These tumors harbor more aggressive clinicopathologic and genomic features than other -mutant tumors. We identified a high-risk group for whom inhibitors may be investigated to improve survival.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4772DOI Listing
February 2021

Complex chest wall surgery to prevent vascular complications after immunotherapy and radiation treatment.

JTCVS Tech 2020 Dec 15;4:329-331. Epub 2020 Aug 15.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.

Chest wall surgery after immunotherapy and radiation can provide cure, prevent catastrophic complications, reduce the duration of immunotherapy, and allow verification of depth of response to therapy.
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http://dx.doi.org/10.1016/j.xjtc.2020.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861462PMC
December 2020

Bias Against Complex Lung Cancer Surgery.

Ann Thorac Surg 2021 Jan 4. Epub 2021 Jan 4.

Department of Surgery, Thoracic Service, Memorial Sloan Kettering Cancer Center, New York, NY.

Background: Lung cancer remains a major public health problem. There remain differences in mortality among socioeconomic and racial groups. Using the STS GTS database, we attempted to determine whether there were differences in treatment choices by thoracic surgeons based on patient's race or insurance.

Methods: Using data from 2012-2017, we analyzed the data from 75,774 patients with a diagnosis of lung cancer who had complete information on race and/or insurance was available and underwent a pulmonary resection. We categorized 66,614 (87.9%) operations into "standard" (lobectomy, bilobectomy, or wedge excision) and 9,160 (12.1%) into complex (pneumonectomy, sleeve or bronchoplastic resection, segmentectomy, or Pancoast resection) operations. Univariate and multiple variable logistic regression models were used to assess associations with receipt of a complex operation.

Results: Patients with private insurance had a higher incidence of complex operations (14.4%) than patients with government insurance (11.6%) (p<0.0001). We also found a higher incidence of complex operations in white patients (12.2%) compared to non-white patients (11.3%) (p=0.0054). On multivariate analysis patients with private insurance were significantly more likely to have a complex operation (odds ratio 1.08, p<0.03) and non-Caucasian patients were less likely to have a complex operation (odds ratio 0.93, p=0.04) respectively.

Conclusions: In this cohort of patients from the STS GTS database, white patients and those with private insurance had a higher incidence of complex operations. Many factors affect the decision to proceed with a complex thoracic surgical operation; type of medical insurance and race may represent two of them.
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http://dx.doi.org/10.1016/j.athoracsur.2020.12.019DOI Listing
January 2021

A Genomic-Pathologic Annotated Risk Model to Predict Recurrence in Early-Stage Lung Adenocarcinoma.

JAMA Surg 2021 Feb 10;156(2):e205601. Epub 2021 Feb 10.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Recommendations for adjuvant therapy after surgical resection of lung adenocarcinoma (LUAD) are based solely on TNM classification but are agnostic to genomic and high-risk clinicopathologic factors. Creation of a prediction model that integrates tumor genomic and clinicopathologic factors may better identify patients at risk for recurrence.

Objective: To identify tumor genomic factors independently associated with recurrence, even in the presence of aggressive, high-risk clinicopathologic variables, in patients with completely resected stages I to III LUAD, and to develop a computational machine-learning prediction model (PRecur) to determine whether the integration of genomic and clinicopathologic features could better predict risk of recurrence, compared with the TNM system.

Design, Setting, And Participants: This prospective cohort study included 426 patients treated from January 1, 2008, to December 31, 2017, at a single large cancer center and selected in consecutive samples. Eligibility criteria included complete surgical resection of stages I to III LUAD, broad-panel next-generation sequencing data with matched clinicopathologic data, and no neoadjuvant therapy. External validation of the PRecur prediction model was performed using The Cancer Genome Atlas (TCGA). Data were analyzed from 2014 to 2018.

Main Outcomes And Measures: The study end point consisted of relapse-free survival (RFS), estimated using the Kaplan-Meier approach. Associations among clinicopathologic factors, genomic alterations, and RFS were established using Cox proportional hazards regression. The PRecur prediction model integrated genomic and clinicopathologic factors using gradient-boosting survival regression for risk group generation and prediction of RFS. A concordance probability estimate (CPE) was used to assess the predictive ability of the PRecur model.

Results: Of the 426 patients included in the analysis (286 women [67%]; median age at surgery, 69 [interquartile range, 62-75] years), 318 (75%) had stage I cancer. Association analysis showed that alterations in SMARCA4 (clinicopathologic-adjusted hazard ratio [HR], 2.44; 95% CI, 1.03-5.77; P = .042) and TP53 (clinicopathologic-adjusted HR, 1.73; 95% CI, 1.09-2.73; P = .02) and the fraction of genome altered (clinicopathologic-adjusted HR, 1.03; 95% CI, 1.10-1.04; P = .005) were independently associated with RFS. The PRecur prediction model outperformed the TNM-based model (CPE, 0.73 vs 0.61; difference, 0.12 [95% CI, 0.05-0.19]; P < .001) for prediction of RFS. To validate the prediction model, PRecur was applied to the TCGA LUAD data set (n = 360), and a clear separation of risk groups was noted (log-rank statistic, 7.5; P = .02), confirming external validation.

