Children and young adults with newly diagnosed rhabdomyosarcoma metastatic to bone treated on Children's Oncology Group studies.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Despite bone metastases being present in 5% of patients at diagnosis, there are limited studies examining these outcomes. We sought to define the prognostic factors, clinical courses, and outcomes of children treated on Children's Oncology Group (COG) clinical trials with RMS metastatic to bone at diagnosis. METHODS: We performed a retrospective analysis of patients diagnosed with bone metastatic RMS enrolled on COG RMS clinical trials (D9802, D9803, ARST0431, or ARST08P1) between 1997 and 2013. RESULTS: RMS metastatic to bone was identified in 154 patients at a median age of 14.9 years at diagnosis. Fifty-eight percent of patients were male, 90% had metastases at additional sites, 74% had alveolar histology, and extremity was the most common primary site (31%). Eighty-six percent of patients (n = 133) received radiation therapy. The 3- and 5-year event-free survival (EFS) was 15.4% and 14.5%, respectively. The 3- and 5-year overall survival (OS) was 30.4% and 18.0%, respectively. We identified alveolar histology, FOXO1 fusion presence, unfavorable primary location, higher Oberlin score, and lack of radiation as poor prognostic characteristics for both EFS and OS in univariate analysis. Lack of radiation was not significant when excluding patients with events prior to 20 weeks. CONCLUSIONS: This study is the largest analysis of patients with bone metastatic RMS, and defines the poor overall outcomes and negative prognostic factors for these patients. They may be eligible for therapy deintensification for improved quality of life or pursuit of novel treatments/approaches, which are desperately needed.

Polygenic risk scores, radiation treatment exposures and subsequent cancer risk in childhood cancer survivors.

Survivors of childhood cancer are at increased risk for subsequent cancers attributable to the late effects of radiotherapy and other treatment exposures; thus, further understanding of the impact of genetic predisposition on risk is needed. Combining genotype data for 11,220 5-year survivors from the Childhood Cancer Survivor Study and the St Jude Lifetime Cohort, we found that cancer-specific polygenic risk scores (PRSs) derived from general population, genome-wide association study, cancer loci identified survivors of European ancestry at increased risk of subsequent basal cell carcinoma (odds ratio per s.d. of the PRS: OR = 1.37, 95% confidence interval (CI) = 1.29-1.46), female breast cancer (OR = 1.42, 95% CI = 1.27-1.58), thyroid cancer (OR = 1.48, 95% CI = 1.31-1.67), squamous cell carcinoma (OR = 1.20, 95% CI = 1.00-1.44) and melanoma (OR = 1.60, 95% CI = 1.31-1.96); however, the association for colorectal cancer was not significant (OR = 1.19, 95% CI = 0.94-1.52). An investigation of joint associations between PRSs and radiotherapy found more than additive increased risks of basal cell carcinoma, and breast and thyroid cancers. For survivors with radiotherapy exposure, the cumulative incidence of subsequent cancer by age 50 years was increased for those with high versus low PRS. These findings suggest a degree of shared genetic etiology for these malignancy types in the general population and survivors, which remains evident in the context of strong radiotherapy-related risk.

Natural Histories and Disease Complications in a Cohort of 151 Children With Gastric or Duodenal Eosinophilia.

