Adaptive plasticity of IL-10+ and IL-35+ Treg cells cooperatively promotes tumor T cell exhaustion.

Regulatory T cells (Treg cells) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. Treg cells subvert beneficial anti-tumor immunity by modulating inhibitory receptor expression on tumor-infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms have remained elusive. Here, we found that the cytokines IL-10 and IL-35 (Ebi3-IL-12α heterodimer) were divergently expressed by Treg cell subpopulations in the tumor microenvironment (TME) and cooperatively promoted intratumoral T cell exhaustion by modulating several inhibitory receptor expression and exhaustion-associated transcriptomic signature of CD8+ TILs. While expression of BLIMP1 (encoded by Prdm1) was a common target, IL-10 and IL-35 differentially affected effector T cell versus memory T cell fates, respectively, highlighting their differential, partially overlapping but non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated cooperative roles for Treg cell-derived IL-10 and IL-35 in promoting BLIMP1-dependent exhaustion of CD8+ TILs that limits effective anti-tumor immunity.

Single-center experience of ex vivo lung perfusion and subsequent lung transplantation.

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.

Prospective Evaluation of Coronavirus Disease 2019 (COVID-19) Vaccine Responses Across a Broad Spectrum of Immunocompromising Conditions: the COVID-19 Vaccination in the Immunocompromised Study (COVICS).

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 r = 0.89, P < .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.

Worldwide Techniques and Outcomes in Robot-assisted Minimally Invasive Esophagectomy (RAMIE): Results From the Multicenter International Registry.

OBJECTIVE: This international multicenter study by the Upper GI International Robotic Association aimed to gain insight in current techniques and outcomes of RAMIE worldwide. BACKGROUND: Current evidence for RAMIE originates from single-center studies, which may not be generalizable to the international multicenter experience. METHODS: Twenty centers from Europe, Asia, North-America, and South-America participated from 2016 to 2019. Main endpoints included the surgical techniques, clinical outcomes, and early oncological results of ramie. RESULTS: A total of 856 patients undergoing transthoracic RAMIE were included. Robotic surgery was applied for both the thoracic and abdominal phase (45%), only the thoracic phase (49%), or only the abdominal phase (6%). In most cases, the mediastinal lymphadenectomy included the low paraesophageal nodes (n=815, 95%), subcarinal nodes (n = 774, 90%), and paratracheal nodes (n = 537, 63%). When paratracheal lymphadenectomy was performed during an Ivor Lewis or a McKeown RAMIE procedure, recurrent laryngeal nerve injury occurred in 3% and 11% of patients, respectively. Circular stapled (52%), hand-sewn (30%), and linear stapled (18%) anastomotic techniques were used. In Ivor Lewis RAMIE, robot-assisted hand-sewing showed the highest anastomotic leakage rate (33%), while lower rates were observed with circular stapling (17%) and linear stapling (15%). In McKeown RAMIE, a hand-sewn anastomotic technique showed the highest leakage rate (27%), followed by linear stapling (18%) and circular stapling (6%). CONCLUSION: This study is the first to provide an overview of the current techniques and outcomes of transthoracic RAMIE worldwide. Although these results indicate high quality of the procedure, the optimal approach should be further defined.

Prolonged Air Leak After Pulmonary Resection Increases Risk of Noncardiac Complications, Readmission, and Delayed Hospital Discharge: A Propensity Score-adjusted Analysis.