Conclusions And Relevance: The findings suggest that integration of tumor genomics and clinicopathologic features improves risk stratification and prediction of recurrence after surgical resection of early-stage LUAD. Improved identification of patients at risk for recurrence could enrich and enhance accrual to adjuvant therapy clinical trials.
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http://dx.doi.org/10.1001/jamasurg.2020.5601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758824PMC
February 2021

Improved Preoperative Risk-Assessment Tools Are Needed to Guide Informed Decision-Making Before Esophagectomy.

Ann Surg 2020 Dec 18;Publish Ahead of Print. Epub 2020 Dec 18.

Department of Surgery, New York Presbyterian Hospital-Weill Cornell Medicine, New York, NY Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.

Objective: We sought to evaluate the performance of two commonly used prediction models for postoperative morbidity in patients undergoing open and minimally invasive esophagectomy.

Summary Background Data: Patients undergoing esophagectomy have a high risk of postoperative complications. Accurate risk assessment in this cohort is important for informed decision-making.

Methods: We identified patients who underwent esophagectomy between January 2016 and June 2018 from our prospectively maintained database. Predicted morbidity was calculated using the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) Surgical Risk Calculator (SRC) and a 5-factor NSQIP-derived frailty index. Performance was evaluated using concordance index (C-index) and calibration curves.

Results: In total, 240 consecutive patients were included for analysis. Most patients (85%) underwent Ivor Lewis esophagectomy. The observed overall complication rate was 39%; the observed serious complication rate was 33%. The SRC did not identify risk of complications in the entire cohort (C-index, 0.553), patients undergoing open esophagectomy (C-index, 0.569), or patients undergoing minimally invasive esophagectomy (C-index, 0.542); calibration curves showed general underestimation. Discrimination of the SRC was lowest for reoperation (C-index, 0.533) and highest for discharge to a facility other than home (C-index, 0.728). Similarly, the frailty index had c-index of 0.513 for discriminating any complication, 0.523 for serious complication, and 0.559 for readmission.

Conclusions: SRC and frailty index did not adequately predict complications after esophagectomy. Procedure-specific risk-assessment tools are needed to guide shared patient-physician decision-making in this high-risk population.
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http://dx.doi.org/10.1097/SLA.0000000000004715DOI Listing
December 2020

Is routine chest radiography necessary after endobronchial ultrasound-guided fine needle aspiration?

Ann Thorac Surg 2020 Oct 20. Epub 2020 Oct 20.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065. Electronic address:

Background: Chest radiography (CXR) is routinely performed after endobronchial ultrasound-guided fine needle aspiration (EBUS-FNA) to detect clinically occult pneumothorax. As the established rate of postprocedure pneumothorax is low, we sought to determine whether this practice can be safely eliminated and to determine potential cost reduction with omission of routine chest radiography.

Methods: Patients who underwent EBUS-FNA between January 1, 2017, and December 31, 2018 were retrospectively identified. Patient factors were summarized using descriptive statistics. Outcomes were compared using χ, Fisher's exact, and ANOVA tests. Univariate regression analysis was used to identify factors predictive of postprocedure pneumothorax.

Results: 757 patients were included for study. 72.4% (548/757) underwent routine CXR in the postanesthesia care unit (PACU). 1.5% (11/757) developed clinically relevant or radiographically evident pneumothorax. Of patients who underwent CXR, 0.5% (3/548) required unplanned admission for postprocedure pneumothorax, and 0.2% (1/548) required tube thoracostomy. Of 209 patients who did not undergo CXR, none developed a clinically evident pneumothorax. In total, only 1 patient (0.1%) experienced symptomatic pneumothorax. The pneumothorax event rate was so low that no association with demographic or clinical factors and no predictive factors could be identified. The number of patients needed to be screened by CXR to identify 1 patient requiring deviation from routine management is 183. The potential total cost reduction if routine CXR were eliminated was $33,950.

Conclusions: The extremely low rate of postprocedure pneumothorax precluded informative statistical analysis. Routine CXR following EBUS-FNA may not be necessary, and omission of routine CXR may confer a cost savings.
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http://dx.doi.org/10.1016/j.athoracsur.2020.08.033DOI Listing
October 2020

External validation of surgical risk preoperative assessment system (SURPAS) in pulmonary resection.

Ann Thorac Surg 2020 Oct 16. Epub 2020 Oct 16.

Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Background: Accurate preoperative risk assessment is necessary for informed decision-making for patients and surgeons. Several preoperative risk calculators are available, but few have been examined in the general thoracic surgical patient population. The Surgical Risk Preoperative Assessment System (SURPAS), a risk-assessment tool applicable to a wide spectrum of surgical procedures, was developed to predict the risks of common adverse postoperative outcomes using a parsimonious set of preoperative input variables. We sought to externally validate the performance of SURPAS for postoperative complications in patients undergoing pulmonary resection.