INTRODUCTION: Eosinophilic gastritis (EoG) and duodenitis (EoD) are rare conditions that are poorly understood. Our aim was to describe the natural history of children with varying degrees of gastric or duodenal eosinophilia with respect to disease complications and histologic and endoscopic longitudinal trajectories. METHODS: The electronic medical record at a tertiary children's hospital was queried to identify patients with EoG, EoD, or EoG + EoD who were cared for between January 2010 and 2022. Multiple logistic regression was performed to explore associations between baseline features and persistence/recurrence of eosinophilia or complications remote from diagnosis. RESULTS: We identified 151 patients: 92 with EoG, 24 with EoD, 12 with EoG + EoD, and 23 with tissue eosinophilia but did not meet histologic criteria for EoG or EoD (low grade). The average age at diagnosis was 10.6 years, and average follow-up was 5.8 years. Twenty-five percent of patients with EoG or EoD had persistence/recurrence of eosinophilia; this was associated with increases in the EoG Endoscopic Reference Score (adjusted odds ratio [aOR] 1.34, confidence interval [CI] 1.03-1.74) on diagnostic endoscopy. Eighteen percent suffered from disease complications, and development of late complications was associated with presenting with a complication (aOR 9.63, CI 1.09-85.20), severity of duodenal endoscopic abnormalities (aOR 8.74, CI 1.67-45.60), and increases in the EoG Endoscopic Reference Score (aOR 1.70, CI 1.11-2.63). DISCUSSION: Patients with gastric and duodenal eosinophilia should be followed closely to monitor for recurrence and complications, especially those presenting with endoscopic abnormalities or complications.

The Pathologic Diagnosis of Pediatric Soft Tissue Tumors in the Era of Molecular Medicine: The Sarcoma Pediatric Pathology Research Interest Group Perspective.

CONTEXT.­: Pediatric soft tissue tumors are one of the areas of pediatric pathology that frequently generate consult requests. Evolving classification systems, ancillary testing methods, new treatment options, research enrollment opportunities, and tissue archival processes create additional complexity in handling these unique specimens. Pathologists are at the heart of this critical decision-making, balancing responsibilities to consider expediency, accessibility, and cost-effectiveness of ancillary testing during pathologic examination and reporting. OBJECTIVE.­: To provide a practical approach to handling pediatric soft tissue tumor specimens, including volume considerations, immunohistochemical staining panel recommendations, genetic and molecular testing approaches, and other processes that impact the quality and efficiency of tumor tissue triage. DATA SOURCES.­: The World Health Organization Classification of Soft Tissue and Bone Tumors, 5th edition, other recent literature investigating tissue handling, and the collective clinical experience of the group are used in this manuscript. CONCLUSIONS.­: Pediatric soft tissue tumors can be difficult to diagnose, and evaluation can be improved by adopting a thoughtful, algorithmic approach to maximize available tissue and minimize time to diagnosis.

Prognosis of children and young adults with newly diagnosed rhabdomyosarcoma metastatic to bone marrow treated on Children's Oncology Group studies.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Metastatic disease occurs in 16% of all RMS cases and has a poor prognosis. There are limited studies examining the outcomes specific to patients with RMS metastatic to bone marrow despite an incidence of 6% at diagnosis. Our study aims to document the outcomes, prognostic factors, and clinical courses of children presenting with RMS metastatic to bone marrow treated on Children's Oncology Group (COG) cooperative trials. METHODS: We performed a retrospective analysis of the patients diagnosed with RMS metastatic to bone marrow between 1997 and 2013 enrolled on one of four COG RMS clinical trials of D9802, D9803, ARST0431, and ARST08P1. RESULTS: We identified 179 cases with RMS metastatic to bone marrow. Patients had a median age of 14.8 years, 58% were male, predominantly alveolar histology (76%), extremity was the most common primary site (32%), and 87% had metastatic disease to additional sites; 83% (n = 149) received radiation as a treatment modality. The 3- and 5-year event-free survival was 9.4% and 8.2%, respectively. The 3- and 5-year overall survival was 26.1% and 12.6%, respectively. Age ≥10 years, alveolar histology, FOXO1 fusion presence, unfavorable primary location, higher Oberlin score, and lack of radiation were identified as poor prognostic/predictive characteristics. CONCLUSIONS: This study represents the largest analysis of RMS metastatic to bone marrow, defining the poor prognostic outcome for these patients. These patients may be eligible for therapy deintensification or early pursuit of novel treatments/approaches that are desperately needed.

Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer.

Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m-2: 1.24, 95% confidence interval (CI): 1.18-1.31), with more than twofold increased risk for survivors treated with ≥200 mg m-2 cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200-299 mg m-2, HR: 2.33 for 300-399 mg m-2 and HR: 2.78 for ≥400 mg m-2). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59-6.63). For patients treated with or without chest irradiation, HRs per 100 mg m-2 of doxorubicin were 1.11 (95% CI: 1.02-1.21) and 1.26 (95% CI: 1.17-1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m-2 cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.

ALK-Rearranged Epithelioid Mesenchymal Neoplasm: Expanding the Spectrum of Tyrosine Kinase-Altered Mesenchymal Tumors.

The anaplastic lymphoma kinase (ALK) gene encodes a receptor tyrosine kinase, and fusions involving this gene have been reported in a variety of mesenchymal neoplasms. ALK-altered tumors with epithelioid morphology have been described in epithelioid inflammatory myofibroblastic sarcoma and epithelioid fibrous histiocytoma. Herein, we describe the clinicopathologic features of 7 ALK-rearranged mesenchymal tumors with epithelioid morphology occurring predominately in the pediatric population. Tumors occurred in 4 females and 3 males with an age ranging from 1 month to 28 years. Five tumors were superficial and solitary, while 1 presented with multiple peritoneal/omental nodules, and 1 presented as a large mediastinal mass. Morphologically, all tumors comprised epithelioid cells arranged in sheets, anastomosing cords, or small clusters embedded in a myxohyaline stroma. The cells had slightly variably sized ovoid nuclei with moderately prominent nucleoli and abundant eosinophilic cytoplasm. Four cases had sparse mitotic figures without necrosis. The remaining 3 tumors (2 deep and 1 superficial) had more than 10 mitoses per 10 high-power fields as well as foci of necrosis. ALK fusions were identified in all cases. The fusion partners included HMBOX1 (n = 1), VCL (n = 1), PRRC2B (n = 1), MYH10 (n = 1), STRN (n = 1), and EML4 (n = 2). One tumor recurred locally 2 years after initial resection; 1 patient had widely metastatic disease (mediastinal tumor). At the time of last follow-up (n = 6), 4 patients were alive without evidence of disease, 1 died due to complications of therapy (peritoneal tumor), and 1 was alive with disease. Our findings expand the spectrum of ALK-rearranged mesenchymal tumors. Our cases predominately occurred in older children and mainly exhibited epithelioid to round cell morphology, as opposed to spindle cell morphology. We also show that tumors in a deep location with higher-grade features follow a more aggressive clinical course.

Virtual Pathology Elective, Real Education: The PathElective.com Experience as a Model for Novel Pathology Pedagogy and a Primer for Curricular Evolution.

CONTEXT.­: PathElective.com was created in response to the pandemic's restrictions on interactions with trainees, and since has been incorporated into many training programs worldwide, serving as a unique means of delivering high-quality pathology and laboratory medical education at multiple levels of training. OBJECTIVE.­: To analyze student usage, performance, and satisfaction to provide insight into the effectiveness of virtual education to guide curricular evolution. DESIGN.­: Squarespace (Squarespace, Inc) was used for website development and to collect website analytics. Students were assessed before and after course participation using a dual-form crossover quiz design. Quiz data were anonymous and analyzed with a paired t test to account for varying student background. A novel analysis was performed aimed at examining the attrition rate of students across multiple modules. RESULTS.­: Over the study period (May 1, 2020 to October 31, 2021), PathElective.com received 577 483 page views, 126 180 visits, 59 928 unique visitors, and 10 278 registered users who earned 15 305 certificates. A total of 7338 premodule and postmodule quiz pairs were analyzed. The overall average increase in score was 13.83% (P = .02). All but 5 of the 56 courses experienced a statistically significant increase in score. All courses received median scores of Very Satisfied/Satisfied in all 6 assessment domains. Aggregate attrition data revealed a unique, negative polynomial relationship (R2 = 0.656). CONCLUSIONS.­: PathElective.com is a free, effective means of enhancing anatomic/clinical pathology training in medical education. These analyses offer a unique perspective on the online user experience and could guide the development of future online medical education resources.

