Contemporary trends in the level of evidence in general thoracic surgery clinical research.

OBJECTIVES: The large volume of scientific publications and the increasing emphasis on high-quality evidence for clinical decision-making present daily challenges to all clinicians, including thoracic surgeons. The objective of this study was to evaluate the contemporary trend in the level of evidence (LOE) for thoracic surgery clinical research. METHODS: All clinical research articles published between January 2010 and December 2017 in 3 major general thoracic surgery journals were reviewed. Five authors independently reviewed the abstracts of each publication and assigned a LOE to each of them using the 2011 Oxford Centre for Evidence-Based Medicine classification scheme. Data extracted from eligible abstracts included study type, study size, country of primary author and type of study designs. Three auditing processes were conducted to establish working definitions and the process was validated with a research methodologist and 2 senior thoracic surgeons. Intra-class correlation coefficient was calculated to assess inter-rater agreement. Chi-square test and Spearman correlation analysis were then used to compare the LOE between journals and by year of publication. RESULTS: Of 2028 publications reviewed and scored, 29 (1.4%) were graded level I, 75 (3.7%) were graded level II, 471 (23.2%) were graded level III, 1420 (70.2%) were graded level IV and 33 (1.6%) were graded level V (lowest level). Most publications (94.9%) were of lower-level evidence (III-V). There was an overall increasing trend in the lower LOE (P < 0.001). Inter-rater reliability was substantial with 95.5% (95%, confidence interval: 0.95-0.96) level of agreement between reviewers. CONCLUSIONS: General thoracic surgery literature consists mostly of lower LOE studies. The number of lower levels of evidence is dominating the recent publications, potentially indicating a need to increase the commitment to produce and disseminate higher-level evidence in general thoracic surgery.

Expanded human NK cells from lung cancer patients sensitize patients' PDL1-negative tumors to PD1-blockade therapy.

Lung cancer remains the leading cause of cancer death worldwide despite the significant progress made by immune checkpoint inhibitors, including programmed death receptor-1 (PD1)/PD ligand 1 (PDL1)-blockade therapy. PD1/PDL1-blockade has achieved unprecedented tumor regression in some patients with advanced lung cancer. However, the majority of patients fail to respond to PD1/PDL1 inhibitors. The high rate of therapy non-response results from insufficient PDL1 expression on most patients' tumors and the presence of further immunosuppressive mechanisms in the tumor microenvironment. Here, we sensitize non-responding tumors from patients with lung cancer to PD1-blockade therapy using highly cytotoxic expanded natural killer (NK) cells. We uncover that NK cells expanded from patients with lung cancer dismantle the immunosuppressive tumor microenvironment by maintaining strong antitumor activity against both PDL1+ and PDL1- patient tumors. In the process, through a contact-independent mechanism involving interferon γ, expanded NK cells rescued tumor killing by exhausted endogenous TILs and upregulated the tumor proportion score of PDL1 across patient tumors. In contrast, unexpanded NK cells, which are susceptible to tumor-induced immunosuppression, had no effect on tumor PDL1. As a result, combined treatment of expanded NK cells and PD1-blockade resulted in robust synergistic tumor destruction of initially non-responding patient tumors. Thus, expanded NK cells may overcome the critical roadblocks to extending the prodigious benefits of PD1-blockade therapy to more patients with lung cancer and other tumor types.

Correction to: Cardiac surgery in patients with Hemophilia:is it safe?

An amendment to this paper has been published and can be accessed via the original article.

Cardiac surgery in patients with Hemophilia:is it safe?

BACKGROUND: The life expectancy of hemophiliacs is similar to that of the general population. As a result, the prevalence of age-related cardiovascular diseases has increased. We present our experience with hemophilia patients who underwent cardiac surgery in our Medical Center between 2004 and 2019. METHODS: All hemophilia patients who underwent cardiac surgery were identified, and their peri-operative data evaluated retrospectively. RESULTS: Ten patients were identified: six with hemophilia-A, one with hemophilia-B, and three with hemophilia-C (factor XI deficiency). Cardiac procedures included ten coronary artery bypass grafts and one aortic valve replacement. Hemophilia-A and B patients were treated with factor substitution, whereas patients with factor XI deficiency were treated with fresh frozen plasma. One patient died, and one patient suffered from non-active gastrointestinal bleeding. CONCLUSIONS: While major cardiac surgery can be performed safely on patients with hemophilia, a multidisciplinary team approach and strict postoperative monitoring are essential in order to achieve optimal results.

