Trends in Epidemiology of Esophageal Cancer in the US, 1975-2018.

Importance: Esophageal cancer (EC) is the 7th most common cancer worldwide and 14th in the US. More data are needed to study the changing incidence patterns of its 2 primary histologic subtypes, squamous cell carcinoma of the esophagus (SCE) and adenocarcinoma of the esophagus (ACE). Objective: To examine temporal trends in incidence rates of EC, ACE, and SCE from 1975 through 2018. Design, Setting, and Participants: In this population-based cross-sectional study, data were derived from 9 Surveillance, Epidemiology, and End Results (SEER) registries from January 1975 through December 2018 and from all 21 registries for January 2000 through December 2018 for patients with a diagnosis of EC from 1975 through 2018 (International Classification of Disease-Oncology, Third Edition codes). Age-adjusted incidence rates (AAIRs) of EC, ACE, and SCE were calculated. The timing and magnitude of the annual percentage change (APC) in incidence were examined using Joinpoint regression analyses. Data analysis was started in 2021 and updated and completed in 2023. Main Outcome and Measures: The APC for age-adjusted EC incidence rates as stratified by histology, anatomical location, stage, sex, age, race and ethnicity, and geographic region. Results: A total of 47 648 patients with a diagnosis of EC were retained for analysis. These included 22 419 (47.1%) with a diagnosis of SCE, 22 217 (46.6%) with ACE, and 3012 (6.3%) with other subtypes. The AAIR for EC changed from 4.14 per 100 000 population in 1975 to 4.18 in 2018, AAIRs of SCE declined from 3.06 in 1975 to 1.15 in 2018 as well as for ACE, and AAIRs increased from 0.42 in 1975 to 2.78 in 2018. From 1975 through 2004, EC incidence significantly increased (APC, 0.53; 95% CI, 0.4 to 0.7) but significantly decreased (APC, -1.03; 95% CI, -1.3 to -0.7) from then until 2018. The APC of SCE significantly continued to decline (-2.80, 95% CI, -3.0 to -2.6), and ACE increased from 2000 to 2006 (APC, 2.51; 95% CI, 1.0 to 4.0) but has since stabilized from 2006 to 2018. Conclusions and Relevance: The results of this cross-sectional study suggest that the incidence of EC modestly declined since 2004 and that the incidence of SCE continued to decline while the incidence rate of ACE plateaued for more than a decade. Understanding factors associated with plateaued rates of ACE may help inform public health interventions.

EMS Care of Adult Hospice Patients- a Position Statement and Resource Document of NAEMSP and AAHPM.

Emergency medical services (EMS) systems are designed to provide care in the field and while transporting patients to a hospital; however, patients enrolled in hospice may not want invasive therapies nor benefit from hospitalization. For many reasons, encounters with hospice patients can be challenging for EMS systems, EMS clinicians, hospice clinicians, hospice patients, and their families.

EMS clinicians should receive hospice-focused education that fosters a basic understanding of hospice, palliative therapies, and advance care planning documents (e.g., Physician Orders for Life Sustaining Treatment). This education should emphasize the ongoing development of end-of-life communication skills.EMS medical directors and local hospice organizations should collaborate to develop hospice patient-centered EMS protocols that address symptom management and delineate appropriate and goal concordant clinical interventions, and that are within the agency-level scope of practice for local EMS clinicians. Partnerships between EMS and hospice organizations can facilitate access to hospice teams who can provide clear guidance on whether to treat-in-place with follow-up care or to transport hospice patients to the hospital.EMS medical directors and local hospice organizations should collaborate to perform needs assessments of hospice patient EMS utilization.EMS medical directors should consider including a focus on EMS care of hospice patients as part of their overall quality management program(s). Ideally these efforts should be collaborative with local hospice agencies in order to facilitate meaningful process improvement strategies that include both EMS and hospice stakeholders.Reimbursement programs should reasonably compensate EMS agencies for scene treatment in place, as well as transport to alternative destinations such as in-patient hospice facilities.

Top Ten Tips Palliative Care Clinicians Should Know About Improving Partnerships With Emergency Medical Services.

Emergency medical services (EMS) clinicians increasingly encounter seriously ill patients and their caregivers in times of distress. When crises arise or care coordination falls short, these high-stakes interactions highlight opportunities to improve care experience and outcomes. Efforts must address wide educational gaps, absence of specialized care protocols, and systematic fragmentation leading to hyperlocal practice. The authors represent cross-sectional expertise in palliative care and EMS. This article describes unmet needs at the EMS-palliative interface, challenges with collaboration, and where directional progress exists.

