Defining Pathologic Upstaging in cT1b Esophageal Cancer: Should We Consider Neoadjuvant Therapy?

INTRODUCTION: Neoadjuvant chemoradiation therapy (NCRT) for cT1b esophageal cancer is not recommended despite the risk of pathologic upstaging with increased depth of penetration. We aimed to (1) define the rate of and factors associated with pathologic upstaging, (2) describe current trends in treatments, and (3) compare overall survival (OS) with and without NCRT for surgically resected cT1b lesions. METHODS: We used the 2020 National Cancer Database to identify patients with cT1b N0 esophageal cancer with or without pathologic upstaging who underwent removal of their tumor. We built multivariable logistic regression models to assess factors associated with pathologic upstaging. Survival was compared using log-rank analysis and modeled using multivariable Cox proportional hazards regressions. RESULTS: Out of 1106 patients with cT1b esophageal cancer, 17.3% (N = 191) had pathologic upstaging. A higher tumor grade (P = 0.002), greater tumor size (P < 0.001), and presence of lympho-vascular invasion (P < 0.001) were associated with pathologic upstaging. 8.0% (N = 114) of patients were treated with NCRT. Five-y OS was 49.4% for patients who received NCRT compared to 67.2% for upfront esophagectomy (P < 0.05). Pathologic upstaging was associated with decreased OS (pathologic upstaging 43.7% versus no pathologic upstaging 67.7%) (hazard ratio 2.12 [95% confidence interval, 1.70-2.65; P < 0.001]). Compared to esophagectomy, endoscopic local tumor excision was associated with a decreased OS (hazard ratio 1.50 [95% confidence interval, 1.19-1.89; P = 0.001]). CONCLUSIONS: Pathologic upstaging of cT1b lesions is associated with decreased OS. Esophagectomy is associated with a survival benefit over endoscopic local tumor excision for these lesions. NCRT is not associated with an increase in OS in cT1b lesions compared to upfront esophagectomy.

Vascularization of the adult mouse lung grafted onto the chick chorioallantoic membrane.

In the later stages of angiogenesis, the vascular sprout transitions into a functional vessel by fusing with a target vessel. Although this process appears to routinely occur in embryonic tissue, the biologic rules for sprout fusion and lumenization in adult regenerating tissue are unknown. To investigate this process, we grafted portions of the regenerating post-pneumonectomy lung onto the chick chorioallantoic membrane (CAM). Grafts from all 4 lobes of the post-pneumonectomy right lung demonstrated peri-graft angiogenesis as reflected by fluorescent plasma markers; however, fluorescent microsphere perfusion primarily occurred in the lobe of the lung that is the dominant site of post-pneumonectomy angiogenesis-namely, the cardiac lobe. Vascularization of the cardiac lobe grafts was confirmed by active tissue growth (p < .05). Functional vascular connections between the cardiac lobe and the CAM vascular network were demonstrated by confocal fluorescence microscopy as well as corrosion casting and scanning electron microscopy (SEM). Bulk transcriptional profiling of the cardiac lobe demonstrated the enhanced expression of many genes relative to alveolar epithelial cell (CD11b-/CD31-) control cells, but only the upregulation of Ereg and Fgf6 compared to the less well-vascularized right upper lobe. The growth of actively regenerating non-neoplastic adult tissue on the CAM demonstrates that functional lumenization can occur between species (mouse and chick) and across the developmental spectrum (adult and embryo).

Waitlist and Transplant Outcomes in Organ Donation After Circulatory Death: Trends in the United States.

