Anaplastic sarcoma of the kidney (DICER1-sarcoma of the kidney): A report from the International Pleuropulmonary Blastoma/DICER1 Registry.

BACKGROUND: Anaplastic sarcoma of the kidney (ASK) is a DICER1-related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1-related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear. METHODS: Individuals with known or suspected DICER1-related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance. RESULTS: Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two-year event-free survival (EFS) for stage I-II ASK was 81.8% (95% confidence interval [CI]: 67.2%-99.6%), compared with 46.6% EFS (95% CI: 24.7%-87.8%) for stage III-IV (p = .07). Two-year overall survival (OS) for stage I-II ASK was 88.9% (95% CI: 75.5%-100.0%), compared with 70.0% (95% CI: 46.7%-100.0%) for stage III-IV (p = .20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02-0.31) and 0.08 (95% CI: 0.02-0.42), respectively. CONCLUSION: ASK is a rare DICER1-related renal neoplasm. In the current report, we identify clinical and treatment-related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors.

Perceptions of the stressful job search for pediatric hematology/oncology fellows.

The pediatric hematology and oncology (PHO) workforce landscape has been evolving over the past decades, with concern for waning interest in the subspecialty. We aimed to evaluate the impact of the initial PHO job search on fellow stress and anxiety, in addition to perceptions of the job search experience and potential areas of improvement. An anonymous survey consisting of demographics, emotional health impacts such as stress and anxiety, and job search experiences was developed and distributed to program leadership at all 74 PHO fellowship programs. At least one representative from 49 (66%) programs responded. Faculty were less likely than fellows to perceive that fellows are struggling to find jobs (p = .0198). However, faculty were more likely than fellows to perceive that fellows are either "extremely stressed" or "stressed" due to job search (p = .0003). By June 2021, 30 of 44 (68%) candidates had been offered a position, and 80% of those had accepted. There were no significant associations between fellow stress level and job offering, proximity to their ideal goals, or change in career type. Common barriers to the job search included geographic constraints and partner employment. Respondents identified centralized job listings, formal training on career development strategies, introduction to various career paths, and more transparency about the search as needed interventions. The perception of difficulty and stress regarding the job search is endorsed by most, identifying a need for more interventions to improve the experience. These data also highlight unmet mentorship and educational needs among PHO fellows in preparing for the job search.

Interprofessional Team-based Care of the Hematopoietic Cell Transplantation Patient With Hepatic Veno-occlusive Disease/Sinusoidal Obstruction Syndrome.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a well-recognized complication of allogeneic and autologous hematopoietic cell transplantation (HCT). The diagnosis and treatment of VOD/SOS require the involvement of multiple specialists covering a wide range of expertise. Interprofessional team-based medical care is standard practice for patients undergoing HCT and has been shown to improve patient and provider satisfaction, enhance efficiency, and improve patient outcomes, particularly for patients in complex medical situations like those with VOD/SOS post-HCT. Interdisciplinary team-based models focus on the synthesis and harmonization of knowledge and methods from different disciplines to create an integrative approach to patient care that both maximizes the expertise of each involved specialist and encourages thought beyond each specialist's discipline. Multidisciplinary team members provide additive support and work collaboratively with the core team to provide knowledge from their field. The composition of the interdisciplinary HCT team should center on the needs of the patient and institutional resources and involve the expertise of additional multidisciplinary team members based on clinical needs. This review focuses on interdisciplinary and multidisciplinary team-based care of patients with VOD/SOS post-HCT and provides an example of a collaborative VOD/SOS team that includes transplant physicians, nurses, pharmacists, nutrition/dietary specialists, and intensive care teams.

Demographics, Motivations, and Experiences of Participants in Transplantation or Cellular Therapy Fellowships.

