Insurance Status and Tumor Necrosis Factor Inhibitor Initiation Among Children With Juvenile Idiopathic Arthritis in the CARRA Registry.

OBJECTIVE: Prompt escalation to tumor necrosis factor inhibitors (TNFis) is recommended for children with juvenile idiopathic arthritis (JIA) and ongoing disease activity despite treatment with conventional disease-modifying antirheumatic drugs (cDMARDs). It is unknown whether these recommendations are equitably followed for children with different insurance types. We assessed the association of insurance coverage on the odds and timing of TNFi use. METHODS: We conducted a retrospective study of children with newly diagnosed JIA in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. We compared the odds of starting a TNFi in the first year and time from cDMARD to TNFi initiation between those with public and private insurance. RESULTS: We identified 1086 children with new JIA diagnoses. Publicly insured children had significantly higher active joint counts and parent/patient global assessment scores at the enrollment visit. They were also more likely to have polyarticular arthritis compared to those with private insurance. Odds of any TNFi use in the first year did not differ between publicly and privately insured children. Publicly insured children were escalated from cDMARD to TNFi more quickly than privately insured children. CONCLUSION: Children who were publicly insured had more severe disease and polyarticular involvement at registry enrollment compared to those who were privately insured. Whereas overall TNFi use did not differ between children with different insurance types, publicly insured children were escalated more quickly, consistent with their increased disease severity. Further research is needed to determine why insurance coverage type is associated with disease severity, including how other socioeconomic factors affect presentation to care.

An Evidence-Based Guideline Improves Outcomes for Patients With Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome.

OBJECTIVE: To compare clinical outcomes in children with hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) who were managed before and after implementation of an evidence-based guideline (EBG). METHODS: A management algorithm for MAS-HLH was developed at our institution based on literature review, expert opinion, and consensus building across multiple pediatric subspecialties. An electronic medical record search retrospectively identified hospitalized patients with MAS-HLH in the pre-EBG (October 15, 2015, to December 4, 2017) and post-EBG (January 1, 2018, to January 21, 2020) time periods. Predetermined outcome metrics were evaluated in the 2 cohorts. RESULTS: After the EBG launch, 57 children were identified by house staff as potential patients with MAS-HLH, and rheumatology was consulted for management. Ultimately, 17 patients were diagnosed with MAS-HLH by the treating team. Of these, 59% met HLH 2004 criteria, and 94% met 2016 classification criteria for MAS complicating systemic juvenile idiopathic arthritis. There was a statistically significant reduction in mortality from 50% before implementation of the EBG to 6% in the post-EBG cohort (P = 0.02). There was a significant improvement in time to 50% reduction in C-reactive protein level in the post-EBG vs pre-EBG cohorts (log-rank P < 0.01). There were trends toward faster time to MAS-HLH diagnosis, faster initiation of immunosuppressive therapy, shorter length of hospital stay, and more rapid normalization of MAS-HLH-related biomarkers in the patients post-EBG. CONCLUSION: While the observed improvements may be partially attributed to advances in treatment of MAS-HLH that have accumulated over time, this analysis also suggests that a multidisciplinary treatment pathway for MAS-HLH contributed meaningfully to favorable patient outcomes.

Development and implementation of the ECHO model in a school setting to address youth electronic cigarette use in Kansas: A protocol.

Introduction: Schools remain at the frontlines of addressing issues, such as e-cigarette use, that impact students. Despite e-cigarette use remaining a significant public health concern in the U.S., schools have limited resources (e.g., staff, capacity, programming) to address it, especially in rural and frontier areas. This ECHO Pilot Project aimed to build capacity and equip schools and school staff in the state of Kansas to address high rates of youth e-cigarette use by providing prevention support and information on best practices for e-cigarette cessation. Methods and analysis: The pilot used the established Project ECHO model to disseminate evidence-based strategies for e-cigarette prevention and cessation among youth to schools across Kansas. The pilot selected 20 interdisciplinary school teams representing both rural and urban middle and high schools across the state to participate in seven ECHO sessions. ECHO sessions proceeded throughout Fall 2021, with the final session in Spring 2022. School participants completed pre-post surveys as well as component-specific surveys following each ECHO session. In addition, each school team created an individualized action plan to comprehensively address e-cigarette use at their school based on the information provided throughout the ECHO. Survey data, school tobacco/nicotine policies, and action plans will be analyzed to assess process and final outcomes. Discussion: If successful, this pilot will demonstrate that the ECHO model is an effective platform for building school staff knowledge and skills to implement evidence-based strategies in both urban and rural settings. It is anticipated that the pilot will build capacity and equip schools and school staff to address high rates of youth e-cigarette use by providing support for school-based prevention programs and referrals for e-cigarette cessation which will lessen the burden of nicotine-related problems in Kansas schools and communities. Finally, the pilot will provide evidence that the ECHO model can be successfully and equitably applied in a school setting and may be a viable method for addressing other public health-related issues faced by schools.

