The distribution of esophageal cancer patients enrolled in care at the Uganda Cancer Institute by sub-regions, districts and ethnicity.

Background: There is limited published data regarding the distribution of esophageal cancer patients by sub-regions, districts and ethnicity in Uganda. Objectives: To study the distribution by sub-regions, districts, ethnicity and sub-regions post-care outcomes of esophageal cancer patients in care over ten years at the Uganda Cancer Institute. Methods: Patients' charts with confirmed diagnoses of esophageal cancer for 2009-2019 were identified. Case information, which included demographics, clinical presentation, distribution by sub-regions, districts, ethnicity and sub-regions post-care outcomes, were retrospectively abstracted. Results: Central 671(34.15%), Southwestern 308(15.67%), Elgon 176(8.95%) and East central 163(8.29%) sub-regions had most patients. Mostly from administrative districts of Wakiso 167(8.50%), Mbarara 51(2.59%), Tororo 53(2.70%), Busia 33(1.68). Baganda, Banyakole, Bagisu and Basoga ethnic groups predominate. Patients from neighbouring countries were mainly from Rwanda 56(2.85%), South Sudan 24(1.22%), then Kenya 21(1.07%), and Rwandese, Dinka and Luo by ethnicity, respectively. Central and Southwestern sub-regions had the most post-care outcomes of the patients regarding living, death, and loss to follow-up. Conclusion: Patients are commonly from the administrative districts of Central, Southwestern, Elgon and East Central sub-regions and neighbouring countries of Rwanda, South Sudan and Kenya. Baganda, Banyakole, Bagisu and Basoga are the main ethnic groups. Central and Southwestern sub-regions are with most post-care outcomes.

Introducing a Novel Innovative Technique for the Recording and Interpretation of Dynamic Coronary Angiography.

In the study of coronary artery disease (CAD), the mechanism of plaque formation and development is still an important subject for investigation. A limitation of current coronary angiography (CAG) is that it can only show static images of the narrowing of arterial channels without identifying the mechanism of the disease or predicting its progression or regression. To address this limitation, the CAG technique has been modified. The new approach emphasizes identifying and analyzing blood flow patterns, employing methodologies akin to those used by hydraulic engineers for fluid or gas movement through domestic or industrial pipes and pumps. With the new technique, various flow patterns and arterial phenomena-such as laminar, turbulent, antegrade, retrograde, and recirculating flow and potentially water hammer shock and vortex formation-are identified, recorded, and classified. These phenomena are then correlated with the presence of lesions at different locations within the coronary vasculature. The formation and growth of these lesions are explained from the perspective of fluid mechanics. As the pathophysiology of CAD and other cardiovascular conditions becomes clearer, new medical, surgical, and interventional treatments could be developed to reverse abnormal coronary flow dynamics and restore laminar flow, leading to improved clinical outcomes.

Predicting the Fracture Toughness of Human Cancellous Bone in Fractured Neck of Femur Patients Using Bone Volume and Micro-Architecture.

The current protocol used to determine if an individual is osteoporotic relies on assessment of the individual's bone mineral density (BMD), which allows clinicians to judge the condition of a patient with respect to their peers. This, in essence, evaluates a person's fracture risk, because BMD is a good surrogate measure for strength and stiffness. In recent studies, the authors were the first to produce fracture toughness (FT) data from osteoporotic (OP) and osteoarthritic (OA) patients, by using a testing technique which basically analyzes the prerequisite stress conditions for the onset of growth of a major crack through cancellous bone tissue. FT depends mainly on bone quantity (BV/TV, bone volume/tissue volume), but also on bone micro-architecture (mArch), the inner trabecular design of the bone. The working research hypothesis of the present study is that mArch offers added prediction power to BV/TV in determining FT parameters. Consequently, our aim was to investigate the use of predictive models for fracture toughness and also to investigate if there are any significant differences between the models produced from samples loaded across (AC, transverse to) the main trabecular orientation and along (AL, in parallel) the trabeculae. In multilinear regression analysis, we found that the strength of the relationships varied for a crack growing in these two orthogonal directions. Adding mArch variables in the Ac direction helped to increase the R2 to 0.798. However, in the AL direction, adding the mArch parameters did not add any predictive power to using BV/TV alone; BV/TV on its own could produce R2 = 0.730. The present results also imply that the anisotropic layout of the trabeculae makes it more difficult for a major crack to grow transversely across them. Cancellous bone models and remodels itself in a certain way to resist fracture in a specific direction, and thus, we should be mindful that architectural quality as well as bone quantity are needed to understand the resistance to fracture.