Emergency Department Embedded Palliative Care Service Creates Value for Health Systems.

Background: Emergency department (ED)-initiated palliative care consultation facilitates goal-concordant care while stewarding resource utilization. Delivery models are being piloted without clear operational and financial sustainability. Objective: To demonstrate that embedding a palliative care consultation service in the ED is clinically meaningful, operationally viable, and yields significant return on investment (ROI). Methods: Quasi-experimental study from August 17, 2020 to August 17, 2021. We established an ED-embedded palliative care consultation service at a 350-bed urban community hospital with 45,000 annual ED visits. A singe palliative care provider stationed in the main ED workstation area from 11 am to 7 pm daily. Matched analysis compared ED-embedded consultations against Floor and intensive care unit (ICU) consultations originating from usual practice. Results: ED consultations increased 10x, without cannibalization, to become the hospital's primary source of palliative care consultations. Clinical outcomes were meaningful, with 49% changing code status, 11% admitting to lower level of care, 11% avoiding hospitalization, 17% newly referred to hospice, and 21% newly referred to palliative care clinic. ED length of stay (LOS) did not lengthen, and ED staff strongly agreed that the service was valuable and unobtrusive. Compared with Floor, ED consultations had 8.1 days shorter hospital LOS (3.0 vs. 11.1 days, p < 0.01) with $5,974 lower median direct costs for index hospitalization ($6,211 vs. $12,005, p < 0.01). Compared with ICU, ED consultations had 4.2 days shorter hospital LOS (3.0 vs. 7.2 days, p < 0.01) with $9,332 lower median direct costs for index hospitalization ($14,093 vs. $23,425, p < 0.01). ROI was 6.7x net of foregone revenue and labor expenses. Conclusions and Relevance: This ED-embedded palliative care consultation service was clinically meaningful, operationally viable, and delivered a 6.7x ROI. ED-palliative partnerships present a quadruple aim opportunity to improve care for seriously ill patients.

Developing a novel integrated geriatric palliative care consultation program for the emergency department.

With the aging of our population, older adults are living longer with multiple chronic conditions, frailty, and life-limiting illnesses, which creates specific challenges for emergency departments (EDs). Older adults and those with serious illnesses have high rates of ED use and hospitalization, and the emergency care they receive may be discordant with their goals and values. In response, new models of care delivery have begun to emerge to address both geriatric and palliative care needs in the ED. However, these programs are typically siloed from one another despite significant overlap. To develop a new combined model, we assembled stakeholders and thought leaders at the intersection of emergency medicine, palliative care, and geriatrics and used a consensus process to define elements of an ideal model of a combined palliative care and geriatric intervention in the ED. This article provides a brief history of geriatric and palliative care integration in EDs and presents the integrated geriatric and palliative care model developed.

The Melbourne epidemic thunderstorm asthma event 2016: a 5-year longitudinal study.

Background: In 2016, Melbourne was struck by the world's largest and most devastating epidemic thunderstorm asthma (ETSA) episode. While affected individuals displayed worsened short-term asthma control, little is known about their longer-term natural history, nor about interventions that restore control. Objective: We assessed the asthma symptomatology and related behaviours of ETSA-affected individuals through a single-centre prospective 5-year longitudinal study. We embedded an open-label observational trial investigating the role of grass pollen sublingual tablet (Oralair) allergen immunotherapy in improving asthma and allergic rhinitis symptoms. Methods: Allergic rhinitis symptom severity, frequency of asthma symptoms and inhaled corticosteroid usage were assessed via questionnaire yearly. In 2018, a subgroup of participants was enrolled in an observational study of Oralair treatment compared to control. The active group received Oralair from 2019 to 2021; both groups were followed-up for 5 years. Subgroup analyses were performed for participants with complete datasets, and who completed the trial per-protocol. Results: Year-on-year data across 5 years was available for 30 participants. The rate of persistent asthma symptoms declined from 37% to 7% in 2016 to 2021. Only 10%-27% of participants reported being completely asymptomatic in any given year. The inhaled preventer prescription rate was 67%, with only 35% being adherent. Twenty-seven participants with available data completed the Oralair trial per-protocol. No significant difference was noted between control and active groups for allergic rhinitis symptoms or asthma control, although the Oralair group saw a significant improvement in asthma control comparing 2019 with 2021. Conclusion: This is the longest documented follow-up of ETSA-affected individuals. Five years following sentinel event, there was progressive reduction but some persistence in asthma symptoms. Oralair allergen immunotherapy did not further improve allergic rhinitis or asthma symptoms compared to control, but there were no further ETSA events to test a protective effect during the study period.