Clinical and Echocardiographic Outcomes after Aortic Valve Repair in Patients with Bicuspid or Unicuspid Aortic Valve.

BACKGROUND: Unicuspid and bicuspid aortic valve (BAV) are congenital cardiac anomalies associated with valvular dysfunction and aortopathies occurring at a young age. OBJECTIVES: To evaluate our experience with aortic valve repair (AVr) in patients with bicuspid or unicuspid aortic valves. METHODS: Eighty patients with BAV or unicuspid aortic valve (UAV) underwent AVr. Mean patient age was 42 ± 14 years and 94% were male. Surgical technique included: aortic root replacement with or without cusp repair in 43 patients (53%), replacement of the ascending aorta at the height of the sino-tubular junction with or without cusp repair in 15 patients (19%), and isolated cusp repair in 22 patients (28%). RESULTS: The anatomical structure of the aortic valve was bicuspid in 68 (85%) and unicuspid in 12 patients (15%). Survival rate was 100% at 5 years of follow-up. Eleven patients (13.7%) underwent reoperation, 8 of whom presented with recurrent symptomatic aortic insufficiency (AI). Late echocardiography in the remaining 69 patients revealed mild AI in 63 patients, moderate recurrent AI in 4, and severe recurrent AI in 2. Relief from recurrent severe AI or reoperations was significantly lower in patients who underwent cusp repair compared with those who did not (P = 0.05). Furthermore, the use of pericardial patch augmentation for the repair was a predictor for recurrence (P = 0.05). CONCLUSIONS: AVr in patients with BAV or UAV is a safe procedure with low morbidity and mortality rates. The use of a pericardial patch augmentation was associated with higher repair failure.

Pericardial Patch Augmentation Is Associated With a Higher Risk of Recurrent Aortic Insufficiency.

BACKGROUND: This study assessed early and late clinical outcomes in patients who underwent aortic valve repair or an aortic valve-sparing operation and investigated predictors for failure. METHODS: Of 227 consecutive patients who underwent aortic valve repair or a valve-sparing operation in our department between 2004 and 2016, 81 (36%) underwent aortic root replacement with or without cusp repair, 97 (42%) ascending aorta replacement with or without cusp repair, and 49 (22%) isolated aortic valve repair. Clinical and echocardiographic follow-up was complete. RESULTS: One patient (0.4%) died in-hospital. Mean clinical and echocardiographic follow-up was 69 ± 40 months (range, 1 to 147 months) and 53 ± 40 months (range, 1 to 147 months), respectively. Fifteen patients (6.6%) died during follow-up, with an overall 5-year survival rate of 94.4%. Recurrent significant (≥3) aortic insufficiency developed in 20 patients (8.8%), 17 of whom underwent reoperation, with a 5-year freedom from reoperation rate of 88%. Predictors for recurrent significant aortic insufficiency or reoperation were greater preoperative aortic insufficiency (grade III to IV vs I to II; relative risk [RR], 1.97; p = 0.023), cusp repair (RR, 2.92; p = 0.001), higher European System for Cardiac Operative Risk Evaluation score (RR, 1.16; p = 0.006), and valve repair with pericardial patch augmentation (RR, 2.34; p = 0.032). CONCLUSIONS: Aortic valve repair and valve-sparing operations can be performed with good early and late clinical outcomes. In our experience, however, the rate of recurrent aortic insufficiency was significant, especially in patients who underwent cusp augmentation with glutaraldehyde-treated autologous pericardial patch.

Establishment of adoptive cell therapy with tumor infiltrating lymphocytes for non-small cell lung cancer patients.

Adoptive cell therapy (ACT) of tumor infiltration lymphocytes (TIL) yields promising clinical results in metastatic melanoma patients, who failed standard treatments. Due to the fact that metastatic lung cancer has proven to be susceptible to immunotherapy and possesses a high mutation burden, which makes it responsive to T cell attack, we explored the feasibility of TIL ACT in non-small cell lung cancer (NSCLC) patients. Multiple TIL cultures were isolated from tumor specimens of five NSCLC patients undergoing thoracic surgery. We were able to successfully establish TIL cultures by various methods from all patients within an average of 14 days. Fifteen lung TIL cultures were further expanded to treatment levels under good manufacturing practice conditions and functionally and phenotypically characterized. Lung TIL expanded equally well as 103 melanoma TIL obtained from melanoma patients previously treated at our center, and had a similar phenotype regarding PD1, CD28, and 4-1BB expressions, but contained a higher percent of CD4 T cells. Lung carcinoma cell lines were established from three patients of which two possessed TIL cultures with specific in vitro anti-tumor reactivity. Here, we report the successful pre-clinical production of TIL for immunotherapy in the lung cancer setting, which may provide a new treatment modality for patients with metastatic NSCLC. The initiation of a clinical trial is planned for the near future.

