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.

Outcomes in ovarian Sertoli-Leydig cell tumor: A report from the International Pleuropulmonary Blastoma/DICER1 and Ovarian and Testicular Stromal Tumor Registries.

OBJECTIVE: Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We sought to describe prognostic factors, treatment and outcomes for individuals with ovarian SLCT. METHODS: Individuals with SLCT were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and pathology was centrally reviewed when available. RESULTS: In total, 191 participants with ovarian SLCT enrolled, with most (92%, 175/191) presenting with FIGO stage I disease. Germline DICER1 results were available for 156 patients; of these 58% had a pathogenic or likely pathogenic germline variant. Somatic (tumor) DICER1 testing showed RNase IIIb hotspot variants in 97% (88/91) of intermediately and poorly differentiated tumors. Adjuvant chemotherapy was administered in 40% (77/191) of cases, and among these, nearly all patients received platinum-based regimens (95%, 73/77), and 30% (23/77) received regimens that included an alkylating agent. Three-year recurrence-free survival for patients with stage IA tumors was 93.6% (95% CI: 88.2-99.3%) compared to 67.1% (95% CI: 55.2-81.6%) for all stage IC and 60.6% (95% CI: 40.3-91.0%) for stage II-IV (p < .001) tumors. Among patients with FIGO stage I tumors, those with mesenchymal heterologous elements treated with surgery alone were at higher risk for recurrence (HR: 74.18, 95% CI: 17.99-305.85). CONCLUSION: Most individuals with SLCT fare well, though specific risk factors such as mesenchymal heterologous elements are associated with poor prognosis. We also highlight the role of DICER1 surveillance in early detection of SLCT, facilitating stage IA resection.

Prevalence of lung cysts in adolescents and adults with a germline DICER1 pathogenic/likely pathogenic variant: a report from the National Institutes of Health and International Pleuropulmonary Blastoma/DICER1 Registry.

BACKGROUND: Pleuropulmonary blastoma (PPB), the hallmark tumour associated with DICER1-related tumour predisposition, is characterised by an age-related progression from a cystic lesion (type I) to a high-grade sarcoma with mixed cystic and solid features (type II) or purely solid lesion (type III). Not all cystic PPBs progress; type Ir (regressed), hypothesised to represent regressed or non-progressed type I PPB, is an air-filled, cystic lesion lacking a primitive sarcomatous component. This study aims to evaluate the prevalence of non-progressed lung cysts detected by CT scan in adolescents and adults with germline DICER1 pathogenic/likely pathogenic (P/LP) variants. METHODS: Individuals were enrolled in the National Cancer Institute Natural History of DICER1 Syndrome study, the International PPB/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Individuals with a germline DICER1 P/LP variant with first chest CT at 12 years of age or older were selected for this analysis. RESULTS: In the combined databases, 110 individuals with a germline DICER1 P/LP variant who underwent first chest CT at or after the age of 12 were identified. Cystic lung lesions were identified in 38% (42/110) with a total of 72 cystic lesions detected. No demographic differences were noted between those with lung cysts and those without lung cysts. Five cysts were resected with four centrally reviewed as type Ir PPB. CONCLUSION: Lung cysts are common in adolescents and adults with germline DICER1 variation. Further study is needed to understand the mechanism of non-progression or regression of lung cysts in childhood to guide judicious intervention.

Exploring the experiences of an exercise-based telerehabilitation program among Canadian community-dwelling adults with stroke.