Scurvy: a rare cause of haemarthrosis.

A male in his 60s with a history of previously treated locally advanced head and neck cancer presented to the emergency department with atraumatic left knee pain and upper and lower extremity ecchymoses that had been present for 3 weeks. His initial laboratory results showed a normocytic anaemia, normal platelet count, slightly abnormal coagulation studies and normal inflammatory markers. Arthrocentesis of the left knee revealed haemarthrosis, and additional laboratory workup found an undetectable serum vitamin C (ascorbic acid) level consistent with scurvy. It was determined that scurvy had predisposed the patient to injury, leading to haemarthrosis. Following vitamin C supplementation, dietary and activity modifications, and acetaminophen as needed, the patient's serum vitamin C level normalised and his left knee pain and swelling improved. Scurvy is a rare cause of haemarthrosis, but it should be recognised in at-risk patients since treatment is effective.

Intermolecular Interactions and Intramolecular Motions in Photomechanical Effect: Nonlinear Thermo- and Photomechanical Behaviors of Azobenzene-Functionalized Amide-Imide Block Copolymers.

To discern multiple intertwined effects, a set of azobenzene-functionalized amide-imide block copolymers, azo(PA-co-PI)-x, where x is amide-block content, viz., [azoPA] = 25, 50, 75 mol %, was synthesized from 2,2-bis{4-[4-(4-aminophenyldiazenyl)phenoxy]phenyl}propane(azoBPA), 4,4'-oxydibenzoyl chloride (ODBC), and 4,4'-oxydiphthalic anhydride (OPDA). Including homopolymers (azoPA and azoPI), this series of amorphous azopolymers possesses a high glass-transition temperature (Tg > 210 °C) and a modulus (E' ∼ 1.23-2.50 GPa). Their photobending (ca. 23-90°) and photostress (ca. 250-380 kPa) were assessed in the form of cantilevers with a linearly polarized 445 nm light. Nonlinear composition/[azoPA] dependencies of the thermo- and photomechanical properties are correlated. As [azoPA] increases from 0 mol %; Tg, E', photostress, and photobending angle initially decrease to reach four separate minima for azo(PA-co-PI)-50; and then all increase with a higher [azoPA]. The trend considerations of film density, dynamic thermomechanical, Fourier transform infrared (FT-IR), and ultraviolet-visible (UV-vis) measurements implicate that (i) intermolecular association and intramolecular segmental mobility collectively influence the photomechanical outcomes and (ii) two types of hydrogen bonding (HB), namely, amide-amide [HB-AA] and amide-imide [HB-AI] coexist in azo(PA-co-PI)-x copolymers, with [HB-AI] being largely responsible for photomechanical outcomes of azo(PA-co-PI)-x with [azoPA] <40-50 mol %, and [HB-AA] for [azoPA] >40-50 mol %. We hypothesize that the "U-shaped" photomechanical effect apparently stems from the cooperative "unzipping" of H bonds in the [HB-AA]* excited state with H bonds in [HB-AI]* being stabilized by electrostatic interactions inherent in an excited intermolecular complex.

United States Best Practice Guidelines for Primary Palliative Care in the Emergency Department.

The growing palliative care needs of emergency department (ED) patients in the United States have motivated the development of ED primary palliative care principles. An expert panel convened to develop best practice guidelines for ED primary palliative care to help guide frontline ED clinicians based on available evidence and consensus opinion of the panel. Results include recommendations for screening and assessment of palliative care needs, ED management of palliative care needs, goals of care conversations, ED palliative care and hospice consults, and transitions of care.

Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer By Suppressing the HER2/AKT Signaling Pathway.

Itraconazole, an FDA-approved antifungal, has antitumor activity against a variety of cancers. We sought to determine the effects of itraconazole on esophageal cancer and elucidate its mechanism of action. Itraconazole inhibited cell proliferation and induced G1-phase cell-cycle arrest in esophageal squamous cell carcinoma and adenocarcinoma cell lines. Using an unbiased kinase array, we found that itraconazole downregulated protein kinase AKT phosphorylation in OE33 esophageal adenocarcinoma cells. Itraconazole also decreased phosphorylation of downstream ribosomal protein S6, transcriptional expression of the upstream receptor tyrosine kinase HER2, and phosphorylation of upstream PI3K in esophageal cancer cells. Lapatinib, a tyrosine kinase inhibitor that targets HER2, and siRNA-mediated knockdown of HER2 similarly suppressed cancer cell growth in vitro Itraconazole significantly inhibited growth of OE33-derived flank xenografts in mice with detectable levels of itraconazole and its primary metabolite, hydroxyitraconazole, in esophagi and tumors. HER2 total protein and phosphorylation of AKT and S6 proteins were decreased in xenografts from itraconazole-treated mice compared to xenografts from placebo-treated mice. In an early phase I clinical trial (NCT02749513) in patients with esophageal cancer, itraconazole decreased HER2 total protein expression and phosphorylation of AKT and S6 proteins in tumors. These data demonstrate that itraconazole has potent antitumor properties in esophageal cancer, partially through blockade of HER2/AKT signaling.

