Vein-first vs. artery-first robotic lobectomy outcomes in non-small cell lung cancer.

Background: Data remains limited as to whether the order of pulmonary vessel division during performance of a lobectomy for non-small cell lung cancer (NSCLC) affects survival outcomes. Some authors have suggested that ligation of the pulmonary veins should be conducted first in order to minimize the spread of tumor cells secondary to manipulation of the lung. This study examines whether there is a difference in outcomes between patients who undergo robotic lobectomies for NSCLC using a vein-first (V-first) vs. artery-first (A-first) technique. Methods: A retrospective review of electronic medical record data was performed for patients who underwent robotic lobectomies from January 2013 to May 2019. Patients were separated into two groups based on the sequence in which the pulmonary vessels were divided: V-first or A-first. Baseline characteristics and postoperative events were recorded and compared between groups using Chi-squared and Student's t-tests. Kaplan-Meier survival curves for overall and recurrence-free survival were constructed and compared with log-rank tests. Results: A total of 374 patients were identified: 94 V-first and 280 A-first patients. There was no significant difference between the V-first and A-first groups with regards to postoperative complications, length of stay, recurrence-free survival, or overall survival. Conclusions: Our study suggests that choosing a V-first vs. A-first technique for a robotic lobectomy does not significantly impact overall survival or cancer recurrence for patients with NSCLC. Further studies are needed to evaluate whether the order of pulmonary vessel resection affects outcomes for patients with NSCLC.

MiR-199a-5p Decreases Esophageal Cancer Cell Proliferation Partially through Repression of Jun-B.

MicroRNA (miR)-199a-5p has been shown to function as a tumor suppressor in some malignancies but its role in esophageal cancer is poorly understood. To further explore its role in esophageal cancer, we sought to investigate the interaction between miR-199a-5p and Jun-B, an important component of the AP1 transcription factor, which contains a potential binding site for miR-199a-5p in its mRNA. We found that levels of miR-199a-5p are reduced in both human esophageal cancer specimens and in multiple esophageal cancer cell lines compared to esophageal epithelial cells. Jun-B expression is correspondingly elevated in these tumor specimens and in several cell lines compared to esophageal epithelial cells. Jun-B mRNA expression and stability, as well as protein expression, are markedly decreased following miR-199a-5p overexpression. A direct interaction between miR-199a-5p and Jun-B mRNA was confirmed by a biotinylated RNA-pull down assay and luciferase reporter constructs. Either forced expression of miR-199a-5p or Jun-B silencing led to a significant decrease in cellular proliferation as well as in AP-1 promoter activity. Our results provide evidence that miR-199a-5p functions as a tumor suppressor in esophageal cancer cells by regulating cellular proliferation, partially through repression of Jun B.

Repair of Tracheal Dehiscence After Heart-Lung Transplant Complicated by SARS-CoV-2 Infection.

Airway complications are a major cause of morbidity after thoracic transplantation. Airway ischemia, necrosis, and tracheobronchial anastomotic dehiscence are associated with early mortality. We describe a case of tracheal anastomotic dehiscence after en bloc heart-lung transplant complicated by severe acute respiratory syndrome coronavirus 2 infection. Timely surgical management and reconstruction with a bovine pericardial patch and double muscle flap were performed. After 8 months of follow-up, there are no airway complications and normalized allograft function.

Correction: Zare et al. Encapsulation of miRNA and siRNA into Nanomaterials for Cancer Therapeutics. Pharmaceutics 2022, 14, 1620.

In the original publication [...].

MiR-214-3p targets Ras-related protein 14 (RAB14) to inhibit cellular migration and invasion in esophageal Cancer cells.

