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Background Cancer cells develop resistance to chemotherapeutic intervention by excessive formation of stress granules (SGs), which are modulated by an oncogenic protein G3BP2. Selective control of G3BP2/SG signaling is a potential means to treat non-small cell lung cancer (NSCLC). Methods Co-immunoprecipitation was conducted to identify the interaction of MG53 and G3BP2. Immunohistochemistry and live cell imaging were performed to visualize the subcellular expression or co-localization. We used shRNA to knock-down the expression MG53 or G3BP2 to test the cell migration and colony formation. The expression level of MG53 and G3BP2 in human NSCLC tissues was tested by western blot analysis. The ATO-induced oxidative stress model was used to examine the effect of rhMG53 on SG formation. Moue NSCLC allograft experiments were performed on wild type and transgenic mice with either knockout of MG53, or overexpression of MG53. Human NSCLC xenograft model in mice was used to evaluate the effect of MG53 overexpression on tumorigenesis. Results We show that MG53, a member of the TRIM protein family (TRIM72), modulates G3BP2 activity to control lung cancer progression. Loss of MG53 results in the progressive development of lung cancer in mg53 -/- mice. Transgenic mice with sustained elevation of MG53 in the bloodstream demonstrate reduced tumor growth following allograft transplantation of mouse NSCLC cells. Biochemical assay reveals physical interaction between G3BP2 and MG53 through the TRIM domain of MG53. Knockdown of MG53 enhances proliferation and migration of NSCLC cells, whereas reduced tumorigenicity is seen in NSCLC cells with knockdown of G3BP2 expression. The recombinant human MG53 (rhMG53) protein can enter the NSCLC cells to induce nuclear translation of G3BP2 and block arsenic trioxide-induced SG formation. The anti-proliferative effect of rhMG53 on NSCLC cells was abolished with knockout of G3BP2. rhMG53 can enhance sensitivity of NSCLC cells to undergo cell death upon treatment with cisplatin. Tailored induction of MG53 expression in NSCLC cells suppresses lung cancer growth via reduced SG formation in a xenograft model. Conclusion Overall, these findings support the notion that MG53 functions as a tumor suppressor by targeting G3BP2/SG activity in NSCLCs.

Background Patients with limited pulmonary function have a high risk for pulmonary complications following lobectomy. Robotic approach is currently the least invasive approach. We hypothesized that robotic lobectomy may be of particular benefit in high-risk patients. Methods We reviewed our institutional Society of Thoracic Surgeons (STS) data on lobectomy patients from 2012 to 2017. Postoperative outcomes were compared between robotic and open lobectomy groups. High-risk patients were identified by pulmonary function test. Risk of pulmonary complication was assessed by binary logistic regression analysis. Results A total of 599 patients underwent lobectomy by robotic ( n  = 287), or by open ( n  = 312) approach, including 189 high-risk patients. Robotic lobectomy patients had a lower rate of prolonged air leak (6% vs. 10%, p  = 0.047), less atelectasis requiring bronchoscopy (6% vs. 16%, p  = 0.02), pneumonia (3% vs. 8%, p  = 0.01), and shorter length of stay (4 vs. 6 days, p  = 0.001). Overall pulmonary complication rate was significantly lower after robotic lobectomy in high-risk patients (28% vs. 45%, p  = 0.02), less in intermediate or low risk patients. No significant difference was seen relative to major complication rate (12% vs. 17%, p  = 0.09). After multivariate analysis, when adjusting for age, gender, smoking history, FEV1, DLCO, cardiopulmonary comorbidities, and prior chest surgery, the robotic approach remained independently associated with decreased pulmonary complications (odds ratio 0.54, 95% confidence interval [0.34–0.85], p  = 0.008). Conclusions Robotic lobectomy has the potential to decrease the risk of postoperative pulmonary complication as compared with traditional open thoracotomy. In particular, patients with limited pulmonary function derive the most benefit from a robotic approach.

Background: The role of preoperative conditioning on postoperative outcomes in thoracic surgery is of growing interest. There is a paucity of data on understanding compliance with a patient-led walking program and its impact on quality of life. Objectives: To understand the feasibility of patient-driven data collection of daily steps via pedometers and to understand the impact of preoperative conditioning on quality of life. Design: A prospective single-institution quality improvement study. Methods: The study included patients who underwent thoracic surgery between 2020 and 2022 who were and were selected to receive a pedometer at their preoperative clinic appointment. A daily step goal was determined, and patients were instructed to record their daily steps. Quality of life was assessed at baseline and at presentation for surgery. Clinical data and postoperative outcomes were derived from the institutional Society of Thoracic Surgery General Thoracic Surgery Database. Results: There were 167 patients provided with pedometers at their presurgical clinic appointment, of whom 43 returned pedometer data (utilization rate 26%). Of the 104 who underwent lung resection, 74 (44.3%) did not record step data, 15 had <6000 median daily steps, and 15 had >6000 median daily steps. Pre-intervention self-perceived outcomes were similar. Post-pedometer data demonstrated higher scores in the domains of general health (p = 0.016), quality of life (p = 0.03), general physical health (p = 0.002), physical performance (p = 0.03), social health (p = 0.009), social performance (p=0.01), and fatigue level (p = 0.01) for patients with higher median step counts. There were no significant differences in postoperative outcomes based on survival, length of stay (p = 0.77), or respiratory complications (p = 0.52). Conclusion: A patient-led walking program using pedometers is feasible for a minority of patients. Higher recorded daily step counts are associated with improved self-perceived quality of life in patients prior to lung surgery. Plain language summary Patient-led walking program for patients undergoing lung surgery In this study, patients undergoing lung surgery were provided with a pedometer and a personalized daily step goal to keep track of their walking prior to their operation. Only a quarter of patients participated in this program. However, patients who participated and recorded high daily step counts also reported better quality of life when presenting for surgery.