PURPOSE: Telerehabilitation is emerging as a means for delivering stroke rehabilitation to address unmet lower extremity rehabilitation needs. However, there is currently limited and low-quality evidence supporting the use telerehabilitation interventions for lower extremity recovery after stroke. Thus, we developed an exercise-based telerehabilitation program (TRAIL) for safe and effective promotion of lower extremity function after stroke. This study reports on the qualitative findings from the feasibility study of the TRAIL program. METHODS: An interpretive description methodology and inductive thematic analysis approach were undertaken. One-on-one semi-structured interviews were conducted on a subset of participants who completed the TRAIL feasibility study. Participants were recruited via email and enrolled into the study based on pre-determined purposeful sampling strategies. RESULTS: Ten participants (6 men, 4 women) completed a semi-structured interview. Two main themes emerged: (i) TRAIL ingredients for success and (ii) telerehabilitation is a viable option for stroke rehabilitation. CONCLUSION: Exercise-based telerehabilitation appears to be well-received by men and women post-stroke when social support, professional guidance, and program resources are offered. TRAIL may also prolong the continuum of care that individuals receive once they are discharged back into the community, and contribute to improvements in mobility, lower extremity strength and balance.

Exercise-based telerehabilitation for individuals with stroke can be delivered safely when clinicians are trained, and social support and program resources are available.Exercise-based telerehabilitation may be viable and accessible for men and women with stroke to extend the opportunity for rehabilitation services within the first year post-event.Synchronously delivered telerehabilitation programs using user-friendly videoconference software is recommended for optimal participant satisfaction.

Measuring LEND Core Competencies Using Trainee Follow-Up Surveys.

OBJECTIVES: Measuring the value-added impact of Leadership Education in Neurodevelopmental Disabilities and Related Disorders (LEND) training on trainees' leadership and career trajectories is necessary to understand program efficacy. In the current study, we leveraged an existing ex post facto design to develop and test a new measure of LEND competencies and compare outcomes of LEND trainees and comparison peers. METHODS: We developed the LEND Outcomes Follow-Up Survey using a multi-step, mixed methods process. A series of focus groups and consultations with key stakeholders identified eight important LEND leadership outcomes: (1) interdisciplinary work; (2) advocacy; (3) intersectional approach; (4) systems perspective; (5) life course perspective; (6) leadership; (7) engagement with maternal and child health populations; and (8) research experience. We developed and piloted this novel survey to measure these LEND leadership outcomes. We used data collected from this novel measure and an existing survey that is used nationally by LEND, to compare the outcomes of 43 LEND trainees and 30 comparison peers at two years post completion of LEND training. RESULTS: We found that, compared to comparison peers, LEND trainees: (1) worked with a greater number of disciplines; (2) were more likely to be engaged in advocacy; (3) were more likely to utilize a systems perspective in their work; (4) were more likely to work with maternal and child health populations; and (5) were more likely to have experience conducting research. CONCLUSIONS: Our findings suggested that LEND training improves LEND leadership outcomes at two years post-completion of LEND training.

TeleRehabilitation with Aims to Improve Lower extremity recovery in community-dwelling individuals who have had a stroke: protocol for a multisite, parallel group, assessor-blinded, randomised attention-controlled trial.

INTRODUCTION: Telerehabilitation is an accessible service delivery model that may support innovative lower extremity rehabilitation programmes that extend the stroke recovery continuum into the community. Unfortunately, there is limited evidence on the provision of exercises for lower extremity recovery after stroke delivered using telerehabilitation. In response, we developed the TeleRehabilitation with Aims to Improve Lower extremity recovery poststroke (TRAIL) programme, a 4-week progressive exercise and self-management intervention delivered synchronously using video-conferencing technology. Our primary hypothesis is that individual within 1-year poststroke who participate in TRAIL will experience significantly greater improvements in functional mobility than individuals in an attention-controlled education programme (EDUCATION). METHODS AND ANALYSIS: In this multisite, parallel group, assessor-blinded randomised attention-controlled trial, 96 community-living stroke survivors within 1-year poststroke will be recruited from five sites (Vancouver, Winnipeg, Toronto, London and Halifax, Canada) from the CanStroke Recovery Trials Platform which is a network of Canadian hospital sites that are affiliated with academic institutions to facilitate participant recruitment and quality trial practices. Participants will be randomised on a 1:1 basis to TRAIL or EDUCATION. Participants randomised to TRAIL will receive eight telerehabilitation sessions where they will perform exercises and receive self-management support to improve lower extremity recovery from a TRAIL physical therapist. The primary outcome will be measured using the Timed Up and Go. Secondary outcomes include lower extremity muscle strength, functional balance, motor impairment, balance self-efficacy, health-related quality of life and health service use for our economic evaluation. Measurements will be taken at baseline, immediately after the intervention, 3-month and 6-month postintervention. ETHICS AND DISSEMINATION: Ethics approval for this research has been obtained by all participating sites. All study participants will provide their informed consent prior to enrolling them in the study. Findings from this trial will be disseminated in peer-reviewed journals and presentations at international scientific meetings. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT04908241.

