Detectable troponin below the 99th percentile predicts survival in patients undergoing coronary angiography.

Background: Cardiac troponin I (cTnI) above the 99th percentile is associated with an increased risk of major adverse events. Patients with detectable cTnI below the 99th percentile are a heterogeneous group with a less well-defined risk profile. The purpose of this study is to investigate the prognostic relevance of detectable cTnI below the 99th percentile in patients undergoing coronary angiography. Methods: The study included 14,776 consecutive patients (mean age of 65.4 ± 12.7 years, 71.3 % male) from the Essen Coronary Artery Disease (ECAD) registry. Patients with cTnI levels above the 99th percentile and patients with ST-segment elevation acute myocardial infarction were excluded. All-cause mortality was defined as the primary endpoint. Results: Detectable cTnI below the 99th percentile was present in 2811 (19.0 %) patients, while 11,965 (81.0 %) patients were below detection limit of the employed assay. The mean follow-up was 4.25 ± 3.76 years. All-cause mortality was 20.8 % for patients with detectable cTnI below the 99th percentile and 15.0 % for those without detectable cTnI. In a multivariable Cox regression analysis, detectable cTnI was independently associated with all-cause mortality with a hazard ratio of 1.60 (95 % CI 1.45-1.76; p < 0.001). There was a stepwise relationship with increasing all-cause mortality and tertiles of detectable cTnI levels with hazard ratios of 1.63 (95 % CI 1.39-1.90) for the first tertile to 2.02 (95 % CI 1.74-2.35) for the third tertile. Conclusions: Detectable cTnI below the 99th percentile is an independent predictor of mortality in patients undergoing coronary angiography with the risk of death growing progressively with increasing troponin levels.

Phase 1b study of batiraxcept in combination with durvalumab in patients with platinum-resistant ovarian cancer.

Combining an immune checkpoint inhibitor with batiraxcept (AVB-S6-500), an AXL inhibitor that acts via selective binding to growth arrest-specific protein 6 (GAS6), may improve anti-tumor immunity in platinum-resistant ovarian cancer (PROC). This phase 1b trial of durvalumab in combination with escalating doses of batiraxcept enrolled patients with recurrent PROC (NCT04019288). The primary objective was to determine the toxicity profile of the combination. Eleven patients were enrolled on the trial. No dose-limiting toxicities were observed, and no objective responses were noted. Median progression free survival (PFS) was 1.81 months (95% confidence interval (CI) 1.71-2.40), and median overall survival (OS) was 4.53 months (95% CI 2.10-24.74). Batiraxcept effectively reduced serum GAS6 levels at 1-h post-treatment, resulting in trough levels below the limit of detection in all cases but one. In conclusion, the combination of batiraxcept and durvalumab was safe and tolerable but did not demonstrate anti-tumor activity in a heterogenous population of patients with recurrent PROC.

Approaches, advantages, and challenges to photon counting detector and multi-energy CT.

Photon counting detector CT (PCD-CT) is the newest major development in CT technology and has been commercially available since 2021. It offers major technological advantages over current standard-of-care energy integrating detector CT (EID-CT) including improved spatial resolution, improved iodine contrast to noise ratio, multi-energy imaging, and reduced noise. This article serves as a foundational basis to the technical approaches and concepts of PCD-CT technology with primary emphasis on detector technology in direct comparison to EID-CT. The article also addresses current technological challenges to PCD-CT with particular attention to cross talk and its causes (e.g., Compton scattering, fluorescence, charge sharing, K-escape) as well as pile-up.

Conversion of sleeve gastrectomy to Roux-en-Y gastric bypass: impact on reflux and weight loss.