Methods: Between January 2016 and December 2018, 2514 patients underwent pulmonary resection at our center. Using data from our institution's prospectively maintained database, we calculated the predicted risks of 12 categories of postoperative outcomes using the latest version of SURPAS. Performance of SURPAS against observed patient outcomes was assessed by discrimination (concordance index [C-index]) and calibration (calibration curves).

Results: The discrimination ability of SURPAS was moderate across all outcomes (C-indices, 0.640-0.788). Calibration curves indicated good calibration for all outcomes except infectious and cardiac complications, discharge to a location other than home, and mortality (all overestimated by SURPAS).

Conclusions: SURPAS demonstrates outcomes for pulmonary resections with reasonable predictive ability. Discretion should be applied when assessing risk for postoperative infectious and cardiac complications, discharge to a location other than home, and mortality. Although the parsimonious nature of SURPAS is one of its strengths, its performance might be improved by including additional factors known to influence outcomes following pulmonary resection, such as sex and pulmonary function.
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http://dx.doi.org/10.1016/j.athoracsur.2020.08.023DOI Listing
October 2020

Performance Comparison Between SURPAS and ACS NSQIP Surgical Risk Calculator in Pulmonary Resection.

Ann Thorac Surg 2020 Oct 16. Epub 2020 Oct 16.

Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Background: Accurate preoperative risk assessment is critical for informed decision making. The Surgical Risk Preoperative Assessment System (SURPAS) and the National Surgical Quality Improvement Program (NSQIP) Surgical Risk Calculator (SRC) predict risks of common postoperative complications. This study compares observed and predicted outcomes after pulmonary resection between SURPAS and NSQIP SRC.

Methods: Between January 2016 and December 2018, 2514 patients underwent pulmonary resection and were included. We entered the requisite patient demographics, preoperative risk factors, and procedural details into the online NSQIP SRC and SURPAS formulas. Performance of the prediction models was assessed by discrimination and calibration.

Results: No statistically significant differences were found between the 2 models in discrimination performance for 30-day mortality, urinary tract infection, readmission, and discharge to a nursing or rehabilitation facility. The ability to discriminate between a patient who will develop a complication and a patient who will not was statistically indistinguishable between NSQIP and SURPAS, except for renal failure. With a C index closer to 1.0, the NSQIP performed significantly better than the SURPAS SRC in discriminating risk of renal failure (C index, 0.798 vs 0.694; P = .003). The calibration curves of predicted and observed risk for each model demonstrate similar performance with a tendency toward overestimation of risk, apart from renal failure.

Conclusions: Overall, SURPAS and NSQIP SRC performed similarly in predicting outcomes for pulmonary resections in this large, single-center validation study with moderate to good discrimination of outcomes. Notably, SURPAS uses a smaller set of input variables to generate the preoperative risk assessment. The addition of thoracic-specific input variables may improve performance.
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http://dx.doi.org/10.1016/j.athoracsur.2020.08.021DOI Listing
October 2020

Thoracic Metastasectomy in Germ Cell Tumor Patients Treated With First-line Versus Salvage Therapy.

Ann Thorac Surg 2021 04 31;111(4):1141-1149. Epub 2020 Aug 31.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Background: Outcomes after thoracic metastasectomy in patients with testicular germ cell tumors (GCTs) who received first-line chemotherapy alone versus salvage chemotherapy remain unexplored.

Methods: We conducted a retrospective review of patients who underwent thoracic metastasectomy for residual GCT between 1997 and 2019 at a single tertiary center. Factors associated with progression-free survival (PFS) and overall survival (OS) were assessed using multivariable Cox regression.

Results: Of 251 patients, 191 received only first-line chemotherapy (76%) and 60 received salvage chemotherapy (24%). Median follow-up was 3.45 years (interquartile range, 1-7.93 years). Among first-line patients without teratoma in the primary tumor, with necrosis in the retroperitoneal nodes and normalized or decreasing serum tumor markers, 17 of 20 had intrathoracic necrosis (85%). Among first-line and salvage patients, respectively, 5-year OS was 93% (95% confidence interval [CI], 89%-98%) versus 63% (95% CI, 51%-78%; P < .001), and 5-year PFS was 69% (95% CI, 62%-77%) versus 40% (95% CI, 29%-56%; P < .001). On multivariable analysis, multiple lung lesions (hazard ratio [HR] = 3.01; 95% CI, 1.50-6.05; P = .002) and brain metastasis (HR = 4.51; 95% CI, 2.34-8.73; P < .001) at diagnosis, salvage chemotherapy (HR = 1.85; 95% CI, 1.10-3.13; P = .021), teratoma (HR = 2.68; 95% CI, 1.50-4.78; P = .001), and viable malignancy (HR = 4.34; 95% CI, 2.44-7.71; P < .001) were associated with worse PFS.

Conclusions: Although GCT patients treated with salvage chemotherapy followed by thoracic metastasectomy have more aggressive disease and poorer PFS, they can achieve encouraging OS. Our findings highlight the integral role of aggressive thoracic metastasectomy in the treatment of GCT patients with residual thoracic disease after first line-only or salvage chemotherapy.
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http://dx.doi.org/10.1016/j.athoracsur.2020.06.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914302PMC
April 2021

How Effective Is Neoadjuvant Therapy Followed by Surgery for Pathologic Single-Station N2 Non-Small Cell Lung Cancer?

