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Background: Many cancers metastasize to the pleura, resulting in effusions that cause dyspnea and discomfort. Regardless of the tissue of origin, pleural malignancies are aggressive and uniformly fatal, with no treatment shown to prolong life. The pleural mesothelial monolayer is joined by tight junctions forming a contained bioreactor-like space, concentrating cytokines and chemokines secreted by the mesothelium, tumor, and infiltrating immune cells. This space represents a unique environment that profoundly influences tumor and immune cell behavior. Defining the pleural secretome is an important step in the rational development localized intrapleural immunotherapy. Method: We measured cytokine/chemokine content of 252 malignant pleural effusion (MPE) samples across multiple cancers using a 40-analyte panel and Luminex multiplexing technology. Results: Eleven analytes were consistently present in concentrations ≥ 10.0 pM: CXCL10/IP10 (geometric mean = 672.3 pM), CCL2/MCP1 (562.9 pM), sIL-6Rα (403.1 pM), IL-6 (137.6 pM), CXCL1/GRO (80.3 pM), TGFß1 (76.8 pM), CCL22/MDC (54.8 pM), CXCL8/IL-8 (29.2 pM), CCL11/Eotaxin (12.6 pM), IL-10 (11.3 pM), and G-CSF (11.0 pM). All are capable of mediating chemotaxis, promotion of epithelial to mesenchymal transition, or immunosuppression, and many of are reportedly downstream of a pro-inflammatory cytokine cascade mediated by cytokine IL-6 and its soluble receptor. Conclusion: The data indicate high concentrations of several cytokines and chemokines across epithelial cancers metastatic to the pleura and support the contention that the pleural environment is the major factor responsible for the clinical course of MPE across cancer types. A sIL-6Rα to IL-6 molar ratio of 2.7 ensures that virtually all epithelial, immune and vascular endothelial cells in the pleural environment are affected by IL-6 signaling. The central role likely played by IL-6 in the pathogenesis of MPE argues in favor of a therapeutic approach targeting the IL-6/IL-6R axis.
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Interleucina-6 , Derrame Pleural Maligno , Humanos , Derrame Pleural Maligno/metabolismo , Derrame Pleural Maligno/patología , Derrame Pleural Maligno/inmunología , Interleucina-6/metabolismo , Neoplasias Pleurales/metabolismo , Neoplasias Pleurales/patología , Neoplasias Pleurales/inmunología , Neoplasias Pleurales/secundario , Citocinas/metabolismo , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias Glandulares y Epiteliales/inmunología , Femenino , Masculino , Anciano , Biomarcadores de Tumor/metabolismo , Quimiocinas/metabolismo , Transducción de Señal , Microambiente Tumoral/inmunología , Persona de Mediana EdadRESUMEN
Human regulatory T cells (Tregs) are crucial regulators of tissue repair, autoimmune diseases, and cancer. However, it is challenging to inhibit the suppressive function of Tregs for cancer therapy without affecting immune homeostasis. Identifying pathways that may distinguish tumor-restricted Tregs is important, yet the transcriptional programs that control intratumoral Treg gene expression, and that are distinct from Tregs in healthy tissues, remain largely unknown. We profiled single-cell transcriptomes of CD4+ T cells in tumors and peripheral blood from patients with head and neck squamous cell carcinomas (HNSCC) and those in nontumor tonsil tissues and peripheral blood from healthy donors. We identified a subpopulation of activated Tregs expressing multiple tumor necrosis factor receptor (TNFR) genes (TNFR+ Tregs) that is highly enriched in the tumor microenvironment (TME) compared with nontumor tissue and the periphery. TNFR+ Tregs are associated with worse prognosis in HNSCC and across multiple solid tumor types. Mechanistically, the transcription factor BATF is a central component of a gene regulatory network that governs key aspects of TNFR+ Tregs. CRISPR-Cas9-mediated BATF knockout in human activated Tregs in conjunction with bulk RNA sequencing, immunophenotyping, and in vitro functional assays corroborated the central role of BATF in limiting excessive activation and promoting the survival of human activated Tregs. Last, we identified a suite of surface molecules reflective of the BATF-driven transcriptional network on intratumoral Tregs in patients with HNSCC. These findings uncover a primary transcriptional regulator of highly suppressive intratumoral Tregs, highlighting potential opportunities for therapeutic intervention in cancer without affecting immune homeostasis.