Polygenic Risk and Chemotherapy-Related Subsequent Malignancies in Childhood Cancer Survivors: A Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study Report.

PURPOSE: Chemotherapeutic exposures are associated with subsequent malignant neoplasm (SMN) risk. The role of genetic susceptibility in chemotherapy-related SMNs should be defined as use of radiation therapy (RT) decreases. PATIENTS AND METHODS: SMNs among long-term childhood cancer survivors of European (EUR; N = 9,895) and African (AFR; N = 718) genetic ancestry from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study were evaluated. An externally validated 179-variant polygenic risk score (PRS) associated with pleiotropic adult cancer risk from the UK Biobank Study (N > 400,000) was computed for each survivor. SMN cumulative incidence comparing top and bottom PRS quintiles was estimated, along with hazard ratios (HRs) from proportional hazards models. RESULTS: A total of 1,594 survivors developed SMNs, with basal cell carcinomas (n = 822), breast cancers (n = 235), and thyroid cancers (n = 221) being the most frequent. Although SMN risk associations with the PRS were extremely modest in RT-exposed EUR survivors (HR, 1.22; P = .048; n = 4,630), the increase in 30-year SMN cumulative incidence and HRs comparing top and bottom PRS quintiles was statistically significant among nonirradiated EUR survivors (n = 4,322) treated with alkylating agents (17% v 6%; HR, 2.46; P < .01), anthracyclines (20% v 8%; HR, 2.86; P < .001), epipodophyllotoxins (23% v 1%; HR, 12.20; P < .001), or platinums (46% v 7%; HR, 8.58; P < .01). This PRS also significantly modified epipodophyllotoxin-related SMN risk among nonirradiated AFR survivors (n = 414; P < .01). Improvements in prediction attributable to the PRS were greatest for epipodophyllotoxin-exposed (AUC, 0.71 v 0.63) and platinum-exposed (AUC,0.68 v 0.58) survivors. CONCLUSION: A pleiotropic cancer PRS has strong potential for improving SMN clinical risk stratification among nonirradiated survivors treated with specific chemotherapies. A polygenic risk screening approach may be a valuable complement to an early screening strategy on the basis of treatments and rare cancer-susceptibility mutations.

Survival of patients with orbital and eyelid rhabdomyosarcoma treated on Children's Oncology Group studies from 1997 to 2013: A report from the Children's Oncology Group.

BACKGROUND: Orbital rhabdomyosarcoma (ORMS) commonly presents as low-risk disease (stage 1, group I-III, embryonal RMS) with excellent outcome. Long-term follow-up of patients with low-risk ORMS and outcomes of less common subgroups of ORMS treated on recent Children's Oncology Group (COG) trials have not been reported. METHODS: Patients with ORMS enrolled on COG trials from 1997 to 2013 were identified. Demographic information and disease characteristics were collected. Outcomes were determined for the following subgroups: 1) low-risk ORMS, 2) resected (group I/II) low-risk ORMS, 3) non-low-risk ORMS, and 4) recurrent ORMS. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan-Meier method. ResultsThe authors identified 218 patients with ORMS. Most tumors were embryonal/botryoid (n = 169; 77.5%), <5 cm (n = 213; 97.7%), group III (n = 170; 78.0%), and without lymph node involvement (N0; n = 215; 98.6%). For 192 patients with low-risk ORMS, the 10-year EFS and OS rates were 85.5% (95% confidence interval [CI], 77.0%-94.0%) and 95.6% (95% CI, 90.8%-100.0%), respectively. Those with group I/II low-risk ORMS (n = 5 in group I; n = 39 in group IIA) had 10-year EFS and OS rates of 88.0% (95% CI, 72.6%-100.0%) and 97.6% (95% CI, 90.0%-100.0%), respectively. Twenty-six patients with non-low-risk ORMS had 5-year EFS and OS rates of 88.5% (95% CI, 75.6%-100.0%) and 95.8% (95% CI, 87.7%-100.0%), respectively. For patients with recurrent ORMS, the 10-year OS rate from the time of recurrence was 69.4% (95% CI, 50.0%-88.8%). CONCLUSIONS: Patients with ORMS had favorable long-term survival outcomes on COG studies from 1997 to 2013, including those who had both low-risk and non-low-risk disease. A significant proportion of patients with recurrent ORMS may achieve long-term survival.