Gastroesophageal Adenocarcinomas With Defective Mismatch Repair: Current Knowledge and Clinical Management.

Esophageal, gastroesophageal junction, and gastric adenocarcinomas, referred to collectively as gastroesophageal adenocarcinomas (GEAs), are a major cause of global cancer-related mortality. Our increasing molecular understanding has led to the addition of biomarker-directed approaches to defined subgroups and has improved survival in selected patients, such as those with HER2 and Claudin18.2 overexpression. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, including GEA, but biomarkers beyond PD-L1 expression are lacking. Mismatch repair deficiency and/or high microsatellite instability (dMMR/MSI-H) is observed in 8% to 22% of nonmetastatic GEA, and 3% to 5% of patients with metastatic disease. dMMR/MSI-H tumors are associated with more favorable prognosis and significant benefit from ICIs, although some heterogeneity exists. The activity of ICIs in advanced dMMR/MSI-H cancer is seen across lines of therapy and should be recommended in the frontline setting. In patients with nonmetastatic dMMR/MSI-H cancer, increasing evidence suggests that perioperative and adjuvant chemotherapy may not provide benefit to the dMMR/MSI-H subgroup. The activity of perioperative chemotherapy-free immune checkpoint regimens in patients with nonmetastatic dMMR/MSI-H cancer is highly promising and underscores the need to identify this unique subgroup. We recommend MMR/MSI testing for all patients with GEA at diagnosis, and review the key rationale and clinical management implications for patient with dMMR/MSI-H tumors across disease stages.

An Ailment with Which I Will Contend: A Narrative Review of 5000 Years of Esophagogastric Cancers and Their Treatments, with Special Emphasis on Recent Advances in Immunotherapeutics.

Esophagogastric cancers are among the most common and deadly cancers worldwide. This review traces their chronology from 3000 BCE to the present. The first several thousand years were devoted to palliation, before advances in operative technique and technology led to the first curative surgery in 1913. Systemic therapies were introduced in 1910, and radiotherapy shortly thereafter. Operative technique improved massively over the 20th century, with operative mortality rates reducing from over 50% in 1933 to less than 5% by 1981. In addition to important roles in palliation, endoscopy became a key nonsurgical curative option for patients with limited-stage disease by the 1990s. The first nonrandomized studies on combination therapies (chemotherapy ± radiation ± surgery) were reported in the early 1980s, with survival benefit only for subsets of patients. Randomized trials over the next decades had similar overall results, with increasing nuance. Disparate conclusions led to regional variation in global practice. Starting with the first FDA approval in 2017, multiple immunotherapies now encompass more indications and earlier lines of therapy. As standards of care incorporate these effective yet expensive therapies, care must be given to disparities and methods for increasing access.

Clinical, Echocardiographic, and Longitudinal Characteristics Associated With Heart Failure With Improved Ejection Fraction.

Heart failure with improved ejection fraction (HFimpEF) has better outcomes than HF with reduced EF (HFrEF). However, factors contributing to HFimpEF remain unclear. This study aimed to evaluate clinical and longitudinal characteristics associated with subsequent HFimpEF. This was a single-center retrospective HFrEF cohort study. Data were collected from 2014 to 2022. Patients with HFrEF were identified using International Classification of Diseases codes, echocardiographic data, and natriuretic peptide levels. The main end points were HFimpEF (defined as EF >40% at ≥3 months with ≥10% increase) and mortality. Cox proportional hazards and mixed effects models were used for analyses. The study included 1,307 patients with HFrEF with a median follow-up of 16.3 months (interquartile range 8.0 to 30.6). The median age was 65 years; 68% were male whereas 57% were White. On follow-up, 38.7% (n = 506) developed HFimpEF, whereas 61.3% (n = 801) had persistent HFrEF. A multivariate Cox regression model identified gender, race, co-morbidities, echocardiographic, and natriuretic peptide as significant covariates of HFimpEF (p <0.05). The HFimpEF group had better survival compared with the persistent HFrEF group (p <0.001). Echocardiographic and laboratory trajectories differed between groups. In this HFrEF cohort, 38.7% transitioned to HFimpEF and approximately 50% met the definition within the first 12 months. In a HFimpEF model, gender, co-morbidities, echocardiographic parameters, and natriuretic peptide were associated with subsequent HFimpEF. The model has the potential to identify patients at risk of subsequent persistent or improved HFrEF, thus informing the design and implementation of targeted quality-of-care improvement interventions.