Variation in cystic fibrosis newborn screening algorithms in the United States.

RATIONALE: Cystic fibrosis (CF) newborn screening (NBS) algorithms in the United States vary by state. Differences in CF NBS algorithms could potentially affect the detection rate of CF newborns and lead to disparities in CF diagnosis amongst different racial and ethnic groups. OBJECTIVES: Generate a database of CF NBS algorithms in the United States and identify processes that may potentially lead to missed diagnoses or lead to healthcare disparities. METHODS: We sent an online survey to state and regional CF and NBS leaders about the type and threshold of immunoreactive trypsinogen (IRT) cutoff used and methods used for CFTR  gene variant analysis. Follow-up by email and phone was done to ensure a response from every state, clarify responses, and resolve discordances. RESULTS: There is wide variation in the NBS algorithms employed by different states. Approximately half the states use a floating IRT cutoff, and half use a fixed IRT cutoff. CFTR variant analysis also varies widely, with two states analyzing only for the F508del variant and four states incorporating CFTR gene sequencing. The other states use CFTR variant panels ranging from 23 to 365 CFTR variants. CONCLUSIONS: CF NBS algorithms vary widely amongst the different states in the United States, which affects the ability of CF NBS to diagnose newborn infants with CF consistently and uniformly across the country and potentially may miss more infants with CF from minority populations. Our results identify an important area for quality improvement in CF NBS.

Type I and Ir pleuropulmonary blastoma (PPB): A report from the International PPB/DICER1 Registry.

BACKGROUND: Pleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood. Type I PPB is a purely cystic lesion that has a microscopic population of primitive small cells with or without rhabdomyoblastic features and may progress to type II or III PPB, whereas type Ir lacks primitive small cells. METHODS: Children with suspected PPB were enrolled in the International PPB/DICER1 Registry. Pathology was centrally reviewed, and follow-up was ascertained annually. RESULTS: Between 2006 and 2022, 205 children had centrally reviewed type I or Ir PPB; 39% of children with type I and 5% of children with type Ir PPB received chemotherapy. Outcomes were favorable, although 11 children (nine with type I and two with type Ir PPB) experienced progression to type II/III (n = 8) or regrowth of type I PPB at the surgical site (n = 3), none of whom received chemotherapy before progression. Age and cyst size in combination were more suitable than either factor alone in predicting whether a particular lesion was type I or Ir PPB. CONCLUSIONS: For young children with type I PPB, outcomes are favorable, but complete resection is indicated because of the risk for progression. Chemotherapy may be useful in a subset of children at increased risk for recurrence/progression. Efforts to risk stratify children with type I PPB to optimize outcomes while reducing treatment-related side effects are underway.

Outcomes for Children With Type II and Type III Pleuropulmonary Blastoma Following Chemotherapy: A Report From the International PPB/DICER1 Registry.