Recent American Society for Transplantation and Cellular Therapy guidelines have sought to establish clinical and research expectations for participants in blood and marrow transplantation (BMT) and cellular therapy (CT) fellowships. However, little is known about participants in BMT/CT fellowships and the value they find from this additional training. We wanted to characterize the demographics, motivations, and experiences of recent participants in BMT/CT fellowships. We developed a 27-item online survey addressing backgrounds, application processes, training experiences, and perceived benefits among physicians who had started a clinical U.S.-based BMT/CT fellowship between 2012 to 2021. Anonymous responses were solicited through program director outreach, society website postings, targeted emails, and social media. Of 105 respondents (44% pediatric trainees), 4% were URMs and 39% were non-U.S. IMGs. The most important motivations for applying were comfort with allogeneic BMT, improved career prospects, and opportunities for research and publication. Almost all respondents (92%) attended donor selection meetings, whereas smaller proportions visited cell processing facilities (65%), HLA laboratories (57%), or good manufacturing practice facilities (22%). Most respondents reported ≥1 publication (26% reported 4+) based on research or experiences during their fellowship. Respondents reported improved post-fellowship comfort with all queried BMT/CT-related competencies. Seventy percent of respondents stated that they would recommend their fellowship highly to others; this corresponded to a Net Promoter Score of +65%, consistent with a strongly positive experience. Most respondents reported currently being in clinical practice (89% at academic centers), with a median of 70% of time currently spent caring for BMT/CT recipients. Although limited by recruitment methods and recall bias, our study demonstrated that BMT/CT fellowships are effective at increasing comfort with BMT/CT management and that most participants would highly recommend this BMT/CT training to others. Nevertheless, our study identified substantial heterogeneity in clinical responsibilities and BMT/CT-related laboratory exposure. The high representation of non-U.S. IMGs underscores the distinct role of BMT/CT fellowships for this group, whereas improved URM recruitment remains an important future direction for the field. Whether advanced fellowships will ever become required for the future BMT/CT workforce, analogous to the additional training required for solid organ transplantation in other medical and pediatric subspecialties, remains uncertain.

Complement component 4 copy number variation and CYP21A2 genotype associations in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder of cortisol biosynthesis caused by CYP21A2 mutations. An increase in gene copy number variation (CNV) exists at the CYP21A2 locus. CNV of C4, a neighboring gene that encodes complement component 4, is associated with autoimmune disease susceptibility. In this study, we performed comprehensive genetic analysis of the RP-C4-CYP21-TNX (RCCX) region in 127 unrelated 21-OHD patients (100 classic, 27 nonclassic). C4 copy number was determined by Southern blot. C4 CNV and serum C4 levels were evaluated in relation to CYP21A2 mutations and relevant phenotypes. We found that the most common CYP21A2 mutation associated with the nonclassic form of CAH, V281L, was associated with high C4 copy number (p = 7.13 × 10(-16)). Large CYP21A2 deletion, a common mutation associated with the classic form of CAH, was associated with low C4 copy number (p = 1.61 × 10(-14)). Monomodular RCCX with a short C4 gene, a risk factor for autoimmune disease, was significantly less frequent in CAH patients compared to population estimates (2.8 vs. 10.6 %; p = 1.08 × 10(-4)). In conclusion, CAH patients have increased C4 CNV, with mutation-specific associations that may be protective for autoimmune disease. The study of CYP21A2 in relation to neighboring genes provides insight into the genetics of CNV hotspots, an important determinant of human health.

Extracellular histone induces plasma hyaluronan-binding protein (factor VII activating protease) activation in vivo.

Plasma hyaluronan-binding protein (PHBP), an activator of factor VII and prourokinase, is a serine protease circulating as a single-chain proenzyme (pro-PHBP). Pro-PHBP converts to the active two-chain form through autoproteolysis, and effectors that modulate autoactivation can regulate PHBP-mediated processes. Here, we show that histone promotes pro-PHBP autoactivation in vivo. Histone bound to pro-PHBP and promoted intermolecular pro-PHBP binding. Histone-mediated pro-PHBP activation in plasma leads to the formations of bradykinin and PHBP-α(2)-antiplasmin complex as well as histone degradation. Pro-PHBP activation was observed in the circulation of mice after injection of histone or lipopolysaccharide, which induced septic response accompanying extracellular histone release. Our results suggest pathophysiological relevance of histone-dependent pro-PHBP activation in hyperinflammatory process.

Hyperferritinemia: A Diagnostic Marker for Disseminated Neonatal Herpes Simplex Virus Infection?