Accuracy and Reliability of Chatbot Responses to Physician Questions.

Importance: Natural language processing tools, such as ChatGPT (generative pretrained transformer, hereafter referred to as chatbot), have the potential to radically enhance the accessibility of medical information for health professionals and patients. Assessing the safety and efficacy of these tools in answering physician-generated questions is critical to determining their suitability in clinical settings, facilitating complex decision-making, and optimizing health care efficiency. Objective: To assess the accuracy and comprehensiveness of chatbot-generated responses to physician-developed medical queries, highlighting the reliability and limitations of artificial intelligence-generated medical information. Design, Setting, and Participants: Thirty-three physicians across 17 specialties generated 284 medical questions that they subjectively classified as easy, medium, or hard with either binary (yes or no) or descriptive answers. The physicians then graded the chatbot-generated answers to these questions for accuracy (6-point Likert scale with 1 being completely incorrect and 6 being completely correct) and completeness (3-point Likert scale, with 1 being incomplete and 3 being complete plus additional context). Scores were summarized with descriptive statistics and compared using the Mann-Whitney U test or the Kruskal-Wallis test. The study (including data analysis) was conducted from January to May 2023. Main Outcomes and Measures: Accuracy, completeness, and consistency over time and between 2 different versions (GPT-3.5 and GPT-4) of chatbot-generated medical responses. Results: Across all questions (n = 284) generated by 33 physicians (31 faculty members and 2 recent graduates from residency or fellowship programs) across 17 specialties, the median accuracy score was 5.5 (IQR, 4.0-6.0) (between almost completely and complete correct) with a mean (SD) score of 4.8 (1.6) (between mostly and almost completely correct). The median completeness score was 3.0 (IQR, 2.0-3.0) (complete and comprehensive) with a mean (SD) score of 2.5 (0.7). For questions rated easy, medium, and hard, the median accuracy scores were 6.0 (IQR, 5.0-6.0), 5.5 (IQR, 5.0-6.0), and 5.0 (IQR, 4.0-6.0), respectively (mean [SD] scores were 5.0 [1.5], 4.7 [1.7], and 4.6 [1.6], respectively; P = .05). Accuracy scores for binary and descriptive questions were similar (median score, 6.0 [IQR, 4.0-6.0] vs 5.0 [IQR, 3.4-6.0]; mean [SD] score, 4.9 [1.6] vs 4.7 [1.6]; P = .07). Of 36 questions with scores of 1.0 to 2.0, 34 were requeried or regraded 8 to 17 days later with substantial improvement (median score 2.0 [IQR, 1.0-3.0] vs 4.0 [IQR, 2.0-5.3]; P < .01). A subset of questions, regardless of initial scores (version 3.5), were regenerated and rescored using version 4 with improvement (mean accuracy [SD] score, 5.2 [1.5] vs 5.7 [0.8]; median score, 6.0 [IQR, 5.0-6.0] for original and 6.0 [IQR, 6.0-6.0] for rescored; P = .002). Conclusions and Relevance: In this cross-sectional study, chatbot generated largely accurate information to diverse medical queries as judged by academic physician specialists with improvement over time, although it had important limitations. Further research and model development are needed to correct inaccuracies and for validation.

Dyspnea-Related Ticagrelor Discontinuation After Percutaneous Coronary Intervention.

BACKGROUND: Nearly 20% of patients on ticagrelor experience dyspnea, which may lead to treatment discontinuation in up to one-third of cases. OBJECTIVES: The authors sought to evaluate the incidence, predictors, and outcomes of dyspnea-related ticagrelor discontinuation after percutaneous coronary intervention (PCI). METHODS: In the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial, after 3 months of ticagrelor plus aspirin, patients were maintained on ticagrelor and randomized to aspirin or placebo for 1 year. The occurrence of dyspnea associated with ticagrelor discontinuation was evaluated among all patients enrolled in the trial. A landmark analysis was performed at 3 months after PCI, that is, the time of randomization. Predictors of dyspnea-related ticagrelor discontinuation were obtained from multivariable Cox regression with stepwise selection of candidate variables. RESULTS: The incidence of dyspnea-related ticagrelor discontinuation was 6.4% and 9.1% at 3 and 15 months after PCI, respectively. Independent predictors included Asian race (lower risk), smoking, prior PCI, hypercholesterolemia, prior coronary artery bypass, peripheral artery disease, obesity, and older age. Among 179 patients who discontinued ticagrelor because of dyspnea after randomization, ticagrelor monotherapy was not associated with a higher risk of subsequent ischemic events (composite of all-cause death, myocardial infarction, or stroke) compared with ticagrelor plus aspirin (5.0% vs 7.1%; P = 0.566). CONCLUSIONS: In the TWILIGHT trial, dyspnea-related ticagrelor discontinuation occurred in almost 1 in 10 patients and tended to occur earlier rather than late after PCI. Several demographic and clinical conditions predicted its occurrence, and their assessment may help identify subjects at risk for therapy nonadherence.