Intraoperative Implantation of Micra Leadless Pacemaker During Valve Surgery.

The Micra transcatheter leadless pacemaker, a single-chamber leadless ventricular pacemaker, is implanted percutaneously through the femoral vein. We present the case of a patient in whom the Micra leadless pacemaker was implanted during valve surgery.

Short- and long-term results after prosthetic mitral valve implantation in patients with severe mitral annulus calcification†.

OBJECTIVES: To investigate short- and long-term outcomes of a conservative decalcification approach in mitral valve replacement (MVR) surgery in the presence of mitral annulus calcification (MAC). METHODS: Of the 1038 patients who underwent MVR, 133 (13%) had significant MAC with at least 30% of the annular circumference heavily calcified. In most patients, the surgical approach to MAC included conservative decalcification, supra-annular prosthesis implantation and insertion of a pericardial patch between the MV annulus and the prosthesis. These patients were matched by a propensity score to a group of patients who underwent MVR without MAC ( n = 118 in each group) and served as a control group. RESULTS: There were 6 early deaths in each group with an overall mortality of 5% ( P = 0.90). Early complications included one major stroke in the non-MAC group and acute renal failure needing dialysis in 2 and 3 patients in the MAC and non-MAC groups, respectively. Mean follow-up was 55 ± 37 months and 99.1% complete. There were 38 (33%) and 33 (29%) late deaths with an estimated survival of 61% and 69% at 6 years in the MAC and non-MAC groups, respectively ( P = 0.55). At follow-up, functional class did not differ between groups ( P = 0.096). Mean echo follow-up time was 40 ± 35 months and was 83% complete. Freedom from moderate or severe mitral regurgitation was 95% and 98%, with an estimated freedom of 95% and 96% at 6 years ( P = 0.20), and mean gradient was 4.9 ± 2.3 mmHg and 5.2 ± 2.0 mmHg for MAC and non-MAC groups, respectively ( P = 0.58). CONCLUSIONS: A conservative approach for dealing with MAC is suitable for the majority of patients. Early and late clinical and echocardiographic outcomes did not differ between the MAC and non-MAC patients, including freedom from early and late occurrence of MV prosthesis paravalvular leak.

Metastatic Lung Lesions as a Preferred Resection Site for Immunotherapy With Tumor Infiltrating Lymphocytes.

Adoptive cell therapy with tumor infiltrating lymphocytes (TIL) yields 50% response rates in metastatic melanoma and shows promising clinical results in other solid tumors. Autologous TIL cultures are isolated from resected tumor tissue, expanded ex vivo to large numbers and reinfused to the preconditioned patient. In this prospective study, we validate the origin of the tumor biopsy and its effect on T-cell function and clinical response. One hundred forty-four patients underwent surgery and 79 patients were treated with TIL adoptive cell therapy. Cultures from lung tissue were compared with other origins. The success rate of establishing TIL culture from lung tissue was significantly higher compared with nonlung tissue (94% vs. 72%, respectively, P≤0.003). Lung-derived TIL cultures gave rise to higher cell numbers (P≤0.011) and exhibited increased in vitro antitumor reactivity. The average fold expansion for lung-derived TIL during a rapid expansion procedure was 1349±557 compared with 1061±473 for nonlung TIL (P≤0.038). Patients treated with TIL cultures of lung origin (compared with nonlung) had prolonged median overall survival (29 vs. 9.5 mo; P≤0.065). Given the remarkable advancement in minimally invasive thoracic surgery and the results of this study, we suggest efforts should be taken to resect lung metastasis rather than other sites to generate TIL cultures for clinical use.

Screening for lung cancer: time for large-scale screening by chest computed tomography.