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Factores de Transcripción con Cremalleras de Leucina de Carácter Básico , Redes Reguladoras de Genes , Neoplasias de Cabeza y Cuello , Humanos , Enfermedades Autoinmunes , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Neoplasias de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Linfocitos T ReguladoresRESUMEN
Introduction: Treatment options for patients with malignant pleural effusions (MPE) are limited due, at least in part, to the unique environment of the pleural space, which drives an aggressive tumor state and governs the behavior of infiltrating immune cells. Modulation of the pleural environment may be a necessary step toward the development of effective treatments. We examine immune checkpoint molecule (ICM) expression on pleural T cells, the secretomes of pleural fluid, pleural infiltrating T cells (PIT), and ability to activate PIT ex vivo. Methods: ICM expression was determined on freshly drained and in vitro activated PIT from breast, lung and renal cell cancer. Secretomics (63 analytes) of activated PIT, primary tumor cultures and MPE fluid was determined using Luminex technology. Complementary digital spatial proteomic profiling (42 analytes) of CD45+ MPE cells was done using the Nanostring GeoMx platform. Cytolytic activity was measured against autologous tumor targets. Results: ICM expression was low on freshy isolated PIT; regulatory T cells (T-reg) were not detectable by GeoMx. In vitro activated PIT coexpressed PD-1, LAG-3 and TIGIT but were highly cytotoxic against autologous tumor and uniquely secreted cytokines and chemokines in the > 100 pM range. These included CCL4, CCL3, granzyme B, IL-13, TNFα, IL-2 IFNγ, GM-CSF, and perforin. Activated PIT also secreted high levels of IL-6, IL-8 and sIL-6Rα, which contribute to polarization of the pleural environment toward wound healing and the epithelial to mesenchymal transition. Addition of IL-6Rα antagonist to cultures reversed tumor EMT but did not alter PIT activation, cytokine secretion or cytotoxicity. Discussion: Despite the negative environment, immune effector cells are plentiful, persist in MPE in a quiescent state, and are easily activated and expanded in culture. Low expression of ICM on native PIT may explain reported lack of responsiveness to immune checkpoint blockade. The potent cytotoxic activity of activated PIT and a proof-of-concept clinical scale GMP-expansion experiment support their promise as a cellular therapeutic. We expect that a successful approach will require combining cellular therapy with pleural conditioning using immune checkpoint blockers together with inhibitors of upstream master cytokines such as the IL-6/IL-6R axis.
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Transición Epitelial-Mesenquimal , Derrame Pleural Maligno , Humanos , Interleucina-6 , Proteómica , Derrame Pleural Maligno/terapia , Citocinas , Linfocitos T Reguladores/patologíaRESUMEN
BACKGROUND/AIM: The earliest cellular and molecular biologic changes in the esophagus that lead to esophageal cancer were evaluated in a mouse model. We correlated numbers of senescent cells with the levels of expression of potentially carcinogenic genes in sorted side population (SP) cells containing esophageal stem cells and non-stem cells in the non-side population cells in the 4-nitroquinolone oxide (NQO)-treated esophagus. MATERIALS AND METHODS: We compared stem cells with non-stem cells from the esophagus of mice treated with the chemical carcinogen 4-NQO (100 µg/ml) in drinking water. We also compared gene expression in human esophagus samples treated with 4-NQO (100 µg/ml media) to non-treated samples. We separated and quantitated the relative levels of expression of RNA using RNAseq analysis. We identified senescent cells by luciferase imaging of p16+/LUC mice and senescent cells in excised esophagus from tdTOMp16+ mice. RESULTS: A significant increase in the levels of RNA for oncostatin-M was found in senescent cells of the esophagus from 4-NQO-treated mice and human esophagus in vitro. CONCLUSION: Induction of OSM in chemically-induced esophageal cancer in mice correlates with the appearance of senescent cells.
