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.

Multivariate models from RNA-Seq SNVs yield candidate molecular targets for biomarker discovery: SNV-DA.

BACKGROUND: It has recently been shown that significant and accurate single nucleotide variants (SNVs) can be reliably called from RNA-Seq data. These may provide another source of features for multivariate predictive modeling of disease phenotype for the prioritization of candidate biomarkers. The continuous nature of SNV allele fraction features allows the concurrent investigation of several genomic phenomena, including allele specific expression, clonal expansion and/or deletion, and copy number variation. RESULTS: The proposed software pipeline and package, SNV Discriminant Analysis (SNV-DA), was applied on two RNA-Seq datasets with varying sample sizes sequenced at different depths: a dataset containing primary tumors from twenty patients with different disease outcomes in lung adenocarcinoma and a larger dataset of primary tumors representing two major breast cancer subtypes, estrogen receptor positive and triple negative. Predictive models were generated using the machine learning algorithm, sparse projections to latent structures discriminant analysis. Training sets composed of RNA-Seq SNV features limited to genomic regions of origin (e.g. exonic or intronic) and/or RNA-editing sites were shown to produce models with accurate predictive performances, were discriminant towards true label groupings, and were able to produce SNV rankings significantly different from than univariate tests. Furthermore, the utility of the proposed methodology is supported by its comparable performance to traditional models as well as the enrichment of selected SNVs located in genes previously associated with cancer and genes showing allele-specific expression. As proof of concept, we highlight the discovery of a previously unannotated intergenic locus that is associated with epigenetic regulatory marks in cancer and whose significant allele-specific expression is correlated with ER+ status; hereafter named ER+ associated hotspot (ERPAHS). CONCLUSION: The use of models from RNA-Seq SNVs to identify and prioritize candidate molecular targets for biomarker discovery is supported by the ability of the proposed method to produce significantly accurate predictive models that are discriminant towards true label groupings. Importantly, the proposed methodology allows investigation of mutations outside of exonic regions and identification of interesting expressed loci not included in traditional gene annotations. An implementation of the proposed methodology is provided that allows the user to specify SNV filtering criteria and cross-validation design during model creation and evaluation.

On-tissue localization of ceramides and other sphingolipids by MALDI mass spectrometry imaging.

A novel MALDI-FTICR imaging mass spectrometry (MALDI-IMS) workflow is described for on-tissue detection, spatial localization, and structural confirmation of low abundance bioactive ceramides and other sphingolipids. Increasingly, altered or elevated levels of sphingolipids, sphingolipid metabolites, and sphingolipid metabolizing enzymes have been associated with a variety of disorders such as diabetes, obesity, lysosomal storage disorders, and cancer. Ceramide, which serves as a metabolic hub in sphingolipid metabolism, has been linked to cancer signaling pathways and to metabolic regulation with involvement in autophagy, cell-cycle arrest, senescence, and apoptosis. Using kidney tissues from a new Farber disease mouse model in which ceramides of all acyl chain lengths and other sphingolipid metabolites accumulate in tissues, specific ceramides and sphingomyelins were identified by on-tissue isolation and fragmentation, coupled with an on-tissue digestion by ceramidase or sphingomyelinase. Multiple glycosphingolipid species were also detected. The newly generated library of sphingolipid ions was then applied to MALDI-IMS of human lung cancer tissues. Multiple tumor specific ceramide and sphingomyelin species were detected and confirmed by on-tissue enzyme digests and structural confirmation. High-resolution MALDI-IMS in combination with novel on-tissue ceramidase and sphingomyelinase enzyme digestions makes it now possible to rapidly visualize the distribution of bioactive ceramides and sphingomyelin in tissues.

No Evidence for Oversizing Hearts and Donor Size Impact on 1-Year Survival in Heart Failure Patients With Left Ventricular Assist Device.

The predicted heart mass (PHM) ratio has recently emerged as a better metric for donor-to-recipient size-matching than weight ratios. It is unknown whether this applies to transplant candidates on left ventricular assist device (LVAD) support. Our study examines if PHM ratio is optimal for size-matching specifically in the LVAD patient population. Patients with LVAD who received a heart transplant from January 1997 to December 2020 in the Scientific Registry of Transplant Recipients database were studied. We compared 5 size-matching metrics, including donor-recipient ratios of weight, height, body mass index, body surface area, and PHM. Single and multivariable Cox proportional hazards models for 1-year mortality were calculated. Our sample consisted of 11,891 patients. In our multivariate analysis, we found that patients in the undersized group with PHM ratios <0.83 had a hazard ratio for 1-year mortality of 1.34 (95% confidence interval 1.08 to 1.65, p = 0.007) suggestive of increased mortality with the use of undersized donors. There was no statistical difference in mortality between the matched (PHM ratio 0.83 to 1.2) and oversized group (PHM ratio ≥1.2). In heart transplant recipients on LVAD support, the PHM ratio provides better risk stratification than other metrics. Use of undersized donor hearts with PHM ratio <0.83 confers higher 1-year mortality. Using oversized donor hearts for transplantation in recipients on LVAD support has no benefit.

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.

WITHDRAWN:Does dehydrated human amnion/chorion membrane enhance esophageal anastomotic healing?

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Update on lung transplantation for emphysema.

Lung transplantation in the modern era remains an evolving field and a viable option for patients suffering from end-stage emphysema. Recent modifications for recipient prioritization has resulted in a modest decrease in the number of patients with emphysema receiving transplants. More time will be required to determine what impact, if any, these modifications will have on the overall survival of patients with end-stage emphysema. Ongoing research will address persistent issues with lung transplantation, most notably, primary graft dysfunction and chronic BOS.

Extramedullary Plasmacytoma of the Right Main Bronchus.

