Approach to multidrug resistant infections in pediatric transplant recipients.

Introduction: There is increasing recognition of infections due to multidrug-resistant Gram negative (MDRGN) bacterial infections among children undergoing solid organ and hematopoietic cell transplantation, which may be associated with morbidity and mortality. Methods: We present two vignettes that highlight the clinical challenges of evaluation, management, and prevention of MDRGN bacterial infections in children prior to and after transplantation. The goal of this discussion is to provide a framework to help develop an approach to evaluation and management of these infections. Results: Source control remains the utmost priority in management of MDR infections and is paired with antibiotic selection guided by in vitro susceptibilities, adverse effect profiles, and clinical response. Identification and confirmation of resistance can be challenging and often requires additional testing for recognition of complex mechanisms. Current antimicrobial approaches to MDRGN infections include use of novel agents, prolonged infusion, and/or combination therapy. We also discuss preventative efforts including infection control, antimicrobial stewardship, targeted pre-emptive or prophylactic treatment, and decolonization. Discussion: The impact of MDRGN infections on patient and graft survival highlights the need to optimize treatment and prevention strategies.

Identification and characterization of stress degradation products of ibrutinib by LC-UV/PDA and LC-Q/TOF-MS studies.

The anticancer drug ibrutinib was subjected to stress degradation studies under the ICH-prescribed hydrolytic, photolytic, oxidative and thermal stress conditions, and its degradation behavior was studied. A significant degradation was noted for the drug under acidic/alkaline hydrolytic, acid/alkaline photolytic, and oxidative conditions. The UPLC-UV/PDA studies revealed the generation of six degradation products (I-VI), and these were adequately resolved from the drug under the developed chromatographic conditions over a Kinetex® C18 (100 mm×4.6 mm; 2.6 µm) column employing isocratic elution method. Detection wavelength was selected as 289 nm. The UPLC-UV/PDA method conditions were extrapolated to UPLC-MS/TOF studies. All the six degradation products were found to be ionized in the total ion chromatogram, and the products could be identified and characterized from their mass spectral data. The possible degradation route of ibrutinib leading to generation of various products was also postulated.

Lemon grass essential oil improves Gladiolus grandiflorus postharvest life by modulating water relations, microbial growth, biochemical activity, and gene expression.

Gladiolus (Gladiolus grandiflorus Andrews) is a high-valued bulbous cut flower. However, the shorter postharvest life of the gladiolus, limits its marketing and commercial value. In the present investigation, the effect of lemon grass (LG) essential oil as an antimicrobial agent was studied towards increasing the vase life of gladiolus. The results revealed that as compared to control (distilled water), treatment with a lower concentration of 5 µL L-1 LG essential oil prolonged the vase life of gladiolus up to 11 days (d). Scanning Electron Microscope (SEM) observation indicated that the sample treated with 5 µL L-1 LG essential oil showed intact vasculature, suggesting reduced microbial blockage at the stem end which was further corroborated by microbial count. Biochemical analysis suggested an increased level of total soluble sugars, carotenoid content, lower MDA accumulation, and higher activity of antioxidant enzymes in LG treated flowers. Moreover, transcripts levels of genes associated with senescence viz., GgCyP1 and GgERS1a were downregulated, while expression of GDAD1 and antioxidant genes such as GgP5C5, GgPOD 1, GgMnSOD, and GgCAT1 were upregulated in LG treated cut spikes as compared to control. Among various treatments we have concluded that, the vase life of the gladiolus cut spike was improved along with the relative fresh flower weight and diameter of flower at the lower dose of 5 µL L-1 LG oil in the vase solution. Thus, LG oil as an eco-friendly agent has the potential to extend the postharvest life of cut flowers.

Clinicopathologic Profile, Management and Outcome of Sinonasal Ameloblastoma-A Systematic Review.