BACKGROUND: MicroRNA (miR)-214-3p is emerging as an important tumor suppressor in esophageal cancer. In this study, we examined the interaction between miR-214-3p and RAB14, a membrane trafficking protein shown to exert oncogenic functions in other malignancies, in esophageal cancer cells. METHODS: Studies were performed in a human esophageal epithelial cell line and a panel of esophageal cancer cell lines, as well in human specimens. MiR-214-3p expression was measured by digital PCR. Biotinylated RNA pull-down and luciferase reporter assays assessed binding. The xCELLigence RTCA system measured cell migration and invasion in real time. A lentiviral expression vector was used to create an esophageal cancer cell line stably expressing miR-214-3p. RESULTS: MiR-214-3p expression was decreased in esophageal cancer cell lines and human specimens compared to non-malignant controls. RAB14 mRNA stability and protein expression were decreased following miR-214-3p overexpression. Binding between miR-214-3p and RAB14 mRNA was observed. Either forced expression of miR-214-3p or RAB14 silencing led to a marked decrease in cellular migration and invasion. Esophageal cancer cells stably expressing miR-214-3p demonstrated decreased growth in a subcutaneous murine model. CONCLUSIONS: These results further support the tumor-suppressive role of miR-214-3p in esophageal cancer cells by demonstrating its ability to regulate RAB14 expression.

Encapsulation of miRNA and siRNA into Nanomaterials for Cancer Therapeutics.

Globally, cancer is amongst the most deadly diseases due to the low efficiency of the conventional and obsolete chemotherapeutic methodologies and their many downsides. The poor aqueous solubility of most anticancer medications and their low biocompatibility make them ineligible candidates for the design of delivery systems. A significant drawback associated with chemotherapy is that there are no advanced solutions to multidrug resistance, which poses a major obstacle in cancer management. Since RNA interference (RNAi) can repress the expression of genes, it is viewed as a novel tool for advanced drug delivery. this is being explored as a promising drug targeting strategy for the treatment of multiple diseases, including cancer. However, there are many obstructions that hinder the clinical uses of siRNA drugs due to their low permeation into cells, off-target impacts, and possible unwanted immune responses under physiological circumstances. Thus, in this article, we review the design measures for siRNA conveyance frameworks and potential siRNA and miRNA drug delivery systems for malignant growth treatment, including the use of liposomes, dendrimers, and micelle-based nanovectors and functional polymer-drug delivery systems. This article sums up the advancements and challenges in the use of nanocarriers for siRNA delivery and remarkably centers around the most critical modification strategies for nanocarriers to build multifunctional siRNA and miRNA delivery vectors. In short, we hope this review will throw light on the dark areas of RNA interference, which will further open novel research arenas in the development of RNAi drugs for cancer.

Cost-benefit analysis of a patient engagement technology (PET) in cardiac, thoracic, and colorectal surgery.

BACKGROUND: Patient engagement technologies (PETs) guide patients through perioperative care, but little is known about their costs-benefits. METHODS: Retrospective cohort study of patients undergoing elective colorectal, cardiac, thoracic surgery 2015-2020. PET was implemented 2018. Patients were propensity-matched in pre-PET, PET, non-PET groups. Costs of surgical encounter and 30 days post-discharge, mortality, length-of-stay, readmissions, complications, satisfaction were compared. RESULTS: Overall, 4,373 patients underwent surgery and 607 (13.9%) patients enrolled in the PET. PET patients did not have increased costs in any specialty. Colorectal PET patients' variable costs of surgical encounter were $102 lower than non-PET, $1495 lower than pre-PET (p = 0.03). Thoracic PET patients' total costs of surgical encounter were $9224 lower than non-PET, $2187 lower than pre-PET (p = 0.03). Thoracic PET patients had lower mean LOS (2.4 days, 5.1 non-PET, 3.1 pre-PET, p = 0.03). PET patient satisfaction ranged 86.0%-97.8%. CONCLUSIONS: Use of a PET did not increase costs and was associated with benefits for patients undergoing elective surgery.

Evolution of technique and results after permanent open repair for pectus deformities.

