Treatment utilization and outcomes in elderly patients with locally advanced esophageal carcinoma: A review of the National Cancer Database

For elderly patients with locally advanced esophageal cancer, therapeutic approaches and outcomes in a modern cohort are not well characterized. Patients ≥70 years old with clinical stage II and III esophageal cancer diagnosed between 1998 and 2012 were identified from the National Cancer Database and stratified based on treatment type. Variables associated with treatment utilization were evaluated using logistic regression and survival evaluated using Cox proportional hazards analysis. Propensity matching (1:1) was performed to help account for selection bias. A total of 21,593 patients were identified. Median and maximum ages were 77 and 90, respectively. Treatment included palliative therapy (24.3%), chemoradiation (37.1%), trimodality therapy (10.0%), esophagectomy alone (5.6%), or no therapy (12.9%). Age ≥80 (OR 0.73), female gender (OR 0.81), Charlson-Deyo comorbidity score ≥2 (OR 0.82), and high-volume centers (OR 0.83) were associated with a decreased likelihood of palliative therapy versus no treatment. Age ≥80 (OR 0.79) and Clinical Stage III (OR 0.33) were associated with a decreased likelihood, while adenocarcinoma histology (OR 1.33) and nonacademic cancer centers (OR 3.9), an increased likelihood of esophagectomy alone compared to definitive chemoradiation. Age ≥80 (OR 0.15), female gender (OR 0.80), and non-Caucasian race (OR 0.63) were associated with a decreased likelihood, while adenocarcinoma histology (OR 2.10) and high-volume centers (OR 2.34), an increased likelihood of trimodality therapy compared to definitive chemoradiation. Each treatment type demonstrated improved survival compared to no therapy: palliative treatment (HR 0.49) to trimodality therapy (HR 0.25) with significance between all groups. Any therapy, including palliative care, was associated with improved survival; however, subsets of elderly patients with locally advanced esophageal cancer are less likely to receive aggressive therapy. Care should be taken to not unnecessarily deprive these individuals of treatment that may improve survival

Preliminary Comments Welcome Cities and Suburbs: Expenditure Patterns in the Urban Fiscal System

ABSTRACT This paper attempts to explain why large cities in the U.S. spend over 11% of their budget on low income assistance, despite economists' prescriptions that such behavior is extremely inefficient. We utilize explanations from urban economics that suggest cities have significant land rents. If city governments can access some of these rents, then local taxation may not be inefficient. Using a sample of the 53 largest cities in the U.S. over 18 years, we find that cities generally lower the welfare of their citizens in response to innovations in the suburbs. We interpret this evidence as being suggestive of rent extraction. We find, however, that these rents are used to support the low income assistance budgets

Identification of a prognostic signature in colorectal cancer using combinatorial algorithm-driven analysis

Acknowledgements The colorectal cancer microarray was provided by the NHS Grampian Biorepository and the majority of the immunostaining was performed in the Grampian Biorepository laboratory (www.biorepository.nhsgrampian.org/). The antibodies were developed in collaboration with Vertebrate Antibodies Ltd (https://vertebrateantibodies.com/)Peer reviewedPublisher PD

A means of assessing deep learning-based detection of ICOS protein expression in colon cancer.

Biomarkers identify patient response to therapy. The potential immune‐checkpoint bi-omarker, Inducible T‐cell COStimulator (ICOS), expressed on regulating T‐cell activation and involved in adaptive immune responses, is of great interest. We have previously shown that open-source software for digital pathology image analysis can be used to detect and quantify ICOS using cell detection algorithms based on traditional image processing techniques. Currently, artificial intelligence (AI) based on deep learning methods is significantly impacting the domain of digital pa-thology, including the quantification of biomarkers. In this study, we propose a general AI‐based workflow for applying deep learning to the problem of cell segmentation/detection in IHC slides as a basis for quantifying nuclear staining biomarkers, such as ICOS. It consists of two main parts: a simplified but robust annotation process, and cell segmentation/detection models. This results in an optimised annotation process with a new user‐friendly tool that can interact with1 other open‐source software and assists pathologists and scientists in creating and exporting data for deep learning. We present a set of architectures for cell‐based segmentation/detection to quantify and analyse the trade‐offs between them, proving to be more accurate and less time consuming than traditional methods. This approach can identify the best tool to deliver the prognostic significance of ICOS protein expression

