Distribution of immune cells and tumor cells across different histologies in the malignant mesothelioma (MM) cohort.

Comparison of cell–cell contact score differences between malignant pleural mesothelioma (MPM) and malignant peritoneal mesothelioma (MPeM).

Comparison of differences in cell–cell contact scores between malignant pleural mesothelioma (MPM) and malignant peritoneal mesothelioma (MPeM) tumors.

Pleural mesothelioma (PM) is an aggressive cancer originating from the mesothelial lining of the pleura, with a rising global incidence since the mid-20th century due to asbestos and erionite exposure. PM accounts for 80–90% of all mesothelioma cases and is histologically classified into three subtypes—epithelioid, sarcomatoid, and biphasic— with epithelioid carrying the most favorable prognosis. Despite advances in surgery, chemotherapy, radiotherapy, and immunotherapy, PM prognosis remains poor, necessitating more effective, multimodal strategies. Hyperthermic intrathoracic chemoperfusion (HITHOC) has emerged as a promising adjunct to cytoreductive surgery by delivering heated chemotherapy directly to the pleural cavity, potentially improving survival—especially in patients with epithelioid PM. Combining HITHOC with post-surgical immunotherapy represents a novel approach to enhancing both local and systemic anti-tumor responses and targeting microscopic disease and distant metastases. This review explores surgical outcomes after surgery for PM, the therapeutic synergy of HITHOC and immunotherapy, ongoing clinical trials evaluating this multimodal strategy, and its implications for future patient care.

MM intra-tumor heterogeneity and survival analysis. (A) Comparison of TMA core cell-type proportions within patients and across patients. Each value in the boxplot represents the Pearson correlation coefficients between cell-type proportions across cores from different patients and cores within individual patients. (B) Kaplan-Meier survival curves of MM patients that categorized into two groups based on intra-tumor heterogeneity: those with high intra-tumor heterogeneity (Shannon entropy > 0.6 quantile) shown in blue, and those with low intra-tumor heterogeneity (Shannon entropy < 0.4 quantile) depicted in yellow.

The effectiveness of COVID-19 vaccination in children and adolescents with prior SARS-CoV-2 infection remains unclear, particularly for Omicron subvariants. We evaluated vaccine effectiveness against reinfection with Omicron BA.1/2, BA.4/5, XBB, and later subvariants among 5- to 17-year-olds using data from the RECOVER initiative, a national electronic health record database covering 37 U.S. pediatric institutions. We emulated target trials by age group and variant period, comparing previously infected participants between January 2022 and August 2023. During the BA.1/2 period, vaccination reduced the risk of reinfection, with effectiveness rates of 62% in children and 65% in adolescents. During the BA.4/5 period, protection effectiveness in children was 57%, whereas no statistically significant protection was observed in adolescents. During the XBB or later period, no significant protection was observed in either group. In summary, COVID-19 vaccination provided protection against reinfection during early and mid-Omicron periods in previously infected pediatric populations, but effectiveness declined for later variants.

The COVID-19 pandemic has been associated with increased neuropsychiatric conditions in children and youths, with evidence suggesting that SARS-CoV-2 infection may contribute additional risks beyond pandemic stressors. This study aims to assess the full spectrum of neuropsychiatric conditions in COVID-19 positive children (ages 5-12) and youths (ages 12-20) compared to a matched COVID-19 negative cohort, accounting for factors influencing infection risk. Using EHR data from 25 institutions in the RECOVER program, we conduct a retrospective analysis of 326,074 COVID-19 positive and 887,314 negative participants matched for risk factors and stratified by age. Neuropsychiatric outcomes are examined 28 to 179 days post-infection or negative test between March 2020 and December 2022. SARS-CoV-2 positivity is confirmed via PCR, serology, or antigen tests, while negativity requires negative test results and no related diagnoses. Risk differences reveal higher frequencies of neuropsychiatric conditions in the COVID-19 positive cohort. Children face increased risks for anxiety, OCD, ADHD, autism, and other conditions, while youths exhibit elevated risks for anxiety, suicidality, depression, and related symptoms. These findings highlight SARS-CoV-2 infection as a potential contributor to neuropsychiatric risks, emphasizing the importance of research into tailored treatments and preventive strategies for affected individuals.

Comparison of cell type distributions between malignant pleural mesothelioma (MPM) and malignant peritoneal mesothelioma (MPeM) within the same histologic subtypes.

Example of 7-plex healthy donor lymphoid tissue as a control and for validation. All channels combined as well as Individual marker channels (pCK: pan-cytokeratin).