OBJECTIVES: To summarize waitlist and transplant outcomes in kidney, liver, lung, and heart transplantation using organ donation after circulatory death (DCD). BACKGROUND: DCD has expanded the donor pool for solid organ transplantation, most recently for heart transplantation. METHODS: The United Network for Organ Sharing registry was used to identify adult transplant candidates and recipients in the most recent allocation policy eras for kidney, liver, lung, and heart transplantation. Transplant candidates and recipients were grouped by acceptance criteria for DCD versus brain-dead donors [donation after brain death (DBD)] only and DCD versus DBD transplant, respectively. Propensity matching and competing-risks regression was used to model waitlist outcomes. Survival was modeled using propensity matching and Kaplan-Meier and Cox regression analysis. RESULTS: DCD transplant volumes have increased significantly across all organs. Liver candidates listed for DCD organs were more likely to undergo transplantation compared with propensity-matched candidates listed for DBD only, and heart and liver transplant candidates listed for DCD were less likely to experience death or clinical deterioration requiring waitlist inactivation. Propensity-matched DCD recipients demonstrated an increased mortality risk up to 5 years after liver and kidney transplantation and up to 3 years after lung transplantation compared with DBD. There was no difference in 1-year mortality between DCD and DBD heart transplantation. CONCLUSIONS: DCD continues to expand access to transplantation and improves waitlist outcomes for liver and heart transplant candidates. Despite an increased risk for mortality with DCD kidney, liver, and lung transplantation, survival with DCD transplant remains acceptable.

Cyst of Hattori: A Rare Cyst in the Posterior Mediastinum.

Sixteen years since their initial description in the literature, posterior mediastinal Mullerian cysts - otherwise known as cysts of Hattori, after their discoverer - remain rare, with only 40 patients reported as of 2020. We report a 43 year old obese female that presented with a 2.6 cm cyst found in the posterior mediastinum by endoscopic ultrasound (EUS) and previously by chest magnetic resonance imaging (MRI) originally diagnosed as a congenital enteric duplication cyst of the esophagus radiologically. Upon surgical excision via a DaVinci thoracoscopy, the cyst was confirmed to be of Mullerian origin by PAX8, WT1, and ER staining. It is possible that the majority of cysts of Hattori remain unrecognized and undiagnosed, given their rarity and resemblance to other pathologies. It is important that this entity become a part of every pathologist's differential for a posterior mediastinal cyst in a female.

Devices for donor lung preservation.

INTRODUCTION: Lung transplantation is the gold standard for the treatment of end stage lung disease but is limited by donor availability. Recently, the donor pool has seen significant expansion with liberalization of donor criteria. However, extended criteria donors can require additional time to prepare for implantation, necessitating additional preservation time of donor lungs. AREAS COVERED: We present a review of current lung transplant storage strategies including new methodologies and technological advancements. The current standard, static cold storage, is a simple and cost-effective method of preserving grafts, but offers little flexibility with limited ability to mitigate ischemic-reperfusion injury, inflammation, and hypothermic tissue damage. Novel ex vivo lung perfusion (EVLP) devices, TransMedics OCS and XVIVO perfusion systems, extend preservation time by perfusing, and ventilating donor lungs while simultaneously allowing for evaluation of lung viability. Perfusate, preservation solutions, additives, temperature regulation, and assessment of organ damage are all critical components when evaluating the success and outcomes of these devices. EXPERT OPINION: EVLP devices are more costly and often require additional resources and personnel support compared to static cold storage, but may provide the opportunity to extend preservation time, perform functional assessment, mitigate ischemic injury, and optimize extended criteria donors.

Risk of recipient age on 1-year mortality after simultaneous heart-lung transplantation.

BACKGROUND: Heart-lung transplantation (HLTx) is relatively uncommon, and there is a paucity of literature to suggest an age at which older recipients may be exposed to excess risk for mortality. This analysis aimed to identify a threshold of age that predicts adverse outcomes after HLTx. METHODS: The United Network of Organ Sharing registry was used to identify adult patients undergoing HLTx from 2005 to 2021. The primary outcome was 1-year mortality. Threshold regression was used to identify the threshold at which age impacts 1-year mortality. Kaplan-Meier analysis was used to model survival, and Cox proportional hazards modeling was used for risk-adjustment. RESULTS: We identified 453 patients undergoing HLTx. Threshold analysis identified that the risk for 1-year mortality was significantly elevated beyond an age of 58 years, and 47 (10.38%) patients were older than this threshold. On Kaplan-Meier analysis, 1-year survival was significantly lower in patients > 58 years compared to younger recipients (64.7% vs. 82.0%, p = .007). After risk adjustment, the hazard ratio for 1-year mortality in recipients older than 58 years was 2.27 (95% confidence interval [1.21-4.28], p = .011). CONCLUSION: A threshold for recipient age of 58 years of age may avoid excess 1-year mortality after HLTx. However, patients older than this threshold demonstrate acceptable early and midterm survival, and the majority survive to 1 year. Advanced age should be considered in patient selection for HLTx, but may not be a contraindication for candidacy particularly in the absence of other risk factors.