PURPOSE: Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Type II and type III PPB have historically been associated with a poor prognosis. METHODS: Patients with known or suspected PPB were enrolled in the International PPB/DICER1 Registry. Medical records were abstracted with follow-up ascertained annually. All PPB diagnoses were confirmed by central pathology review. Beginning in 2007, the IVADo regimen (ifosfamide, vincristine, actinomycin-D, and doxorubicin) was recommended as a potential treatment regimen for children with type II and type III PPB. This regimen was compared with a historical control cohort. RESULTS: From 1987 to 2021, 314 children with centrally confirmed type II and type III PPB who received upfront chemotherapy were enrolled; 132 children (75 with type II and 57 with type III) received IVADo chemotherapy. Adjusted analyses suggest improved overall survival for children treated with IVADo in comparison with historical controls with an estimated hazard ratio of 0.65 (95% CI, 0.39 to 1.08). Compared with localized disease, distant metastasis at diagnosis was associated with worse PPB event-free survival and overall survival with hazard ratio of 4.23 (95% CI, 2.42 to 7.38) and 4.69 (95% CI, 2.50 to 8.80), respectively. CONCLUSION: The use of IVADo in children with type II and type III PPB resulted in similar-to-improved outcomes compared with historical controls. Inferior outcomes with metastatic disease suggest the need for novel therapies. This large cohort of uniformly treated children with advanced PPB serves as a benchmark for future multicenter therapeutic studies for this rare pediatric tumor.

Telemedicine in the Amish and Mennonite communities of Wisconsin.

The Plain Community (PC) is a medically underserved group found predominantly in the northeastern and midwestern USA. Due to the community's founder population with few converts and infrequent outside marriage, metabolic and genetic disorders are more prevalent. Individuals in the PC experience geographic, financial, and cultural barriers when accessing healthcare. In Wisconsin, a collaboration between clinicians at a rural community health clinic and the academic medical clinic established an outreach clinic for medical genetics located in a rural location closer to a Wisconsin PC which consists of both Amish and Mennonite communities. However, patients with acute medical concerns requiring more urgent genetics care must travel to the academic center. Telemedicine (TM) is a technology that increases access to healthcare, often reducing financial and travel barriers. Using survey tools, we explored whether TM could be used to provide genetic services to individuals in the Wisconsin PC at an outreach clinic. Results indicated that 36% of survey participants responded favorably to receiving services by TM at a clinic designed for the PC. Members of the Mennonite community are significantly more likely to consider receiving services via TM than those of the Amish community. The results of the surveys indicate potential utility of TM at the outreach clinic as alternative way to improve access to genetic and other subspecialty services for the PC.

A model to evaluate interprofessional training effectiveness: feasibility and five-year outcomes of a multi-site prospective cohort study.

OBJECTIVES: Assessing the impact of interdisciplinary training programs is highly desirable and needed. However, there are currently no established methods to prospectively assess long-term outcomes of trainees compared to individuals who did not receive training. Our objective was to test the feasibility of a longitudinal, prospective cohort design to evaluate training outcomes, and to use this method to evaluate Leadership Education in Neurodevelopmental Disabilities and Related Disorders (LEND) training outcomes. METHODS: LEND trainees were matched to comparison peers and followed annually for up to five years using a pre-existing outcomes survey. We assessed study feasibility using recruitment and retention data over five years. We then looked at preliminary efficacy of LEND training in LEND trainees compared to comparison peers using the pre-existing outcomes survey. RESULTS: Overall, 68.3% of eligible trainees participated in the Outcomes Study across five years, and 66.0% were matched to comparison peers. On average, 84.4% of LEND trainees and 79.9% of comparison peers completed the outcomes survey annually. Attrition was low at 0.9% for LEND trainees and 2.6% for comparison peers over five years. LEND training demonstrated preliminary efficacy in promoting leadership development: LEND trainees began their careers engaged in more leadership activities than comparison peers, and the rate of growth in their participation in leadership activities was greater. CONCLUSIONS: The design used to assess outcomes is a feasible approach that can be widely used to assess training program outcomes. Analyses suggest that LEND training is efficacious in increasing involvement in leadership activities over time after graduation.

Early Identification of Hearing Loss and Language Development at 32 Months of Age.