Transcriptional upregulation of c-MET is associated with invasion and tumor budding in colorectal cancer

c-MET and its ligand HGF are frequently overexpressed in colorectal cancer (CRC) and increased c-MET levels are found in CRC liver metastases. This study investigated the role of the HGF/c-MET axis in regulating migration/invasion in CRC, using pre-clinical models and clinical samples. Pre-clinically, we found marked upregulation of c-MET at both protein and mRNA levels in several invasive CRC cells. Down-regulation of c-MET using RNAi suppressed migration/invasion of parental and invasive CRC cells. Stimulation of CRC cells with rh-HGF or co-culture with HGF-expressing colonic myofibroblasts, resulted in significant increases in their migratory/invasive capacity. Importantly, HGF-induced c-MET activation promoted rapid downregulation of c-MET protein levels, while the MET transcript remained unaltered. Using RNA in situ hybridization (RNA ISH), we further showed that MET mRNA, but not protein levels, were significantly upregulated in tumor budding foci at the invasive front of a cohort of stage III CRC tumors (p < 0.001). Taken together, we show for the first time that transcriptional upregulation of MET is a key molecular event associated with CRC invasion and tumor budding. This data also indicates that RNA ISH, but not immunohistochemistry, provides a robust methodology to assess MET levels as a potential driving force of CRC tumor invasion and metastasis

ICOSeg: real-time ICOS protein expression segmentation from immunohistochemistry slides using a lightweight conv-transformer network.

In this article, we propose ICOSeg, a lightweight deep learning model that accurately segments the immune-checkpoint biomarker, Inducible T-cell COStimulator (ICOS) protein in colon cancer from immunohistochemistry (IHC) slide patches. The proposed model relies on the MobileViT network that includes two main components: convolutional neural network (CNN) layers for extracting spatial features; and a transformer block for capturing a global feature representation from IHC patch images. The ICOSeg uses an encoder and decoder sub-network. The encoder extracts the positive cell's salient features (i.e., shape, texture, intensity, and margin), and the decoder reconstructs important features into segmentation maps. To improve the model generalization capabilities, we adopted a channel attention mechanism that added to the bottleneck of the encoder layer. This approach highlighted the most relevant cell structures by discriminating between the targeted cell and background tissues. We performed extensive experiments on our in-house dataset. The experimental results confirm that the proposed model achieves more significant results against state-of-the-art methods, together with an 8× reduction in parameters

The adaptive immune and immune checkpoint landscape of neoadjuvant treated esophageal adenocarcinoma using digital pathology quantitation

Acknowledgments The samples used in this research were received from the Northern Ireland Biobank, which has ethical approval to use de-identified tissue samples from the Belfast Health and Social Care Tissue Pathology archive (REC:11/NI/0013). The Northern Ireland Molecular Pathology Laboratory, was responsible for construction of tissue microarrays, slide staining, and scanning. We are grateful to the NVIDIA Corporation for supporting our research via the GPU Grant Program for researchers. The research leading to these results has also received funding from Invest Northern Ireland. The authors thank Mr. Ken Arthur for the construction of the original tissue microarrays used in this study. Funding This study was funded by a CRUK Accelerator Grant (A20256) to JJ and MST. CRUK had no role in the study design, collection, analysis, and interpretation of the data or in the writing of the report.Peer reviewedPublisher PD

Colonic epithelial cathelicidin (LL-37) expression intensity is associated with progression of colorectal cancer and presence of CD8+ T cell infiltrate

Colorectal cancer (CRC) remains a leading cause of cancer mortality. Here, we define the colonic epithelial expression of cathelicidin (LL-37) in CRC. Cathelicidin exerts pleotropic effects including anti-microbial and immunoregulatory functions. Genetic knockout of cathelicidin led to increased size and number of colorectal tumours in the azoxymethane-induced murine model of CRC. We aimed to translate this to human disease. The expression of LL-37 in a large (n = 650) fully characterised cohort of treatment-naïve primary human colorectal tumours and 50 matched normal mucosa samples with associated clinical and pathological data (patient age, gender, tumour site, tumour stage [UICC], presence or absence of extra-mural vascular invasion, tumour differentiation, mismatch repair protein status, and survival to 18 years) was assessed by immunohistochemistry. The biological consequences of LL-37 expression on the epithelial barrier and immune cell phenotype were assessed using targeted quantitative PCR gene expression of epithelial permeability (CLDN2, CLDN4, OCLN, CDH1, and TJP1) and cytokine (IL-1β, IL-18, IL-33, IL-10, IL-22, and IL-27) genes in a human colon organoid model, and CD3+ , CD4+ , and CD8+ lymphocyte phenotyping by immunohistochemistry, respectively. Our data reveal that loss of cathelicidin is associated with human CRC progression, with a switch in expression intensity an early feature of CRC. LL-37 expression intensity is associated with CD8+ T cell infiltrate, influenced by tumour characteristics including mismatch repair protein status. There was no effect on epithelial barrier gene expression. These data offer novel insights into the contribution of LL-37 to the pathogenesis of CRC and as a therapeutic molecule