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Neoplasias Esofágicas , Nitroquinolinas , Humanos , Animales , Ratones , Carcinógenos , Óxidos , Mutágenos , Neoplasias Esofágicas/inducido químicamente , Neoplasias Esofágicas/genética , ARN , Oncostatina MRESUMEN
BACKGROUND: With the increasing use of computed tomography scans for lung cancer screening and surveillance of other cancers, thoracic surgeons are being referred patients with lung lesions for biopsies. Electromagnetic navigational bronchoscopy-guided lung biopsy is a relatively new technique for bronchoscopic biopsy. Our objective was to evaluate the diagnostic yields and safety of electromagnetic navigational bronchoscopy-guided lung biopsy. METHODS: We conducted a retrospective review of patients who underwent an electromagnetic navigational bronchoscopy biopsy, performed by a thoracic surgical service, and evaluated its safety and diagnostic accuracy. RESULTS: In total, 110 patients (men 46, women 64) underwent electromagnetic navigational bronchoscopy sampling of pulmonary lesions (n = 121; median size 27 mm; interquartile range 17-37 mm). There was no procedure-related mortality. Pneumothorax requiring pigtail drainage occurred in 4 patients (3.5%). Ninety-three (76.9%) of the lesions were malignant. Eighty-seven (71.9%) of the 121 lesions had an accurate diagnosis. Accuracy increased with increased lesion size (P = .0578) with a yield of 50% for lesions <2 cm, increasing to 81% for lesions ≥2 cm. The lesions that demonstrated a positive "bronchus sign" had a yield of 87% (45/52) compared with 61% (42/69) in lesions with a negative "bronchus sign" (P = .0359). CONCLUSION: Thoracic surgeons can perform electromagnetic navigational bronchoscopy safely, with minimal morbidity and with good diagnostic yields. Accuracy increases with the presence of a bronchus sign and increasing lesion size. Patients with larger tumors and the bronchus sign may be candidates for this approach to biopsy. Further work is required to define the role of electromagnetic navigational bronchoscopy in the diagnosis of pulmonary lesions.
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Broncoscopía , Neoplasias Pulmonares , Masculino , Humanos , Femenino , Broncoscopía/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/patología , Detección Precoz del Cáncer , Biopsia/métodos , Pulmón/diagnóstico por imagen , Pulmón/patología , Fenómenos ElectromagnéticosRESUMEN
OBJECTIVE: Robotic-assisted minimally invasive esophagectomy accounts for a growing proportion of esophagectomies, potentially due to improved technical capabilities simplifying the challenging aspects of standard minimally invasive esophagectomy. However, there is limited evidence directly comparing both operations. The objective is to evaluate the short-term and long-term outcomes of robotic-assisted minimally invasive esophagectomy in comparison with the minimally invasive esophagectomy approach for patients with esophageal cancer over a 7-year period at a high-volume center. The primary end points of this study were overall survival and disease-free survival. Secondary end points included operation-specific morbidity, lymph node yield, readmission status, and in-hospital, 30-day, and 90-day mortality. METHODS: Patients who underwent robotic-assisted minimally invasive esophagectomy or standard minimally invasive esophagectomy over a 7-year period were identified from a prospectively maintained database. Inclusion criteria were patients with stage I to III disease, operations performed past the learning curve, and no evidence of scleroderma or cirrhosis. A 1:3 propensity match (robotic-assisted minimally invasive esophagectomy:minimally invasive esophagectomy) for multiple clinical covariates was performed to identify the final study cohort. Perioperative outcomes were compared between the 2 operations. RESULTS: A total of 734 patients undergoing minimally invasive esophagectomy (n = 630) or robotic-assisted minimally invasive esophagectomy (n = 104) for esophageal cancer were identified. After exclusions and matching, a total cohort of 246 patients undergoing robotic-assisted minimally invasive esophagectomy (n = 65) or minimally invasive esophagectomy (n = 181) were identified. There was no difference in overall survival (P = .69) or disease-free survival (P = .70). There were no significant differences in rates of major morbidity: pneumonia (17% vs 17%, P = .34), chylothorax (8% vs 9%, P = .95), recurrent laryngeal nerve injury (0% vs 1.5%, P = 1), anastomotic leak (5% vs 4%, P = .49), intraoperative complications (9% vs 8%, P = .73), or complete resection rates (99% vs 96%, P = .68). There was no difference in in-hospital (P = .89), 30-day (P = .66) or 90-day mortality (P = .73) between both cohorts. The robotic-assisted minimally invasive esophagectomy cohort yielded a higher median lymph node harvest in comparison with the minimally invasive esophagectomy cohort (32 vs 29, P = .02). CONCLUSIONS: Robotic-assisted minimally invasive esophagectomy may improve lymphadenectomy in patients undergoing esophagectomy for cancer. Minimally invasive esophagectomy and robotic-assisted minimally invasive esophagectomy are otherwise associated with similar mortality, morbidity, and perioperative outcomes. Further prospective study is required to investigate whether improved lymph node resection may translate to improved oncologic outcomes.