BACKGROUND: Sleeve gastrectomy (SG) is the most commonly performed weight loss operation, and its 2 most common complications are postoperative reflux and weight recurrence. There is limited evidence to guide decision-making in treating these conditions. OBJECTIVES: To determine the efficacy of conversion of SG to Roux-en-Y gastric bypass (RYGB) for GERD management and weight loss. SETTING: Forty-one hospitals in Michigan. METHODS: We conducted a retrospective cohort study examining patients who underwent conversion of SG to RYGB from 2014 to 2022. The primary outcomes were changes in GERD-HRQL scores, anti-reflux medication use, and weight from baseline to 1 year after conversion. Secondary outcomes included 30-day postoperative complications and resource utilization. RESULTS: Among 2133 patients undergoing conversion, 279 (13%) patients had baseline and 1-year GERD-HRQL survey data and anti-reflux medication data. GERD-HRQL scores decreased significantly from 24.6 to 6.6 (P < .01). Among these, 207 patients (74%) required anti-reflux medication at baseline, with only 76 patients (27%) requiring anti-reflux medication at 1 year postoperatively (P < .01). Of the 380 patients (18%) with weight loss data, mean weight decreased by 68.4lbs, with a 24.3% decline in total body weight and 51.5% decline in excess body weight. In terms of 30-day complications, 308 (14%) patients experienced any complication and 89 (4%) experienced a serious complication, but there were no leaks, perforations, or deaths. Three-hundred and fifty-five (17%) patients presented to the emergency department and 64 (3%) patients underwent reoperation. CONCLUSIONS: This study represents the largest reported experience with conversion from SG to RYGB. We found that conversion to RYGB is associated with significant improvement in GERD symptoms, reduction in anti-reflux medication use, and significant weight loss and is therefore an effective treatment for GERD and weight regain after SG. However, the risks and benefits of conversion surgery should be carefully considered, especially in patients with significant comorbidity burden.

Safety and efficacy of semaglutide in post kidney transplant patients with type 2 diabetes or Post-Transplant diabetes.

Objective: Type 2 diabetes mellitus (T2DM) and post-transplant diabetes mellitus (PTDM) are common in renal transplant recipients. Semaglutide has demonstrated efficacy and safety in patients with T2DM. To date, only a limited number of studies have investigated its use in renal transplant patients. This study assessed the safety and efficacy of semaglutide in post-renal transplant patients. Methods: A retrospective study was conducted at king Abdulaziz Medical City-Riyadh, Saudi Arabia. The subjects of the study were adults and adolescents (>14 years) who had undergone a kidney transplant and had pre-existing T2DM or PTDM. The study subjects were given semaglutide during the study period, from January 2018 to July 2022. The data were collected over a period of 18 months. Results: A total of 39 patients were included, 29 (74 %) of whom were male. A significant decrease in hemoglobin A1c (HbA1c) was observed during the follow-up period when compared to baseline (8.4 %±1.3 % at baseline vs. 7.4 %±1.0 % at 13-18 months (p < 0.001). A significant reduction in weight was also noted at follow-up as compared to baseline (99.5 kg ± 17.7 vs 90.7 kg ± 16.8 at 13-18 months (p < 0.001). No significant changes were found in renal graft function markers. Conclusion: Semaglutide was found to significantly reduce HbA1c levels and weight in post renal transplant patients with diabetes. No significant changes in markers of renal graft function were observed.

Simultaneous Rhinoplasty and Septal Perforation Repair Using the Bone-Cartilaginous Unit.

BACKGROUND: Various techniques are employed for septal perforation repair, but success rates still vary. Numerous mucosal flaps are used for septal perforation closure; however, a scaffold is essential for proper positioning and enhanced mucosal growth. OBJECTIVES: To assess the effectiveness of using a septal bone/cartilage composite graft (BC unit) to close septal perforations in rhinoplasty patients and evaluate patient satisfaction. METHODS: This case series included patients with septal perforation undergoing rhinoplasty and perforation repair from 2019 to 2023. BC units were used to cover the cartilaginous perforations in all patients. Patients were followed for a minimum of one year, assessing surgical results and postoperative satisfaction using the 10-Item Standardized Cosmesis and Health Nasal Outcomes Survey (SCHNOS). RESULTS: In this study, 31 patients (22 female, 9 male) aged 34.80 ± 10.31 years (19-59 years) were enrolled. Nine had prior septoplasty, while four had undergone septorhinoplasty. The preoperative perforation size ranged from 6 to 27 mm (mean 14.1 mm). At final follow-up, 26 cases (83.8%) achieved complete closure, while three had incomplete closures, and two experienced reperforation. Analysis revealed a notable mean decrease of 31.93 (SD = 26.47) in obstruction domain scores (SCHNOS-O) and a mean decrease of 44.19 (SD = 25.37) in cosmesis domain scores (SCHNOS-C). CONCLUSIONS: Septal perforation repair and rhinoplasty can be safely and effectively performed concurrently using BC units for suitable candidates.

Removal of Spinal Instrumentation Is Not Required to Successfully Treat Postoperative Wound Infections in Most Cases.