Semin Thorac Cardiovasc Surg 2021 Spring;33(1):206-216. Epub 2020 Aug 25.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

The optimal treatment strategy for pathologic single-station N2 (pN2a1) non-small cell lung cancer (NSCLC)-surgery first followed by adjuvant treatment (SF) or neoadjuvant therapy followed by surgery (NS)-remains unclear. We compared disease-free survival (DFS) and overall survival (OS) after NS versus SF for pN2a1 NSCLC. We retrospectively identified patients with pN2a1 NSCLC resected between 2000 and 2018. Patients in the SF group had cN0 disease and were treated with surgery before adjuvant chemotherapy; patients in the NS group had known preoperative nodal disease, cN2 disease, and were treated with neoadjuvant therapy before surgery. The matching-weights procedure was applied to generate a cohort with similar characteristics between groups. DFS and OS were calculated using the Kaplan-Meier approach and compared between groups using weighted log-rank test and Cox proportional hazards models. We identified 227 patients with pN2a1 disease: 121 treated with SF and 106 with NS. After the matching-weights procedure, 5- and 10-year DFS were 45% and 27% for SF versus 26% and 21% for NS (log-rank P = 0.056; hazard ratio [HR], 1.61; 95% confidence interval [CI], 0.98-2.65); 5- and 10-year OS were 49% and 30% for SF versus 43% and 20% for NS (log-rank P = 0.428; HR, 1.24; 95% CI, 0.67-2.28). SF and NS for pN2a1 NSCLC resulted in similar survival. A study comparing SF for known preresectional pN2a1 with occult pN2a1 disease could be a next step. Further investigation of SF for known N2a1 versus occult pN2a1 disease could power a clinical trial focused on N2a NSCLC.
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http://dx.doi.org/10.1053/j.semtcvs.2020.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904958PMC
August 2020

TEAD4 promotes tumor development in patients with lung adenocarcinoma via ERK signaling pathway.

Biochim Biophys Acta Mol Basis Dis 2020 12 12;1866(12):165921. Epub 2020 Aug 12.

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address:

Objective: Whether TEAD4 itself plays a vital role in the tumorigenesis and development of lung adenocarcinoma remains unclear. In our study, we aim to investigate the expression pattern and biological functions of TEAD4 and further investigate the potential mechanisms.

Methods: Clinical tumor and paired normal samples were collected for preparing tissue microarray. Western blot and immunohistochemical (IHC) staining of TEAD4 expression in these tissues were conducted to explore the expression pattern. Moreover, A549 cell line was select for investigating the function of TEAD4 for lung adenocarcinoma in vitro and in vivo. RNA sequencing was finally performed to further detect the potential downstream genes.

Results: The elevated TEAD4 expression level was observed in tumor tissues and the patients with higher TEAD4 expression tended to have worse overall survival. The knockdown of TEAD4 inhibits A549 cells proliferation ability and migration ability. A total of 431 differentially expressed genes (DEGs), including 239 down-regulated genes and 191 up-regulated genes, were finally identified and some of DEGs were validated. Moreover, knockdown of TEAD4 led to the down-regulation of pERK, which maybe the potential TEAD4-targeted signaling pathway to play the pro-tumorigenic function.

Conclusions: The expression level of TEAD4 is high in lung adenocarcinoma tumor tissues and positively associated with worse prognosis. Up-regulation of TEAD4 may lead to excessive transcription and phosphorylation of ERK proteins and therefore accelerates the process of tumor development. Our results demonstrate that overexpression of TEAD4 is a new mechanism of dysregulation of Hippo pathway.
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http://dx.doi.org/10.1016/j.bbadis.2020.165921DOI Listing
December 2020

The Underlying Tumor Genomics of Predominant Histologic Subtypes in Lung Adenocarcinoma.

J Thorac Oncol 2020 12 10;15(12):1844-1856. Epub 2020 Aug 10.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York; Fiona and Stanley Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Introduction: The purpose of the study is to genomically characterize the biology and related therapeutic opportunities of prognostically important predominant histologic subtypes in lung adenocarcinoma (LUAD).

Methods: We identified 604 patients with stage I to III LUAD who underwent complete resection and targeted next-generation sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform. Tumors were classified according to predominant histologic subtype and grouped by architectural grade (lepidic [LEP], acinar or papillary [ACI/PAP], and micropapillary or solid [MIP/SOL]). Associations among clinicopathologic factors, genomic features, mutational signatures, and recurrence were evaluated within subtypes and, when appropriate, quantified using competing-risks regression, with adjustment for pathologic stage and extent of resection.