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Neoplasias Esofágicas , Procedimientos Quirúrgicos Robotizados , Humanos , Esofagectomía/efectos adversos , Procedimientos Quirúrgicos Robotizados/efectos adversos , Resultado del Tratamiento , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Neoplasias Esofágicas/patología , Procedimientos Quirúrgicos Mínimamente Invasivos/efectos adversos , Estudios RetrospectivosRESUMEN
BACKGROUND: The safety of lung transplantation using ex vivo lung perfusion (EVLP) has been confirmed in multiple clinical studies; however, limited evidence is currently available regarding the potential effects of EVLP on posttransplant graft complications and survival with mid- to long-term follow-up. In this study, we reviewed our institutional data to better understand the impact of EVLP. METHODS: Lungs placed on EVLP from 2014 through 2020 and transplant outcomes were retrospectively analyzed. Data were compared between lungs transplanted and declined after EVLP, between patients with severe primary graft dysfunction (PGD3) and no PGD3 after EVLP, and between matched patients with lungs transplanted with and without EVLP. RESULTS: In total, 98 EVLP cases were performed. Changes in metabolic indicators during EVLP were correlated with graft quality and transplantability, but not changes in physiological parameters. Among 58 transplanted lungs after EVLP, PGD3 at 72 h occurred in 36.9% and was associated with preservation time, mechanical support prior to transplant, and intraoperative transfusion volume. Compared with patients without EVLP, patients who received lungs screened with EVLP had a higher incidence of PGD3 and longer ICU and hospital stays. Lung grafts placed on EVLP exhibited a significantly higher chance of developing airway anastomotic ischemic injury by 30 days posttransplant. Acute and chronic graft rejection, pulmonary function, and posttransplant survival were not different between patients with lungs screened on EVLP versus lungs with no EVLP. CONCLUSION: EVLP use is associated with an increase of early posttransplant adverse events, but graft functional outcomes and patient survival are preserved.
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Trasplante de Pulmón , Pulmón , Humanos , Circulación Extracorporea , Pulmón/fisiología , Trasplante de Pulmón/efectos adversos , Perfusión , Estudios RetrospectivosRESUMEN
In lung transplantation, postoperative outcomes favor intraoperative use of extracorporeal membrane oxygenation (ECMO) over cardiopulmonary bypass (CBP). We investigated the effect of intraoperative support strategies on endothelial injury biomarkers and short-term posttransplant outcomes. Adults undergoing bilateral lung transplantation with No-Support, venoarterial (V-A) ECMO, or CPB were included. Plasma samples pre- and post-transplant were collected for Luminex assay to measure endothelial injury biomarkers including syndecan-1 (SYN-1), intercellular adhesion molecule-1 (ICAM-1), and matrix metalloprotease-9. Fifty five patients were included for analysis. The plasma level of SYN-1 at arrival in the intensive care unit was significantly higher with CPB compared to V-A ECMO and No-Support (P < 0.01). The rate of primary graft dysfunction grade 3 (PGD3) at 72 hours was 60.0% in CPB, 40.1% in V-A ECMO, and 15% in No-Support (Pâ¯=â¯0.01). Postoperative plasma levels of SYN-1 and ICAM-1 were significantly higher in recipients who developed PGD3 at 72 hours. SYN-1 levels were also significantly higher in patients who developed acute kidney injury and hepatic dysfunction after transplant. Postoperative, SYN-1 upon intensive care arrival was found to be a significant predictive biomarker of PGD3, acute kidney injury, and hepatic dysfunction following lung transplantation. CPB is associated with higher plasma concentrations of SYN-1, a marker of endothelial glycocalyx degradation, upon arrival to the intensive care unit. Higher levels of SYN-1 are predictive of end-organ dysfunction following lung transplantation. Our data suggests that intraoperative strategies aimed at modulating endothelial injury will help improve lung transplantation outcomes.