INTRODUCTION: Controversy exists regarding whether spinal implants need to be removed to treat postoperative deep wound infections (DWIs). This retrospective study aimed to determine whether the removal or retention of implants impacts the successful treatment of a DWI after spine surgery. METHODS: Postoperative spine surgery patients presenting with signs of infection who underwent irrigation and debridement (I&D) at Twin Cities Spine Surgeons at Abbott Northwestern Hospital, Minnesota, USA, were studied. First, the persistence of infection when implants were retained or removed was assessed. Second, we analyzed the persistence of infection with respect to the number of I&D, the use of vacuum-assisted closure (VAC) treatment, pseudoarthrosis status, and functional outcomes. RESULTS: One hundred thirty-five patients were included. Treatment of infection with retention of implants occurred in 64% (87/135); of these, 7% (6/87) had a persistent infection. Of patients with implant removal (36%, 48/135), 6% (3/48) had a persistent infection. Thus, we observed no difference between treatment with implants present compared to implants removed (p = 1.0). Fifty of the 135 patients (37%) received I&D and primary wound closure, and 85 (63%) patients received I&D and VAC treatment. There was no statistical difference between primary wound closure and VAC treatment (p = 0.15) with respect to persistence. Repeat I&D with VAC (three or more times) had a significantly lower rate of recurrence than those with two I&Ds. Pseudoarthrosis and persistent infection were unrelated. At minimum one-year follow-up, achieving a minimum clinically important difference in functional outcome was independent of persistent infection status. CONCLUSION: Persistent infection was unrelated to the retention of implants. When VAC treatment was deemed necessary, more than two I&Ds resulted in a significantly better cure for infection. Those with a persistent infection were no more likely to exhibit pseudoarthrosis than those with no persistent infection. All patients showed improvement in functional outcomes at minimum one-year follow-up.

No Improvement in Intention-to-treat Survival and Increasing Liver Nonutilization Rate During the MELD Era.

BACKGROUND: Although post liver transplant survival rates have significantly improved during the past 2-3 decades, the trend in intention-to-treat (ITT) survival (survival from waitlist addition) has not been well studied. METHODS: We conducted a retrospective analysis of Scientific Registry of Transplant Recipients data to determine the trend in ITT survival in liver transplant candidates. Adult (age ≧ 18 y) patients who were on the waitlist between the time period of March 1, 2002, to December 31, 2019 (n = 200 816) and deceased liver donors that were registered between the same time period (n = 152 593) were analyzed. RESULTS: We found a constant increase in posttransplant survival rates; however, the ITT survival rates showed no statistically significant improvement through the study period. We observed significant linear increase in waitlist dropout rates over time. We also observed linear increase in liver nonutilization rate in both entire cases and brain-dead cases. Donor risk index increased significantly over the years; however, it was mostly driven by increase in donation after circulatory death cases; without donation after circulatory death cases, donor risk index was stable throughout the 17 y we observed. CONCLUSIONS: The reason of the increased liver nonutilization rate is unclear; however, it is possible that reluctance to use high-risk organ to maintain better posttransplant outcomes contributed to this increase, which also could have led to increase in waitlist dropout rates and no improvements in ITT survival. Further investigation is warranted on the increased nonutilization rates to improve over all contribution of liver transplant to patient care.

Congestive Hepatopathy: Pathophysiology, Workup, and Imaging Findings with Pathologic Correlation.

Liver congestion is increasingly encountered in clinical practice and presents diagnostic pitfalls of which radiologists must be aware. The complex altered hemodynamics associated with liver congestion leads to diffuse parenchymal changes and the development of benign and malignant nodules. Distinguishing commonly encountered benign hypervascular lesions, such as focal nodular hyperplasia (FNH)-like nodules, from hepatocellular carcinoma (HCC) can be challenging due to overlapping imaging features. FNH-like lesions enhance during the hepatic arterial phase and remain isoenhancing relative to the background liver parenchyma but infrequently appear to wash out at delayed phase imaging, similar to what might be seen with HCC. Heterogeneity, presence of an enhancing capsule, washout during the portal venous phase, intermediate signal intensity at T2-weighted imaging, restricted diffusion, and lack of uptake at hepatobiliary phase imaging point toward the diagnosis of HCC, although these features are not sensitive individually. It is important to emphasize that the Liver Imaging Reporting and Data System (LI-RADS) algorithm cannot be applied in congested livers since major LI-RADS features lack specificity in distinguishing HCC from benign hypervascular lesions in this population. Also, the morphologic changes and increased liver stiffness caused by congestion make the imaging diagnosis of cirrhosis difficult. The authors discuss the complex liver macro- and microhemodynamics underlying liver congestion; propose a more inclusive approach to and conceptualization of liver congestion; describe the pathophysiology of liver congestion, hepatocellular injury, and the development of benign and malignant nodules; review the imaging findings and mimics of liver congestion and hypervascular lesions; and present a diagnostic algorithm for approaching hypervascular liver lesions. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Clinical and genomic landscape of RAS mutations in gynecologic cancers.