Risk factors associated with Pneumocystis jirovecii pneumonia in juvenile myositis in North America.

OBJECTIVES: Pneumocystis jirovecii pneumonia (PJP) is associated with significant morbidity and mortality in adult myositis patients; however, there are few studies examining PJP in juvenile myositis [juvenile idiopathic inflammatory myopathy (JIIM)]. The purpose of this study was to determine the risk factors and clinical phenotypes associated with PJP in JIIM. METHODS: An research electronic data capture (REDCap) questionnaire regarding myositis features, disease course, medications and PJP infection characteristics was completed by treating physicians for 13 JIIM patients who developed PJP (PJP+) from the USA and Canada. Myositis features and medications were compared with 147 JIIM patients without PJP (PJP-) from similar geographic regions who enrolled in National Institutes of Health natural history studies. RESULTS: PJP+ patients were more often of Asian ancestry than PJP- patients [odds ratio (OR) 8.7; 95% CI 1.3, 57.9]. Anti- melanoma differentiation associated protein 5 (MDA5) autoantibodies (OR 12.5; 95% CI 3.0, 52.4), digital infarcts (OR 43.8; 95% CI 4.2, 460.2), skin ulcerations (OR 12.0; 95% CI 3.5, 41.2) and interstitial lung disease (OR 10.6; 95% CI 2.1, 53.9) were more frequent in PJP+ patients. Before PJP diagnosis, patients more frequently received pulse steroids, rituximab and more immunosuppressive therapy compared with PJP- patients. Seven PJP+ patients were admitted to the intensive care unit and four patients died due to PJP or its complications. CONCLUSIONS: PJP is a severe infection in JIIM that can be associated with mortality. Having PJP was associated with more immunosuppressive therapy, anti-MDA5 autoantibodies, Asian race and certain clinical features, including digital infarcts, cutaneous ulcerations and interstitial lung disease. Prophylaxis for PJP should be considered in juvenile myositis patients with these features.

Distinct clinical and immunological features of SARS-CoV-2-induced multisystem inflammatory syndrome in children.

BACKGROUNDPediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail.METHODSWe retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS).RESULTSTwenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort.CONCLUSIONMIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.FUNDINGThis work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children's Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.

PD-L1 Expression Patterns in Microsatellite Instability-High Intestinal Adenocarcinoma Subtypes.

OBJECTIVES: To investigate patterns of programmed death protein-1 (PD-L1) expression in microsatellite instability (MSI)-high intestinal carcinomas and correlate them with pathologic and molecular features. METHODS: One hundred and fifteen MSI-high and 41 microsatellite stable carcinomas were included. Tumor sections were immunohistochemically labeled for PD-L1. The results were correlated with histologic subtypes, MSI, and BRAF status. RESULTS: As expected, MSI status was associated with PD-L1 expression. Among 115 MSI-high tumors, PD-L1 expression was observed on tumor cells in 28 tumors and on tumor-associated inflammatory cells in 77 tumors. Medullary carcinoma demonstrated more frequent PD-L1 expression on tumor cells than mucinous and typical adenocarcinoma. PD-L1 expression was more frequent in medullary and typical adenocarcinoma than in mucinous adenocarcinoma based on combined positive scores. Tumors with more nucleotide shifts by PCR-based MSI testing were more likely to express PD-L1. CONCLUSIONS: Expression of PD-L1 is different among different histologic subtypes of MSI-high intestinal carcinomas.

Mesenteric tumour deposits arising from small-intestine neuroendocrine tumours are frequently associated with fibrosis and IgG4-expressing plasma cells.