OBJECTIVE: The aim of the study was to determine whether prolonged air leak (PAL) is associated with postoperative morbidity and mortality following pulmonary resection after adjusting for differences in baseline characteristics using propensity score analysis. SUMMARY BACKGROUND DATA: Patients with PAL after lung resection have worse outcomes than those without PAL. However, adverse postoperative outcomes may also be secondary to baseline risk factors, such as poor lung function. METHODS: Patients who underwent pulmonary resection for lung cancer/nodules (1/2009-6/2014) were stratified by the presence of PAL [n = 183 with/1950 without; defined as >5 d postoperative air leak; n = 189 (8.3%)]; probability estimates for propensity for PAL from 31 pretreatment/intraoperative variables were generated. Inverse probability-of-treatment weights were applied and outcomes assessed with logistic regression. RESULTS: Standardized bias between groups was significantly reduced after propensity weighting (mean = 0.18 before vs 0.08 after, P < 0.01). After propensity weighting, PAL was associated with increased odds of empyema (OR = 8.5; P < 0.001), requirement for additional chest tubes for pneumothorax (OR = 7.5; P < 0.001), blood transfusion (OR = 2; P = 0.03), pulmonary complications (OR = 4; P < 0.001), unexpected return to operating room (OR = 4; P < 0.001), and 30-day readmission (OR = 2; P = 0.009). Among other complications, odds of cardiac complications (P = 0.493), unexpected ICU admission (P = 0.156), and 30-day mortality (P = 0.270) did not differ. Length of hospital stay was prolonged (5.04 d relative effect, 95% confidence interval, 3.77-6.30; P < 0.001). CONCLUSIONS: Pulmonary complications, readmission, and delayed hospital discharge are directly attributable to having a PAL, whereas cardiac complications, unexpected admission to the ICU, and 30-day mortality are not after propensity score adjustment.

Fighting Fire With Fire: Oncolytic Virotherapy for Thoracic Malignancies.

Thoracic malignancies are associated with high mortality rates. Conventional therapy for many of the patients with thoracic malignancies is obviated by a high incidence of locoregional recurrence and distant metastasis. Fortunately, developments in immunotherapy provide effective strategies for both local and systemic treatments that have rapidly advanced during the last decade. One promising approach to cancer immunotherapy is to use oncolytic viruses, which have the advantages of relatively high tumor specificity, selective replication-mediated oncolysis, enhanced antigen presentation, and potential for delivery of immunogenic payloads such as cytokines, with subsequent elicitation of effective antitumor immunity. Several oncolytic viruses including adenovirus, coxsackievirus B3, herpes virus, measles virus, reovirus, and vaccinia virus have been developed and applied to thoracic cancers in preclinical murine studies and clinical trials. This review discusses the current state of oncolytic virotherapy in lung cancer, esophageal cancer, and metastatic malignant pleural effusions and considers its potential as an emergent therapeutic for these patients.

The ideal approach for treatment of cT1N+ and cT2Nany esophageal cancer.: a NCDB analysis.

BACKGROUND: Neoadjuvant therapy followed by surgery is recommended for locally advanced esophageal cancer. With the inaccuracies of clinical staging particularly for cT1N+ and cT2Nany tumors, some have proposed consideration of surgery followed by adjuvant treatment. Our objective is to evaluate the efficacy of neoadjuvant therapy vs surgery followed by adjuvant therapy, and to identify the ideal sequence of treatment in patients with cT1N+ and cT2Nany tumors. METHODS: We performed an analysis utilizing the National Cancer Database (2006-2015) identifying all patients with cT1N+ and cT2Nany esophageal cancer undergoing esophagectomy. The treatment was stratified as: neoadjuvant therapy (NT), adjuvant therapy (AT) and combination therapy of neoadjuvant and adjuvant (CT) groups and outcomes were analyzed. RESULTS: We identified 2795 patients with 81.9% (n=2289) receiving NT, 10.2% (n=285) AT, and 7.9% (n=221) CT. There were no significant differences noted in survival among AT, NT, and CT group in cT1N+(P=0.376), cT2N-(P=0.436), cT2N+(P=0.261) esophageal cancer by multivariate analysis using Cox regression model. This relationship held true in both squamous cell carcinoma and adenocarcinoma. CONCLUSION: In clinical T1N+, T2Nany patients, there was no evident superiority of NT over AT. Surgery followed by adjuvant therapy can be considered to be an alternative option in these patients. Further prospective studies are needed to validate these findings.

Lung transplantation for the treatment of irreversible acute respiratory distress syndrome.