BackgroundMinimally invasive esophagectomy is associated with significant morbidity, which can substantially influence the hospital length of stay for patients. Anastomotic leak is the most devastating complication. Minimizing major postoperative complications can facilitate adherence to a clinical pathway protocol and can decrease hospital length of stay.MethodsThis is a retrospective study of 130 patients who underwent an elective laparoscopic and thoracoscopic Ivor Lewis esophagectomy for esophageal carcinoma between August 2014 and June 2018. A total of 112 patients (86%) underwent neoadjuvant chemoradiation. All of the 130 patients underwent a laparoscopic gastric devascularization procedure a median of 15 days prior to the esophagectomy. The target discharge date was postoperative day number 8.ResultsThirty patients (23.08%) had postoperative complications. Atrial fibrillation (20 patients) [15.38%] was the most frequent complication. Four patients (3.1%) developed an anastomotic leak. There was one postoperative death (0.77%) in the cohort of patients. The median length of stay was 8 days. The mean length of stay for patients without complications was 8 days ± 1.2 days and 12.4 days ± 7.1 days for patients with one or more complications (p = 0.002).ConclusionThe development of postoperative complications after minimally invasive Ivor Lewis esophagectomy significantly increases hospital length of stay. Performing the operation with a specialized tandem surgical team and including preoperative ischemic preconditioning of the stomach minimizes overall and anastomotic complications and facilitates on time hospital discharge as defined by a perioperative clinical pathway protocol.

Aging is associated with chronic oxidative stress and inflammation that affect tissue repair and regeneration capacity. MG53 is a TRIM family protein that facilitates repair of cell membrane injury in a redox-dependent manner. Here, we demonstrate that the expression of MG53 was reduced in failing human hearts and aged mouse hearts, concomitant with elevated NF-κB activation. We evaluated the safety and efficacy of longitudinal, systemic administration of recombinant human MG53 (rhMG53) protein in aged mice. Echocardiography and pressure-volume loop measurements revealed beneficial effects of rhMG53 treatment in improving heart function of aged mice. Biochemical and histological studies demonstrated that the cardioprotective effects of rhMG53 are linked to suppression of NF-κB–mediated inflammation, reducing apoptotic cell death and oxidative stress in the aged heart. Repetitive administration of rhMG53 in aged mice did not have adverse effects on major vital organ functions. These findings support the therapeutic value of rhMG53 in treating age-related decline in cardiac function.

Sulfur mustard (SM) and nitrogen mustard (NM) are vesicant agents that cause skin injury and blistering through complicated cellular events, involving DNA damage, free radical formation, and lipid peroxidation. The development of therapeutic approaches targeting the multi-cellular process of tissue injury repair can potentially provide effective countermeasures to combat vesicant-induced dermal lesions. MG53 is a vital component of cell membrane repair. Previous studies have demonstrated that topical application of recombinant human MG53 (rhMG53) protein has the potential to promote wound healing. In this study, we further investigate the role of MG53 in NM-induced skin injury. Compared with wild-type mice, mg53−/− mice are more susceptible to NM-induced dermal injuries, whereas mice with sustained elevation of MG53 in circulation are resistant to dermal exposure of NM. Exposure of keratinocytes and human follicle stem cells to NM causes elevation of oxidative stress and intracellular aggregation of MG53, thus compromising MG53′s intrinsic cell membrane repair function. Topical rhMG53 application mitigates NM-induced dermal injury in mice. Histologic examination reveals the therapeutic benefits of rhMG53 are associated with the preservation of epidermal integrity and hair follicle structure in mice with dermal NM exposure. Overall, these findings identify MG53 as a potential therapeutic agent to mitigate vesicant-induced skin injuries.