Results: MIP/SOL tumors had higher tumor mutational burden (p < 0.001), fraction of genome altered (p = 0.001), copy number amplifications (p = 0.021), rate of whole-genome doubling (p = 0.008), and number of oncogenic pathways altered ( p < 0.001) as compared with LEP and ACI/PAP tumors. Across all tumors, mutational signatures attributed to APOBEC activity were associated with the highest risk of postresection recurrence: SBS2 (p = 0.021) and SBS13 (p = 0.005). Three oncogenic pathways (p53, Wnt, Myc) were altered with statistical significance in MIP/SOL tumors. Compared with LEP and ACI/PAP tumors, MIP/SOL tumors had a higher frequency of targetable BRAF-V600E mutations (p = 0.046). Among ACI/PAP tumors, alterations in the cell cycle (p < 0.001) and PI3K (p = 0.002) pathways were associated with recurrence; among MIP/SOL tumors, only PI3K alterations were associated with recurrence (p = 0.049).

Conclusions: These results provide the first in-depth assessment of tumor genomic profiling of predominant LUAD histologic subtypes, their associations with recurrence, and their correlation with targetable driver alterations in patients with surgically resected LUAD.
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http://dx.doi.org/10.1016/j.jtho.2020.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704768PMC
December 2020

Intentional Segmentectomy for Clinical T1 N0 Non-small Cell Lung Cancer: Survival Differs by Segment.

Ann Thorac Surg 2021 03 31;111(3):1028-1035. Epub 2020 Jul 31.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Background: Outcomes after segmentectomy compare favorably with those after lobectomy in patients with stage I non-small cell lung cancer (NSCLC). Whether long-term outcomes vary by segmentectomy location is unclear. We investigated whether disease-free survival (DFS) and overall survival (OS) differ by segmentectomy location after intentional segmentectomy for clinical T1 N0 M0 NSCLC.

Methods: Patients who received intentional segmentectomy for cT1 N0 M0 NSCLC from 2000 to 2018 were reviewed. Patients with prior lung cancer, forced expiratory volume in 1 second of less than 50%, or R1/R2 resection were excluded. Segmentectomy groups were left (L) basilar, L segment 6, L lingula, L trisegment; right (R): basilar (R_Bas), segment 6 (R_S6), and R upper. The 5- and 10-year DFS and OS were estimated using Kaplan-Meier and compared between groups using the log-rank test. Factors associated with DFS and OS were determined using Cox proportional hazards models.

Results: In total, 416 patients met the inclusion criteria. Segmentectomy groups differed with regard to surgical approach, mediastinal lymphadenectomy, lymphovascular invasion, tumor histology, margin distance, and adjuvant therapy. Long-term outcomes were worst after R_S6 resection (5-year DFS, 57.6% [95% confidence interval {CI}, 45.7%-72.7%]; OS, 66.3% [95% CI, 54.7%-80.3%]) and best after R_Bas resection (5-year DFS, 77.1% [95% CI, 59.2%-100%]; OS, 79.5% [95% CI, 60.9%-100%]). On multivariable analysis, R_S6 resection was independently associated with DFS vs R_Bas (hazard ratio, 2.89; 95% CI, 1.18-7.08; P = .02) and OS vs R_Bas (hazard ratio, 4.35; 95% CI, 1.61-11.76; P = .004).

Conclusions: Resection of R_S6 is independently associated with worse DFS and OS in patients receiving intentional segmentectomy for cT1 N0 M0 NSCLC and may warrant more extensive resection, complete lymph node dissection, and closer postoperative surveillance.
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http://dx.doi.org/10.1016/j.athoracsur.2020.05.166DOI Listing
March 2021

Unproductive Effects of ALK Gene Amplification and Copy Number Gain in Non-Small-Cell Lung Cancer. ALK Gene Amplification and Copy Gain in NSCLC.

Int J Mol Sci 2020 Jul 12;21(14). Epub 2020 Jul 12.

Department of Mental and Physical Health and Preventive Medicine, Pathology Unit, University of Campania "L. Vanvitelli", 80138 Naples, Italy.

The Anaplastic Lymphoma Kinase (ALK) gene is known to be affected by several genetic alterations, such as rearrangement, amplification and point mutation. The main goal of this study was to comprehensively analyze amplification (-A) and gene copy number gain () in a large cohort of non-small-cell lung cancer (NSCLC) patients in order to evaluate the effects on mRNA and protein expression. locus number status was evaluated in 578 NSCLC cases by fluorescence in situ hybridization (FISH). In addition, ALK immunohistochemistry and ALK mRNA in situ hybridization were performed. Out of 578 cases, 17 cases showed -A. In addition, 14 cases presented K-CNG and 72 cases presented chromosome 2 polyploidy. None of those carrying -A and -CNG showed either ALK immunohistochemical expression or ALK mRNA expression through in situ hybridization. We observed a high frequency of extra copies of the gene. : Our findings demonstrated that -A is not involved in mRNA production and consequently is not involved in protein production; these findings support the hypothesis that -A might not play a role in the pathogenesis of NSCLC, underlining the absence of a specific clinical application.
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http://dx.doi.org/10.3390/ijms21144927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404032PMC
July 2020

Recommendations for Implementing Lung Cancer Screening with Low-Dose Computed Tomography in Europe.

Cancers (Basel) 2020 Jun 24;12(6). Epub 2020 Jun 24.

Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy.