BACKGROUND: Despite advances in critical care for acute respiratory distress syndrome (ARDS), some survivors in the acute phase are unable to wean from extracorporeal membrane oxygenation (ECMO) or mechanical ventilation. To date, little is known regarding whether lung transplantation confers a survival benefit for irreversible ARDS. METHODS: This retrospective study was conducted using the United Network for Organ Sharing database (May 2005-December 2018). Patients with restrictive lung disease were divided into two groups: patients with and without ARDS. Propensity score matching identified recipients without ARDS for the control group. RESULTS: A total of 63 patients with ARDS were waitlisted for lung transplantation, while 39 received a lung transplant after a median waitlist duration of 8 days. Seventy-eight patients were matched as controls. In the ARDS group, the median age was 30 years, and the median lung allocation score was 88.4. Among the 39 recipients, 30 (76.9%) received ECMO support prior to transplantation. Lung transplantation for ARDS and restrictive lung disease showed similar 90-day (87.2% vs. 88.5%, p = .80), 1-year (82.1% vs. 85.9%, p = .52), and 3-year (69.2% vs. 65.4%, p = .94) survival rates. CONCLUSIONS: Lung transplantation provides acceptable outcomes in selected patients with irreversible ARDS.

Racial disparities in local therapy for early stage non-small-cell lung cancer.

OBJECTIVES: This study investigated disparities in the delivery of definitive therapy for early stage non-small-cell lung cancer (ESNSCLC) between Caucasian (CS) and African American (AA) populations. METHODS: The National Cancer Data Base was queried for AA and CS patients, diagnosed with c stage I Non small cell lung cancer between 2004 and 2015. Trends in surgery, stereotactic ablative radiotherapy (SABR), or external beam radiation therapy (EBRT) were compared. Kaplan-Meier and Cox hazards models were used to compare 5-year overall survival (5YOS). RESULTS: A total of 174,338 (90.6%) patients were CS and 18,077 (9.4%) patients were AA. AA patients were less likely to receive surgery (60.3% vs. 66.9%; p < .001) and more likely to receive EBRT (12.4% vs. 10.6%; p < .001); however, there was no significant difference in rates of SABR (8.8% vs. 9.2%; p = .066). From 2004 to 2015, the surgery rates increased for AA patients from 44.4% to 61.8% and for CS patients from 57.6% to 65.6%. AA patients had worse 5YOS on an unadjusted analysis (46.7% vs. 47.9%; p = .009). When adjusted for definitive treatment, AA patients had improved survival (hazard ratio = 0.97, 95% confidence interval = 0.94-0.99). CONCLUSION: Improvements in the delivery of surgery and equal utilization of definitive radiation therapy are at least partially responsible for closing the survival gap between AA and CS patients with ESNSCLC.

Higher lymph node harvest in patients with a pathologic complete response after neoadjuvant therapy for esophageal cancer is associated with improved survival.

BACKGROUND AND OBJECTIVES: Lymph node harvest during esophagectomy has been associated with improved survival for esophageal cancer but the value of enhanced lymph node harvest following complete pathologic response (pCR) is debated. This study investigated if increasing lymph node harvest in esophageal cancer patients with a pCR after neoadjuvant therapy and esophagectomy is associated with improved survival. METHODS: We queried the National Cancer Data Base for patients with esophageal cancer between 2004 and 2014 who underwent neoadjuvant chemotherapy or chemoradiation therapy followed by esophagectomy found to have pCR. Multivariable Cox modeling was utilized to evaluate the impact of increasing lymph node counts on overall survival (OS). RESULTS: A total of 1373 patients met inclusion criteria. A National Comprehensive Cancer Network compliant lymphadenectomy of ≥15 nodes was associated with improved survival (66.7% vs 51.1%; P < .001). Cox modeling showed that the first node cutoff to demonstrate a statistically significant improvement in OS was ≥7 nodes (hazard ratio [HR], 95% confidence interval [CI]: 0.81, 0.68-0.97; 5-year OS: 54.2%) with a trend of decreasing and statistically significant HRs until ≥25 nodes (HR, 95% CI: 0.52, 0.37-0.72; 5-year OS: 68.4%). CONCLUSIONS: High negative node counts after neoadjuvant therapy and esophagectomy are associated with improved survival in patients with pCR.