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BACKGROUND: Right middle lobe syndrome is part of a spectrum of relatively rare but serious conditions that may occur following right upper lobectomy. We aimed to assess whether the preoperative middle lobe bronchial angle on CT predicted patients at risk of developing middle lobe syndrome. METHOD: All patients who had a complete upper lobectomy over 4 years were retrospectively reviewed for clinical and imaging findings of middle lobe syndrome. Patients with previous lung surgery, preoperative chemo- or radiation therapy, or more extensive surgical resection were excluded. Patient demographics and symptoms, the surgical, pathologic and bronchoscopy reports, and pre- and post-operative chest imaging, to include 3D CT reconstructions and measurements of the middle lobe angles in a subset of patients, were retrospectively reviewed. RESULT: One hundred and twenty-eight patients met inclusion criteria. Ten (8%) had middle lobe syndrome based on symptoms and imaging features. Eight had severe middle lobe consolidation. Two had postoperative onset of wheezing, with middle lobe bronchial abnormality on CT. The pre- and postoperative middle lobe bronchial angles of 14 patients without middle lobe syndrome were compared to 10 patients with middle lobe syndrome. The middle lobe bronchus was completely obliterated postoperatively and could not be determined in 1 patient. There was no significant difference between the pre- and postoperative angles in patients with or without middle lobe syndrome. CONCLUSION: Middle lobe syndrome occurred in 8% of patients with right upper lobectomy. The preoperative middle lobe bronchial angle did not predict patients at risk for developing middle lobe syndrome.
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Neoplasias Pulmonares , Síndrome del Lóbulo Medio , Humanos , Síndrome del Lóbulo Medio/diagnóstico por imagen , Síndrome del Lóbulo Medio/etiología , Síndrome del Lóbulo Medio/patología , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Neumonectomía/efectos adversos , Neumonectomía/métodos , Pulmón/cirugía , Bronquios/diagnóstico por imagen , Bronquios/cirugíaRESUMEN
BACKGROUND: Single-center studies support benefits of venoarterial extracorporeal membrane oxygenation (VA-ECMO) as a method of intraoperative support. Propensity-matched data from a large cohort, however, are currently lacking. Therefore, our goal was to compare outcomes of intraoperative VA-ECMO and cardiopulmonary bypass (CPB) during bilateral lung transplantation (LTx) with a propensity analysis. METHODS: We performed a retrospective analysis of 795 consecutive primary adult LTx patients (June 1, 2011-December 26, 2020) using no intraoperative support (n = 210), VA-ECMO (n = 150), or CPB (n = 197). Exclusion criteria included LTx on venovenous-ECMO, single/redo LTx, ex vivo lung perfusion, and concomitant solid-organ transplantation or cardiac procedure. Propensity analysis was performed comparing patients who underwent intraoperative CPB or VA-ECMO. RESULTS: The propensity CPB group required more blood products at 72 hours (P = .02) and longer intensive care unit length of stay (P < .001) and ventilator dependence days (P < .001). There were no differences in cerebrovascular accident (P = 1), reintubation (P = .4), dialysis (P = .068), in-hospital mortality (P = .33), and 1-year (P = .67) and 3-year (P = .32) survival. The CPB group had a higher incidence of grade 3 primary graft dysfunction at 72 hours (P < .001). Neither support strategy was a predictor of 1- and 3-year mortality in our multivariable model (VA-ECMO, P = .72 and P = .57; CPB, P = .45 and P = .91, respectively). CONCLUSIONS: Intraoperative VA-ECMO during lung transplantation was associated with fewer postoperative blood transfusions, shorter length of mechanical ventilation, and lower incidence of a grade 3 primary graft dysfunction at 72 hours. Although there were some differences in the postoperative course between the VA-ECMO and CPB groups, support type was not associated with differences in survival.
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Trasplante de Pulmón , Disfunción Primaria del Injerto , Adulto , Humanos , Estudios Retrospectivos , Resultado del Tratamiento , Trasplante de Pulmón/métodos , Puente Cardiopulmonar/métodosRESUMEN
Esophagectomy and colon interposition in the adult patient, either for primary alimentary reconstruction or as a secondary replacement after initial resection/reconstruction for malignant or benign disease, remains a valuable tool in the thoracic surgeon's armamentarium. It is important for surgeons to remain versed in the complexities of the operation, including preoperative preparation and decision making, operative procedural and technical variations, and recognition and timely treatment of postoperative complications. In this article, we present technical details of the procedure, a review of selected published studies, long-term results, and indications and outcomes for revisional surgery.