Lung cancer screening (LCS) with low-dose computed tomography (LDCT) was demonstrated in the National Lung Screening Trial (NLST) to reduce mortality from the disease. European mortality data has recently become available from the Nelson randomised controlled trial, which confirmed lung cancer mortality reductions by 26% in men and 39-61% in women. Recent studies in Europe and the USA also showed positive results in screening workers exposed to asbestos. All European experts attending the "Initiative for European Lung Screening (IELS)"-a large international group of physicians and other experts concerned with lung cancer-agreed that LDCT-LCS should be implemented in Europe. However, the economic impact of LDCT-LCS and guidelines for its effective and safe implementation still need to be formulated. To this purpose, the IELS was asked to prepare recommendations to implement LCS and examine outstanding issues. A subgroup carried out a comprehensive literature review on LDCT-LCS and presented findings at a meeting held in Milan in November 2018. The present recommendations reflect that consensus was reached.
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http://dx.doi.org/10.3390/cancers12061672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352874PMC
June 2020

Propensity-matched Analysis Demonstrates Long-term Risk of Respiratory and Cardiac Mortality After Pneumonectomy Compared With Lobectomy for Lung Cancer.

Ann Surg 2020 Jun 11. Epub 2020 Jun 11.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Objective: We sought to quantify and characterize long-term consequences of pneumonectomy, with particular attention to nononcologic mortality.

Summary Of Background Data: Pneumonectomy is associated with profound changes in cardiopulmonary physiology. Studies of long-term outcomes after pneumonectomy typically report generalized measures, such as disease-free and overall survival.

Methods: Patients undergoing lobectomy or pneumonectomy for lung cancer at our institution from 2000 to 2018 were reviewed. Propensity-score matching was performed for 12 clinicopathologic factors. Ninety-day complications and deaths were compared. Five-year cumulative incidence of oncologic and nononcologic mortality were compared using competing risks approaches.

Results: From 3339 lobectomy and 355 pneumonectomy patients identified, we derived 318 matched pairs. At 90 days, rates of overall complications were similar (46% for pneumonectomy vs 43% for lobectomy; P = 0.40), but rates of major complications (21% vs 13%; P = 0.005) and deaths (6.9% vs 1.9%; P = 0.002) were higher the pneumonectomy cohort. The cumulative incidence of oncologic mortality was not significantly different between cohorts (P = 0.9584). However, the cumulative incidence of nononcologic mortality was substantially higher in the pneumonectomy cohort for both date of surgery and 1-year landmark analyses (P < 0.0001 and P = 0.0002, respectively). Forty-five pneumonectomy patients (18%) died of nononcologic causes 1-5 years after surgery; pneumonia (n = 21) and myocardial infarction (n = 10) were the most common causes. In pneumonectomy patients, preexisting cardiac comorbidity and low diffusion capacity of the lungs for carbon monoxide were predictive of nononcologic mortality.

Conclusions: Compared to lobectomy, excess mortality after pneumonectomy extends beyond 1 year and is driven primarily by nononcologic causes. Pneumonectomy patients require lifelong monitoring and may benefit from expeditious assessment and intervention at the initial signs of illness.
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http://dx.doi.org/10.1097/SLA.0000000000004065DOI Listing
June 2020

Commentary: Echoes of war.

Authors:
Gaetano Rocco

J Thorac Cardiovasc Surg 2020 08 10;160(2):594-595. Epub 2020 Apr 10.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2020.03.130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151486PMC
August 2020

Time-varying analysis of readmission and mortality during the first year after pneumonectomy.

J Thorac Cardiovasc Surg 2020 Jul 7;160(1):247-255.e5. Epub 2020 Mar 7.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Objectives: Mortality rates of 5% to 10% after pneumonectomy have remained constant during the last decade. To understand the patterns of outcomes after pneumonectomy, we investigated the time-varying risks of readmission and death during the first postoperative year and examined the contributions of specific causes to these patterns over time.

Methods: We retrospectively reviewed all pneumonectomies for lung cancer at our institution from 2000 to 2018. The time-varying instantaneous risk of all-cause readmission and mortality up to 1 year after pneumonectomy was estimated using parametric analyses and was repeated for each primary cause of readmission (oncologic, infectious, pulmonary, cardiac, or other) and death (oncologic or nononcologic).

Results: In our cohort of 355 patients who underwent pneumonectomy, risk of readmission was highest immediately after discharge and was halved by 14 days. This risk reached a nadir and remained constant from 4 to 8 months, after which it gradually increased. Pulmonary causes accounted for most readmissions within 90 days, after which oncologic causes predominated. Likewise, the overall risk of death was highest immediately after surgery, was halved by 7 days, reached a nadir at 90 days, and then increased throughout the remainder of the first year. All deaths during the first 90 days after surgery were due to nononcologic causes.

Conclusions: Nononcologic causes of readmission and death predominate in the first 90 days after pneumonectomy, after which oncologic causes prevail. We also identify specific causes that pose the highest risk of readmission immediately after discharge. Efforts are warranted to define the effects of specific causes of readmission on overall mortality after pneumonectomy.
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http://dx.doi.org/10.1016/j.jtcvs.2020.02.086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348691PMC
July 2020

Prognostic factors following complete resection of non-superior sulcus lung cancer invading the chest wall.