The impact of COVID-19 on thoracic surgery residency programs in the US: A program director survey.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) has altered how the current generation of thoracic surgery residents are being trained. The aim of this survey was to determine how thoracic surgery program directors (PDs) are adapting to educating residents during the COVID-19 pandemic. METHODS: Thoracic surgery PDs of integrated, traditional (2 or 3 year), and combined 4 + 3 general/thoracic surgery training programs in the United States were surveyed between 17th April and 1st May 2020 during the peak of the COVID-19 pandemic in much of the United States. The 15-question electronic survey queried program status, changes to the baseline surgical practice, changes to didactic education, deployment/scheduling of residents, and effect of the pandemic on case logs and preparedness for resident graduation. RESULTS: All 23 institutions responding had ceased elective procedures, and most had switched to telemedicine clinic visits. Online virtual didactic sessions were implemented by 91% of programs, with most (69.6%) observing same or increased attendance. PDs reported that 82.7% of residents were on a non-standard schedule, with most being deployed in a 1 to 2 week on, 1 to 2 week off block schedule. Case volumes were affected for both junior and graduating trainees, but a majority of PDs report that graduating residents will graduate on time without perceived negative effect on first career/fellowship position. CONCLUSIONS: The COVID-19 pandemic has radically changed the educational approach of thoracic surgery programs. PDs are adapting educational delivery to optimize training and safety during the pandemic. Long-term effects remain uncertain and require additional study.

Characteristics of Malignant Pleural Effusion Resident CD8+ T Cells from a Heterogeneous Collection of Tumors.

While T cell-based cancer immunotherapies have shown great promise, there remains a need to understand how individual metastatic tumor environments impart local T cell dysfunction. At advanced stages, cancers that metastasize to the pleural space can result in a malignant pleural effusion (MPE) that harbors abundant tumor and immune cells, often exceeding 108 leukocytes per liter. Unlike other metastatic sites, MPEs are readily and repeatedly accessible via indwelling catheters, providing an opportunity to study the interface between tumor dynamics and immunity. In the current study, we examined CD8+ T cells within MPEs collected from patients with heterogeneous primary tumors and at various stages in treatment to determine (1) if these cells possess anti-tumor activity following removal from the MPE, (2) factors in the MPE that may contribute to their dysfunction, and (3) the phenotypic changes in T cell populations that occur following ex vivo expansion. Co-cultures of CD8+ T cells with autologous CD45- tumor containing cells demonstrated cytotoxicity (p = 0.030) and IFNγ production (p = 0.003) that inversely correlated with percent of myeloid derived suppressor cells, lactate, and lactate dehydrogenase (LDH) within the MPE. Ex vivo expansion of CD8+ T cells resulted in progressive differentiation marked by distinct populations expressing decreased CD45RA, CCR7, CD127, and increased inhibitory receptors. These findings suggest that MPEs may be a source of tumor-reactive T cells and that the cellular and acellular components suppress optimal function.

Outcomes after lung transplantation for patients with occupational lung diseases.

Occupational lung diseases (OLD) including silicosis, asbestosis, and pneumoconiosis progress to end stage lung disease requiring lung transplantation (LT). Prognosis and treatment of OLDs are poorly understood and a paucity of data exists regarding LT outcomes. Additionally, transplant operative complexity for patients with OLD is high. A single center retrospective review of all single and bilateral LT recipients between May 2005 and Oct 2016 was performed. Patients were grouped by OLD, and nearest neighbor matching was performed at a ratio of 1:3 cases to controls. Thirty cases were matched to 88 controls. Seventeen patients (57%) with OLD required intraoperative support with either extra-corporeal membrane oxygenation (ECMO) or cardiopulmonary bypass (P = 0.02), and 5 (17%) required delayed chest closure (P = 0.05) which was more frequent than matched controls. In addition, operative time was significantly longer in patients with OLD (P = 0.03). Despite these factors, there were no significant differences in immediate post-operative outcomes including mechanical ventilator support, post-operative ECMO, and tracheostomy. Chronic lung allograft dysfunction and long-term survival were also similar between cases and controls. OLDs should not preclude LT. The operation should be performed at experienced centers.

Evaluation of a simulation-based mini-elective on medical student interest in cardiac surgery.