Single Dose Pharmacokinetics of Oral Tenofovir in Plasma, Peripheral Blood Mononuclear Cells, Colonic Tissue, and Vaginal Tissue

HIV seroconversion outcomes in preexposure prophylaxis (PrEP) trials of oral tenofovir (TFV)-containing regimens are highly sensitive to drug concentration, yet less-than-daily dosing regimens are under study. Description of TFV and its active moiety, TFV diphosphate (TFV-DP), in blood, vaginal tissue, and colon tissue may guide the design and interpretation of PrEP clinical trials. Six healthy women were administered a single oral dose of 300 mg tenofovir disoproxil fumarate (TDF) and 4.3 mg (12.31 MBq, 333 μCi) [superscript 14]C-TDF slurry. Blood was collected every 4 h for the first 24 h, then at 4, 8, 11, and 15 days postdosing. Colonic and vaginal samples (tissue, total and CD4+ cells, luminal fluid and cells) were collected 1, 8 and 15 days postdose. Samples were analyzed for TFV and TFV-DP. Plasma TFV demonstrated triphasic decay with terminal elimination half-life median [interquartile range (IQR)] 69 h (58–77). Peripheral blood mononuclear cell (PBMC) TFV-DP demonstrated biphasic peaks (median 12 h and 96 h) followed by a terminal 48 h (38–76) half-life; C[subscript max] was 20 fmol/million cells (2–63). One day postdose, the TFV-DP paired colon:vaginal tissue concentration ratio was 1 or greater in all subjects' tissue homogenates, median 124 (range 1–281), but was not sustained. The ratio was lower and more variable in cells extracted from tissue. Among all sample types, TFV and TFV-DP half-life ranged from 23 to 139 h. PBMC TFV-DP rose slowly in the hours after dosing indicating that success with exposure-driven dosing regimens may be sensitive to timing of the dose prior to exposure. Colonic tissue homogenate TFV-DP concentrations were greater than in vaginal homogenate at 24 h, but not in cells extracted from tissue. These and the other pharmacokinetic findings will guide the interpretation and design of future PrEP trials.National Center for Advancing Translational Sciences (U.S.) (Grant UL1RR025005)National Institutes of Health (U.S.)National Institutes of Health (U.S.) (Roadmap for Medical Research

Biological Case Against Downlisting the Whooping Crane and for Improving Implementation under the Endangered Species Act

The Whooping Crane (Grus americana; WHCR) is a large, long-lived bird endemic to North America. The remnant population migrates between Aransas National Wildlife Refuge, USA, and Wood Buffalo National Park, Canada (AWBP), and has recovered from a nadir of 15-16 birds in 1941 to ~540 birds in 2022. Two ongoing reintroduction efforts in Louisiana and the Eastern Flyway together total ~150 birds. Evidence indicates the U.S. Fish and Wildlife Service (USFWS) is strongly considering downlisting the species from an endangered to a threatened status under the Endangered Species Act (ESA). We examined the current status of the WHCR through the lens of ESA threat factors, the USFWS’s Species Status Assessment (SSA) framework, and other avian downlisting actions to determine if the action is biologically warranted. Our research indicates that WHCRs are facing an intensification of most threat drivers across populations and important ranges. The AWBP is still relatively small compared to other crane species and most birds of conservation concern. To date, only one avian species has been downlisted from an endangered status with an estimated population of \u3c3,000 individuals. Representation in terms of WHCRs historic genetic, geographic, and life history variation remains limited. Also, the lack of spatial connectivity among populations, reliance of the reintroduced populations on supplementation, and continued habitat loss suggest that WHCR populations may not be resilient to large stochastic disturbances. Given that reintroduced populations are not self-sustaining, neither supplies true redundancy for the AWBP. Proposed downlisting before recovery plan population criteria have been met is objectively unwarranted 3 and reflects USFWS inconsistency across ESA actions. Only by incorporating basic quantitative criteria and added oversight into ESA listing decisions can we avoid an action as misguided as downlisting the Whooping Crane without consideration of its recovery plan criteria or ostensibly its population ecology