Eur J Cardiothorac Surg 2020 07;58(1):78-85

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Objectives: Locally advanced non-small-cell lung cancer (NSCLC) with chest wall invasion carries a high risk of recurrence and portends poor survival (30-40% and 20-50%, respectively). No studies have identified prognostic factors in patients who underwent R0 resection for non-superior sulcus NSCLC.

Methods: A retrospective review was conducted for all chest wall resections for NSCLC from 2004 to 2018. Patients with superior sulcus tumours, partial (<1 rib) or incomplete (R1/R2) resection or distant metastasis were excluded. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Cox proportional hazards modelling was used to determine factors associated with DFS and OS.

Results: A total of 100 patients met inclusion criteria. Seventy-three (73%) patients underwent induction therapy, and all but 12 (16%) patients experienced a partial radiological response. A median of 3 ribs was resected (range 1-7), and 67 (67%) patients underwent chest wall reconstruction. The 5-year DFS and OS were 36% and 45%, respectively. Pathological N2 status [hazard ratio (HR) 3.12, confidence interval (CI) 1.56-6.25; P = 0.001], intraoperative blood transfusion (HR 2.24, CI 1.28-3.92; P = 0.005) and preoperative forced vital capacity (per % forced vital capacity, HR 0.97, CI 0.96-0.99; P = 0.013) were associated with DFS. Increasing pathological stage, lack of radiological response to induction therapy (HR 7.35, CI 2.35-22.99; P = 0.001) and cardiovascular comorbidity (HR 2.43, CI 1.36-4.36; P = 0.003) were associated with OS.

Conclusions: We demonstrate that blood transfusion and forced vital capacity are associated with DFS after R0 resection for non-superior sulcus NSCLC, while radiological response to induction therapy greatly influences OS. We confirm that pathological nodal status and pathological stage are reproducible determinants of DFS and OS, respectively.
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http://dx.doi.org/10.1093/ejcts/ezaa027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305839PMC
July 2020

International Delphi survey of the ESTS/AATS/ISTH task force on venous thromboembolism prophylaxis in thoracic surgery: the role of extended post-discharge prophylaxis.

Eur J Cardiothorac Surg 2020 05;57(5):854-859

Department of Surgery, McMaster University, Hamilton, ON, Canada.

Objectives: Venous thromboembolic events can be successfully prevented with chemical and/or mechanical prophylaxis measures, but evidence-based guidelines in thoracic surgery are limited, particularly regarding extended post-discharge prophylaxis. This study attempts to gather an international consensus on best practices to inform the development of such guidelines.

Methods: A series of 3 surveys was distributed to the ESTS/AATS/ISTH (European Society of Thoracic Surgeons, American Association of Thoracic Surgeons, International Society for Thrombosis and Haemostasis) venous thromboembolic events prophylaxis working group starting January 2017. This iterative Delphi consensus process sought to gather a consensus on (i) risk factors; (ii) preferred agents; (iii) duration; and (iv) perceived barriers to an extended thromboprophylaxis approach. Participant responses were expressed on a 10-point scale, and the results were summarized and circulated to all respondents in subsequent rounds. A coefficient of variance of ≤0.3 was identified pre hoc to identify agreement.

Results: A total of 21 Working Group members completed the surveys, composed of 19% non-surgeon thrombosis experts, and 48% from North America. Respondents largely saw agreement regarding risk factors that indicate a need for extended thromboprophylaxis. The group agreed that low-molecular-weight heparin is a suitable agent for use post-discharge, but there was a wide variety in response regarding agents, duration and barriers to extended prophylaxis, where no consensus was observed across the three rounds.

Conclusions: There is strong agreement around indications for extended venous thromboembolic events thromboprophylaxis after thoracic surgery, but there is little consensus regarding the agents and duration to be employed. Further research is required to better inform guideline development.
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http://dx.doi.org/10.1093/ejcts/ezz319DOI Listing
May 2020

Morbidity and mortality of lobectomy or pneumonectomy after neoadjuvant treatment: an analysis from the ESTS database.

Eur J Cardiothorac Surg 2020 04;57(4):740-746

University Hospital Strasbourg, Strasbourg, France.

Objectives: To evaluate the postoperative complications and 30-day mortality rates associated with neoadjuvant chemotherapy before major anatomic lung resections registered in the European Society of Thoracic Surgeons (ESTS) database.

Methods: Retrospective analysis on 52 982 anatomic lung resections registered in the ESTS database (July 2007-31 December 2017) (6587 pneumonectomies and 46 395 lobectomies); 5143 patients received neoadjuvant treatment (9.7%) (3993 chemotherapy alone and 1150 chemoradiotherapy). To adjust for possible confounders, a propensity case-matched analysis was performed. The postoperative outcomes (morbidity and 30-day mortality) of matched patients with and without induction treatment were compared.