Objective: Open correction of pectus deformities has evolved since its origin. We performed a Ravitch type repair using a permanent titanium plate fixed with screws and describe the procedure with outcomes after our modifications. Methods: A retrospective review of 61 pectus excavatum and pectus carinatum cases from August 2013 to April 2021 was performed. Data were extracted from medical records and reported. In January 2016, we began administering satisfaction surveys at the 6-month postoperative visit; results are reported. Results: The mean age of our cohort was 24.5 years; 43 (70%) were male. Fifty-four underwent pectus excavatum repair, 6 pectus carinatum repair, and 1 mixed repair. Median Haller index was 3.8. Mean operative duration was 98 minutes; mean blood loss was 116.4 mL. Median chest tube duration was 5.0 days; median hospital stay was 4 days. Reexploration for bleeding was 30% in the first 10 patients. Protocol changes including postponing chemical deep vein thrombosis prophylaxis, using intraoperative hemostatic agents, and using shorter implantation screws decreased this to 0% for the remaining cases. The most frequent complication was urinary retention (21.3%). Postoperative surveys were completed for 37 of 50 patients. Seventy-five percent reported health improved, 65% reported exercise capacity improved, 75% reported breathing improved, and 59% reported chest pain improved. Self-esteem improved from 6.6 ± 2.5 (of 10) before surgery to 8.2 ± 2.1 after surgery. Ninety percent were satisfied and 86% would have the operation again. Conclusions: Ravitch type repair with permanent titanium plate fixation is a safe and effective procedure for correction of pectus excavatum and carinatum. Most patients experience improvement in preoperative symptoms.

Local SARS-CoV-2 Peptide-Specific Immune Responses in Lungs of Convalescent and Uninfected Human Subjects.

Multi-specific and long-lasting T cell immunity have been recognized as indicators for long term protection against pathogens including the novel coronavirus SARS-CoV-2, the causative agent of the COVID-19 pandemic. Functional significance of peripheral memory T cells in individuals recovering from COVID-19 (COVID-19 + ) are beginning to be appreciated; but little is known about lung resident memory T cells (lung TRM) in SARS-CoV-2 infection. Here, we utilize a perfused three dimensional (3D) human lung tissue model and identify pre-existing local T cell immunity against SARS-CoV-2 proteins in lung tissues. We report ex vivo maintenance of functional multi-specific IFN-γ secreting lung TRM in COVID-19 + and their induction in lung tissues of vaccinated COVID-19 + . Importantly, we identify SARS-CoV-2 peptide-responding B cells and IgA + plasma cells in lung tissues of COVID-19 + in ex vivo 3D-tissue models. Our study highlights the importance of balanced and local anti-viral immune response in the lung with persistent induction of TRM and IgA + plasma cells for future protection against SARS-CoV-2 infection. Further, our data suggest that inclusion of multiple viral antigens in vaccine approaches may broaden the functional profile of memory T cells to combat the severity of coronavirus infection.

MicroRNA-141-3p regulates cellular proliferation, migration, and invasion in esophageal cancer by targeting tuberous sclerosis complex 1.

MicroRNA (miR)-141-3p, which functions as an oncogene in multiple malignancies, has been shown to be highly overexpressed in esophageal cancer cells in our previous work. miR-141-3p is predicted to bind the messenger RNA (mRNA) of tuberous sclerosis complex 1 (TSC1), a tumor suppressor, with high affinity. In this study, we investigated the expression and functional interaction between miR-141-3p and TSC1 in esophageal cancer cells. Experiments were conducted in four esophageal cancer lines and in tumor cells isolated from human esophageal cancer specimens by laser capture microdissection. miR-141-3p expression was measured by real time and droplet digital PCR. Biotinylated RNA pull-down and luciferase reporter assays were used to assess binding. miR-141-3p function was tested by assessing proliferation, migration, invasion, and induction of autophagy following its silencing. We found that miR-141-3p levels were increased in TE7, OE33, and TE10 esophageal cancer cells compared to FLO-1 cells, with similar heterogeneity observed in human esophageal cancer specimens. Silencing of miR-141-3p led to increased TSC1 protein expression in these cells and was associated with increased TSC1 translation. Binding studies reveal that miR-141-3p binds to each of the predicted binding sites in the 3'-untranslated region of TSC1 mRNA. Following miR-141-3p silencing, TE7, OE33, and TE10 cells exhibited decreased proliferation, migration, and invasion, as well as enhanced autophagy. Importantly, these phenotypic effects were replicated by overexpression of TSC1 alone in these cells. Our results indicate that miR-141-3p functions in an oncogenic capacity in a subset of esophageal cancer cells, in part by suppressing TSC1 expression.