Esophageal Cancer: Overview, Risk Factors, and Reasons for the Rise.

PURPOSE OF REVIEW: Esophageal cancer (EC) is a common cancer affecting many regions of the world and carries significant morbidity and mortality. In this article, we review the key risk factors and their associated impact on the changing incidence and prevalence of EC subtypes within different global regions. We also highlight potential reasons for the ever-changing epidemiology of this prevalent cancer type. RECENT FINDINGS: There has been a shift in incidence of Esophageal Adenocarcinoma (AC) and Squamous Cell Carcinoma (SCC) within certain populations primarily due to an increase prevalence of primary risk factors. In Western nations, more often the United States, there has been a shift from SCC predominance to the majority of new cases of EC being adenocarcinoma. This shift within the United States has largely correlated with a rise in obesity. The prevalence of AC in Asia is also starting to rise as more countries adopt a western diet. The pathophysiology, associated risk factors, and presentation of ESCC and AC are different. This difference is seen in varying lifestyles, population health, and certain genetic risks. With further development closer analysis of primary risk factors and implementation of policies and programs that promote public health literacy, there is a potential to decrease esophageal cancer's global disease burden.

Clinical, Echocardiographic, and Longitudinal Characteristics Associated with Heart Failure with Improved Ejection Fraction.

Background: Heart failure (HF) with improved ejection fraction (HFimpEF) has better outcomes than HF with reduced ejection fraction (HFrEF). However, factors contributing to HFimpEF remain unclear. This study aimed to evaluate clinical and longitudinal characteristics associated with subsequent HFimpEF. Methods: This was a single-center retrospective HFrEF cohort study. Data were collected from 2014 to 2022. Patients with HFrEF were identified using ICD codes, echocardiographic data, and natriuretic peptide levels. The main endpoints were HFimpEF (defined as ejection fraction >40% at ≥3 months with ≥10% increase) and mortality. Cox proportional hazards and mixed effects models were used for analyses. Results: The study included 1307 HFrEF patients with a median follow-up of 16.3 months (IQR 8.0-30.6). The median age was 65 years; 68% were male while 57% were white. On follow-up, 39% (n=506) developed HFimpEF, while 61% (n=801) had persistent HFrEF. A multivariate Cox regression model identified sex, race comorbidities, echocardiographic, and natriuretic peptide as significant covariates of HFimpEF ( p <0.05). The HFimpEF group had better survival compared to the persistent HFrEF group ( p <0.001). Echocardiographic and laboratory trajectories differed between groups. Conclusion: In this HFrEF cohort, 39% transitioned to HFimpEF and approximately 50% met the definition within the first 12 months. In a HFimpEF model, sex, comorbidities, echocardiographic parameters, and natriuretic peptide were associated with subsequent HFimpEF. The model has the potential to identify patients at risk of subsequent persistent or improved HFrEF, thus informing the design and implementation of targeted quality-of-care improvement interventions.

Eosinophils Exert Antitumorigenic Effects in the Development of Esophageal Squamous Cell Carcinoma.