Although the prognosis of neonatal herpes simplex virus (HSV) infection has improved with intravenous acyclovir, the morbidity and mortality of disseminated disease remains high. Transaminitis and thrombocytopenia have been reported to be sensitive markers of neonatal HSV disease; however, early diagnosis remains a challenge due to a lack of specific clinical and laboratory indicators for this disease process. Ferritin, an acute phase reactant known for its use in diagnosing hemophagocytic lymphohistiocytosis, has recently been reported as extremely elevated in neonates with disseminated HSV due to its high inflammatory nature. We report three cases of neonates at a single institution with hyperferritinemia in the setting of disseminated HSV. Based on this case series, we discuss whether ferritin can be used as an early diagnostic marker in the setting of suspected neonatal HSV disease. [Pediatric Annals. 2021;50(6):e264-e267.].

Tenascin-X haploinsufficiency associated with Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia.

CONTEXT: The gene for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, CYP21A2, is flanked by the gene encoding tenascin-X (TNXB), a connective tissue extracellular matrix protein that has been linked to both autosomal dominant and autosomal recessive Ehlers-Danlos syndrome (EDS). A contiguous deletion of CYP21A2 and TNXB has been described. OBJECTIVE: The objective of the study was to determine the frequency and clinical significance of TNXB haploinsufficiency in CAH patients. DESIGN, SETTING, AND PARTICIPANTS: A total of 192 consecutive unrelated CAH patients being seen as part of an observational study at the National Institutes of Health Clinical Center (Bethesda, MD) were prospectively studied during 2006-2010. Patients were evaluated for clinical evidence of EDS, including cardiac evaluation. DNA was analyzed by PCR, multiplex ligation-dependent probe amplification, Southern blot, and TNXB sequencing. Tenascin-X expression was evaluated by Western blot analysis of fibroblasts and immunostaining of the skin. CAH patients with TNXB haploinsufficiency were compared with age-matched CAH patients with normal TNXB (controls). Phenotyping of 7 parents with TNXB haploinsufficiency was performed. MAIN OUTCOME MEASURES: The frequency of TNXB haploinsufficiency among CAH patients and the frequency of EDS symptomatology among CAH patients with TNXB haploinsufficiency and controls. RESULTS: TNXB haploinsufficiency, here termed CAH-X syndrome, was present in 7% of CAH patients. Twelve of 91 patients carrying a CYP21A2 deletion (13%) carried a contiguous deletion that extended into TNXB. One patient carried a TNXB premature stop codon. Twelve of 13 patients with CAH-X had EDS clinical features. Patients with CAH-X were more likely than age-matched controls to have joint hypermobility (P < .001), chronic joint pain (P = .003), multiple joint dislocations (P = .004), a structural cardiac valve abnormality by echocardiography (P = .02), and reduced tenascin-X expression by Western blot and immunostaining. A subset of parents had clinical findings. CONCLUSIONS: Clinical evaluation for connective tissue dysplasia should be routinely performed in CAH patients, especially those harboring a CYP21A2 deletion.

Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia.

CONTEXT: Patients with congenital adrenal hyperplasia (CAH) often suffer from long-term complications secondary to chronic glucocorticoid therapy and suboptimal treatment regimens. OBJECTIVE: The aim of the study was to describe clinical characteristics of a large cohort of pediatric and adult CAH patients. DESIGN AND SETTING: We conducted a cross-sectional study of 244 CAH patients [183 classic, 61 nonclassic (NC)] included in a Natural History Study at the National Institutes of Health. MAIN OUTCOME MEASURE(S): Outcome variables of interest were height sd score, obesity, hypertensive blood pressure (BP), insulin resistance, metabolic syndrome, bone mineral density, hirsutism (females), and testicular adrenal rest (TART). RESULTS: The majority had elevated or suppressed androgens, with varied treatment regimens. Mean adult height SD score was -1.0 ± 1.1 for classic vs. -0.4 ± 0.9 for NC patients (P = 0.015). Obesity was present in approximately one third of patients, across phenotypes. Elevated BP was more common in classic than NC patients (P ≤ 0.01); pediatric hypertensive BP was associated with suppressed plasma renin activity (P = 0.001). Insulin resistance was common in classic children (27%) and adults (38% classic, 20% NC); 18% of adults had metabolic syndrome. The majority (61%) had low vitamin D; 37% of adults had low bone mineral density. Hirsutism was common (32% classic; 59% NC women). TART was found in classic males (33% boys; 44% men). CONCLUSIONS: Poor hormonal control and adverse outcomes are common in CAH, necessitating new treatments. Routine monitoring of classic children should include measuring BP and plasma renin activity. Osteoporosis prophylaxis and TART screening should begin during childhood. A longitudinal study is under way.