BACKGROUND: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications. METHODS: Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by Kaplan-Meier method, and multivariable analysis was performed using Cox proportional-hazards model. RESULTS: Of 3328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs 60 years non-mutated), had higher prevalence of endometriosis (27.3% vs 16.9%), and lower grades (grade 1/2, 43.2% vs 8.1%, all p<0.0001). Highest prevalence of KRAS mutation was in mesonephric-like endometrial (100%, n=9/9), mesonephric-like ovarian (83.3%, n=5/6), mucinous ovarian (60.4%), and low-grade serous ovarian (44.4%) cancers. After adjustment for age, cancer type, and grade, RAS mutation was associated with worse overall survival (HR=1.3, p=0.001). Specific mutations were in KRAS (13.5%), NRAS (2.0%), and HRAS (0.51%), most commonly KRAS G12D (28.4%) and G12V (26.1%). Common co-mutations were PIK3CA (30.9%), PTEN(28.8%), ARID1A (28.0%), and TP53 (27.9%), of which 64.7% were actionable. RAS+MAPK pathway-targeted therapies were administered to 62 patients with RAS-mutated cancers. While overall survival was significantly higher with therapy (8.4 years [95%CI 5.5-12.0] vs 5.5 years [95%CI 4.6-6.6], HR=0.67, p=0.031), this effect did not persist in multivariable analysis. CONCLUSION: RAS mutations in gynecologic cancers have a distinct histopathologic distribution and may impact overall survival. PIK3CA, PTEN, and ARID1A are potentially actionable co-alterations. RAS pathway-targeted therapy should be considered.

Consensus on managing open ankle fractures in the frail patient.

Aims: Ankle fractures are common injuries and the third most common fragility fracture. In all, 40% of ankle fractures in the frail are open and represent a complex clinical scenario, with morbidity and mortality rates similar to hip fracture patients. They have a higher risk of complications, such as wound infections, malunion, hospital-acquired infections, pressure sores, veno-thromboembolic events, and significant sarcopaenia from prolonged bed rest. Methods: A modified Delphi method was used and a group of experts with a vested interest in best practice were invited from the British Foot and Ankle Society (BOFAS), British Orthopaedic Association (BOA), Orthopaedic Trauma Society (OTS), British Association of Plastic & Reconstructive Surgeons (BAPRAS), British Geriatric Society (BGS), and the British Limb Reconstruction Society (BLRS). Results: In the first stage, there were 36 respondents to the survey, with over 70% stating their unit treats more than 20 such cases per year. There was a 50:50 split regarding if the timing of surgery should be within 36 hours, as per the hip fracture guidelines, or 72 hours, as per the open fracture guidelines. Overall, 75% would attempt primary wound closure and 25% would utilize a local flap. There was no orthopaedic agreement on fixation, and 75% would permit weightbearing immediately. In the second stage, performed at the BLRS meeting, experts discussed the survey results and agreed upon a consensus for the management of open elderly ankle fractures. Conclusion: A mutually agreed consensus from the expert panel was reached to enable the best practice for the management of patients with frailty with an open ankle fracture: 1) all units managing lower limb fragility fractures should do so through a cohorted multidisciplinary pathway. This pathway should follow the standards laid down in the "care of the older or frail orthopaedic trauma patient" British Orthopaedic Association Standards for Trauma and Orthopaedics (BOAST) guideline. These patients have low bone density, and we should recommend full falls and bone health assessment; 2) all open lower limb fragility fractures should be treated in a single stage within 24 hours of injury if possible; 3) all patients with fragility fractures of the lower limb should be considered for mobilisation on the day following surgery; 4) all patients with lower limb open fragility fractures should be considered for tissue sparing, with judicious debridement as a default; 5) all patients with open lower limb fragility fractures should be managed by a consultant plastic surgeon with primary closure wherever possible; and 6) the method of fixation must allow for immediate unrestricted weightbearing.