BACKGROUND AND AIMS: Eosinophils are present in several solid tumors and have context-dependent function. Our aim is to define the contribution of eosinophils in esophageal squamous cell carcinoma (ESCC), as their role in ESCC is unknown. METHODS: Eosinophils were enumerated in tissues from 2 ESCC cohorts. Mice were treated with 4-NQO for 8 weeks to induce precancer or 16 weeks to induce carcinoma. The eosinophil number was modified by a monoclonal antibody to interleukin-5 (IL5mAb), recombinant IL-5 (rIL-5), or genetically with eosinophil-deficient (ΔdblGATA) mice or mice deficient in eosinophil chemoattractant eotaxin-1 (Ccl11-/-). Esophageal tissue and eosinophil-specific RNA sequencing was performed to understand eosinophil function. Three-dimensional coculturing of eosinophils with precancer or cancer cells was done to ascertain direct effects of eosinophils. RESULTS: Activated eosinophils are present in higher numbers in early-stage vs late-stage ESCC. Mice treated with 4-NQO exhibit more esophageal eosinophils in precancer vs cancer. Correspondingly, epithelial cell Ccl11 expression is higher in mice with precancer. Eosinophil depletion using 3 mouse models (Ccl11-/- mice, ΔdblGATA mice, IL5mAb treatment) all display exacerbated 4-NQO tumorigenesis. Conversely, treatment with rIL-5 increases esophageal eosinophilia and protects against precancer and carcinoma. Tissue and eosinophil RNA sequencing revealed eosinophils drive oxidative stress in precancer. In vitro coculturing of eosinophils with precancer or cancer cells resulted in increased apoptosis in the presence of a degranulating agent, which is reversed with NAC, a reactive oxygen species scavenger. ΔdblGATA mice exhibited increased CD4 T cell infiltration, IL-17, and enrichment of IL-17 protumorigenic pathways. CONCLUSION: Eosinophils likely protect against ESCC through reactive oxygen species release during degranulation and suppression of IL-17.

Clinicopathological characteristics and treatment outcomes of oesophageal cancer patients in Uganda.

Background: Oesophageal cancer is the seventh most common cancer and the sixth leading cause of cancer death worldwide, and its incidence varies globally. In Uganda, the incidence and trend are on the increase. However, there is a paucity of published data regarding this population's oesophageal cancer clinicopathologic characterisation and treatment outcomes. Objectives: To study the patients' clinicopathologic characteristics and treatment outcomes of oesophageal cancer over 10 years at the Uganda Cancer Institute. Methods: Patients' charts with histologically confirmed diagnoses of oesophageal cancer for 2009-2019 were identified. Case information, which included patient demographics, history of alcohol use or smoking, tumour location, histological type, tumour grade, clinical TNM (Tumour, Node, Metastasis) staging treatment exposure and treatment outcomes, was evaluated retrospectively. The median survival time was estimated with the Kaplan-Meier method and the median follow-up period was estimated using the reverse Kaplan-Meier. Results: 1,965 oesophageal cancer patients were identified; 1,380(70.23%) were males and 585(29.77 %) females, their mean age was 60.20 years (±12.66). Most males had a history of both alcohol consumption and smoking 640(46.38%). The lower third of the oesophagus was the most common anatomical location 771(39.24%). The majority had squamous cell carcinoma histological type 1,783(90.74%) followed by adenocarcinomas 182(9.26%) in the distal oesophagus. Poorly differentiated tumour grade 743(37.81%) was predominant. The majority of the patients were in stage IVB, 733(37.30%), and most patients were planned for the best supportive care, 731(37.20%). Radiation alone was offered to 621(31.60%) and feeding gastrostomy to 249(12.70%). Treatment outcomes: at the time of the current analysis, 58.68% had died, 1.48% were alive and 39.84% were lost to follow-up. The median follow-up period was 65 months (IQR:35.83-83.30) with a median survival time of 4.47 months (95% CI: 4.17-4.80). Conclusion: Treatment outcomes of Ugandan oesophageal cancer patients seeking care are poor as most patients present with advanced disease. There is a significant loss of follow-up after treatment initiation. Therefore, reduction in exposure to known modifiable risk factors, early detection and timely referral for treatment strategies are needed to improve outcomes of these patients in our population. Designing interventions to improve treatment adherence is necessary.

Remote monitoring titration clinic to implement guideline-directed therapy for heart failure patients with reduced ejection fraction: a pilot quality-improvement intervention.

Introduction: Guideline-directed medical therapy (GDMT) is the recommended treatment for heart failure with reduced ejection fraction (HFrEF). However, the implementation remains limited, with suboptimal use and dosing. The study aimed to assess the feasibility and effect of a remote monitoring titration program on GDMT implementation. Methods: HFrEF patients were randomly assigned to receive either usual care or a quality-improvement remote titration with remote monitoring intervention. The intervention group used wireless devices to transmit heart rate, blood pressure, and weight data daily, which were reviewed by physicians and nurses every 2-4 weeks. Medication tolerance was assessed via phone, and dosage instructions were given. This workflow was repeated until target doses were reached or further adjustments were not tolerated. A 4-GDMT score measured use and target dosage, with the primary endpoint being the score at 6 months follow-up. Results: Baseline characteristics were similar (n = 55). A median of 85% of patients complied with transmitting device data every week. At the 6-month follow-up, the intervention group had a 4-GDMT score of 64.6% compared to 56.5% in the usual care group (p = 0.01), with a difference of 8.1% (95% CI: 1.7%-14.5%). Similar results were seen at the 12-month follow-up [difference 12.8% (CI: 5.0%-20.6%)]. The intervention group showed a positive trend in ejection fraction and natriuretic peptides, with no significant difference between groups. Conclusions: The study suggests that a full-scale trial is feasible and that utilizing a remote titration clinic with remote monitoring has the potential to enhance the implementation of guideline-directed therapy for HFrEF.