Lung cancer is the leading cause of cancer death worldwide. Age and smoking are the primary risk factors for lung cancer. Treatment based on surgical removal in the early stages of the disease results in better survival. Screening programmes for early detection that used chest radiography and sputum cytology failed to attain reduction of lung cancer mortality. Screening by low-dose computed tomography (CT) demonstrated high rates of early-stage lung cancer detection in a high-risk population. Nevertheless, no mortality advantage was manifested in small randomised control trials. A large randomised control trial in the U.S.A., the National Lung Screening Trial (NLST), showed a significant relative reduction of 20% in lung cancer mortality and 6.7% reduction in total mortality, yet no reduction was evidenced in the late-stage prevalence. Screening for lung cancer by low-dose CT reveals a high level of false-positive lesions, which necessitates further noninvasive and invasive evaluations. Based primarily on the NLST eligible criteria, new guidelines have recently been developed by major relevant organisations. The overall recommendation coming out of this collective work calls for lung cancer screening by low-dose CT to be performed in medical centres manned by specialised multidisciplinary teams, as well as for a mandatory, pre-screening, comprehensive discussion with the patient about the risks and advantages involved in the process. Lung cancer screening is on the threshold of a new era, with ever more questions still left open to challenge future studies.

Tracheostomy after cardiac surgery: timing of tracheostomy as a risk factor for mortality.

OBJECTIVES: The optimal timing for tracheostomy after cardiac surgery in patients undergoing prolonged ventilation is controversial. The aim of this study was to assess the effect of tracheostomy timing on short- and long-term mortality of these patients. DESIGN: Retrospective study of prospectively collected data. SETTING: Cardiac surgical intensive care unit (ICU) in a tertiary-care, university-affiliated hospital. PARTICIPANTS: All patients undergoing tracheostomy after cardiac surgery between September 2004 and March 2013 were included. INTERVENTIONS: The authors compared the outcome in 2 groups of patients according to the timing of tracheostomy: Group I, early-intermediate tracheostomy (0-14 days) and Group II, late tracheostomy (≥15 days). MEASUREMENTS AND MAIN RESULTS: During the study period, 6,069 patients underwent cardiac surgery; among them, 199 patients (3.26%) received a tracheostomy. There were 90 patients in Group I and 109 patients in Group II. There was no significant difference in the severity of the patients' illness between the groups. The mortality rate at 3 months, 6 months, 1 year, and 2 years was 37%, 48%, 56%, and 58% in Group I, respectively, and 58%, 70%, 74%, and 77% in Group II, respectively (p< 0.01). CONCLUSIONS: Early-intermediate (0-14 days) tracheostomy after cardiac surgery in patients requiring prolonged mechanical ventilation was associated with reduced mortality compared with late tracheostomy (≥15 days).

Resection and heated pleural chemoperfusion in patients with thymic epithelial malignant disease and pleural spread: a single-institution experience.

OBJECTIVE: Our objective was to evaluate whether resection and heated pleural chemoperfusion (HPCP) is an effective treatment for de novo stage IVa thymoma (DNT) and thymic carcinoma (TC) and for thymoma with pleural relapse (TPR). METHODS: A retrospective study was conducted of patients undergoing resection and HPCP in 1 center. HPCP with cisplatinum ± doxorubicin (adriamycin) was performed for 60 minutes using a standard roller pump and a modified heat exchanger to a maximal intrapleural temperature of 43°C. Follow-up included at least 1 annual computed tomographic scan until death or March 2012. RESULTS: Thirty-five patients, 17 DNT, 14 TPR, and 4 TC, completed 42 intended treatments and were followed up for 4 to 202 months (median, 62 months). Seven patients had repeated HPCP at an interval of 2 to 12 years. There was no systemic toxicity. Ninety-day mortality was 2.5%. Major and minor morbidity occurred in 12% each. Five-, 10-, and 15-year overall survivals for DNT, TPR, and TC were 81%, 73%, 58% (DNT), 67%, 56%, 28% (TPR), and 0%, 0%, 0% (TC). Five- and 10-year progression-free survival was 61%, 43% for DNT and 48%, 18% for TPR. Presently, 11 of 17 DNT patients are alive (6, no evidence of disease), and 8 of 14 TPR are alive (6, no evidence of disease). Median survival for thymoma was 157 months. Overall survival was unrelated to any preoperative or intraoperative variable. Progression-free survival was improved in R0 compared with R1-2 resection (P < .001). Local control achieved in 21 (57%) of 37 procedures in thymoma patients was related only to completeness of resection (P = .015). CONCLUSIONS: (1) Lung-sparing resection and HPCP is feasible and safe. (2) In thymoma with pleural spread it offers excellent survival despite moderate pleural control. (3) Preliminary results with stage IVa TC are disappointing.