This study examines the relationship between the early identification of hearing loss and language outcomes for deaf/hard of hearing (D/HH) children, with bilateral or unilateral hearing loss and with or without additional disabilities. It was hypothesized that hearing loss identified by 3 months of age would be associated with better language outcomes. Using a prospective, longitudinal design, 86 families completed developmental instruments at two time points: at an average age of 14.8 months and an average age of 32.1 months. Multiple regression examined how hearing loss identified by 3 months of age contributed to later language outcomes while controlling for developmental level at the first time point. Hearing loss identified by 3 months of age was positively associated with better language outcomes for D/HH children at 32 months of age; however, D/HH children still exhibited language delays, compared to normative scores for same-aged hearing peers for reported measures. Language outcomes of children with unilateral hearing loss were not better than those of children with mild-to-moderate bilateral hearing loss. Children with additional disabilities and more severe bilateral hearing loss had lower language scores than those without.

Rapid Transition to Telemedicine During the COVID-19 Pandemic: Medical Genetics Experience.

BACKGROUND: The coronavirus SARS-CoV-2 (COVID-19) pandemic interrupted delivery of outpatient health care to minimize risk of exposure. This pandemic threatened to increase longstanding national concerns about access to both initial and follow-up genetics clinics services. The Medical Genetics Clinic at the University of Wisconsin-Madison Waisman Center (WCMGC) rapidly transitioned to offering appointments using telemedicine in March 2020 when the public health emergency for COVID-19 pandemic was declared. METHODS: Datasets were reviewed for the periods April - July 2019 (pre-COVID baseline) and April - July 2020 (COVID project data). Patient schedules were accessed to determine the number of appointments kept, no-shows, and late cancellations. A telephone survey was utilized to assess patient satisfaction with telemedicine. RESULTS: Fewer appointments were missed and providers completed more clinic visits after transitioning to telemedicine. Patients and their families were equally satisfied with care received and were amenable to telemedicine use in the future. Telemedicine allowed WCMGC to continue serving patients during a period of restricted on-site services, suggesting its continuation would improve access to genetic services.

Using Feasibility Data and Codesign to Refine a Group-Based Health Literacy Intervention for New Parents.

Few health literacy interventions exist for new parents. We developed a group-based health literacy program ("Parenting Plus"), which was initially tested in a feasibility study in 2018. In this brief report, we describe how feasibility findings were incorporated into the Parenting Plus program. Using a codesign process with patient partners (feasibility study participants) and health staff to revise the program, version 2 was tested in a single-site pilot using pre- and post-intervention testing. Parents older than age 16 years whose child was between ages 4 and 26 weeks were recruited from nurse home visits in western Sydney, Australia. Interested participants attended the free 4-week health literacy program (four 2-hour sessions) delivered by a trained facilitator. Piloting suggested the revised program is acceptable to new parents, has good retention (93% over the course of 4 weeks), and can improve health literacy skills, including access to reliable health information and services. Our iterative development and codesign approach integrated learnings from various sources to inform the design of an evidence-based health literacy intervention. We now move to an effectiveness implementation hybrid trial to test intervention effectiveness (health literacy skill development) and support translation of research findings into routine practice. [HLRP: Health Literacy Research and Practice. 2021;5(4):e276-e282.].

Aluminum dust exposure and risk of neurodegenerative diseases in a cohort of male miners in Ontario, Canada.

OBJECTIVES: We estimated associations between respirable aluminum exposure through McIntyre Powder (MP), a fine-sized aluminum and aluminum compound powder, and neurological disease in a retrospective cohort of mining workers from Ontario, Canada. Outcomes included Alzheimer's disease, Alzheimer's with other dementias, Parkinson's disease, parkinsonism, and motor neuron disease. METHODS: The cohort was created by linking a database of mining workers' work history to healthcare records. This analysis included 36 826 male miners potentially exposed to MP between 1943 and 1979, followed up for disease diagnosis between 1992 and 2018. Exposure was assessed using two approaches, self-reported and historical records. Neurological diseases were ascertained using physician billing and hospital discharge records. Poisson regression models were used to estimate associations between MP exposure and neurological outcomes using incidence rate ratios (RR) and 95% confidence intervals (95% CI). RESULTS: Exposure to self-reported MP was associated with an elevated incidence rate of Parkinson's disease (RR 1.34, 95% CI 1.14-1.57). The rate of Parkinson's disease appeared to increase with the duration of exposure assessed by historical records. Having ever been exposed to MP was positively associated with an elevated rate of Alzheimer's with other dementias (RR 1.12, 95% CI 1.06-1.19) but not Alzheimer's disease alone. CONCLUSION: This study found that miners who were exposed to MP (respirable aluminum) had elevated rates of Parkinson's disease. The rate of Parkinson's disease appeared to increase with the duration of exposure assessed by historical records.