Results: 8.2% of all patients undergoing lobectomies and 20% of all patients undergoing pneumonectomies received induction treatment. Lobectomy analysis: propensity score analysis yielded 3824 pairs of patients with and without induction treatment. The incidence of cardiopulmonary complications was higher in the neoadjuvant group (626 patients, 16% vs 446 patients, 12%, P < 0.001), but 30-day mortality rates were similar (71 patients, 1.9% vs 75 patients, 2.0%, P = 0.73). The incidence of bronchopleural fistula and prolonged air leak >5 days were similar between the 2 groups (neoadjuvant: 0.5% vs 0.4%, P = 0.87; 9.2% vs 9.9%, P = 0.27). Pneumonectomy analysis: propensity score analysis yielded 1312 pairs of patients with and without induction treatment. The incidence of cardiopulmonary complications was higher in the treated patients compared to those without neoadjuvant treatment (neoadjuvant 275 cases, 21% vs 18%, P = 0.030). However, the 30-day mortality was similar between the matched groups (neoadjuvant 68 cases, 5.2% vs 5.3%, P = 0.86). Finally, the incidence of bronchopleural fistula was also similar between the 2 groups (neoadjuvant 1.8% vs 1.4%, P = 0.44).

Conclusions: Neoadjuvant chemotherapy is not associated with an increased perioperative risk after either lobectomy or pneumonectomy, warranting a more liberal use of this approach for patients with locally advanced operable lung cancer.
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http://dx.doi.org/10.1093/ejcts/ezz287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825477PMC
April 2020

Methodology and timing of standardization.

J Thorac Dis 2019 Sep;11(Suppl 16):S2050-S2052

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

In the last decade, uniportal VATS has increasingly been used for major lung resections as it has revolutionised the way thoracic surgeons treat pulmonary lesions. Uniportal VATS has represented an authentic innovation in thoracic surgery because it represents an ideal link between reduced morbidity and enhanced recovery. From the first feasibility studies, Uniportal VATS has been assessed in terms of postoperative morbidity, mortality, and overall oncologic value yielding similar outcomes compared to open thoracotomy or three-port VATS. The Uniportal VATS Interest Group (UVIG) is a working group inside the European Society of Thoracic Surgeons (ESTS) with a particular interest in Uniportal VATS as the preferred approach to intrathoracic conditions amenable to surgical diagnosis and treatment. The first aim of UVIG was to define a consensus statement on the indications and techniques of uniportal VATS. The first consensus paper among international experts in uniportal VATS lobectomy was obtained through a Delphi process through three rounds of voting to enhance its validity. The Delphi process was used to define the procedure and to optimise the indications, perioperative management and training of Uniportal VATS. The main features of this process including the anonymity of participants, the iterative process, and, controlled feedback were reported in the consensus statement.
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http://dx.doi.org/10.21037/jtd.2019.02.35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783712PMC
September 2019

What is the European Society of Thoracic Surgeons (ESTS) Uniportal VATS Interest Group (UVIG)?

J Thorac Dis 2019 Sep;11(Suppl 16):S2048-S2049

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (Email:

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http://dx.doi.org/10.21037/jtd.2019.06.55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783706PMC
September 2019

What counts more: the patient, the surgical technique, or the hospital? A multivariable analysis of factors affecting perioperative complications of pulmonary lobectomy by video-assisted thoracoscopic surgery from a large nationwide registry.

Eur J Cardiothorac Surg 2019 Dec;56(6):1097-1103

Department of Thoracic Surgery, University Hospital "Mazzini", Teramo, Italy.

Objectives: Inherent technical aspects of pulmonary lobectomy by video-assisted thoracoscopic surgery (VATS) may limit surgeons' ability to deal with factors predisposing to complications. We analysed complication rates after VATS lobectomy in a prospectively maintained nationwide registry.

Methods: The registry was queried for all consecutive VATS lobectomy procedures from 49 Italian Thoracic Units. Baseline condition, tumour features, surgical techniques, devices, postoperative care, complications, conversions and the reasons thereof were detailed. Univariable and multivariable regressions were used to assess factors potentially linked to complications.

Results: Four thousand one hundred and ninety-one VATS lobectomies in 4156 patients (2480 men, 1676 women) were analysed. The median age-adjusted Charlson index of the patients was 4 (interquartile range 3-6). Grade 1 and 2 and Grade 3-5 complications were observed in 20.1% and in 5.8%, respectively. Ninety-day mortality was 0.55%. The overall conversion rate was 9.2% and significantly higher in low-volume centres (<100 cases, P < 0.001), but there was no significant difference between intermediate- and high-volume centres under this aspect. Low-volume centres were significantly more likely to convert due to issues with difficult local anatomy, but not significantly so for bleeding. Conversion, lower case-volume, comorbidity burden, male gender, adhesions, blood loss, operative time, sealants and epidural analgesia were significantly associated with increased postoperative morbidity.

Conclusions: VATS lobectomy is a safe procedure even in medically compromised patients. An improved classification system for conversions is proposed and prevention strategies are suggested to reduce conversion rates and possibly complications in less-experienced centres.
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http://dx.doi.org/10.1093/ejcts/ezz187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967789PMC
December 2019