Citations

Abstract Eosinophils play an important role in mediating itch and inflammation in dermatitis. The role of the eosinophil granule protein eosinophil peroxidase (EPX) in mediating inflammation and itch was tested in a dermatitis mouse model. Mice were sensitized to trimellitic anhydride (TMA) and subsequently challenged chronically on the ear to establish dermatitis. Loss of EPX (in EPX−/− mice) or blocking EPX with the drug resorcinol significantly reduced dermatitis in mice exposed to TMA. Resorcinol also reduced levels of thymic stromal lymphopoietin protein (TSLP) in skin. Further studies showed that EPX increased different cytokines in keratinocytes in cell culture via 2 distinct mechanisms. EPX-induced TSLP expression requires lysophosphatidic acid signaling while EPX-induced expression of TNF-α, CSF2, CSF3, and IL1a required IL-1 signaling. We also showed that blocking IL-1 reduced inflammation in skin following TMA exposure in mice. Thus, EPX is an important mediator of inflammation and itch, that are mediated via at least 2 pathways. This suggests that both EPX and its signaling pathways may provide novel therapeutic strategies in dermatitis.

BACKGROUND AND OBJECTIVES: The Patient-Generated Subjective Global Assessment (PG-SGA) is a standardized tool for assessing malnutrition in patients with cancer. The primary aim of this study was to assess the impact of preoperative nutritional status as measured by PG-SGA on survival in patients requiring surgical intervention and/or radiotherapy for spinal metastases. METHODS: Patients with spinal metastases who underwent surgery and/or radiation therapy for symptomatic spinal metastases were enrolled in the AO Spine Metastatic Tumor Research and Outcomes Network, a prospective international multicenter research registry, between September 2017 and August 2022. Using the PG-SGA, nutritional status was classified into 3 categories: A, well nourished; B, moderately malnourished; and C, severely malnourished. RESULTS: A total of 589 patients met the inclusion criteria; 362 were classified as well nourished (61%), 159 were moderately malnourished (27%), and 68 were severely malnourished (12%). The median survival was 491 days, 328 days, and 117 days for well-nourished, moderately malnourished, and severely malnourished patients, respectively. In the multivariate analyses, severe malnourishment (HR 2.5 95% CI 1.4-4.3, P < .01) and an ECOG performance status of 3 or 4 (HR 2.7 95% CI 1.2-6.0) remained associated with significantly worse survival. CONCLUSION: Malnutrition as measured by the PG-SGA demonstrated to be significantly and independently associated with postoperative survival. The PG-SGA is a simple and useful tool to identify spinal metastases patients at risk of early postoperative mortality, and inclusion in the preoperative evaluation of these patients should be considered.

Technological innovations have improved many barriers in lung transplantation, but high rates of acute and chronic rejection still limit lung allograft survival. This may be explained by the unique environment of the lung. As a mucosal barrier organ, the lung is constantly exposed to the external environment, leading to unique immunological features that are not seen in other transplantable solid organ allografts such as hearts, kidneys, and livers. Thus, the higher rates of rejection and poor long-term survival of lung transplant recipients may stem from the global immunosuppression strategies that are indiscriminately used for all solid organ grafts. Data from our laboratory, and others, have demonstrated that the unique immunoregulatory pathways of the lung may require different strategies for long-term graft survival. For example, depletion of CD8 + T cells typically contributes to the acceptance of transplanted organs. However, these cells facilitate lung allograft acceptance through interferon gamma mediated nitric oxide production. Interestingly CD8 + T cells modify and polarize eosinophils to produce nitric oxide as a means of tolerance induction. Such eosinophils also function to maintain long-term lung allograft acceptance by interfering with humoral alloimmunity. For most other organs eosinophils are suspected to contribute to graft rejection. In this review, we aim to describe the cytokine pathways involved in lung allograft rejection or tolerance, contrast such pathways to those evident in other solid organs, and discuss the need for further studies that can be used to design rational methods for altering the cytokine environment to improve lung allograft survival.