Heated tobacco product IQOS induces unique metabolic signatures in human bronchial epithelial cells.

Metabolic signatures are lacking for heated tobacco products, making it crucial to identify new biosignatures of lung damage. This will enable the establishment of product-specific guidelines and an understanding of associated toxicity. https://bit.ly/3TkhBox.

"Air That Once Was Breath" Part 1: Wildfire-Smoke-Induced Mechanisms of Airway Inflammation - "Climate Change, Allergy and Immunology" Special IAAI Article Collection: Collegium Internationale Allergologicum Update 2023.

BACKGROUND: Wildfires are a global concern due to their wide-ranging environmental, economic, and public health impacts. Climate change contributes to an increase in the frequency and intensity of wildfires making smoke exposure a more significant and recurring health concern for individuals with airway diseases. Some of the most prominent effects of wildfire smoke exposure are asthma exacerbations and allergic airway sensitization. Likely due to the delayed recognition of its health impacts in comparison with cigarette smoke and industrial or traffic-related air pollution, research on the composition, the mechanisms of toxicity, and the cellular/molecular pathways involved is poor or non-existent. SUMMARY: This review discusses potential underlying pathological mechanisms of wildfire-smoke-related allergic airway disease and asthma. We focused on major gaps in understanding the role of wildfire smoke composition in the development of airway disease and the known and potential mechanisms involving cellular and molecular players of oxidative injury at the epithelial barrier in airway inflammation. We examine how PM2.5, VOCs, O3, endotoxin, microbes, and toxic gases may affect oxidative stress and inflammation in the respiratory mucosal barrier. We discuss the role of AhR in mediating smoke's effects in alarmin release and IL-17A production and how glucocorticoid responsiveness may be impaired by IL-17A-induced signaling and epigenetic changes leading to steroid-resistant severe airway inflammation. KEY MESSAGE: Effective mitigation of wildfire-smoke-related respiratory health effects would require comprehensive research efforts aimed at a better understanding of the immune regulatory effects of wildfire smoke in respiratory health and disease.

Defining and Grading Infections in Clinical Trials Involving Hematopoietic Cell Transplantation: A Report From the BMT CTN Infectious Disease Technical Committee.

The Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) was established in 2001 to conduct large multi-institutional clinical trials addressing important issues towards improving the outcomes of HCT and other cellular therapies. Trials conducted by the network investigating new advances in HCT and cellular therapy not only assess efficacy but require careful capturing and severity assessment of adverse events and toxicities. Adverse infectious events in cancer clinical trials are typically graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). However, there are limitations to this framework as it relates to HCT given the associated immunodeficiency and delayed immune reconstitution. The BMT-CTN Infection Grading System is a monitoring tool developed by the BMT CTN to capture and monitor infectious complications and differs from the CTCAE by its classification of infections based on their potential impact on morbidity and mortality for HCT recipients. Here we offer a report from the BMT CTN Infectious Disease Technical Committee regarding the rationale, development, and revising of BMT-CTN Infection Grading System and future directions as it applies to future clinical trials involving HCT and cellular therapy recipients.

Neuroinvasive West Nile Virus Infection in Immunosuppressed and Immunocompetent Adults.