A phase 2 study of neoadjuvant chemotherapy plus durvalumab in resectable locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Patients with locally advanced head and neck squamous cell cancer (HNSCC) are treated with surgery followed by adjuvant (chemo) radiotherapy or definitive chemoradiation, but recurrence rates are high. Immune checkpoint blockade improves survival in patients with recurrent/metastatic HNSCC; however, the role of chemo-immunotherapy in the curative setting is not established. METHODS: This phase 2, single-arm, multicenter study evaluated neoadjuvant chemo-immunotherapy with carboplatin, nab-paclitaxel, and durvalumab in patients with resectable locally advanced HNSCC. The primary end point was a hypothesized pathologic complete response rate of 50%. After chemo-immunotherapy and surgical resection, patients received study-defined, pathologic risk adapted adjuvant therapy consisting of either durvalumab alone (low risk), involved field radiation plus weekly cisplatin and durvalumab (intermediate risk), or standard chemoradiation plus durvalumab (high risk). RESULTS: Between December 2017 and November 2021, 39 subjects were enrolled at three centers. Oral cavity was the most common primary site (69%). A total of 35 of 39 subjects underwent planned surgical resection; one subject had a delay in surgery due to treatment-related toxicity. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. Post treatment imaging demonstrated an objective response rate of 57%. Pathologic complete response and major pathologic response were achieved in 29% and 49% of subjects who underwent planned surgery, respectively. The 1-year progression-free survival was 83.8% (95% confidence interval, 67.4%-92.4%). CONCLUSIONS: Neoadjuvant carboplatin, nab-paclitaxel, and durvalumab before surgical resection of HNSCC were safe and feasible. Although the primary end point was not met, encouraging rates of pathologic complete response and clinical to pathologic downstaging were observed.

Eosinophils exert direct and indirect anti-tumorigenic effects in the development of esophageal squamous cell carcinoma.

Background/Aims: Eosinophils are present in several solid tumors and have context-dependent function. Our aim is to define the contribution of eosinophils in esophageal squamous cell carcinoma (ESCC), since their role in ESCC is unknown. Methods: Eosinophils were enumerated in tissues from two ESCC cohorts. Mice were treated with 4-nitroquinolone-1-oxide (4-NQO) for 8 weeks to induce pre-cancer or 16 weeks to induce carcinoma. Eosinophil number was modified by monoclonal antibody to IL-5 (IL5mAb), recombinant IL-5 (rIL-5), or genetically with eosinophil-deficient (ΔdblGATA) mice or mice deficient in eosinophil chemoattractant eotaxin-1 ( Ccl11 -/- ). Esophageal tissue and eosinophil specific RNA-sequencing was performed to understand eosinophil function. 3-D co-culturing of eosinophils with pre-cancer or cancer cells was done to ascertain direct effects of eosinophils. Results: Activated eosinophils are present in higher numbers in early stage versus late stage ESCC. Mice treated with 4-NQO exhibit more esophageal eosinophils in pre-cancer versus cancer. Correspondingly, epithelial cell Ccl11 expression is higher in mice with pre-cancer. Eosinophil depletion using three mouse models ( Ccl11 -/- mice, ΔdblGATA mice, IL5mAb treatment) all display exacerbated 4-NQO tumorigenesis. Conversely, treatment with rIL-5 increases esophageal eosinophilia and protects against pre-cancer and carcinoma. Tissue and eosinophil RNA-sequencing revealed eosinophils drive oxidative stress in pre-cancer. In vitro co-culturing of eosinophils with pre-cancer or cancer cells resulted in increased apoptosis in the presence of a degranulating agent, which is reversed with N-acetylcysteine, a reactive oxygen species (ROS) scavenger. ΔdblGATA mice exhibited increased CD4 T cell infiltration, IL-17, and enrichment of IL-17 pro-tumorigenic pathways. Conclusion: Eosinophils likely protect against ESCC through ROS release during degranulation and suppression of IL-17.