BACKGROUND: Integrated cardiothoracic (CT) surgery training programs are an increasingly popular pathway to train CT surgeons. Identifying and engaging medical students early is important to generate interest and ensure highly qualified applicants are aware of opportunities provided by a career in CT surgery. METHODS: An optional CT surgery "mini-elective" was developed for preclinical medical students consisting of five 2-hour sessions covering major procedures in cardiac surgery. Each session had an inital 1 hour lecture immediatly followed by a hands on simulation component. Sessions were taught by CT surgery faculty and residents. A precourse and postcourse survey was administered to identify interest in and awareness of the field of CT surgery. RESULTS: There were 22 students enrolled in the course who provided precourse surveys, while 21 provided postcourse surveys. CT surgery was a career consideration for 95.4% of students who took the mini-elective. nine percent of the students who had either scrubbed or observed a CT case precourse, increased to 33.3% postcourse (P = .11). With regards to mentorship, 23.8% felt they could easily find a mentor in CT surgery precourse, increasing to 66.7% postcourse (P = .01). Eighty-one percent of students reported that the mini-elective significantly increased their CT knowledge over the standard cardiovascular curriculum, and 100% of those completing the course were "extremely satisfied" with the experience. CONCLUSIONS: A CT surgery mini-elective increased awareness and interest in the field among preclinical medical students. Longitudinal exposure and mentorship provided in programs such as this will be key to the continued recruitment of high-quality medical students to the field.

Extreme chromosome 17 copy number instability is a prognostic factor in patients with gastroesophageal adenocarcinoma: A retrospective cohort study.

Gastric and esophageal cancers frequently show genomic instability and aneuploidy. Chromosomal copy number instability (CIN) is a form of genomic instability that exerts pleiotropic effects on cellular biology and is a source of genetic heterogeneity in a population of cells. CIN results in cell-to-cell variation in chromosome copy number which can be detected and quantified by fluorescence in situ hybridization (FISH). CIN is a biomarker associated with differential response to a number of chemotherapy compounds. We quantified chromosome 17 copy number instability (CIN-17) in 348 gastroesophageal adenocarcinomas by centromeric FISH in cases that were tested for HER2 amplification. We evaluated the association between CIN-17 and clinical outcome after surgical and nonsurgical treatment. CIN-17 was detected in 45.4% (158/348) and extreme CIN-17 in 28.4% (99/348). Extreme CIN-17 had no association with outcome in surgically treated patients. However, in patients treated with conventional radiation and/or chemotherapy, extreme CIN-17 was associated with 55% reduction in overall mortality (hazard ratio, 0.448; 95% confidence interval, 0.263-0.763) after adjusting for age and clinical stage at diagnosis. Extreme CIN-17 is detected in over a quarter of gastroesophageal adenocarcinomas and is a favorable prognostic marker in patients treated nonoperatively.

MAN2A1-FER Fusion Gene Is Expressed by Human Liver and Other Tumor Types and Has Oncogenic Activity in Mice.