Importance: West Nile virus (WNV) is the leading cause of human arboviral disease in the US, peaking during summer. The incidence of WNV, including its neuroinvasive form (NWNV), is increasing, largely due to the expanding distribution of its vector, the Culex mosquito, and climatic changes causing heavy monsoon rains. However, the distinct characteristics and outcomes of NWNV in individuals who are immunosuppressed (IS) and individuals who are not IS remain underexplored. Objective: To describe and compare clinical and radiographic features, treatment responses, and outcomes of NWNV infection in individuals who are IS and those who are not IS. Design, Setting, and Participants: This retrospective cohort study used data from the Mayo Clinic Hospital system collected from July 2006 to December 2021. Participants were adult patients (age ≥18 years) with established diagnosis of NWNV infection. Data were analyzed from May 12, 2020, to July 20, 2023. Exposure: Immunosuppresion. Main Outcomes and Measures: Outcomes of interest were clinical and radiographic features and 90-day mortality among patients with and without IS. Results: Of 115 participants with NWNV infection (mean [SD] age, 64 [16] years; 75 [66%] male) enrolled, 72 (63%) were not IS and 43 (37%) were IS. Neurologic manifestations were meningoencephalitis (98 patients [85%]), encephalitis (10 patients [9%]), and myeloradiculitis (7 patients [6%]). Patients without IS, compared with those with IS, more frequently reported headache (45 patients [63%] vs 18 patients [42%]) and myalgias (32 patients [44%] vs 9 patients [21%]). In contrast, patients with IS, compared with those without, had higher rates of altered mental status (33 patients [77%] vs 41 patients [57%]) and myoclonus (8 patients [19%] vs 8 patients [4%]). Magnetic resonance imaging revealed more frequent thalamic T2 fluid-attenuated inversion recovery hyperintensities in individuals with IS than those without (4 patients [11%] vs 0 patients). Individuals with IS had more severe disease requiring higher rates of intensive care unit admission (26 patients [61%] vs 24 patients [33%]) and mechanical ventilation (24 patients [56%] vs 22 patients [31%]). The 90-day all-cause mortality rate was higher in the patients with IS compared with patients without IS (12 patients [28%] vs 5 patients [7%]), and this difference in mortality persisted after adjusting for Glasgow Coma Scale score (adjusted hazard ratio, 2.22; 95% CI, 1.07-4.27; P = .03). Individuals with IS were more likely to receive intravenous immunoglobulin than individuals without IS (12 individuals [17%] vs 24 individuals [56%]), but its use was not associated with survival (hazard ratio, 1.24; 95% CI, 0.50-3.09; P = .64). Conclusions and Relevance: In this cohort study of individuals with NWNV infection, individuals with IS had a higher risk of disease complications and poor outcomes than individuals without IS, highlighting the need for innovative and effective therapies to improve outcomes in this high-risk population.

"Air That Once Was Breath" Part 2: Wildfire Smoke and Airway Disease - "Climate Change, Allergy and Immunology" Special IAAI Article Collection: Collegium Internationale Allergologicum Update 2023.

BACKGROUND: Population growth and climate change have led to more frequent and larger wildfires, increasing the exposure of individuals to wildfire smoke. Notably, asthma exacerbations and allergic airway sensitization are prominent outcomes of such exposure. SUMMARY: Key research questions relate to determining the precise impact on individuals with asthma, including the severity, duration, and long-term consequences of exacerbations. Identifying specific risk factors contributing to vulnerability, such as age, genetics, comorbidities, or environmental factors, is crucial. Additionally, reliable biomarkers for predicting severe exacerbations need exploration. Understanding the long-term health effects of repeated wildfire smoke exposures in individuals with asthma and addressing healthcare disparities are important research areas. KEY MESSAGES: This review discusses the need for comprehensive research efforts to better grasp wildfire smoke-induced respiratory health, particularly in vulnerable populations such as farmworkers, firefighters, pregnant women, children, the elderly, and marginalized communities. Effective mitigation would require addressing the current limitations we face by supporting research aimed at a better understanding of wildfire smoke-induced airway disease.

Phase 1b study of intraperitoneal ipilimumab and nivolumab in patients with recurrent gynecologic malignancies with peritoneal carcinomatosis.

BACKGROUND: Intravenous immune checkpoint blockade (ICB) has shown poor response rates in recurrent gynecologic malignancies. Intraperitoneal (i.p.) ICB may result in enhanced T cell activation and anti-tumor immunity. METHODS: In this phase 1b study, registered at Clinical. TRIALS: gov (NCT03508570), initial cohorts received i.p. nivolumab monotherapy, and subsequent cohorts received combination i.p. nivolumab every 2 weeks and i.p. ipilimumab every 6 weeks, guided by a Bayesian design. The primary objective was determination of the recommended phase 2 dose (RP2D) of the combination. Secondary outcomes included toxicity, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). FINDINGS: The trial enrolled 23 patients: 18 with ovarian cancer, 2 with uterine cancer, and 3 with cervical cancer. Study evaluable patients (n = 16) received a median of 2 prior lines of therapy (range: 1-8). Partial response was observed in 2 patients (12.5%; 1 ovarian, 1 uterine), and complete response was observed in 1 patient (6.3%) with cervical cancer, for an ORR of 18.8% (95% confidence interval: 4.0%-45.6%). The median duration of response was 14.8 months (range: 4.1-20.8), with one complete response ongoing. Median PFS and OS were 2.7 months and not reached, respectively. Grade 3 or higher immune-related adverse events occurred in 2 (8.7%) patients. CONCLUSIONS: i.p. administration of dual ICB is safe and demonstrated durable responses in a subset of patients with advanced gynecologic malignancy. The RP2D is 3 mg/kg i.p. nivolumab every 2 weeks plus 1 mg/kg ipilimumab every 6 weeks. FUNDING: This work was funded by Bristol Myers Squibb (CA209-9C7), an MD Anderson Cancer Center Support Grant (CA016672), the Ovarian Cancer Moon Shots Program, the Emerson Collective Fund, and a T32 training grant (CA101642).