AIMS: Mesenteric tumour deposits frequently occur in small-intestine neuroendocrine tumours. In many instances, these mesenteric tumour deposits are surrounded by a dense fibrotic stroma and have associated lymphoplasmacytic inflammation. The aim of this study was to examine whether mesenteric tumour deposits in patients with small-intestine NETs neuroendocrine tumours show histological and immunophenotypic overlap with IgG4-related sclerosing mesenteritis. METHODS AND RESULTS: Sixty-six mesenteric tumour deposits from 66 patients with small-intestine neuroendocrine tumours with blocks available for further studies were identified from our archives. Cases were assessed for clinicopathological features and the presence of IgG4-positive and IgG-positive plasma cells by immunohistochemistry. Ratios of IgG4-positive to IgG-positive plasma cells were calculated. Seventeen mesenteric tumour deposits (26%) showed >40 IgG4-positive plasma cells per high-power field, and the majority of cases (68%) showed at least some staining of IgG4-positive plasma cells. Mesenteric tumour deposits with >20 IgG4-positive plasma cells per high-power field tended to be larger (25.9 ± 13.0 mm versus 18.6 ± 15.8 mm; P = 0.07), and had more IgG-positive plasma cells (88 ± 24 versus 36 ± 37; P < 0.01) and a higher IgG4-positive/IgG-positive plasma cell ratio (0.66 ± 0.18 versus 0.17 ± 0.25; P < 0.01). All but one mesenteric tumour deposit with >20 IgG4-positve plasma cells had a ratio of >40%. CONCLUSIONS: IgG4 expression is frequent in mesenteric tumour deposits from small-intestine neuroendocrine tumours. Undersampling of tumour on biopsies of mesenteric tumour deposits could potentially cause diagnostic confusion with IgG4-related sclerosing mesenteritis.

Human Papillomavirus-Driven Squamous Lesions: High-Risk Genotype Found in Conjunctival Papillomas, Dysplasia, and Carcinoma.

BACKGROUND: Human papillomavirus (HPV) is a causative agent for intraepithelial squamous neoplasms, particularly on mucosal surfaces. HPV has a well-established association with squamous cell carcinoma (SCC) of the oropharynx and genital tract, and recent studies suggest a potential role in ocular and periocular squamous neoplasms. Multiple high-risk HPV genotypes are associated with histologically similar squamous neoplasms, and some HPV genotypes have been differentially associated with high- or low-grade lesions. METHODS: Squamous lesions were screened with immunohistochemical markers p16 and Ki-67 to compare expression in conjunctival papillomas (n = 21) to papillomas with high-grade dysplasia, SCC in situ, and invasive SCC (n = 40). Polymerase chain reaction was performed using the Roche COBAS HPV assay to identify the 14 most common high-risk HPV genotypes. RESULTS: Compared with squamous papillomas, the lesions showing high-grade dysplasia or worse expressed p16 with greater intensity and in a greater percentage of the lesion. A trend toward mild Ki-67 expression in papillomas versus marked Ki-67 expression in high-grade squamous lesions was also observed. HPV-16 was present in 7 of the SCC in situ and invasive SCC lesions but none of the papillomas. CONCLUSIONS: HPV may have an important role in squamous lesions of the conjunctiva. In addition to positive polymerase chain reaction results, strong and diffuse p16 expression with marked Ki-67 is strongly suggestive of an HPV-driven lesion.

Multicomponent Palliative Care Interventions in Advanced Chronic Diseases: A Systematic Review.

BACKGROUND: Many patients live with serious chronic or terminal illnesses. Multicomponent palliative care interventions have been increasingly utilized in patient care; however, it is unclear what is being implemented and who is delivering these interventions. OBJECTIVES: To (1) describe the delivery of multicomponent palliative care interventions, (2) characterize the disciplines delivering care, (3) identify the components being implemented, and (4) analyze whether the number of disciplines or components being implemented are associated with positive outcomes. DESIGN: Systematic review. STUDY SELECTION: English-language articles analyzing multicomponent palliative care interventions. OUTCOMES MEASURED: Delivery of palliative interventions by discipline, components of palliative care implemented, and number of positive outcomes (eg, pain, quality of life). RESULTS: Our search strategy yielded 71 articles, which detailed 64 unique multicomponent palliative care interventions. Nurses (n = 64, 88%) were most often involved in delivering care, followed by physicians (n = 43, 67%), social workers (n = 33, 52%), and chaplains (n = 19, 30%). The most common palliative care components patients received were symptom management (n = 56, 88%), psychological support/counseling (n = 52, 81%), and disease education (n = 48, 75%). Statistical analysis did not uncover an association between number of disciplines or components and positive outcomes. CONCLUSIONS: While there has been growth in multicomponent palliative care interventions over the past 3 decades, important aspects require additional study such as better inclusion of key groups (eg, chronic obstructive pulmonary disease, end-stage renal disease, minorities, older adults); incorporating core components of palliative care (eg, interdisciplinary team, integrating caregivers, providing spiritual support); and developing ways to evaluate the effectiveness of interventions that can be readily replicated and disseminated.

Expression of PD-1 and PD-L1 in poorly differentiated neuroendocrine carcinomas of the digestive system: a potential target for anti-PD-1/PD-L1 therapy.