Rare Case of Tracheal Fibromyxoma in Obstructive Tracheal Mass.

A 77-year-old male with a history of chronic obstructive pulmonary disease (COPD) who presented with cough, congestion, and stridor and was found to have a near obstructing tracheal mass. He subsequently underwent excision of the mass. On pathologic examination, it was diagnosed as fibromyxoma of the trachea. Primary tumors of the trachea are rare, and fibromyxoma of the trachea is extremely rare. This is the third report of a fibromyxoma on the tracheal wall. In this report the clinical manifestations, and surgical management were compared with the other two reported cases.

Phase I Trial Characterizing the Pharmacokinetic Profile of N-803, a Chimeric IL-15 Superagonist, in Healthy Volunteers.

The oncotherapeutic promise of IL-15, a potent immunostimulant, is limited by a short serum t 1/2 The fusion protein N-803 is a chimeric IL-15 superagonist that has a >20-fold longer in vivo t 1/2 versus IL-15. This phase 1 study characterized the pharmacokinetic (PK) profile and safety of N-803 after s.c. administration to healthy human volunteers. Volunteers received two doses of N-803, and after each dose, PK and safety were assessed for 9 d. The primary endpoint was the N-803 PK profile, the secondary endpoint was safety, and immune cell levels and immunogenicity were measures of interest. Serum N-803 concentrations peaked 4 h after administration and declined with a t 1/2 of ∼20 h. N-803 did not cause treatment-emergent serious adverse events (AEs) or grade ≥3 AEs. Injection site reactions, chills, and pyrexia were the most common AEs. Administration of N-803 was well tolerated and accompanied by proliferation of NK cells and CD8+ T cells and sustained increases in the number of NK cells. Our results suggest that N-803 administration can potentiate antitumor immunity.

Neuropilin-2b facilitates resistance to tyrosine kinase inhibitors in non-small cell lung cancer.

OBJECTIVE: Innate and acquired resistance is the principle factor limiting the efficacy of tyrosine kinase inhibitors in lung cancer. We have observed a dramatic upregulation of the cell surface co-receptor neuropilin-2b in lung cancers clinically treated with tyrosine kinase inhibitors correlating with acquired resistance. We hypothesize that neuropilin-2b plays a functional role in acquired tyrosine kinase inhibitor resistance. METHODS: Non-small cell lung cancer proliferation and survival were determined during chronic tyrosine kinase inhibitor exposure in the presence or absence of neuropilin-2b knock-down. Interactions of neuropilin-2a and neuropilin-2b isoforms with PTEN and GSK3ß were assessed by immunoprecipitation. Neuropilin-2a and neuropilin-2b mutants deleted for their cytoplasmic domains were used to identify regions responsible for neuropilin-2b-GSK3ß interaction. Because GSK3ß is known to phosphorylate and degrade PTEN, phospho-PTEN and total PTEN levels were assessed after transfection of neuropilin-2a and neuropilin-2b wild-type and mutant constructs. RESULTS: Non-small cell lung cancer cells chronically treated with gefitinib or osimertinib developed drug resistance and exhibited logarithmic growth in the presence of endothelial growth factor receptor tyrosine kinase inhibitors. However, neuropilin-2b knockdown cells remained sensitive to gefitinib. Likewise, neuropilin-2b knockdown suppressed and neuropilin-2a knockdown enhanced cellular migration. Acquired drug resistance and cell migration correlated with neuropilin-2b-dependent AKT activation with the intermediate step of GSK3ß-dependent PTEN degradation. A specific binding site for GSK3ß on the cytoplasmic domain of neuropilin-2b was identified with truncated protein constructs and computer modeling. CONCLUSIONS: Neuropilin-2b facilitates non-small cell lung cancer resistance to tyrosine kinase inhibitors, and this biological effect relates to AKT activation. Neuropilin-2b GSK3ß interactions appear to be essential for PTEN degradation and AKT activation in lung cancer cells. Disruption of the neuropilin-2b GSK3ß interaction may represent a novel treatment strategy to preserve sensitivity to tyrosine kinase inhibitors in non-small cell lung cancer.