Cohort profile: Risk and risk factors for female breast cancer after treatment for childhood and adolescent cancer: an internationally pooled cohort.

PURPOSE: The International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer was established in 2018 to address gaps in knowledge of risk and risk factors for breast cancer subsequent to childhood/adolescent cancer by pooling individual patient data from seven cohorts. Initially, the pooled cohort will focus on three clinically relevant questions regarding treatment-related subsequent breast cancer risk in female survivors, which are the risk related to low-dose radiotherapy exposure to the chest, specific chemotherapy agents and attained age. PARTICIPANTS: The consortium database includes pooled data on 21 892 female survivors from seven cohorts in North America and Europe with a primary cancer diagnosis at <21 years of age, and survival ≥5 years from diagnosis. FINDINGS TO DATE: This is a newly established pooled study. The cohort profile summarised the data collected from each included cohort, including childhood cancer diagnosis information and treatment details (ie, radiotherapy fields and cumulative doses, and chemotherapy agents and cumulative doses for each agent). Included cohorts' follow-up started 1951-1981 and ended 2013-2021, respectively, for a median follow-up duration of 24.3 (IQR 18.0-32.8) years since primary cancer diagnosis. The median age at primary cancer diagnosis was 5.4 (IQR 2.5-11.9) years. And the median attained age at last follow-up was 32.2 (IQR 24.0-40.4) years. In all, 4240 (19.4%) survivors were treated with radiotherapy to the chest and 9308 (42.5%) with anthracyclines. At the end of the follow-up, 835 females developed a first subsequent breast cancer, including 635 invasive breast cancer only, 184 carcinomas in situ only (172 ductal carcinomas in situ and 12 lobular carcinomas in situ), and 16 with both an invasive and in situ diagnosis at the same moment. The cumulative incidences of subsequent breast cancer (both invasive and in situ) 25 and 35 years after primary cancer diagnosis were 2.2% and 6.2%, respectively. FUTURE PLANS: The consortium is intended to serve as a model and robust source of childhood/adolescent cancer survivor data for elucidating other knowledge gaps on subsequent breast cancer risk, and risk of other subsequent malignancies (including data on males) in the future.

A Comprehensive Approach to the Management of Patients With HLHS and Related Malformations: An Analysis of 83 Patients (2015-2021).

Background: Some patients with hypoplastic left heart syndrome (HLHS) and HLHS-related malformations with ductal-dependent systemic circulation are extremely high-risk for Norwood palliation. We report our comprehensive approach to the management of these patients designed to maximize survival and optimize the utilization of donor hearts. Methods: We reviewed our entire current single center experience with 83 neonates and infants with HLHS and HLHS-related malformations (2015-2021). Standard-risk patients (n = 62) underwent initial Norwood (Stage 1) palliation. High-risk patients with risk factors other than major cardiac risk factors (n = 9) underwent initial Hybrid Stage 1 palliation, consisting of application of bilateral pulmonary bands, stent placement in the patent arterial duct, and atrial septectomy if needed. High-risk patients with major cardiac risk factors (n = 9) were bridged to transplantation with initial combined Hybrid Stage 1 palliation and pulsatile ventricular assist device (VAD) insertion (HYBRID + VAD). Three patients were bridged to transplantation with prostaglandin. Results: Overall survival at 1 year = 90.4% (75/83). Operative Mortality for standard-risk patients undergoing initial Norwood (Stage 1) Operation was 2/62 (3.2%). Of 60 survivors: 57 underwent Glenn, 2 underwent biventricular repair, and 1 underwent cardiac transplantation. Operative Mortality for high-risk patients with risk factors other than major cardiac risk factors undergoing initial Hybrid Stage 1 palliation without VAD was 0/9: 4 underwent transplantation, 1 awaits transplantation, 3 underwent Comprehensive Stage 2 (with 1 death), and 1 underwent biventricular repair. Of 9 HYBRID + VAD patients, 6 (67%) underwent successful cardiac transplantation and are alive today and 3 (33%) died while awaiting transplantation on VAD. Median length of VAD support was 134 days (mean = 134, range = 56-226). Conclusion: A comprehensive approach to the management of patients with HLHS or HLHS-related malformations is associated with Operative Mortality after Norwood of 2/62 = 3.2% and a one-year survival of 75/83 = 90.4%. A subset of 9/83 patients (11%) were stabilized with HYBRID + VAD while awaiting transplantation. VAD facilitates survival on the waiting list during prolonged wait times.