Sinonasal ameloblastoma (SNA) is considered to be a subtype of ameloblastoma. It differs from gnathic ameloblastoma in terms of clinicopathologic features, management and prognosis. Thus, the objective of the present review was to study the complications, survival, recurrence rate and outcomes following the management of SNA. The electronic search process was conducted on PubMed-Medline, Embase, and Scopus. Google Scholar was used to search grey literature. Quality assessment of the case reports (CR) and case series (CS) was done based on CARE guidelines. The initial search resulted in 2111 articles. 15 studies (13 CR and 2 CS) were found to meet the eligibility criteria. The majority of the studies described histological features of SNA, which were consistent with ameloblastomas of gnathic origin. There were no SNA-related deaths reported in the included studies. Five studies described endoscopic surgeries to remove SNAs, and three SNAs were treated with post-surgery radiotherapy. Data from included studies suggest that sinonasal ameloblastomas are histologically similar to gnathic ameloblastomas, but their clinical presentation is different. They may cause complete or partial obstruction of the nasal cavity and the sinus. They appear to affect an older demographic, and their resection may be accompanied by the excision of a large portion of the maxilla, necessitating maxillofacial prosthetic rehabilitation.

Evaluation of Root Anatomy and Canal Configuration of Human Permanent Maxillary First Molar Using Cone-Beam Computed Tomography: A Systematic Review.

The aim of this paper is to review the literature on root canal configuration (RCC) and the frequency of occurrence of a second mesiobuccal canal (MB) in human permanent maxillary first molars where cone-beam computed tomography (CBCT) is used. Online electronic databases such as PubMed-Medline, Embase, Scopus and Cochrane Library were searched using appropriate keywords from the earliest available date until 12th June 2022, without restriction on language. In the mesiobuccal root, type I was the most frequent (33.29%), followed by types II and IV (27.18% and 26.36%, respectively). Moreover, 68.2% of maxillary first molars had a second MB canal. For both the distobuccal and palatal roots, type I was the most prevalent, with 99.08% and 97.83% occurrence, respectively. All other types were infrequent. Type I RCC is most frequent in all the roots of the maxillary first molars. Hence, care must be taken during biomechanical preparation of the MB roots.

In Vitro Comparison of the Wettability of a Bioceramic Root Canal Sealer on Dentin With and Without Erbium-Doped Yttrium Aluminum Garnet (Er:YAG) Laser Irradiation.

INTRODUCTION: To evaluate and compare the wettability of bioceramic root canal sealer (BioRoot™ RCS, Septodont, Saint-Maur-des-Fossés, France) on dentin with and without erbium-doped yttrium aluminum garnet (Er:YAG) laser irradiation using different frequencies and energies. METHODS: A hundred single-rooted tooth samples were divided into five groups of 20 samples each. Each group was treated with different methods before sealer application as follows: Group 1: Treated with 2 ml 17% ethylenediaminetetraacetic acid (EDTA) irrigant for one minute (control group); group 2: Irradiated with Er:YAG laser for one minute (8 Hz frequency and 200mJ energy); group 3: Irradiated with Er:YAG laser for one minute (8 Hz frequency and 400mJ energy); group 4: Irradiated with Er:YAG laser for one minute (16 Hz frequency and 200mJ energy); group 5: (n=20) samples irradiated with Er:YAG laser for one minute (16 Hz frequency and 400mJ energy). Bioceramic root canal sealer application was done onto the treated dentin specimen using a micropipette. The contact angle of the drop of the sealer with the dentin surface was measured after five minutes using a contact angle analyzer. RESULTS: There was no significant difference in wettability between Er:YAG laser using 8Hz frequency and 200mJ energy and Er:YAG laser using 8Hz frequency and 400mJ energy. However, there was a significant difference between the other two groups of Er:YAG laser using 16Hz frequency and 400mJ energy and Er: YAG laser using 16Hz frequency and 200mJ energy. CONCLUSION: Contact angle was found to be lowest in the group that was irradiated with Er:YAG laser for one minute (16 Hz frequency and 400mJ energy) before the sealer application. The test findings demonstrated that the control group had the highest contact angle (low wettability) and it was statistically significant with all other groups.

Epidemiology and outcomes of invasive aspergillosis among pediatric immunocompromised patients: A 12-year single-center experience.