Spatiotemporal Clusters of ERK Activity Coordinate Cytokine-induced Inflammatory Responses in Human Airway Epithelial Cells.

RATIONALE: Spatially coordinated ERK signaling events ("SPREADs") transmit radially from a central point to adjacent cells via secreted ligands for EGFR and other receptors. SPREADs maintain homeostasis in non-pulmonary epithelia, but it is unknown whether they play a role in the airway epithelium or are dysregulated in inflammatory disease. OBJECTIVES: (1) To characterize spatiotemporal ERK activity in response to pro-inflammatory ligands, and (2) to assess pharmacological and metabolic regulation of cytokine-mediated SPREADs. METHODS: SPREADs were measured by live-cell ERK biosensors in human bronchial epithelial cell lines (HBE1 and 16HBE) and primary human bronchial epithelial (pHBE) cells, in both submerged and biphasic Air-Liquid Interface (ALI) culture conditions (i.e., differentiated cells). Cells were exposed to pro-inflammatory cytokines relevant to asthma and chronic obstructive pulmonary disease (COPD), and to pharmacological treatments (gefitinib, tocilizumab, hydrocortisone) and metabolic modulators (insulin, 2-deoxyglucose) to probe the airway epithelial mechanisms of SPREADs. Phospho-STAT3 immunofluorescence was used to measure localized inflammatory responses to IL-6. RESULTS: Pro-inflammatory cytokines significantly increased the frequency of SPREADs. Notably, differentiated pHBE cells display increased SPREAD frequency that coincides with airway epithelial barrier breakdown. SPREADs correlate with IL-6 peptide secretion and localized pSTAT3. Hydrocortisone, inhibitors of receptor signaling, and suppression of metabolic function decreased SPREAD occurrence. CONCLUSIONS: Pro-inflammatory cytokines modulate SPREADs in human airway epithelial cells via both secreted EGFR and IL6R ligands. SPREADs correlate with changes in epithelial barrier permeability, implying a role for spatiotemporal ERK signaling in barrier homeostasis and dysfunction during inflammation. The involvement of SPREADs in airway inflammation suggests a novel signaling mechanism that could be exploited clinically to supplement corticosteroid treatment for asthma and COPD.

Hypoxemic Respiratory Failure and Coccidioidomycosis-Associated Acute Respiratory Distress Syndrome.

Background: Severe coccidioidomycosis presenting with respiratory failure is an uncommon manifestation of disease. Current knowledge of this condition is limited to case reports and small case series. Methods: A retrospective multicenter review of patients with coccidioidomycosis-associated acute respiratory distress syndrome (CA-ARDS) was conducted. It assessed clinical and laboratory variables at the time of presentation, reviewed the treatment course, and compared this cohort with a national database of patients with noncoccidioidomycosis ARDS. Survivors and nonsurvivors of coccidioidomycosis were also compared to determine prognostic factors. Results: In this study, CA-ARDS (n = 54) was most common in males, those of Hispanic ethnicity, and those with concurrent diabetes mellitus. As compared with the PETAL network database (Prevention and Early Treatment of Acute Lung Injury; n = 1006), patients with coccidioidomycosis were younger, had fewer comorbid conditions, and were less acidemic. The 90-day mortality was 15.4% for patients with coccidioidomycosis, as opposed to 42.6% (P < .0001) for patients with noncoccidioidomycosis ARDS. Patients with coccidioidomycosis who died, as compared with those who survived, were older, had higher APACHE II scores (Acute Physiology and Chronic Health Evaluation), and did not receive corticosteroid therapy. Conclusions: CA-ARDS is an uncommon but morbid manifestation of infection. When compared with a national database, the overall mortality appears favorable vs other causes of ARDS. Patients with CA-ARDS had a low overall mortality but required prolonged antifungal therapy. The utility of corticosteroids in this condition remains unconfirmed.