BACKGROUND & AIMS: Human tumors and liver cancer cell lines express the product of a fusion between the first 13 exons in the mannosidase α class 2A member 1 gene (MAN2A1) and the last 6 exons in the FER tyrosine kinase gene (FER), called MAN2A1-FER. We investigated whether MAN2A1-FER is expressed by human liver tumors and its role in liver carcinogenesis. METHODS: We performed reverse transcription polymerase chain reaction analyses of 102 non-small cell lung tumors, 61 ovarian tumors, 70 liver tumors, 156 glioblastoma multiform samples, 27 esophageal adenocarcinomas, and 269 prostate cancer samples, as well as 10 nontumor liver tissues and 20 nontumor prostate tissues, collected at the University of Pittsburgh. We also measured expression by 15 human cancer cell lines. We expressed a tagged form of MAN2A1-FER in NIH3T3 and HEP3B (liver cancer) cells; Golgi were isolated for analysis. MAN2A1-FER was also overexpressed in PC3 or DU145 (prostate cancer), NIH3T3 (fibroblast), H23 (lung cancer), and A-172 (glioblastoma multiforme) cell lines and knocked out in HUH7 (liver cancer) cells. Cells were analyzed for proliferation and in invasion assays, and/or injected into flanks of severe combined immunodeficient mice; xenograft tumor growth and metastasis were assessed. Mice with hepatic deletion of PTEN were given tail-vein injections of MAN2A1-FER. RESULTS: We detected MAN2A1-FER messenger RNA and fusion protein (114 kD) in the hepatocellular carcinoma cell line HUH7, as well as in liver tumors, esophageal adenocarcinoma, glioblastoma multiforme, prostate tumors, non-small cell lung tumors, and ovarian tumors, but not nontumor prostate or liver tissues. MAN2A1-FER protein retained the signal peptide for Golgi localization from MAN2A1 and translocated from the cytoplasm to Golgi in cancer cell lines. MAN2A1-FER had tyrosine kinase activity almost 4-fold higher than that of wild-type FER, and phosphorylated the epidermal growth factor receptor at tyrosine 88 in its N-terminus. Expression of MAN2A1-FER in 4 cell lines led to epidermal growth factor receptor activation of BRAF, MEK, and AKT; HUH7 cells with MAN2A1-FER knockout had significant decreases in phosphorylation of these proteins. Cell lines that expressed MAN2A1-FER had increased proliferation, colony formation, and invasiveness and formed larger (>2-fold) xenograft tumors in mice, with more metastases, than cells not expressing the fusion protein. HUH7 cells with MAN2A1-FER knockout formed smaller xenograft tumors, with fewer metastases, than control HUH7 cells. HUH7, A-172, and PC3 cells that expressed MAN2A1-FER were about 2-fold more sensitive to the FER kinase inhibitor crizotinib and the epidermal growth factor receptor kinase inhibitor canertinib; these drugs slowed growth of xenograft tumors from MAN2A1-FER cells and prevented their metastasis in mice. Hydrodynamic tail-vein injection of MAN2A1-FER resulted in rapid development of liver cancer in mice with hepatic disruption of Pten. CONCLUSIONS: Many human tumor types and cancer cell lines express the MAN2A1-FER fusion, which increases proliferation and invasiveness of cancer cell lines and has liver oncogenic activity in mice.

Does delayed esophagectomy after endoscopic resection affect outcomes in patients with stage T1 esophageal cancer? A propensity score-based analysis.

BACKGROUND: Although endoscopic resection (ER) may be sufficient treatment for early-stage esophageal cancer, additional treatment is recommended when there is a high risk of cancer recurrence. It is unclear whether delaying esophagectomy by performing and assessing the success of ER affects outcomes as compared with immediate esophagectomy without ER. Additionally, long-term survival after sequential ER and esophagectomy required further investigation. METHODS: Between 2011 and 2015, 48 patients with stage T1 esophageal cancer underwent esophagectomy after ER with curative intent at our institution. Two-to-one propensity score methods were used to identify 96 matched-control patients who were treated with esophagectomy only using baseline patient, tumor characteristics and surgical approach. Time from initial evaluation to esophagectomy, relapse-free survival, overall survival, and postoperative complications were compared between the propensity-matched groups. RESULTS: In the ER + esophagectomy group, the time from initial evaluation to esophagectomy was significantly longer than in the esophagectomy only group (114 vs. 8 days, p < 0.001). The incidence of dense adhesion (p = 0.347), operative time (p = 0.867), postoperative surgical complications (p = 0.966), and postoperative length of hospital stay (p = 0.125) were not significantly different between the groups. Moreover, recurrence-free survival and overall survival were also similar between the two groups (p = 0.411 and p = 0.817, respectively). CONCLUSIONS: Treatment of stage T1 esophageal cancer with ER prior to esophagectomy did not increase the difficulty of performing esophagectomy or the incidence of postoperative complications and did not affect survival after esophagectomy. These results suggest that ER can be recommended for patients with stage T1 cancer even if esophagectomy is warranted eventually.

Esophageal Cancer: Associations With (pN+) Lymph Node Metastases.