The association of immune cells and cellular neighborhood proportion with overall survival in all malignant mesothelioma (MM) as well as for malignant pleural mesothelioma (MPM) and malignant peritoneal mesothelioma (MPeM) separately.

The COVID-19 pandemic has been associated with increased neuropsychiatric conditions in children and youths, with evidence suggesting that SARS-CoV-2 infection may contribute additional risks beyond pandemic stressors. This study aimed to assess the full spectrum of neuropsychiatric conditions in COVID-19 positive children (ages 5-12) and youths (ages 12-20) compared to a matched COVID-19 negative cohort, accounting for factors influencing infection risk. Using EHR data from 25 institutions in the RECOVER program, we conducted a retrospective analysis of 326,074 COVID-19 positive and 887,314 negative participants matched for risk factors and stratified by age. Neuropsychiatric outcomes were examined 28 to 179 days post-infection or negative test between March 2020 and December 2022. SARS-CoV-2 positivity was confirmed via PCR, serology, or antigen tests, while negativity required negative test results and no related diagnoses. Risk differences revealed higher frequencies of neuropsychiatric conditions in the COVID-19 positive cohort. Children faced increased risks for anxiety, OCD, ADHD, autism, and other conditions, while youths exhibited elevated risks for anxiety, suicidality, depression, and related symptoms. These findings highlight SARS-CoV-2 infection as a potential contributor to neuropsychiatric risks, emphasizing the importance of research into tailored treatments and preventive strategies for affected individuals.

Clinical features, cell count, tumor percentage, and density associated with each core, including marker percentage, density and intensity for each core.

IMPORTANCE:Prior studies have demonstrated the effectiveness of COVID-19 vaccines in children and adolescents. However, the benefits of vaccination in these age groups with prior infection remain underexplored. OBJECTIVE:To evaluate the effectiveness of COVID-19 vaccination in preventing reinfection with various Omicron subvariants (BA.1/2, BA.4/5, XBB, and later) among 5- to 17-year-olds with prior SARS-CoV-2 infection. DESIGN:A target trial emulation through nested designs with distinct study periods. SETTING:The study utilized data from the Research COVID to Enhance Recovery (RECOVER) initiative, a national electronic health record (EHR) database comprising 37 U.S. children's hospitals and health institutions. PARTICIPANTS:Individuals aged 5-17 years with a documented history of SARS-CoV-2 infection prior to the study start date during a specific variant-dominant period (Delta, BA.1/2, or BA.4/5) who received a subsequent dose of COVID-19 vaccine during the study periods were compared with those with a documented history of infection who did not receive SARS-CoV-2 vaccine during the study period. Those infected within the Delta-Omicron composite period (December 1, 2021, to December 31, 2021) were excluded. The study period was from January 1, 2022, to August 30, 2023, and focused on adolescents aged 12 to 17 years and children aged 5 to 11 years. EXPOSURES:At least received one COVID-19 vaccination during the study period vs. no receipt of any COVID-19 vaccine during the study period. MAIN OUTCOMES AND MEASURES:The primary outcome is documented SARS-CoV-2 reinfection during the study period (both asymptomatic and symptomatic cases). The effectiveness of the COVID-19 vaccine was estimated as (1- hazard ratio) *100%, with confounders adjusted by a combination of propensity score matching and exact matching. RESULTS:The study analyzed 87,573 participants during the BA.1/2 period, 229,326 during the BA.4/5 period, and 282,981 during the XBB or later period. Among vaccinated individuals, significant protection was observed during the BA.1/2 period, with effectiveness rates of 62% (95% CI: 38%-77%) for children and 65% (95% CI: 32%-81%) for adolescents. During the BA.4/5 period, vaccine effectiveness was 57% (95% CI: 25%-76%) for children, but not statistically significant for adolescents (36%, 95% CI: -16%-65%). For the XBB period, no significant protection was observed in either group, with effectiveness rates of 22% (95% CI: -36%-56%) in children and 34% (95% CI: -10%-61%) in adolescents. CONCLUSIONS AND RELEVANCE:COVID-19 vaccination provides significant protection against reinfection for children and adolescents with prior infections during the early and mid-Omicron periods. This study also highlights the importance of addressing low vaccination rates in pediatric populations to enhance protection against emerging variants.

Comparison of clinical parameters between malignant pleural mesothelioma (MPM) and malignant peritoneal mesothelioma (MPeM) for various cell types.