Rationale and design of a randomized study comparing the Watchman FLX device to DOACs in patients with atrial fibrillation.

BACKGROUND: Percutaneous left atrial appendage (LAA) closure (LAAC) was developed as a nonpharmacologic alternative to oral anticoagulants (OACs) in patients with atrial fibrillation (AF) who are at an increased risk for stroke or systemic embolism. The Watchman device permanently seals off the LAA to prevent thrombi from escaping into the circulation. Previous randomized trials have established the safety and efficacy of LAAC compared to warfarin. However, direct OACs (DOACs) have become the preferred pharmacologic strategy for stroke prevention in patients with AF, and there is limited data comparing Watchman FLX to DOACs in a broad AF patient population. CHAMPION-AF is designed to prospectively determine whether LAAC with Watchman FLX is a reasonable first-line alternative to DOACs in patients with AF who are indicated for OAC therapy. STUDY DESIGN: A total of 3,000 patients with a CHA2DS2-VASc score ≥2 (men) or ≥3 (women) were randomized to Watchman FLX or DOAC in a 1:1 allocation at 142 global clinical sites. Patients in the device arm were to be treated with DOAC and aspirin, DOAC alone, or DAPT for at least 3 months postimplant followed by aspirin or P2Y12 inhibitor for 1-year. Control patients were required to take an approved DOAC for the duration of the trial. Clinical follow-up visits are scheduled at 3- and 12-months, and then annually through 5 years; LAA imaging is required at 4 months in the device group. Two primary end points will be evaluated at 3 years: (1) composite of stroke (ischemic/hemorrhagic), cardiovascular death, and systemic embolism compared for noninferiority, and (2) nonprocedural bleeding (International Society on Thrombosis and Haemostasis [ISTH] major and clinically relevant nonmajor bleeding) tested for superiority in the device arm against DOACs. The third primary noninferiority end point is the composite of ischemic stroke and systemic embolism at 5 years. Secondary end points include 3- and 5-year rates of (1) ISTH-defined major bleeding and (2) the composite of cardiovascular death, all stroke, systemic embolism, and nonprocedural ISTH bleeding. CONCLUSIONS: This study will prospectively evaluate whether LAAC with the Watchman FLX device is a reasonable alternative to DOACs in patients with AF. CLINICAL TRIAL REGISTRATION: NCT04394546.

Enhanced Thromboresistance and Endothelialization of a Novel Fluoropolymer-Coated Left Atrial Appendage Closure Device.

BACKGROUND: Device-related thrombus (DRT) after left atrial appendage closure (LAAC) procedures is a rare but potentially serious event. Thrombogenicity and delayed endothelialization play a role in the development of DRT. Fluorinated polymers are known to have thromboresistant properties that may favorably modulate the healing response to an LAAC device. OBJECTIVES: The goal of this study was to compare the thrombogenicity and endothelial coverage (EC) after LAAC between the conventional uncoated WATCHMAN FLX (WM) and a novel fluoropolymer-coated WATCHMAN FLX (FP-WM). METHODS: Canines were randomized for implantation with WM or FP-WM devices and given no postimplant antithrombotic/antiplatelet agents. The presence of DRT was monitored by using transesophageal echocardiography and verified histologically. The biochemical mechanisms associated with coating were assessed by using flow loop experiments to quantify albumin adsorption, platelet adhesion, and porcine implants to quantify EC and the expression of markers of endothelial maturation (ie, vascular endothelial-cadherin/p120-catenin). RESULTS: Canines implanted with FP-WM exhibited significantly less DRT at 45 days than those implanted with WM (0% vs 50%; P < 0.05). In vitro experiments showed significantly greater albumin adsorption (52.8 [IQR: 41.0-58.3] mm2 vs 20.6 [IQR: 17.2-26.6] mm2; P = 0.03) and significantly less platelet adhesion (44.7% [IQR: 27.2%-60.2%] vs 60.9% [IQR: 39.9%-70.1%]; P < 0.01) on FP-WM. Porcine implants showed significantly greater EC by scanning electron microscopy (87.7% [IQR: 83.4%-92.3%] vs 68.2% [IQR: 47.6%-72.8%]; P = 0.03), and higher vascular endothelial-cadherin/p120-catenin expression after 3 months on FP-WM compared with WM. CONCLUSIONS: The FP-WM device showed significantly less thrombus and reduced inflammation in a challenging canine model. Mechanistic studies indicated that the fluoropolymer-coated device binds more albumin, leading to reduced platelet binding, less inflammation, and greater EC.