Invasive aspergillosis (IA) remains a common cause of mortality in pediatric immunocompromised populations. Much of our knowledge of IA stems from adult literature. We conducted a retrospective evaluation of cases of proven or probable IA, defined according to the 2019 EORTC/MSG criteria, in patients with underlying immunocompromising conditions at Boston Children's Hospital from January 1, 2007 to January 1, 2019. We estimated survival curves over 12 weeks using the Kaplan-Meier method for all-cause mortality, and we used univariate Cox proportional hazards modeling to evaluate for mortality risk factors. We identified 59 cases, 29% with proven and 71% with probable IA. Pulmonary IA was the most common presentation (78%). The median age at diagnosis was 11 years (range, 0.5-28). Hematopoietic cell transplantation (HCT) was the most frequent predisposing underlying condition (41%). Among affected patients, 44.8% were neutropenic and 59.3% were lymphopenic at diagnosis. The 12-week all-cause mortality rate was 25.4%; HCT recipients comprised the majority of deaths (9/15) with a hazard ratio of 2.47 [95% CI, 0.87-6.95]. No patients with congenital immunodeficiencies (n = 8) died within 12 weeks of IA diagnosis. Other risk factors that were significantly associated with mortality included mechanical ventilation at diagnosis, intensive care unit stay, and lymphopenia; treatment with an Aspergillus-active azole was associated with decreased mortality.In conclusion, our study found that in pediatric immunocompromised hosts, IA is associated with a high 12-week all-cause mortality rate, with a particular impact on the HCT population. LAY ABSTRACT: This study explores the epidemiology, outcomes and predictors of mortality of invasive aspergillosis (IA) at a high-volume pediatric center for immunocompromised hosts. Much of our understanding of pediatric IA is extrapolated from the adult literature. Our study found that IA is associated with a high 12-week all-cause mortality rate, with a particular impact on the hematopoietic cell transplantation study cohort.

H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive childhood tumor of the brainstem with currently no curative treatment available. The vast majority of DIPGs carry a histone H3 mutation leading to a lysine 27-to-methionine exchange (H3K27M). We engineered human induced pluripotent stem cells (iPSCs) to carry an inducible H3.3-K27M allele in the endogenous locus and studied the effects of the mutation in different disease-relevant neural cell types. H3.3-K27M upregulated bivalent promoter-associated developmental genes, producing diverse outcomes in different cell types. While being fatal for iPSCs, H3.3-K27M increased proliferation in neural stem cells (NSCs) and to a lesser extent in oligodendrocyte progenitor cells (OPCs). Only NSCs gave rise to tumors upon induction of H3.3-K27M and TP53 inactivation in an orthotopic xenograft model recapitulating human DIPGs. In NSCs, H3.3-K27M leads to maintained expression of stemness and proliferative genes and a premature activation of OPC programs that together may cause tumor initiation.

Progressive multifocal leukoencephalopathy presenting with acute sensorineural hearing loss in an intestinal transplant recipient.

A 20-year-old male presented 3.5 years after intestinal transplantation with rapidly progressive sensorineural hearing loss. Initial brain imaging was consistent with inflammation and/or demyelination. Lumbar puncture was initially non-diagnostic and a broad infectious workup was unrevealing. Three months after presentation, a repeat LP detected JC virus for which tests had not earlier been conducted. He continued to deteriorate despite withdrawal of prior immunosuppression and addition of mirtazapine, maraviroc, and steroids. He died of progressive neurologic decompensation 5 months after his initial presentation. This case highlights progressive multifocal leukoencephalopathy (PML) as a rare complication after solid organ transplantation and acute sensorineural hearing loss as an unusual first presenting symptom of PML. JC virus should be considered in the differential diagnosis of acute sensorineural hearing loss in any immunocompromised patient.

Two light responsive WRKY genes exhibit positive and negative correlation with picroside content in Picrorhiza kurrooa Royle ex Benth, an endangered medicinal herb.