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Neoplasias Esofágicas , Midazolam , Adulto , Humanos , Colon/cirugía , Colon/patología , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/patología , Esofagectomía/métodos , Complicaciones Posoperatorias/cirugíaRESUMEN
Objective: This study's objective was to evaluate the scholastic and career effects of receiving either the American Association for Thoracic Surgery (AATS) Foundation research scholarship or surgical investigator program. Methods: AATS annual reports and recipient listings were used to generate the awardees. MEDLINE and SCOPUS were used to assess publications, citations, and H-Index for awardees. The National Institutes of Health (NIH) RePorter was used to collate NIH grant awarding to awardees. Publicly available institutional profiles were used to assess promotion status and leadership positions. Results: Awardees of the research scholarship had a median of 4733 citations and a median H-Index of 33. The surgical investigator program recipients had a median of 1346 citations with a median H-Index of 17. Across both funding mechanisms, 45% secured subsequent NIH funding. Most awardees received an academic promotion, with 62% of the research scholarship awardees promoted to full professor and 37% of the surgical investigator program to associate professor. Approximately half (48%) of all awardees hold leadership positions, with most being a clinical director or division chief. Conclusions: Receiving the AATS Foundation research scholarship or surgical investigator program positions early-career cardiothoracic surgeons for a promising future in academic surgery.
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Postoperative acute respiratory distress syndrome (ARDS) following a general thoracic procedure is associated with high morbidity and mortality. Extracorporeal membrane oxygenation (ECMO) offers an alternate means of cardiopulmonary support in the setting of refractory respiratory failure. We report indications and outcomes patients who after complex general thoracic surgery developed ARDS requiring ECMO support. We performed a retrospective analysis of all patients requiring venovenous (VV) ECMO support in the postoperative period following a general thoracic surgical procedure from January 2011 to December 2019. Exclusion criteria include those who underwent a cardiac procedure, venoarterial (VA) ECMO, cardiothoracic transplantation, or required ECMO only for intraoperative support. Forty instances of postoperative VV ECMO were utilized in patients who underwent a surgery with the thoracic surgical service. Lung procedures were the most common index operations performed (45%) followed by esophageal procedures (40%). Mean time to ECMO initiation from the index operation was 5.45 days with a range of 0 days to 1.3 months. Median length of ECMO support was 9.41 days with a range of 12 hours to 33 days. Patients were cannulated in an elective (70%) or emergent (30%) fashion. ECMO-related complications included a major bleeding event in seven patients. Thirty day survival was 62.5% for the entire cohort and 52.5% of patients were discharged from the hospital and 80.95% of these patients were still alive 90 days after discharge. ECMO is a viable means of cardiopulmonary support that can provide a survival advantage for patients who experience severe refractory respiratory failure following a complex general thoracic surgery.
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Síndrome de Dificultad Respiratoria , Insuficiencia Respiratoria , Cirugía Torácica , Procedimientos Quirúrgicos Torácicos , Humanos , Estudios Retrospectivos , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/terapia , Procedimientos Quirúrgicos Torácicos/efectos adversos , Procedimientos Quirúrgicos Torácicos/métodos , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/terapiaRESUMEN
Tumor-associated macrophages (TAMs) exert profound influence over breast cancer progression, promoting immunosuppression, angiogenesis, and metastasis. Neuropilin-2 (NRP2), consisting of the NRP2a and NRP2b isoforms, is a co-receptor for heparin-binding growth factors including VEGF-C and Class 3 Semaphorins. Selective upregulation in response to environmental stimuli and independent signaling pathways endow the NRP2 isoforms with unique functionality, with NRP2b promoting increased Akt signaling via receptor tyrosine kinases including VEGFRs, MET, and PDGFR. Although NRP2 has been shown to regulate macrophage/TAM biology, the role of the individual NRP2a/NRP2b isoforms in TAMs has yet to be evaluated. Using transcriptional profiling and spectral flow cytometry, we show that NRP2 isoform expression was significantly higher in TAMs from murine mammary tumors. NRP2a/NRP2b levels in human breast cancer metastasis were dependent upon the anatomic location of the tumor and significantly correlated with TAM infiltration in both primary and metastatic breast cancers. We define distinct phenotypes of NRP2 isoform-expressing TAMs in mouse models of breast cancer and within malignant pleural effusions from breast cancer patients which were exclusive of neuropilin-1 expression. Genetic depletion of either NRP2 isoform in macrophages resulted in a dramatic reduction of LPS-induced IL-10 production, defects in phagosomal processing of apoptotic breast cancer cells, and increase in cancer cell migration following co-culture. By contrast, depletion of NRP2b, but not NRP2a, inhibited production of IL-6. These results suggest that NRP2 isoforms regulate both shared and unique functionality in macrophages and are associated with distinct TAM subsets in breast cancer.