Role of Alicyclic Conformation-Isomerization in the Photomechanical Performance of Azobenzene-Functionalized Cross-Linked Polyimides Containing Tetra-Substituted Cyclohexane Moieties.

The classical "chair-twist boat-boat" conformational dynamics (CD) of cyclohexane is thermally activated. Here we report on the photoinduced/azobenzene-assisted CD of bilaterally fused cyclohexane moieties contributing to large photomechanical response of cross-linked azobenzene-functionalized polyimides (X-azoPI), based on 1,2,4,5-cyclohexane-tetracarboxylic-dianhydride (CHDA), exhibiting a photobending angle and photogenerated stress, up to ∼90° and 370 kPa, respectively. In contrast, X-azoPI containing planar pyromellitimide (PMDI) or cage-like bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic-diimide (BCDI) show smaller photomechanical responses. The superior photomechanical performance of X-azoPI with constrained cyclohexane-diimide (CHDI) units is attributed to an increased mobility of segments comprising "hinged" p-phenylene rings, azobenzene, and CHDI units in the cross-link sites. Blue light irradiation initiates the motions driven by photoisomerization/reorientation of azobenzenes connected to CHDI units, whose CD is then amplified, leading to longer-range segmental mobility, more local free volume, and culminating in large photoinduced bending. The trapping of redistributed CHDI's stereoisomers in X-azoPI backbone at Troom is implicated for the observed photothermal memory.

Colitis-induced IL11 promotes colon carcinogenesis.

Colitis increases the risk of colorectal cancer; however, the mechanism of the association between colitis and cancer remains largely unknown. To identify colitis-associated cancer promoting factors, we investigated gene expression changes caused by dextran sulfate sodium (DSS)-induced colitis in mice. By analyzing gene expression profiles, we found that IL11 was upregulated in DSS-induced colitis tissue and 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP)/DSS-induced colon tumours in mice as well as in human colorectal cancer. By characterizing the activation/phosphorylation of STAT3 (pSTAT3), we found that pSTAT3 was induced transiently in colitis, but maintained at higher levels from hyper-proliferative dysplastic lesions to tumours. Using the IL11 receptor (IL11Rα1) knockout mice, we found that pSTAT3 in the newly regenerated crypt epithelial cells in colitis is abolished in IL11Rα1+/- and -/- mice, suggesting that colitis-induced IL11 activates STAT3 in colon crypt epithelial cells. Moreover, colitis-promoted colon carcinogenesis was significantly reduced in IL11Rα1+/- and -/- mice. To determine the roles of the IL11 in colitis, we found that the inhibition of IL11 signalling by recombinant IL11 antagonist mutein during colitis was sufficient to attenuate colitis-promoted carcinogenesis. Together, our results demonstrated that colitis-induced IL11 plays critical roles in creating cancer promoting microenvironment to facilitate the development of colon cancer from dormant premalignant cells.

Emergency Department Admission Triggers for Palliative Consultation May Decrease Length of Stay and Costs.