Morbidity and 30-day mortality after decortication for parapneumonic empyema and pleural effusion among patients in the Society of Thoracic Surgeons' General Thoracic Surgery Database.

OBJECTIVE: We analyzed the Society of Thoracic Surgeons' Database to describe the results of surgical decortication. METHODS: A review of patients undergoing pulmonary decortication, excluding hemothorax and malignancy, from 2009 to 2016 was performed. Preoperative factors, length of stay, discharge status, readmission, morbidity, and mortality were compared between open and video-assisted thoracoscopic surgery approaches. Multivariable models identified risk factors for morbidity and mortality. RESULTS: Of 7316 patients undergoing decortication, 6961 (95.2%) had a primary diagnosis of empyema. Video-assisted thoracoscopic surgery was used in 4435 patients (60.6%) and increased during the study period. Median length of stay was 4 days (interquartile range, 2-7) preoperatively and 7 days (interquartile range, 5-11) postoperatively. Mortality occurred in 228 patients (3.1%). Complications occurred in 2875 patients (39.3%), and major morbidity occurred in 1138 patients (15.6%). Transitional care after discharge occurred in 1922 patients (26.3%). Readmission within 30 days occurred in 452 patients (8.7%). Compared with video-assisted thoracoscopic surgery, mortality, major morbidity, prolonged length of stay, and discharge to other than home were higher with thoracotomy. In multivariable analysis, age, estimated glomerular filtration rate less than 60, chronic obstructive pulmonary disease, body mass index, American Society of Anesthesiologists level, Zubrod score, and thoracotomy were associated with increased mortality, morbidity, discharge to transitional care, and prolonged length of stay. Each additional preoperative hospital day (up to 5 days) increased mortality. Readmission, major morbidity, prolonged length of stay, and discharge to transitional care were all higher when preoperative hospitalization extended beyond 5 days. CONCLUSIONS: Surgeons participating in the Society of Thoracic Surgeons General Thoracic Surgery Database perform decortication for parapneumonic empyema and pleural effusion with limited mortality despite substantial postoperative morbidity. Further study is required to describe selection criteria for video-assisted thoracoscopic surgery and determine indications for surgical intervention to reduce delays in operative intervention.

MiR-199a-3p decreases esophageal cancer cell proliferation by targeting p21 activated kinase 4.

Although microRNA (miR) 199a-3p functions as a tumor suppressor in multiple malignancies, its expression and role in esophageal cancer have not been studied. Based on our previous observation that miR-199a-3p is markedly downregulated in esophageal cancer cell lines relative to esophageal epithelial cells, we examined the function of miR-199a-3p in these cells. MiR-199a-3p is predicted to bind with high affinity to the mRNA of p21 activated kinase 4 (PAK4). This kinase has been shown to be overexpressed in several malignancies and to modulate proliferation and motility. The current study is designed to determine whether miR-199a-3p regulates the expression of PAK4 in esophageal cancer cells and to understand the functional consequences of this interaction. Herein, we demonstrate reduced expression of miR-199a-3p in human esophageal cancer specimens and cell lines compared to esophageal epithelial cells, with associated increased expression of PAK4. Forced expression of miR-199a-3p decreases expression of PAK4 in esophageal cancer cell lines. Mechanistic studies reveal that miR-199a-3p binds to the 3'UTR of PAK4 mRNA. This interaction results in reduced levels of PAK4 mRNA due to decreased mRNA stability. Downregulation of PAK4 leads to decreased cyclin D1 (CD1) transcription and protein expression, resulting in markedly impaired cellular proliferation. When PAK4 expression is rescued, both CD1 transcription and protein return to baseline levels. Our results show that miR-199a-3p functions as a tumor suppressor in esophageal cancer cells through repression of PAK4. These findings suggest that both miR-199a-3p and PAK4 may be novel therapeutic targets in the treatment of esophageal cancer.