Poorly differentiated neuroendocrine carcinoma of the digestive system has a dismal prognosis with limited treatment options. This study aimed to investigate expression of the PD-1/PD-L1 pathway in these tumors. Thirty-seven patients with a poorly differentiated neuroendocrine carcinoma of the digestive system were identified. Their electronic medical records, pathology reports, and pathology slides were reviewed for demographics, clinical history, and pathologic features. Tumor sections were immunohistochemically labeled for PD-1 and PD-L1, and expression of PD-1 and PD-L1 on tumor and tumor-associated immune cells was analyzed and compared between small cell and large cell neuroendocrine carcinomas. The mean age of patients was 61 years old with 18 men and 19 women. The colorectum (n=20) was the most common primary site; other primary sites included the pancreaticobiliary system, esophagus, stomach, duodenum, and ampulla. Expression of PD-1 was detected on tumor cells (n=6, 16%) as well as on tumor-associated immune cells (n=23, 63%). The 6 cases with PD-1 expression on tumor cells also had the expression on immune cells. Expression of PD-L1 was visualized on tumor cells in 5 cases (14%) and on tumor-associated immune cells in 10 cases (27%). There was no difference in PD-1 and PD-L1 expression between small cell and large cell neuroendocrine carcinomas. In conclusion, PD-1/PD-L1 expression is a frequent occurrence in poorly differentiated neuroendocrine carcinomas of the digestive system. Checkpoint blockade targeting the PD-1/PD-L1 pathway may have a potential role in treating patients with this disease.

Patients with Systemic Lupus Erythematosus Have Increased Risk of Short-term Adverse Events after Total Hip Arthroplasty.

OBJECTIVE: Total hip arthroplasty (THA) is performed more frequently in patients with systemic lupus erythematosus (SLE) than in the general population. However, whether patients with SLE have higher complication rates than patients with osteoarthritis (OA) is unknown. This study compares adverse events (AE) in SLE with OA controls. METHODS: Patients in our institution's registry were eligible. SLE was identified by the International Classification of Diseases, 9th ed code. AE were identified by chart review and questionnaire. Patients with SLE were matched with OA controls. Multivariate regression was performed to identify independent predictors of AE. RESULTS: Fifty-eight patients with SLE THA were matched with 116 OA controls. Of the patients with SLE, 47.4% had Charlson-Deyo comorbidity scores (excluding SLE) > 1 versus 13.1% of OA (p < 0.0001). Length of stay was longer for SLE (6.0 days vs 4.7 days, p = 0.0008). Patients with SLE had more falls (10.3% vs 1.7%, p = 0.017), deep vein thrombosis (5.2% vs 0%, p = 0.036), acute renal disease (8.6% vs 0%, p = 0.004), wound infections (6.9% vs 0.9%, p = 0.043), and revision surgeries (5.2% vs 0%, p = 0.036). In a logistic regression controlling for comorbidities, SLE had an increased risk of AE (OR 3.77, 95% CI 1.74-8.16). Comorbidity scores were not significantly associated with AE. Among those with SLE, there were no significant differences in AE in those taking corticosteroids. CONCLUSION: SLE is an independent risk factor for AE after THA. Patients with SLE had higher rates of falls, acute renal disease, infections, and revision surgeries than matched OA controls. Further research is needed to understand the causes of increased AE in patients with SLE.

Smoothelin and caldesmon are reliable markers for distinguishing muscularis propria from desmoplasia: a critical distinction for accurate staging colorectal adenocarcinoma.

An accurate distinction between deep muscularis propria invasion versus subserosal invasion by colonic adenocarcinoma is essential for the accurate staging of cancer and subsequent optimal patient management. However, problems may arise in pathologic staging when extensive desmoplasia blurs the junction between deep muscularis propria and subserosal fibroadipose tissue. To address this issue, forty-three (43) cases of colonic adenocarcinoma resections from 2007-2009 at The Methodist Hospital in Houston, TX were reviewed. These cases were selected to address possible challenges in differentiating deep muscularis propria invasion from superficial subserosal invasion based on H&E staining alone. Immunohistochemical staining using smooth muscle actin (SMA), smoothelin, and caldesmon were performed on 51 cases: 8 cases of pT1 tumors (used mainly as control); 12 pT2 tumors; and 31 pT3 tumors. All 51 (100%) had diffuse, strong (3+) immunoreactivity for caldesmon and smoothelin in the muscularis propria with a granular cytoplasmic staining pattern. However, the desmoplastic areas of these tumors, composed of spindled fibroblasts and myofibroblasts, showed negative immunostaining for caldesmon and smoothelin (0/35). SMA strongly stained the muscularis propria and weakly (1+) or moderately (2+) stained the spindled fibroblasts in the desmoplastic areas (the latter presumably because of myofibroblastic differentiation). Compared to SMA, caldesmon and smoothelin are more specific stains that allow better delineation of the muscularis propria from the desmoplastic stromal reaction which provides a critical aide for proper staging of colonic adenocarcinoma and subsequent patient care.