Background: Emergency department (ED) initiated palliative consultation impacts downstream care utilization. Various admission consult triggers have been proposed without clear best practice or outcomes. Objective: This 18-month single-center study evaluated the clinical, operational, and financial impact of simplified admission triggers for ED-initiated palliative consults as compared to downstream Floor and intensive care unit (ICU) palliative consults initiated per usual practice. Methods: We distilled ED admission triggers into three criteria to ensure bedside actionability and sustainability: (1) end-stage illness, (2) functional limitation, and (3) clinician would not be surprised if the patient died this hospitalization. Eligible patients met all criteria, and received consultation within 24 hours of admission. We compared ED-initiated consults against Floor and ICU consults from March 1, 2018, to September 30, 2019, with matched cohort analysis to evaluate financial outcomes. Results: While overall palliative consult volume remained intentionally steady, the proportion of ED-initiated consults significantly increased (7% vs. 19%, p < 0.001). ED consistently comprised 15-25% of all monthly palliative consults. Compared with Floor, ED had similar ED length of stay (LOS) and inpatient mortality. Among live discharges, ED were more likely to be referred to hospice than Floor (59% vs. 47%, p = 0.24) or ICU (59% vs. 34%, p = 0.02). In a matched cohort analysis, ED demonstrated median cost avoidance of $9,082 per patient versus Floor ($5,578 vs. $14,660, p < 0.001) and $15,138 per patient versus ICU ($5,578 vs. $20,716, p < 0.001). ED had significantly shorter median LOS before consult than Floor (0 vs. 3 days, p < 0.001) or ICU (0 vs. 3 days, p < 0.001), which did not differ between live discharges or inpatient deaths. Overall hospital LOS was disproportionately shorter for ED, with a net difference-in-differences of 1-3.5 days compared to Floor and ICU. Conclusions: Simple ED admission triggers to expedite palliative engagement are associated with a 50-75% reduction in both hospital LOS and costs when compared against usual palliative consultation practice. ED initiation reduces both lead time before consultation and subsequent downstream hospitalization length.

Gastrointestinal pharmacology: practical tips for the esophagologist.

Gastroesophageal reflux disease (GERD) is primarily a motor disorder, and its pathogenesis is multifactorial. As a consequence, treatment should be able to address the underlying pathophysiology. Proton pump inhibitors (PPIs) are the mainstay of medical therapy for GERD, but these drugs only provide the control of symptoms and lesions without curing the disease. However, continuous acid suppression with PPIs is recommended for patients with Barrett's esophagus because of their potential chemopreventive effects. In addition to the antisecretory activity, these compounds display several pharmacological properties, often overlooked in clinical practice. PPIs can indeed affect gastric motility, exert a mucosal protective effect, and an antioxidant, anti-inflammatory, and antineoplastic activity, also protecting cancer cells from developing chemo- or radiotherapeutic resistance. Even in the third millennium, current pharmacologic approaches to address GERD are limited. Reflux inhibitors represent a promise unfulfilled, effective and safe prokinetics are lacking, and antidepressants, despite being effective in selected patients, give rise to adverse events in a large proportion of them. While waiting for new drug classes (like potassium-competitive acid blockers), reassessing old drugs (namely alginate-containing formulations), and paving the new avenue of esophageal mucosal protection are, at the present time, the only reliable alternatives to acid suppression.

Recent insights into the biology of Barrett's esophagus.

Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), an aggressive cancer with a poor prognosis. Our understanding of the pathogenesis and Barrett's metaplasia is incomplete, and this has limited the development of new therapeutic targets and agents, risk stratification ability, and management strategies. This review outlines current insights into the biology of BE and addresses controversies surrounding cell of origin, cellular reprogramming theories, updates on esophageal epithelial barrier function, and the significance of goblet cell metaplasia and its association with malignant change. Further research into the basic biology of BE is vital as it will underpin novel therapies and improve our ability to predict malignant progression and help identify the minority of patients who will develop EAC.

GEAMP, a novel gastroesophageal junction carcinoma cell line derived from a malignant pleural effusion.

Gastroesophageal junction (GEJ) cancer remains a clinically significant disease in Western countries due to its increasing incidence, which mirrors that of esophageal cancer, and poor prognosis. To develop novel and effective approaches for prevention, early detection, and treatment of patients with GEJ cancer, a better understanding of the mechanisms driving pathogenesis and malignant progression of this disease is required. These efforts have been limited by the small number of available cell lines and appropriate preclinical animal models for in vitro and in vivo studies. We have established and characterized a novel GEJ cancer cell line, GEAMP, derived from the malignant pleural effusion of a previously treated GEJ cancer patient. Comprehensive genetic analyses confirmed a clonal relationship between GEAMP cells and the primary tumor. Targeted next-generation sequencing identified 56 nonsynonymous alterations in 51 genes including TP53 and APC, which are commonly altered in GEJ cancer. In addition, multiple copy-number alterations were found including EGFR and K-RAS gene amplifications and loss of CDKN2A and CDKN2B. Histological examination of subcutaneous flank xenografts in nude and NOD-SCID mice showed a carcinoma with mixed squamous and glandular differentiation, suggesting GEAMP cells contain a subpopulation with multipotent potential. Finally, pharmacologic inhibition of the EGFR signaling pathway led to downregulation of key downstream kinases and inhibition of cell proliferation in vitro. Thus, GEAMP represents a valuable addition to the limited number of bona fide GEJ cancer cell lines.