Esophageal and Esophagogastric Junction Cancers, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Cancers originating in the esophagus or esophagogastric junction constitute a major global health problem. Esophageal cancers are histologically classified as squamous cell carcinoma (SCC) or adenocarcinoma, which differ in their etiology, pathology, tumor location, therapeutics, and prognosis. In contrast to esophageal adenocarcinoma, which usually affects the lower esophagus, esophageal SCC is more likely to localize at or higher than the tracheal bifurcation. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability status, and the expression of programmed death-ligand 1, has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, ipilimumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with locally advanced esophageal or esophagogastric junction cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on the management of recurrent or metastatic disease.

Early follow-up quality of life and mental health of patients with congenital vascular malformations cared for in a multi-disciplinary specialist centre.

OBJECTIVE: The study aimed to evaluate the early follow-up quality of life (QoL), pain and mental health of patients with congenital vascular malformation (CVM) from a variety of treatment options. METHODS: All patients with CVM who received care and had follow-up between February 1st 2018 and January 31st 2020 were included. The health-related QoL, pain, and mental health were assessed with RAND Health Care 36-Item Short Form Survey (SF-36), visual analogue score for pain (VAS-P) and Hospital Anxiety and Depression Scale (HADS). Paired t-test was used for all analyses. p < .05 were considered significant. RESULTS: In total, 110 patients with a mean age of 36.9 years were included in this study. In all patients following care, significant improvement was found in the bodily pain domain of SF-36 and VAS-P (both p = .01). This was largely driven by high-flow vascular malformation patients who responded better to embolo-sclerotherapy, which revealed significant improvement in the bodily pain domain of SF-36 (p = .002) and VAS-P (p = .02). Patients who received supportive treatment only reported significant improvement in mental health (p = .004) and social functioning (p = .03) domains of SF-36. Meanwhile, patients treated with embolo-sclerotherapy reported significant improvement only in VAS-P (p = .02). CONCLUSIONS: This study concluded that the effects of care on early follow-up QoL, pain and mental health of patients with CVM were heterogenous. Future research should therefore, include larger sample size and longer term follow-up to understand the various factors that affect the QoL and mental health of these patients, as well as the holistic approaches to manage them.

Consumer-Led Screening for Atrial Fibrillation: Frontier Review of the AF-SCREEN International Collaboration.

The technological evolution and widespread availability of wearables and handheld ECG devices capable of screening for atrial fibrillation (AF), and their promotion directly to consumers, has focused attention of health care professionals and patient organizations on consumer-led AF screening. In this Frontiers review, members of the AF-SCREEN International Collaboration provide a critical appraisal of this rapidly evolving field to increase awareness of the complexities and uncertainties surrounding consumer-led AF screening. Although there are numerous commercially available devices directly marketed to consumers for AF monitoring and identification of unrecognized AF, health care professional-led randomized controlled studies using multiple ECG recordings or continuous ECG monitoring to detect AF have failed to demonstrate a significant reduction in stroke. Although it remains uncertain if consumer-led AF screening reduces stroke, it could increase early diagnosis of AF and facilitate an integrated approach, including appropriate anticoagulation, rate or rhythm management, and risk factor modification to reduce complications. Companies marketing AF screening devices should report the accuracy and performance of their products in high- and low-risk populations and avoid claims about clinical outcomes unless improvement is demonstrated in randomized clinical trials. Generally, the diagnostic yield of AF screening increases with the number, duration, and temporal dispersion of screening sessions, but the prognostic importance may be less than for AF detected by single-time point screening, which is largely permanent, persistent, or high-burden paroxysmal AF. Consumer-initiated ECG recordings suggesting possible AF always require confirmation by a health care professional experienced in ECG reading, whereas suspicion of AF on the basis of photoplethysmography must be confirmed with an ECG. Consumer-led AF screening is unlikely to be cost-effective for stroke prevention in the predominantly young, early adopters of this technology. Studies in older people at higher stroke risk are required to demonstrate both effectiveness and cost-effectiveness. The direct interaction between companies and consumers creates new regulatory gaps in relation to data privacy and the registration of consumer apps and devices. Although several barriers for optimal use of consumer-led screening exist, results of large, ongoing trials, powered to detect clinical outcomes, are required before health care professionals should support widespread adoption of consumer-led AF screening.