Implications of Pathologic Complete Response Beyond Mediastinal Nodal Clearance With High-Dose Neoadjuvant Chemoradiation Therapy in Locally Advanced, Non-Small Cell Lung Cancer.

PURPOSE: To determine, in a retrospective analysis of a large cohort of stage III non-small cell lung cancer patients treated with curative intent at our institution, whether having a pathologic complete response (pCR) influenced overall survival (OS) or freedom from recurrence (FFR) in patients who underwent definitive (≥60 Gy) neoadjuvant doses of chemoradiation (CRT). METHODS AND MATERIALS: At our institution, 355 patients with locally advanced non-small cell lung cancer were treated with curative intent with definitive CRT (January 2000-December 2013), of whom 111 underwent mediastinal reassessment for possible surgical resection. Ultimately 88 patients received trimodality therapy. Chi-squared analysis was used to compare categorical variables. The Kaplan-Meier analysis was performed to estimate OS and FFR, with Cox regression used to determine the absolute hazards. RESULTS: Using high-dose neoadjuvant CRT, we observed a mediastinal nodal clearance (MNC) rate of 74% (82 of 111 patients) and pCR rate of 48% (37 of 77 patients). With a median follow-up of 34.2 months (range, 3-177 months), MNC resulted in improved OS and FFR on both univariate (OS: hazard ratio [HR] 0.455, 95% confidence interval [CI] 0.272-0.763, P = .004; FFR: HR 0.426, 95% CI 0.250-0.726, P = .002) and multivariate analysis (OS: HR 0.460, 95% CI 0.239-0.699, P = .001; FFR: HR 0.455, 95% CI 0.266-0.778, P = .004). However, pCR did not independently impact OS (P = .918) or FFR (P = .474). CONCLUSIONS: Mediastinal nodal clearance after CRT continues to be predictive of improved survival for patients undergoing trimodality therapy. However, a pCR at both the primary and mediastinum did not further improve survival outcomes. Future therapies should focus on improving MNC to encourage more frequent use of surgery and might justify use of preoperative CRT over chemotherapy alone.

Restrictive Transfusion Practices After Esophagectomy Are Associated With Improved Outcome: A Review of the Society of Thoracic Surgeons General Thoracic Database.

OBJECTIVE: Blood transfusion has been associated with poor outcomes in many disciplines, yet transfusion practices and related outcomes in esophagectomy are unknown. We analyzed the Society of Thoracic Surgeons General Thoracic Database to determine patient factors associated with transfusion after esophagectomy, risk-adjusted variation in transfusion practice among institutions, and the association of transfusion practice with mortality. METHODS: We performed a retrospective review of patients undergoing esophagectomy for cancer from October 2008 to December 31, 2014. Patient comorbidities and procedure variables were used to construct a risk model for transfusion. Using this model, each institution was assigned an observed to expected (O:E) transfusion rate. We examined institutional factors associated with variation in O:E transfusion rate. Finally, O:E transfusion rate was compared to risk-adjusted mortality to determine if there was an association of transfusion practice and survival. RESULTS: Seven thousand one hundred thirty-seven patients underwent esophagectomy at 182 institutions during the study period. The median unadjusted transfusion rate was 23.1%. The risk model for transfusion demonstrated patients who received transfusions were more likely to be older, female, and have low preoperative hemoglobin and other comorbidities, such as CAD, COPD, and low creatinine clearance. Patients who received a minimally invasive procedure were less likely to have received a transfusion.After adjusting for the characteristics above, 13 centers (7.1%) were classified as having lower than average O:E transfusion rate and 16 centers (8.7%) were classified as higher than average O:E transfusion rate.Institutions with lower than expected transfusion rates also had lower risk-adjusted perioperative mortality than institutions with higher than expected transfusion rates (median [IQR] = 0.90 [0.77-0.94] vs. 0.99 [0.94-1.06], P = 0.028). CONCLUSION: Age, female sex, CAD, COPD, renal insufficiency, and open technique are associated with transfusion after esophagectomy, while tumor stage and preoperative chemoradiation are not. There is wide variation in transfusion practice. Centers with lower than expected transfusion rate also had lower than expected perioperative mortality. At an institutional level, lower transfusion rates are associated with improved outcomes.