Picrorhiza kurrooa is an endangered herb known to produce the medicinally important picrosides through isoprenoid pathway. The present work showed the functionality of WRKY motifs (TGAC cis-acting elements) present in the promoters of regulatory genes 3-hydroxy-3-methylglutaryl coenzyme A reductase (Pkhmgr) and 1-deoxy-d-xylulose-5-phosphate synthase (Pkdxs) of the picrosides biosynthetic pathway by electrophoretic mobility shift assay. Also, the two WRKY genes, PkdWRKY and PksWRKY, were characterized and found to contain double and single characteristic WRKY domains, respectively along with a zinc-finger motif in each domain. Expression analysis revealed that PkdWRKY and PksWRKY exhibited a positive and negative correlation, respectively, with picrosides content under the environment of light and in different tissues. Functional evaluation in yeast showed DNA binding ability of both PksWRKY and PkdWRKY; however, only PkdWRKY exhibited transcriptional activation ability. Transient overexpression of PkdWRKY and PksWRKY in tobacco modulated the expression of selected native genes of tobacco involved in MVA and MEP pathway suggesting functionality of PkdWRKY and PksWRKY in planta. Collectively, data suggested that PkdWRKY and PksWRKY might be positive and negative regulators, respectively in the picrosides biosynthetic pathway.

Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort.

PURPOSE: The HIT-2000-BIS4 trial aimed to avoid highly detrimental craniospinal irradiation (CSI) in children < 4 years of age with nonmetastatic medulloblastoma by systemic chemotherapy, intraventricular methotrexate, and risk-adapted local radiotherapy. PATIENTS AND METHODS: From 2001-2011, 87 patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for nonresponse or progression. After 2006, local radiotherapy was introduced for nonresponders or patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (LCA). DNA methylation profiles of infantile sonic hedgehog-activated medulloblastoma (SHH-INF) were subdivided into iSHH-I and iSHH-II subtypes in the HIT-2000-BIS4 cohort and a validation cohort (n = 71) from the HIT group and Russia. RESULTS: Five years after diagnosis, patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN; n = 42) had 93% progression-free survival (5y-PFS), 100% overall survival (5y-OS), and 93% CSI-free (5y-CSI-free) survival. Patients with CMB/LCA (n = 45) had 37% 5y-PFS, 62% 5y-OS, and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in patients with CMB/LCA. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH-INF subgroup. Group 3 patients (5y-PFS, 36%; n = 14) relapsed more frequently than the SHH-INF group (5y-PFS, 93%; n = 28) or group 4 patients (5y-PFS, 83%; n = 6; P < .001). SHH-INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I, 73%, v iSHH-II, 83%; P = .25; n = 99). Intelligence quotient (IQ) was significantly lower in patients after CSI (mean IQ, 90 [no radiotherapy], v 74 [CSI]; P = .012). CONCLUSION: Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in patients with non-wingless (WNT)/non-SHH disease with CMB/LCA was not improved by local radiotherapy. Patients with group 4 disease had more favorable survival rates than those with group 3 medulloblastoma.

Germline Elongator mutations in Sonic Hedgehog medulloblastoma.

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children1,2, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma3. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype4 and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U34) position5,6. Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems7-9. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.

A Primary Care-Based Quality Improvement Initiative to Increase Identification of Pediatric International Travelers.

Children who travel internationally to visit friends and relatives (VFRs) are at risk for travel-related illness, but underuse pretravel health services. Although primary care clinics can identify travelers and address pretravel health needs, to date, there are few published reports on effective primary care-based pretravel interventions. We developed a quality improvement initiative to increase traveler identification at a primary care clinic serving families that frequently travel to VFRs. Interventions included a screening question asked at all clinic visits, provider and staff training, travel fliers, and health recommendation sheets for families. Interventions were implemented during 2017 and 2018 peak travel seasons. Travel visit rates and characteristics during the intervention period were compared with pre-intervention baseline periods (April-August, 2015-16). Surveys with providers were conducted to assess disruptiveness of the interventions, and rates of duplicate travel visits were assessed. A total of 738 unique travel events were identified during peak travel seasons from 2015 to 2018, encompassing travel to 29 countries across five continents. Overall, there were 428 unique travel events (3.0% of all clinic visits) during peak seasons 2017-18, compared with 310 unique travel events (2.2% of all clinic visits) during peak seasons 2015-16 (rate ratio 1.34 [95% CI: 1.16-1.56], P < 0.001). None of the 18 healthcare providers or staff surveyed found new travel screening processes to be disruptive or bothersome. Implementation of a primary care-based multimodal travel screening and education initiative was associated with a significantly increased rate of travel visits.

Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.

PURPOSE: The identification of a heritable tumor predisposition often leads to changes in management and increased surveillance of individuals who are at risk; however, for many rare entities, our knowledge of heritable predisposition is incomplete. METHODS: Families with childhood medulloblastoma, one of the most prevalent childhood malignant brain tumors, were investigated to identify predisposing germline mutations. Initial findings were extended to genomes and epigenomes of 1,044 medulloblastoma cases from international multicenter cohorts, including retrospective and prospective clinical studies and patient series. RESULTS: We identified heterozygous germline mutations in the G protein-coupled receptor 161 (GPR161) gene in six patients with infant-onset medulloblastoma (median age, 1.5 years). GPR161 mutations were exclusively associated with the sonic hedgehog medulloblastoma (MBSHH) subgroup and accounted for 5% of infant MBSHH cases in our cohorts. Molecular tumor profiling revealed a loss of heterozygosity at GPR161 in all affected MBSHH tumors, atypical somatic copy number landscapes, and no additional somatic driver events. Analysis of 226 MBSHH tumors revealed somatic copy-neutral loss of heterozygosity of chromosome 1q as the hallmark characteristic of GPR161 deficiency and the primary mechanism for biallelic inactivation of GPR161 in affected MBSHH tumors. CONCLUSION: Here, we describe a novel brain tumor predisposition syndrome that is caused by germline GPR161 mutations and characterized by MBSHH in infants. Additional studies are needed to identify a potential broader tumor spectrum associated with germline GPR161 mutations.

Limiting Vancomycin Exposure in Pediatric Oncology Patients With Febrile Neutropenia May Be Associated With Decreased Vancomycin-Resistant Enterococcus Incidence.

BACKGROUND: Limited data exists regarding the effects of empiric antibiotic use in pediatric oncology patients with febrile neutropenia (FN) on the development of antibiotic resistance. We evaluated the impact of a change in our empiric FN guideline limiting vancomycin exposure on the development of vancomycin-resistant Enterococcus in pediatric oncology patients. METHODS: Retrospective, quasi-experimental, single-center study using interrupted timeseries analysis in oncology patients aged ≤18 years with at least 1 admission for FN between 2009 and 2015. Risk strata incorporated diagnosis, chemotherapy phase, Down syndrome, septic shock, and typhlitis. Microbiologic data and inpatient antibiotic use were obtained by chart review. Segmented Poisson regression was used to compare VRE incidence and antibiotic days of therapy (DOT) before and after the intervention. RESULTS: We identified 285 patients with 697 FN episodes pre-intervention and 309 patients with 691 FN episodes postintervention. The proportion of high-risk episodes was similar in both periods (49% vs 48%). Empiric vancomycin DOT/1000 FN days decreased from 315 pre-intervention to 164 post-intervention (P < .01) in high-risk episodes and from 199 to 115 in standard risk episodes (P < .01). Incidence of VRE/1000 patient-days decreased significantly from 2.53 pre-intervention to 0.90 post-intervention (incidence rate ratio, 0.14; 95% confidence interval, 0.04-0.47; P = .002). CONCLUSIONS: A FN guideline limiting empiric vancomycin exposure was associated with a decreased incidence of VRE among pediatric oncology patients. Antimicrobial stewardship interventions are feasible in immunocompromised patients and can impact antibiotic resistance.

YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis.

YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions are sufficient to drive malignant transformation in mice, and the resulting tumors share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is mediated by MAMLD1 and independent of YAP1-Ser127 phosphorylation. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, suggesting a role for these transcription factors in YAP1-MAMLD1-driven tumorigenesis. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumor induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.