Extramedullary plasmacytomas are rare tumors that typically involve the head and neck region. Only three reports exist in the literature of extramedullary plasmacytomas that involve the lower airways. We report the case of a 54-year-old woman with EMP of the right mainstem bronchus treated with sleeve resection.

Survival after adjuvant radiation therapy in localized small cell lung cancer treated with complete resection.

OBJECTIVES: To determine whether there is an overall survival (OS) benefit to the addition of thoracic radiation therapy (RT) following R0 resection of pathologic (p) T1 or pT2 N0 M0 small cell lung cancer. METHODS: Using the National Cancer Database, we performed a retrospective cohort analysis. Patients who underwent R0 resection for pT1 or p2 N0 M0 small cell lung cancer, stratified by receipt of adjuvant thoracic RT, were compared on the basis of OS using hierarchical Cox Proportional hazards models. RESULTS: Of 4969 patients diagnosed with pT1or pT2 N0 M0 SCLC from 2004 to 2014, 1617 (33%) underwent R0 resection of their primary tumor; of these resected patients, 146 (9.0%) had adjuvant thoracic RT. In unadjusted analysis, there was no significant difference in OS between groups (median survival: surgery alone, 62.2 months vs surgery+RT, 43.8 months; P = .1436). In multivariable analysis, RT was not associated with improved survival (P = .099). There was no significant difference in unadjusted or adjusted survival associated with receipt of RT in both a young and healthy cohort (P = .647 for unadjusted and P = .858 for adjusted) and a matched cohort (P = .867 and P = .954). In the matched cohort, improved OS was associated with younger patient age (adjusted hazard ratio, 1.07; 95% confidence interval, 1.04-1.10; P < .001), female sex (adjusted hazard ratio, 0.68, 95% confidence interval, 0.47-0.97; P = .035), and smaller tumors (adjusted hazard ratio, 1.02; 95% confidence interval, 1.01-1.03; P = .005). Having 2 or more comorbidities was associated with worse OS (adjusted hazard ratio, 2.16; 95% confidence interval, 1.21-3.86; P = .009). CONCLUSIONS: Although complete resection was accomplished in a minority of patients, for these patients, survival was good. The addition of thoracic RT to complete resection does not appear to confer additional survival benefit.

The use of gamma-irradiation and ultraviolet-irradiation in the preparation of human melanoma cells for use in autologous whole-cell vaccines.

BACKGROUND: Human cancer vaccines incorporating autologous tumor cells carry a risk of implantation and subsequent metastasis of viable tumor cells into the patient who is being treated. Despite the fact that the melanoma cell preparations used in a recent vaccine trial (Mel37) were gamma-irradiated (200 Gy), approximately 25% of the preparations failed quality control release criteria which required that the irradiated cells incorporate 3H-thymidine at no more than 5% the level seen in the non-irradiated cells. We have, therefore, investigated ultraviolet (UV)-irradiation as a possible adjunct to, or replacement for gamma-irradiation. METHODS: Melanoma cells were gamma- and/or UV-irradiated. 3H-thymidine uptake was used to assess proliferation of the treated and untreated cells. Caspase-3 activity and DNA fragmentation were measured as indicators of apoptosis. Immunohistochemistry and Western blot analysis was used to assess antigen expression. RESULTS: UV-irradiation, either alone or in combination with gamma-irradiation, proved to be extremely effective in controlling the proliferation of melanoma cells. In contrast to gamma-irradiation, UV-irradiation was also capable of inducing significant levels of apoptosis. UV-irradiation, but not gamma-irradiation, was associated with the loss of tyrosinase expression. Neither form of radiation affected the expression of gp100, MART-1/MelanA, or S100. CONCLUSION: These results indicate that UV-irradiation may increase the safety of autologous melanoma vaccines, although it may do so at the expense of altering the antigenic profile of the irradiated tumor cells.

Closure of a Post-Transplant Bronchial Dehiscence With Endobronchial Fibrin Sealant.

Airway complications after lung transplantation are well described and can lead to significant morbidity and mortality. Treatment options for anastomotic dehiscence include expectant management, placement of endobronchial stents, or surgical repair. The use of fibrin sealant instilled by bronchoscopy to seal a dehiscence has not been well described. Our patient is a 57-year-old man who underwent orthotropic bilateral lung transplantation for end-stage chronic obstructive pulmonary disease. He was found to have a partial bronchial anastomosis dehiscence and was subsequently treated with endobronchial fibrin sealant glue instillation. This case illustrates the successful use of endobronchial fibrin sealant for bronchial anastomosis dehiscence.

IL-2 and Beyond in Cancer Immunotherapy.

The development of the T- and natural killer (NK) cell growth factor IL-2 has been a sentinel force ushering in the era of immunotherapy in cancer. With the advent of clinical grade recombinant IL-2 in the mid-1980s, oncologists could for the first time directly manipulate lymphocyte populations with systemic therapy. By itself, recombinant IL-2 can induce clinical responses in up to 15% of patients with metastatic cancer or renal cell carcinoma. When administered with adoptively transferred tumor-reactive lymphocytes, IL-2 promotes T cell engraftment and response rates of up to 50% in metastatic melanoma patients. Importantly, these IL-2-driven responses can yield complete and durable responses in a subset of patients. However, the use of IL-2 is limited by toxicity and concern of the expansion of T regulatory cells. To overcome these limitations and improve response rates, other T cell growth factors, including IL-15 and modified forms of IL-2, are in clinical development. Administering T cell growth factors in combination with other agents, such as immune checkpoint pathway inhibitors, may also improve efficacy. In this study, we review the development of T- and NK cell growth factors and highlight current combinatorial approaches based on these reagents.