Biotinylated Micro-RNA Pull Down Assay for Identifying miRNA Targets.

microRNA (miRNA) directly associates with its target transcripts (mRNA). This protocol describes a method for detection of direct interaction between miRNA and mRNA. The result of interaction helps screening the specific target mRNAs for a miRNA.

The Society of Thoracic Surgeons General Thoracic Surgery Database: 2016 Update on Research.

The Society of Thoracic Surgeons General Thoracic Surgery Database has grown to more than 500,000 case records. Clinical research supported by the database is increasingly used to advance patient outcomes. This research review from the General Thoracic Surgery Database in 2014 and 2015 discusses 6 recent publications and an ongoing study on longitudinal outcomes in lung cancer surgery from The Society of Thoracic Surgeons Task Force for Linked Registries and Longitudinal Follow-up. A lack of database variables specific for certain uncommon procedures limits the ability to study these operations; inclusion of clinical descriptors for selected infrequent but clinically important thoracic disorders is suggested.

Overexpression of miR-199a-5p decreases esophageal cancer cell proliferation through repression of mitogen-activated protein kinase kinase kinase-11 (MAP3K11).

Studies examining the oncogenic or tumor suppressive functions of dysregulated microRNAs (miRs) in cancer cells may also identify novel miR targets, which can themselves serve as therapeutic targets. Using array analysis, we have previously determined that miR-199a-5p was the most downregulated miR in two esophageal cancer cell lines compared to esophageal epithelial cells. MiR-199a-5p is predicted to bind mitogen-activated protein kinase kinase kinase 11 (MAP3K11) mRNA with high affinity. In this study, we observed that MAP3K11 is markedly overexpressed in esophageal cancer cell lines. Forced expression of miR-199a-5p in these cells leads to a decrease in the mRNA and protein levels of MAP3K11, due to decreased MAP3K11 mRNA stability. A direct binding interaction between miR-199a-5p and MAP3K11 mRNA is demonstrated using biotin pull-down assays and heterologous luciferase reporter constructs and confirmed by mutational analysis. Finally, forced expression of miR-199a-5p decreases proliferation of esophageal cancer cells by inducing G2/M arrest. This effect is mediated, in part, by decreased transcription of cyclin D1, due to reduced MAP3K11-mediated phosphorylation of c-Jun. These findings suggest that miR-199a-5p acts as a tumor suppressor in esophageal cancer cells and that its downregulation contributes to enhanced cellular proliferation by targeting MAP3K11.

Competition between RNA-binding proteins CELF1 and HuR modulates MYC translation and intestinal epithelium renewal.

The mammalian intestinal epithelium is one of the most rapidly self-renewing tissues in the body, and its integrity is preserved through strict regulation. The RNA-binding protein (RBP) ELAV-like family member 1 (CELF1), also referred to as CUG-binding protein 1 (CUGBP1), regulates the stability and translation of target mRNAs and is implicated in many aspects of cellular physiology. We show that CELF1 competes with the RBP HuR to modulate MYC translation and regulates intestinal epithelial homeostasis. Growth inhibition of the small intestinal mucosa by fasting in mice was associated with increased CELF1/Myc mRNA association and decreased MYC expression. At the molecular level, CELF1 was found to bind the 3'-untranslated region (UTR) of Myc mRNA and repressed MYC translation without affecting total Myc mRNA levels. HuR interacted with the same Myc 3'-UTR element, and increasing the levels of HuR decreased CELF1 binding to Myc mRNA. In contrast, increasing the concentrations of CELF1 inhibited formation of the [HuR/Myc mRNA] complex. Depletion of cellular polyamines also increased CELF1 and enhanced CELF1 association with Myc mRNA, thus suppressing MYC translation. Moreover, ectopic CELF1 overexpression caused G1-phase growth arrest, whereas CELF1 silencing promoted cell proliferation. These results indicate that CELF1 represses MYC translation by decreasing Myc mRNA association with HuR and provide new insight into the molecular functions of RBPs in the regulation of intestinal mucosal growth.