The presence of anti-HLA donor-specific antibodies in lung allograft recipients does not correlate with C4d immunofluorescence in transbronchial biopsy specimens.

CONTEXT: C4d immunofluorescence (IF) is a surrogate for development of donor-specific antibodies (DSAs) against human leukocyte antigen (HLA) class I and II antigens in kidney and heart biopsy specimens for monitoring of antibody-mediated (humoral) allograft rejection (AMR). Use of C4d IF in monitoring of lung allografts has shown conflicting results. OBJECTIVE: To determine if C4d IF can be used as a reliable marker for AMR and if it correlates with the presence of DSAs and histologic findings on biopsy. DESIGN: All transbronchial biopsies in lung allograft recipients, performed at our institution in a 3-year period, were reviewed. A cohort of 92 patients with 110 corresponding biopsies met the inclusion criteria of (1) having a resulted DSA within 2 weeks of biopsy and (2) having C4d immunofluorescence studies performed and confirmed. RESULTS: Twenty-nine patients (31.5%) were positive for DSAs and 63 patients (68.5%) did not develop DSAs. Positive C4d capillary IF was seen in 18 of 110 total biopsy specimens (16.4%). Eight of these biopsy samples were from patients positive for DSAs and 10 were from patients negative for DSAs. The correlation coefficient between the presence of DSAs and C4d IF was 0.1628 (P = .09). CONCLUSIONS: A significant proportion of DSA-positive patients had negative C4d IF results and frequently have no histologic changes on biopsy specimens. DSA-negative patients can be positive for C4d and may show the same histologic changes as reported for DSA-positive patients. Diagnosis of AMR in lung may require a collaborative approach combining clinical data, DSA status, and histology.

A study of metastatic carcinoma found in hernia sacs between 2006 and 2012 at one institution.

Hernia sacs are generally regarded as routine specimens in the daily practice of surgical pathology. However, unexpected findings including carcinoma can occasionally arise in these seemingly benign specimens. To ascertain the prevalence of metastatic carcinoma found within hernia sacs and to determine the importance of routine histologic examination of hernia sacs, we conducted a retrospective study of all hernia sacs with a diagnosis of metastatic carcinoma reported in our hospital system between January 2006 and December 2012. Of 3117 total herniorrhaphy specimens between 2006 and 2012, 11 (0.35%) were found to have metastatic carcinoma. Interestingly, in 3 cases, the initial diagnosis of cancer was made during histologic examination of the hernia sac. Metastatic carcinoma in hernia sacs is a rare occurrence; however, it is encountered in routine practice. It is recommended that herniorrhaphy specimens not be discarded and, instead, be regarded as peritoneal biopsies for routine histologic examination.

Disparities in symptom burden and renal transplant eligibility: a pilot study.

BACKGROUND: Patients with end-stage renal disease (ESRD) on hemodialysis (HD) suffer from a high symptom burden. However, there is significant heterogeneity within the HD population; certain subgroups, such as the elderly, may experience disproportionate symptom burden. OBJECTIVES: The study's objective was to propose a category of HD patients at elevated risk for symptom burden (those patients who are not transplant candidates) and to compare symptomatology among transplant ineligible versus eligible HD patients. DESIGN: This was a cross-sectional study. SETTING/SUBJECTS: English-speaking, cognitively intact patients receiving HD and who were either transplant eligible (n=25) or ineligible (n=32) were recruited from two urban HD units serving patients in the greater New York City region. MEASUREMENTS: In-person interviews were conducted to ascertain participants' symptom burden using the Dialysis Symptom Index (DSI), perceived symptom bother and attribution (whether the symptom was perceived to be related to HD treatment), and quality of life using the SF-36. Participants' medical records were reviewed to collect demographic and clinical data. RESULTS: Transplant ineligible (versus eligible) patients reported an average of 13.9±4.6 symptoms versus 9.2±4.4 symptoms (p<0.01); these differences persisted after adjustment for multiple factors. A greater proportion of transplant ineligible (versus eligible) patients attributed their symptoms to HD and were more likely to report greater bother on account of the symptoms. Quality of life was also significantly lower in the transplant ineligible group. CONCLUSIONS: Among HD patients, transplant eligibility is associated with symptom burden. Our pilot data suggest that consideration be given to employing transplant status as a method of identifying HD patients at risk for greater symptom burden and targeting them for palliative interventions.