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Neoplasias de la Mama , Neuropilina-2 , Animales , Neoplasias de la Mama/patología , Femenino , Humanos , Ratones , Neuropilina-1/genética , Neuropilina-2/genética , Neuropilina-2/metabolismo , Isoformas de Proteínas , Macrófagos Asociados a TumoresRESUMEN
Metastasis to the pleural and peritoneal cavities is a common terminal pathway for a wide variety of cancers. This article explores how these unique environments both promote aggressive tumor behavior and suppresses anti-tumor immunity, and ways in which local delivery of protein therapeutics can leverage the contained nature of these spaces to a therapeutic advantage, achieving high intra-cavital concentrations while minimizing systemic toxicity.
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Derrame Pleural Maligno , Humanos , Inmunoterapia , Derrame Pleural Maligno/metabolismo , Cirugía Torácica Asistida por VideoRESUMEN
BACKGROUND: We studied humoral responses after coronavirus disease 2019 (COVID-19) vaccination across varying causes of immunodeficiency. METHODS: Prospective study of fully vaccinated immunocompromised adults (solid organ transplant [SOT], hematologic malignancy, solid cancers, autoimmune conditions, human immunodeficiency virus [HIV]) versus nonimmunocompromised healthcare workers (HCWs). The primary outcome was the proportion with a reactive test (seropositive) for immunoglobulin G to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain. Secondary outcomes were comparisons of antibody levels and their correlation with pseudovirus neutralization titers. Stepwise logistic regression was used to identify factors associated with seropositivity. RESULTS: A total of 1271 participants enrolled: 1099 immunocompromised and 172 HCW. Compared with HCW (92.4% seropositive), seropositivity was lower among participants with SOT (30.7%), hematological malignancies (50.0%), autoimmune conditions (79.1%), solid tumors (78.7%), and HIV (79.8%) (P < .01). Factors associated with poor seropositivity included age, greater immunosuppression, time since vaccination, anti-CD20 monoclonal antibodies, and vaccination with BNT162b2 (Pfizer) or adenovirus vector vaccines versus messenger RNA (mRNA)-1273 (Moderna). mRNA-1273 was associated with higher antibody levels than BNT162b2 or adenovirus vector vaccines after adjusting for time since vaccination, age, and underlying condition. Antibody levels were strongly correlated with pseudovirus neutralization titers (Spearman râ =â 0.89, Pâ <â .0001), but in seropositive participants with intermediate antibody levels, neutralization titers were significantly lower in immunocompromised individuals versus HCW. CONCLUSIONS: Antibody responses to COVID-19 vaccines were lowest among SOT and anti-CD20 monoclonal recipients, and recipients of vaccines other than mRNA-1273. Among those with intermediate antibody levels, pseudovirus neutralization titers were lower in immunocompromised patients than HCWs. Additional SARS-CoV-2 preventive approaches are needed for immunocompromised persons, which may need to be tailored to the cause of immunodeficiency.
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COVID-19 , Infecciones por VIH , Adulto , Anticuerpos Antivirales , Vacuna BNT162 , COVID-19/prevención & control , Vacunas contra la COVID-19 , Infecciones por VIH/complicaciones , Humanos , Huésped Inmunocomprometido , Estudios Prospectivos , SARS-CoV-2 , VacunaciónRESUMEN
OBJECTIVES: Oesophagectomy was always recommended after noncurative endoscopic resection (ER). And the optimal time interval from ER to oesophagectomy remains unclear. This study was to explore the effect of interval on pathologic stage and prognosis. METHODS: We included 155 patients who underwent ER for cT1N0M0 oesophageal cancer and then received subsequent oesophagectomy from 2009 to 2019. Overall survival and disease-free survival (DFS) were analysed to find an optimal cut-off of interval from ER to oesophagectomy. In addition, pathologic stage after ER was compared to that of oesophagectomy. Logistic regression model was built to identify risk factors for pathological upstage. RESULTS: The greatest difference of DFS was found in the groups who underwent oesophagectomy before and after 30 days (P = 0.016). Among total 155 patients, 106 (68.39%) received oesophagectomy within 30 days, while 49 (31.61%) had interval over 30 days. Comparing the pathologic stage between ER and oesophagectomy, 26 patients had upstage and thus had worse DFS (hazard ratio = 3.780, P = 0.042). T1b invasion, lymphovascular invasion and interval >30-day group had a higher upstage rate (P = 0.014, P < 0.001 and P < 0.001, respectively). And they were independent risk factors for pathologic upstage (odds ratio = 3.782, 4.522 and 2.844, respectively). CONCLUSIONS: It was the first study exploring the relationship between time interval and prognosis in oesophageal cancer. The longer interval between noncurative ER and additional oesophagectomy was associated with a worse DFS, so oesophagectomy was recommended performed within 1 month after ER. Older age, T1b stage, lymphovascular invasion and interval >30 days were significantly associated with pathologic upstage, which is related to the worse outcome too.