OBJECTIVES: To identify the associations of lymph node metastases (pN+), number of positive nodes, and pN subclassification with cancer, treatment, patient, geographic, and institutional variables, and to recommend extent of lymphadenectomy needed to accurately detect pN+ for esophageal cancer. SUMMARY BACKGROUND DATA: Limited data and traditional analytic techniques have precluded identifying intricate associations of pN+ with other cancer, treatment, and patient characteristics. METHODS: Data on 5806 esophagectomy patients from the Worldwide Esophageal Cancer Collaboration were analyzed by Random Forest machine learning techniques. RESULTS: pN+, number of positive nodes, and pN subclassification were associated with increasing depth of cancer invasion (pT), increasing cancer length, decreasing cancer differentiation (G), and more regional lymph nodes resected. Lymphadenectomy necessary to accurately detect pN+ is 60 for shorter, well-differentiated cancers (<2.5 cm) and 20 for longer, poorly differentiated ones. CONCLUSIONS: In esophageal cancer, pN+, increasing number of positive nodes, and increasing pN classification are associated with deeper invading, longer, and poorly differentiated cancers. Consequently, if the goal of lymphadenectomy is to accurately define pN+ status of such cancers, few nodes need to be removed. Conversely, superficial, shorter, and well-differentiated cancers require a more extensive lymphadenectomy to accurately define pN+ status.

KRAS and TP53 mutations in bronchoscopy samples from former lung cancer patients.

Mutations in the KRAS and TP53 genes have been found frequently in lung tumors and specimens from individuals at high risk for lung cancer and have been suggested as predictive markers for lung cancer. In order to assess the prognostic value of these two genes' mutations in lung cancer recurrence, we analyzed mutations in codon 12 of the KRAS gene and in hotspot codons of the TP53 gene in 176 bronchial biopsies obtained from 77 former lung cancer patients. Forty-seven patients (61.0%) showed mutations, including 35/77 (45.5%) in the KRAS gene and 25/77 (32.5%) in the TP53 gene, among them 13/77 (16.9%) had mutations in both genes. When grouped according to past or current smoking status, a higher proportion of current smokers showed mutations, in particular those in the TP53 gene (P = 0.07), compared with ex-smokers. These mutations were found in both abnormal lesions (8/20 or 40%) and histologically normal tissues (70/156 or 44.9%) (P = 0.812). They consisted primarily of G to A transition and G to T transversion in both the KRAS (41/56 or 73.2%) and TP53 (24/34 or 70.6%) genes, consistent with mutations found in lung tumors of smoking lung cancer patients. Overall, recurrence-free survival (RFS) among all subjects could be explained by age at diagnosis, tumor stage, tumor subtype, and smoking (P < 0.05, Cox proportional hazard). Therefore, KRAS and TP53 mutations were frequently detected in bronchial tissues of former lung cancer patients. However, the presence of mutation of bronchial biopsies was not significantly associated with a shorter RFS time. © 2016 Wiley Periodicals, Inc.

Esophageal sphincter device for gastroesophageal reflux disease.

BACKGROUND: Patients with gastroesophageal reflux disease who have a partial response to proton-pump inhibitors often seek alternative therapy. We evaluated the safety and effectiveness of a new magnetic device to augment the lower esophageal sphincter. METHODS: We prospectively assessed 100 patients with gastroesophageal reflux disease before and after sphincter augmentation. The study did not include a concurrent control group. The primary outcome measure was normalization of esophageal acid exposure or a 50% or greater reduction in exposure at 1 year. Secondary outcomes were 50% or greater improvement in quality of life related to gastroesophageal reflux disease and a 50% or greater reduction in the use of proton-pump inhibitors at 1 year. For each outcome, the prespecified definition of successful treatment was achievement of the outcome in at least 60% of the patients. The 3-year results of a 5-year study are reported. RESULTS: The primary outcome was achieved in 64% of patients (95% confidence interval [CI], 54 to 73). For the secondary outcomes, a reduction of 50% or more in the use of proton-pump inhibitors occurred in 93% of patients, and there was improvement of 50% or more in quality-of-life scores in 92%, as compared with scores for patients assessed at baseline while they were not taking proton-pump inhibitors. The most frequent adverse event was dysphagia (in 68% of patients postoperatively, in 11% at 1 year, and in 4% at 3 years). Serious adverse events occurred in six patients, and in six patients the device was removed. CONCLUSIONS: In this single-group evaluation of 100 patients before and after sphincter augmentation with a magnetic device, exposure to esophageal acid decreased, reflux symptoms improved, and use of proton-pump inhibitors decreased. Follow-up studies are needed to assess long-term safety. (Funded by Torax Medical; ClinicalTrials.gov number, NCT00776997.).