Objective: This study evaluated the surgical and long-term patient-reported quality of life outcomes of patients undergoing esophagectomy with gastric advancement. Methods: A retrospective review was performed of all patients undergoing esophagectomy with gastric advancement from 2005 to 2016. Quality of life outcomes were evaluated using the European Organization for research and treatment of cancer quality of life questionnaire - esophageal cancer module (QLQ-OES18), which covered 10 symptom scales: dysphagia, trouble swallowing saliva, choking when swallowing, eating, dry mouth, trouble with taste, trouble with coughing, trouble speaking, reflux, and pain. Results: A total of 129 patients were followed up to 16 years (791.3 patient-years). The median age was 63.5 (IQR 55.9-69.3) years, and 79.9% were male. Eighty-six percentage (111/129) of patients had esophageal malignancy as their operative indication. Median survival was 7.1 years, with patients with benign disease experiencing longer postoperative survival ( P = .006). The response rate to QLQ-OES18 surveys was 53.7% (22/41; median follow-up: 10.4 years). Patients who experienced early postoperative complications were more likely to report trouble with coughing ( P = .032) than those who did not experience early complications. However, postoperative leaks were not associated with worsened QOL. Of note, age ≥ 65 years, obesity status, surgical indication, location of the primary esophageal lesion, tumor stage, and the occurrence of delayed postoperative complications were not associated with long-term QOL (all P > .05). Conclusion: Patients undergoing esophagectomy with gastric advancement generally had good quality of life 10 years postoperatively, though early postoperative complications and gender appeared to influence symptom burden. These findings may improve pre and postoperative patient counseling.

Study Design This study is part of the AO Spine Metastatic Tumor Research and Outcomes Network [MTRON], an international multicenter prospective observational registry including patients with spinal metastases. Objectives This study aims to elucidate the incidence of surgical complications, their risk factors and consequent effects on survival outcomes, hospital length of stay, and overall health-related quality of life (HRQOL) parameters in a large cohort of patients affected by spinal metastases who were surgically treated. Methods Available data from February 2017 to July 2023 were analyzed. The primary outcome of this study was the evaluation of the incidence of intraoperative and postoperative adverse events (AEs). The secondary outcomes included the assessment of risk factors for surgery-related AEs and the impact of AEs on survival, length of hospital stay and quality of life. Results Among the 1267 patients analyzed, 6.9% experienced intraoperative AEs and 19.3% experienced at least 1 postoperative AE. Several factors resulted to be associated to the occurrence of postoperative AEs: age, smoking habit, poor Eastern Cooperative Oncology Group (ECOG) Performance status, previous radiation therapy at the index target, duration of surgery, number of instrumented levels, simultaneous anterior and posterior approach, presence of metastases at other sites, multiple spinal metastases. Postoperative AEs were associated with reduced survival rates, increased hospital length of stay and poorer HRQOL outcomes, particularly in domains such as neurological function and mental health. In general, surgery substantially improves HRQOL across multiple domains, with these benefits persisting over time despite the occurrence of AEs. However, patients with preoperative risk factors, including comorbidities, smoking, neurological impairment, and prior radiation therapy, experienced less improvement. Conclusions The negative impact of AEs on overall survival and HRQOL could be associated with the presence of some preoperative parameters of frailty that are detected as risk factors for AEs occurrence. This finding emphasizes the need for personalized preoperative assessments and optimized perioperative care strategies.

OBJECTIVE In many individuals, type 2 diabetes (T2D) remains poorly controlled despite taking multiple glucose-lowering therapies. Several studies have demonstrated that endogenous hypercortisolism is prevalent among these individuals. We tested whether cortisol-directed therapy improves their glycemic control. RESEARCH DESIGN AND METHODS In this prospective, multicenter, double-blind study, 136 individuals with T2D (hemoglobin A1c [HbA1c] 7.5%–11.5% [58–102 mmol/mol] on multiple medications) and hypercortisolism (by dexamethasone suppression test) were randomized 2:1 to the glucocorticoid receptor antagonist mifepristone (300–900 mg once daily; n = 91) or placebo (n = 45) for 24 weeks, with stratification by presence/absence of an adrenal imaging abnormality. The primary end point was the change in HbA1c. Secondary end points included changes in glucose-lowering medications, weight, and waist circumference and safety. RESULTS Mean baseline HbA1c in the study cohort was 8.55% (69.9 mmol/mol). At 24 weeks, the least squares mean (LSM) difference from placebo in HbA1c was −1.32% (95% CI −1.81 to −0.83; P &lt; 0.001). Participants receiving mifepristone experienced reductions in body weight and waist circumference (placebo-adjusted LSM differences of −5.12 kg [95% CI −8.20 to −2.03] and −5.1 cm [−8.23 to −1.99], respectively). Of participants on mifepristone, 46% discontinued therapy, compared with 18% on placebo. Adverse events with mifepristone (&gt;10% of participants) included hypokalemia, fatigue, nausea, vomiting, headache, peripheral edema, diarrhea, and dizziness, consistent with mifepristone’s known tolerability profile. Increases in blood pressure also occurred. CONCLUSIONS In individuals with inadequately controlled T2D and hypercortisolism, cortisol-directed medical therapy with mifepristone reduced HbA1c, with a manageable tolerability profile.