Background Locally advanced esophageal carcinoma is typically treated with neoadjuvant chemoradiation and esophagectomy (trimodality therapy). We compared the long-term oncologic outcomes of minimally invasive Ivor Lewis esophagectomy (M-ILE) cohort with a propensity score weighted cohort of open Ivor Lewis esophagectomy (O-ILE) cases after trimodality therapy. Methods This is a retrospective review of 223 patients diagnosed with esophageal carcinoma who underwent neoadjuvant chemoradiation followed by M-ILE or O-ILE from April 2009 to February 2019. Inverse probability of treatment weighting (IPTW) adjustment was used to balance the baseline characteristics between study groups. Kaplan–Meier survival curves were calculated for overall survival and recurrence-free survival comparing the two groups. Multivariate Cox proportional hazards regression models were used to determine predictive variables for overall and recurrence-free survival. Results The IPTW cohort included patients with esophageal carcinoma who underwent M-ILE (n = 142) or O-ILE (n = 68). The overall rate of postoperative adverse events was not significantly different after IPTW adjustment between the O-ILE and M-ILE trimodality groups (53.4% vs. 39.2%, p  = 0.089). The 3-year overall survival (OS) for the M-ILE group was 59.4% (95% CI: 49.8–67.8) compared to 55.7% (95% CI: 39.2–69.4) for the O-ILE group ( p  = 0.670). The 3-year recurrence-free survival for the M-ILE group was 59.9% (95% CI: 50.2–68.2) compared to 61.6% (95% CI: 41.9–76.3) for the O-ILE group ( p  = 0.357). A complete response to neoadjuvant chemoradiation was significantly predictive of improved OS and RFS. Conclusion The overall and recurrence-free survival rates for M-ILE were not significantly different from O-ILE for esophageal carcinoma after trimodality therapy. Complete response to neoadjuvant chemoradiation was predictive of improved overall and recurrence- free survival.

Aaron Newman and his colleagues introduce a next-generation sequencing–based approach for the cost-effective detection and quantitation of tumor-derived circulating DNA in both early- and advanced-stage tumors and with high levels of sensitivity and specificity. CAPP-Seq (cancer personalized profiling by deep sequencing) can simultaneously detect multiple mutations and mutation types, including rearrangements. Here, utility is demonstrated for non–small-cell lung cancer. Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non–small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of patients with stage II–IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ∼0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.

Background The published rates of morbidity and mortality remain relatively high for patients who undergo laparoscopic and thoracoscopic Ivor Lewis esophagectomy. We report the postoperative and oncologic outcomes of a large cohort of patients with esophageal carcinoma who were uniformly treated with laparoscopic and thoracoscopic Ivor Lewis esophagectomy following neoadjuvant chemoradiation. Methods This is a retrospective observational study of 112 patients diagnosed with esophageal carcinoma who underwent total laparoscopic and thoracoscopic Ivor Lewis esophagectomy from May 2014 to May 2018. All of the patients received neoadjuvant chemoradiation consisting of 45 to 50.4 Gray of radiation and 3–5 cycles of carboplatin and paclitaxel chemotherapy. Perioperative morbidity and 90-day mortality were recorded. The overall and disease-free survival rates were estimated by Kaplan Meier techniques. Results A total of 112 patients completed induction chemoradiation followed by a total laparoscopic and thoracoscopic Ivor Lewis esophagectomy. There were 87 (77.68%) males and 25 (22.32%) females with a mean age of 61.6 years ± 10.4. A total of 28 (25%) patients had one or more complications. A total of 4 patients (3.57%) had an anastomotic leak. The 90-day mortality rate was 0.89%. The 3-year overall survival rate was 64.7% and the 3-year disease-free survival rate was 70.2%. Conclusion The current outcomes suggest that laparoscopic and thoracoscopic Ivor Lewis esophagectomy can be performed with minimal overall and anastomotic complications following neoadjuvant chemoradiation.

BackgroundControversy exists as to what constitutes a learning curve to achieve competency, and how the initial learning period of robotic thoracic surgery should be approached.MethodsWe conducted a systematic review of the literature published prior to December 2018 using PubMed/MEDLINE for studies of surgeons adopting the robotic approach for anatomic lung resection or thymectomy. Changes in operating room time and outcomes based on number of cases performed, type of procedure, and existing proficiency with video-assisted thoracoscopic surgery (VATS) were examined.ResultsTwelve observational studies were analyzed, including nine studies on robotic lung resection and three studies on thymectomy. All studies showed a reduction in operative time with an increasing number of cases performed. A steep learning curve was described for thymectomy, with a decrease in operating room time in the first 15 cases and a plateau after 15–20 cases. For anatomic lung resection, the number of cases to achieve a plateau in operative time ranged between 15–20 cases and 40–60 cases. All but two studies had at least some VATS experience. Six studies reported on experience of over one hundred cases and showed continued gradual improvements in operating room time.ConclusionThe learning curve for robotic thoracic surgery appears to be rapid with most studies indicating the steepest improvement in operating time occurring in the initial 15–20 cases for thymectomy and 20–40 cases for anatomic lung resection. Existing data can guide a standardized robotic curriculum for rapid adaptation, and aid credentialing and quality monitoring for robotic thoracic surgery programs.