Importance The profile of gastrointestinal (GI) tract outcomes associated with the postacute and chronic phases of COVID-19 in children and adolescents remains unclear. Objective To investigate the risks of GI tract symptoms and disorders during the postacute (28-179 days after documented SARS-CoV-2 infection) and the chronic (180-729 days after documented SARS-CoV-2 infection) phases of COVID-19 in the pediatric population. Design, Setting, and Participants This retrospective cohort study was performed from March 1, 2020, to September 1, 2023, at 29 US health care institutions. Participants included pediatric patients 18 years or younger with at least 6 months of follow-up. Data analysis was conducted from November 1, 2023, to February 29, 2024. Exposures Presence or absence of documented SARS-CoV-2 infection. Documented SARS-CoV-2 infection included positive results of polymerase chain reaction analysis, serological tests, or antigen tests for SARS-CoV-2 or diagnosis codes for COVID-19 and postacute sequelae of SARS-CoV-2. Main Outcomes and Measures GI tract symptoms and disorders were identified by diagnostic codes in the postacute and chronic phases following documented SARS-CoV-2 infection. The adjusted risk ratios (ARRs) and 95% CI were determined using a stratified Poisson regression model, with strata computed based on the propensity score. Results The cohort consisted of 1 576 933 pediatric patients (mean [SD] age, 7.3 [5.7] years; 820 315 [52.0%] male). Of these, 413 455 patients had documented SARS-CoV-2 infection and 1 163 478 did not; 157 800 (13.6%) of those without documented SARS-CoV-2 infection had a complex chronic condition per the Pediatric Medical Complexity Algorithm. Patients with a documented SARS-CoV-2 infection had an increased risk of developing at least 1 GI tract symptom or disorder in both the postacute (8.64% vs 6.85%; ARR, 1.25; 95% CI, 1.24-1.27) and chronic (12.60% vs 9.47%; ARR, 1.28; 95% CI, 1.26-1.30) phases compared with patients without a documented infection. Specifically, the risk of abdominal pain was higher in COVID-19–positive patients during the postacute (2.54% vs 2.06%; ARR, 1.14; 95% CI, 1.11-1.17) and chronic (4.57% vs 3.40%; ARR, 1.24; 95% CI, 1.22-1.27) phases. Conclusions and Relevance In this cohort study, the increased risk of GI tract symptoms and disorders was associated with the documented SARS-CoV-2 infection in children or adolescents during the postacute or chronic phase. Clinicians should note that lingering GI tract symptoms may be more common in children after documented SARS-CoV-2 infection than in those without documented infection.

Immunotherapies have shown modest clinical benefit thus far for malignant mesothelioma (MM). A deeper understanding of immune cell spatial distribution within the tumor immune microenvironment (TIME) is needed to identify interactions between tumor and different immune cell types that might impact the effectiveness of potential immunotherapies. We performed multiplex immunofluorescence (mIF) using tissue microarrays (TMAs, n=3) of samples from patients with malignant peritoneal (n=25) and pleural (n=88) mesothelioma (MPeM and MPM, respectively) to elucidate the spatial distributions of major immune cell populations and their association with LAG3, BAP1, NF2, and MTAP expression, the latter as a proxy for CDKN2A/B. We also analyzed the relationship between the spatial distribution of major immune cell types with MM patient prognosis and clinical features. The distribution of immune cells within the TIME is similar between MPM and MPeM. However, there is a higher level of interaction between immune cells and tumor cells in MPM than MPeM. Within MPM tumors, there is increased amount of interaction between tumor cells and CD8+ T cells in BAP1-low than in BAP1-high expressing tumors. The cell-cell interactions identified in this investigation have potential implications for the immune response against MM tumors and could be a factor in the different behaviors of MPM and MPeM. Our findings provide a valuable resource for the MM cancer research community and exemplifies the utility of spatial resolution within single-cell analyses. Our mesothelioma spatial atlas mIF dataset is available at https://mesotheliomaspatialatlas.streamlit.app/.