OBJECTIVE Despite the use of multiple glucose-lowering medications, glycemic targets are not met in a significant fraction of people with type 2 diabetes. In this prospective, observational study we assessed the prevalence of hypercortisolism, a potential contributing factor to inadequate glucose control. RESEARCH DESIGN AND METHODS Individuals with type 2 diabetes and HbA1c 7.5%–11.5% (58–102 mmol/mol) on two or more glucose-lowering medications with or without micro-/macrovascular complications or taking multiple blood pressure–lowering medications were screened with a 1-mg dexamethasone suppression test. Common causes of false-positive DSTs were excluded. The primary end point was the prevalence of hypercortisolism, defined as post-DST cortisol &gt;1.8 μg/dL (50 nmol/L). Characteristics associated with hypercortisolism were assessed with multiple logistic regression. The percentage and characteristics of participants with hypercortisolism and adrenal imaging abnormalities were also assessed. RESULTS Post-DST cortisol was unsuppressed in 252 of 1,057 participants (prevalence 23.8%; 95% CI 21.3, 26.5). Hypercortisolism prevalence was 33.3% among participants with cardiac disorders and 36.6% among those taking three or more blood pressure–lowering medications. Adrenal imaging abnormalities were reported in 34.7% of participants with hypercortisolism. Use of sodium–glucose cotransporter 2 inhibitors (odds ratio 1.558), maximum-dose glucagon-like peptide 1 receptor agonists (1.544), tirzepatide (1.981), or a higher number of blood pressure–lowering medications (1.390); older age (1.316); BMI &lt;30 kg/m2 (1.639); non-Latino/Hispanic ethnicity (3.718); and use of fibrates (2.676) or analgesics (1.457) were associated with higher prevalence (all P &lt; 0.03). CONCLUSIONS Hypercortisolism was associated with hyperglycemia in approximately one-quarter of individuals with inadequately controlled type 2 diabetes despite multiple medications.

Abstract Food allergy can be life threatening and often develops early in life, especially in infants and children with atopic dermatitis. Food allergy is induced in neonatal mice with skin barrier mutations (Flaky Tail, FT+/− mice with filaggrin and mattrin gene mutations) by epicutaneous sensitization with co-exposures to the food allergen peanut extract (PNE), the environmental allergen Alternaria alternata (Alt), and detergent (4% SDS); oral PNE-challenge induces anaphylaxis. Sensitization in these neonates also induces eosinophil infiltration into the skin and elevates skin expression of eotaxins (CCL11 and CCL24). However, roles for eosinophils in food allergy are not known. In this study, the iPhil+/− FT+/− pups, which have an inducible eosinophil-deficiency upon injection of diphtheria toxin (DTX), were sensitized and then received PNE by gavage to assess anaphylaxis. DTX depletion of eosinophils, during sensitization and oral PNE-challenge, blocked the recruitment and activation of mast cells, blocked the Alt+PNE-induced increase in plasma IL-33 and OSM, attenuated serum PNE-specific IgE/IgG1/IgG2b, and blocked oral-PNE-induced anaphylaxis. Anti-IL-5 depletion of eosinophils during sensitization/challenge also blocked anaphylaxis. When eosinophils were depleted during allergen-skin-sensitization and restored before oral PNE-challenge, anaphylaxis was blocked. In contrast, when eosinophils were present during allergen-skin-sensitization but then depleted during oral PNE-challenge, anaphylaxis was not blocked. Together, these data indicate that although eosinophils are not necessary during oral food allergen-induced anaphylaxis, eosinophils have a critical role during the development of food allergy early in life by regulating the sensitization-induced increase in mast cell numbers and food allergen-specific IgE.

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR &amp;lt;1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510