Programmed Death Ligand 1 Expression and Related Markers in Pleuropulmonary Blastoma.

INTRODUCTION: Pleuropulmonary blastoma (PPB), a rare childhood neoplasm of the lung, is linked to pathogenic DICER1 variants. We investigated checkpoint inhibitor markers including Programmed Death Ligand 1 (PD-L1), PD1, CD8 and tumor mutational burden (TMB) in PPB. MATERIAL AND METHODS: Cases were collected from departmental archives and the International PPB/DICER1 Registry. Immunohistochemistry (IHC) for PD-L1, PD-1, CD8 and DNA mismatch repair (MMR) genes were performed. In addition, normal-tumor paired whole exome sequencing (WES) was performed in two cases. RESULTS: Twenty-five PPB cases were studied, consisting of Type I (n = 8, including 2 Ir), Type II (n = 8) and Type III (n = 9). PD-L1 combined positive score (CPS) of 1, 4 and 80 was seen in three (3/25, 12.0%) cases of Type II PPB with negative staining in the remaining cases. PD-1 and CD8 stains demonstrated positive correlation (P < .05). The density of PD1 and CD8 in the interface area was higher than within tumor (P < .05). The MMR proteins were retained. TMB was 0.65 mutations/Mb in type II PPB with high expression of PD-L1, and 0.94 mutations/Mb in one negative PD-L1 case with metastatic tumor. CONCLUSION: A small subpopulation of PPB patient might benefit from checkpoint immunotherapy due to positive PD-L1 staining.

Expression of p53 is significantly associated with recurrence-free survival and overall survival in pleuropulmonary blastoma (PPB): a report from the International Pleuropulmonary Blastoma/DICER1 Registry.

Pleuropulmonary blastoma (PPB) is a primary embryonal malignancy of childhood that is characterized by distinct morphologic types: type Ir (regressed), type I (cystic), type II (cystic and solid), and type III (solid). Prognosis varies by PPB type. Most cases are associated with a germline pathogenic mutation in DICER1; however, there is limited data on the factor(s) at a cellular level that drive progression from type I to type III. In this study, we evaluated the expression of p53 and its prognostic implications. A total of 143 PPB cases were included in the study with the following distribution in PPB types: Ir (14%), I (23%), II (32%), and III (31%). P53 expression by immunohistochemistry (IHC) was recorded as four groups: 0%, 1-25%, 26-75%, and 76-100%. All type I PPBs showed 0-25% p53 expression compared to the higher p53 expression (>25%) in type III PPB (p < 0.0001), to support the argument that p53 has a role in tumor progression. In addition, type Ir with the architectural hallmarks of type I PPB, but lacking the primitive cell population, has negligible p53 expression. High p53 expression (staining observed in >25% of the tumor cells) was significantly associated with age over 1 year (p = 0.0033), neoadjuvant therapy (p = 0.0009), positive resection margin (p = 0.0008) and anaplasia (p < 0.0001). P53 expression was significantly associated with recurrence-free survival (p < 0.0001) and overall survival (p = 0.0350), with higher p53 expression associated with worse prognosis. Comparisons of concordance statistics showed no significant difference in prognostication when using morphologic types compared to p53 expression groups (p = 0.647). TP53 sequence was performed in 16 cases; the most common variant identified was a missense variant (12 cases), and in one case a frameshift truncating variant was noted. Based on these findings, we recommend performing p53 IHC in all newly diagnosed cases of types II and III PPB to further aid in risk stratification.