Importance:Obesity is associated with increased severity of COVID-19. Whether obesity is associated with an increased risk of post-acute sequelae of SARS-CoV-2 infection (PASC) among pediatric populations, independent of its association with acute infection severity, is unclear. Objective:To quantify the association of body mass index (BMI) status before SARS-CoV-2 infection with pediatric PASC risk, controlling for acute infection severity. Design, Setting, and Participants:This retrospective cohort study occurred at 26 US children's hospitals from March 2020 to May 2023 with a minimum follow-up of 179 days. Eligible participants included children and young adults aged 5 to 20 years with SARS-CoV-2 infection. Data analysis was conducted from October 2023 to January 2024. Exposures:BMI status assessed within 18 months before infection; the measure closest to the index date was selected. The BMI categories included healthy weight (≥5th to <85th percentile for those aged 5-19 years or ≥18.5 to <25 for those aged >19 years), overweight (≥85th to <95th percentile for those aged 5-19 years or ≥25 to <30 for for those aged >19 years), obesity (≥95th percentile to <120% of the 95th percentile for for those aged 5-19 years or ≥30 to <40 for those aged >19 years), and severe obesity (≥120% of the 95th percentile for those aged 5-19 years or ≥40 for those aged >19 years). Main Outcomes And Measures:To identify PASC, a diagnostic code specific for post-COVID-19 conditions was used and a second approach used clusters of symptoms and conditions that constitute the PASC phenotype. Relative risk (RR) for the association of BMI with PASC was quantified by Poisson regression models, adjusting for sociodemographic, acute COVID severity, and other clinical factors. Results:A total of 172 136 participants (mean [SD] age at BMI assessment 12.6 [4.4] years; mean [SD] age at cohort entry, 13.1 [4.4] years; 90 187 female [52.4%]) were included. Compared with participants with healthy weight, those with obesity had a 25.4% increased risk of PASC (RR, 1.25; 95% CI, 1.06-1.48) and those with severe obesity had a 42.1% increased risk of PASC (RR, 1.42; 95% CI, 1.25-1.61) when identified using the diagnostic code. Compared with those with healthy weight, there was an increased risk for any occurrences of PASC symptoms and conditions among those with obesity (RR, 1.11; 95% CI, 1.06-1.15) and severe obesity (RR, 1.17; 95% CI, 1.14-1.21), and the association held when assessing total incident occurrences among those with overweight (RR, 1.05; 95% CI, 1.00-1.11), obesity (RR, 1.13; 95% CI, 1.09-1.19), and severe obesity (RR, 1.18; 95% CI, 1.14-1.22). Conclusions And Relevance:In this cohort study, elevated BMI was associated with a significantly increased PASC risk in a dose-dependent manner, highlighting the need for targeted care to prevent chronic conditions in at-risk children and young adults.

Immune cell phenotypes associated with clinical features. A, Prevalence of all cell types in MPM epithelioid (n = 45), biphasic (n = 16), and sarcomatoid (n = 7) subtypes (left) and MPeM epithelioid (n = 12) and biphasic (n = 3) subtypes (right) presented as the proportion of total cells. Statistical analysis was performed using one-sided Multiple Mann–Whitney nonparametric U tests. *, P < 0.05. B, Bubble plot illustrating significance levels, in which circle size corresponds to the level of significance, and circle color indicates which of the two comparisons on the y-axis shows higher levels of the cell type plotted on the x-axis. C, Box plots displaying cell-type proportion across different clinical subgroups in patients with MPM and MPeM. Statistical analysis was conducted using one-sided multiple Mann–Whitney U tests. P < 0.05 was considered significant. The center of the box plot represents the median, with the box boundaries indicating the 25th and 75th percentiles. Whiskers extend to the minimum and maximum values in the dataset.

We investigated the risks of post-acute and chronic adverse kidney outcomes of SARS-CoV-2 infection in the pediatric population via a retrospective cohort study using data from the RECOVER program. We included 1,864,637 children and adolescents under 21 from 19 children's hospitals and health institutions in the US with at least six months of follow-up time between March 2020 and May 2023. We divided the patients into three strata: patients with pre-existing chronic kidney disease (CKD), patients with acute kidney injury (AKI) during the acute phase (within 28 days) of SARS-CoV-2 infection, and patients without pre-existing CKD or AKI. We defined a set of adverse kidney outcomes for each stratum and examined the outcomes within the post-acute and chronic phases after SARS-CoV-2 infection. In each stratum, compared with the non-infected group, patients with COVID-19 had a higher risk of adverse kidney outcomes. For patients without pre-existing CKD, there were increased risks of CKD stage 2+ (HR 1.20; 95% CI: 1.13-1.28) and CKD stage 3+ (HR 1.35; 95% CI: 1.15-1.59) during the post-acute phase (28 days to 365 days) after SARS-CoV-2 infection. Within the post-acute phase of SARS-CoV-2 infection, children and adolescents with pre-existing CKD and those who experienced AKI were at increased risk of progression to a composite outcome defined by at least 50% decline in estimated glomerular filtration rate (eGFR), eGFR <15 mL/min/1.73m2, End Stage Kidney Disease diagnosis, dialysis, or transplant.