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Adenocarcinoma , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Humanos , Esofagectomía/efectos adversos , Carcinoma de Células Escamosas/patología , Pronóstico , Adenocarcinoma/patología , Estudios RetrospectivosRESUMEN
BACKGROUND: Methods to assess competency in cardiothoracic training are essential. Here, we report a system that allows us to better assess competency from the perspective of both the trainee and educator. We hypothesized that postprocedural cognitive burden measurement (by the trainee) with immediate feedback (from the educator) could aid in identifying barriers to the acquisition of skills and knowledge so that training curricula can be individualized. METHODS: The National Aeronautics and Space Administration Task Load Index (NASA-TLX), a validated instrument to measure cognitive load, was administered with an online platform after bronchoscopy, esophagogastroduodenoscopy, and video-assisted thoracoscopic surgery for 11 residents. Immediate postprocedure feedback and standardized debriefing occurred for each procedure. RESULTS: Mean NASA-TLX scores were highest (indicating greater cognitive load) for esophagogastroduodenoscopy and video-assisted thoracoscopic surgery (P < .001). When comparing subscale measures, mental demand was significantly higher for video-assisted thoracoscopic surgery (P = .026) compared with the other procedures, whereas physical demand was highest for esophagogastroduodenoscopy (P = .018). Self-reported frustration was similar for all case types (P = .247). Cognitive burden decreased with a greater number of procedures for bronchoscopy (P = .027). Significant improvement was noted by the trainee at the end of the rotation in self-assessed procedural competency and preparedness for thoracic board topics (all P < .05). Postprocedure feedback by the attending surgeon correlated with more frequent completion of self-evaluations by the residents. CONCLUSIONS: Longitudinal assessment of cognitive load in combination with postprocedural feedback identified barriers to skill acquisition for both residents and educators. This information allows for individualized rotation development as a step toward a competency-based curriculum.
Asunto(s)
Internado y Residencia , Cirujanos , Competencia Clínica , Cognición , Curriculum , Retroalimentación , HumanosRESUMEN
BACKGROUND: While robotic-assisted lung resection has seen a significant rise in adoption, concerns remain regarding initial programmatic outcomes and potential increased costs. We present our initial outcomes and cost analysis since initiation of a robotic lung resection program. METHODS: Patients undergoing either video-assisted thoracoscopic lobectomy or segmentectomy (VATS) or robotic-assisted lobectomy or segmentectomy (RALS) between August of 2014 and January of 2017 underwent retrospective review. Patients underwent 1:1 propensity matching based on preoperative characteristics. Perioperative and 30-day outcomes were compared between groups. Detailed activity-based costing analysis was performed on individual patient encounters taking into effect direct and indirect controllable costs, including robotic operative supplies. RESULTS: There were no differences in 30-day mortality between RALS (n = 74) and VATS (n = 74) groups (0% vs 1.4%; P = 1). RALS patients had a decreased median length of stay (4 days vs 7 days; P < .001) and decreased median chest tube duration (3 days vs 5 days, P < .001). Total direct costs, including direct supply costs, were not significantly different between RALS and VATS ($6621 vs $6483; P = .784). Median total operating costs and total unit support costs, which are closely correlated to length of stay, were lower in the RALS group. Overall median controllable costs were significantly different between RALS and VATS ($16,352 vs $21,154; P = .025). CONCLUSIONS: A potentially cost-advantageous robotic-assisted pulmonary resection program can be initiated within the context of an existing minimally invasive thoracic surgery program while maintaining good clinical outcomes when compared with traditional VATS. Process-of-care changes associated with RALS may account for decreased costs in this setting.