Hematologic indices in individuals with pathogenic germline DICER1 variants.

Pathogenic germline variants in DICER1 underlie an autosomal dominant, pleiotropic tumor-predisposition disorder. Murine models with the loss of DICER1 in hematopoietic stem cell progenitors demonstrate hematologic aberrations that include reductions in red and white blood cell counts, hemoglobin volume, and impaired maturation resulting in dysplasia. We investigated whether hematologic abnormalities such as those observed in DICER1-deficient mice were observed in humans with a pathogenic germline variant in DICER1. A natural history study of individuals with germline pathogenic DICER1 variants and family controls conducted through the National Cancer Institute (NCI) evaluated enrollees at the National Institutes of Health Clinical Center during a comprehensive clinical outpatient visit that included collecting routine clinical laboratory studies. These were compared against normative laboratory values and compared between the DICER1 carriers and controls. There were no statistical differences in routine clinical hematology laboratory studies observed in DICER1 carriers and family controls. A review of the medical history of DICER1 carriers showed that none of the individuals in the NCI cohort developed myelodysplastic syndrome or leukemia. Query of the International Pleuropulmonary Blastoma/DICER1 Registry revealed 1 DICER1 carrier who developed a secondary leukemia after treatment of pleuropulmonary blastoma. We found limited evidence that the hematologic abnormalities observed in murine DICER1 models developed in our cohort of DICER1 carriers. In addition, no cases of myelodysplastic syndrome were observed in either the NCI cohort or the International Pleuropulmonary Blastoma/DICER1 Registry; 1 case of presumed secondary leukemia was reported. Abnormalities in hematologic indices should not be solely attributed to DICER1. This trial was registered at www.clinicaltrials.gov as #NCT01247597.

Childhood Rhabdomyosarcoma of the Female Genital Tract: Association with Pathogenic DICER1 Variation, Clinicopathological Features, and Outcomes.

STUDY OBJECTIVE: Rhabdomyosarcomas (RMSs) of the female genital tract (FGT) have been recently shown to be associated with germline pathogenic variation in DICER1, which can underlie a tumor predisposition disorder. We sought to determine the incidence of a pathogenic variation in DICER1 in a cohort of RMSs of the FGT, as well as to evaluate the clinicopathological features and outcomes of the patients. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: We retrospectively reviewed medical records of the patients diagnosed with RMS of the FGT between 1990 and 2019. Molecular genetic sequencing of the tumor to detect an RNase IIIb domain hot spot mutation in DICER1 samples was performed in 7 patients. Individuals with a missense mutation in the tumor were also screened for a loss of function germline mutation in DICER1. RESULTS: Of 210 cases of pediatric RMS, 11 arose from the FGT. Molecular genetic sequencing of the tumor samples revealed a somatic missense mutation in the RNase IIIb domain of DICER1 in a total of 3 patients, 2 patients with embryonal RMS of the cervix/uterus, and 1 patient with ovarian embryonal RMS. As a result of genetic testing for the loss of function germline mutation in DICER1, a heterozygous pathogenic variant was also found in 2 of these patients. CONCLUSION: Despite the limited number of patients, our findings suggest that it is important to be aware of the possible association between RMS of FGT and pathogenic germline DICER1 variants because the detection of this mutation in a patient or relatives can provide the opportunity for surveillance of related conditions that might improve long-term outcomes and survival.

Massive and Microscopic: Autoethnographic Affects in the Time of COVID.

This essay uses several of the prompts from the Massive::Microscopic experiment as a jumping off point for considering how affect theory and critical autoethnography offer us a framework for understanding, creating, and acting together in the time of COVID. Through stories of cloud-watching, mindfulness meditation, and other encounters with atmospheres and movements, we connect individual experiences of the pandemic to Buddhist understandings of a universal "we." As a research practice committed to joining microscopic with macro lived experience, critical autoethnography offers a speculative method for collective reckoning with our infinitesimal selves in relation to the infinite of a pandemic.