Resolving medulloblastoma cellular architecture by single-cell genomics.

Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.

Second-generation molecular subgrouping of medulloblastoma: an international meta-analysis of Group 3 and Group 4 subtypes.

In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with distinct genomic features and clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4 MB subtypes through the analysis of a series of 1501 medulloblastomas with DNA-methylation profiling data, including 852 with matched transcriptome data. Using multiple complementary bioinformatic approaches, we compared the concordance of subtype calls between published cohorts and analytical methods, including assessments of class-definition confidence and reproducibility. While the lowest complexity solutions continued to support the original consensus subgroups of Group 3 and Group 4, our analysis most strongly supported a definition comprising eight robust Group 3/Group 4 subtypes (types I-VIII). Subtype II was consistently identified across all component studies, while all others were supported by multiple class-definition methods. Regardless of analytical technique, increasing cohort size did not further increase the number of identified Group 3/Group 4 subtypes. Summarizing the molecular and clinico-pathological features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events amongst subtypes, and identified highly disparate survival outcomes, further supporting their biological and clinical relevance. Collectively, this study provides continued support for consensus Groups 3 and 4 while enabling robust derivation of, and categorical accounting for, the extensive intertumoral heterogeneity within Groups 3 and 4, revealed by recent high-resolution subclassification approaches. Furthermore, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) which may additionally inform medulloblastoma subclassification. Outputs from this study will help shape definition of the next generation of medulloblastoma clinical protocols and facilitate the application of enhanced molecularly guided risk stratification to improve outcomes and quality of life for patients and their families.

Human T-cell lymphotrophic virus in solid-organ transplant recipients: Guidelines from the American society of transplantation infectious diseases community of practice.

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of Human T-cell lymphotrophic virus 1 (HTLV)-1 in the pre- and post-transplant period. HTLV-1 is an oncogenic human retrovirus rare in North America but endemic in the Caribbean and parts of Africa, South America, Asia, and Oceania. While most infected persons do not develop disease, <5% will develop adult T-cell leukemia/lymphoma or neurological disease. No proven antiviral treatment for established HTLV-1 infection is available. The effect of immunosuppression on the development of HTLV-1-associated disease in asymptomatically infected recipients is not well characterized, and HTLV-1-infected individuals should be counseled that immunosuppression may increase the risk of developing HTLV-1-associated disease and they should be monitored post-transplant for HTLV-1-associated disease. Currently approved screening assays do not distinguish between HTLV-1 and HTLV-2, and routine screening of deceased donors without risk factors in low seroprevalence areas is likely to result in significant organ wastage and is not recommended. Targeted screening of donors with risk factors for HTLV-1 infection and of living donors (as time is available to perform confirmatory tests) is reasonable.

Pediatric post-transplant hepatic kaposi sarcoma due to donor-derived human herpesvirus 8.

In areas of the world where human herpesvirus 8 (HHV-8) is endemic, Kaposi sarcoma (KS) is a common SOT-associated cancer. In the United States, where the virus is not prevalent, PTKS is rare, and there is little literature on pediatric PTKS. We present a North American female who underwent deceased donor, left lateral segment liver transplant for biliary atresia at age 11 months. The donor was a male with no known history of KS, originally from an HHV-8-endemic country. Three months after transplantation, the patient developed liver nodules and portal vein thrombosis. Analysis of needle biopsy established the diagnosis of KS and confirmed that the transformed cells were donor-derived. HHV-8 viremia was detected, and ganciclovir dosing (which had been started prophylactically) was increased. Immunosuppression was changed from tacrolimus to sirolimus. After further disease progression, 8 cycles of paclitaxel were administered. Under this treatment, her nodules regressed, HHV-8 viremia resolved, and she had marked clinic improvement. Notably, the adult recipient of the right liver lobe from the same donor also developed PTKS. This is one of few pediatric PTKS cases described in the literature. It contributes to the mechanistic understanding of PTKS development, illustrating the risk posed by donors from HHV-8-endemic countries, as well as the potential for strong PTKS correlation between multiple recipients of organs from a single shared donor.