Selective Immunoreactivity for WT1 Carboxy-Terminus Distinguishes Desmoplastic Small Round Cell Tumor From its Histologic Mimics.

Desmoplastic small round cell tumor (DSRCT) is an aggressive pediatric round cell sarcoma containing a characteristic EWSR1-WT1 gene fusion. In the absence of genetic data, distinguishing DSRCT from other small round cell tumors of childhood can be problematic due to overlapping histologic and immunohistochemical features. We studied the utility of immunohistochemistry with antibodies targeting both the amino-terminal and carboxy-terminal regions of the Wilms tumor-1 (WT1) protein in differentiating these groups of tumors. The study cohort included 33 cases of genetically confirmed pediatric round cell tumors (10 DSRCTs, 12 Wilms tumors, 10 Ewing sarcomas, and 1 CIC-rearranged sarcoma). Immunoreactivities and immunolocalization of both the WT1 amino-terminus and carboxy-terminus were scored and documented. All DSRCTs displayed selective reactivity for only the WT1 carboxy-terminus (10/10), while dual immunoreactivity for both the WT1 carboxy-terminus (12/12) and amino-terminus antibodies (12/12) were characteristic of Wilms tumors. CIC-rearranged sarcoma showed variable WT1 nuclear immunopositivity (1/1, 1/1) and Ewing sarcomas were consistently WT1-negative for both the WT1 amino-terminus (0/10) and carboxy-terminus (0/10). Dual WT1 amino-terminus and carboxy-terminus immunohistochemistry remains a helpful diagnostic tool in discriminating intraabdominal small round cell tumors, which serves as an adjunct to the genetic information in preventing misdiagnosis.

Congenital spindle cell rhabdomyosarcoma: An international cooperative analysis.

BACKGROUND: Spindle cell rhabdomyosarcoma (RMS) is a rare variant of RMS accounting for up to 10% of cases in infants. In older children and adults, spindle cell RMS is associated with MYOD1 mutations and a poor prognosis. In infants, it is associated with recurring fusions involving NCOA2 and VGLL2. Reports in the literature suggest a favorable prognosis for this subset, however, little is known about treatment and outcome data of infants with spindle cell RMS. METHODS: Characteristics, treatment, and outcome of an international cohort of 40 patients aged ≤ 12 months with spindle cell RMS treated from 1997 to 2018 were evaluated. RESULTS: Localized disease (LD) was diagnosed in 39 patients. The median age at diagnosis was 2.5 months (range 0-12 months). Expert pathologic review confirmed the diagnosis of spindle cell RMS in all patients. Among 26 tumors that had molecular evaluation, 13 had rearrangements of NCOA and/or VGLL. Multimodal treatment of infants with LD included conventional (age adjusted) chemotherapy (n = 37), resection (n = 31) and radiotherapy (RT) (n = 5, brachytherapy in 3). Complete remission was achieved in 37/39 patients. Progressive disease occurred in two infants, relapsed disease in three. Microscopically complete surgical resection was associated with five-year event-free survival (EFS) and overall survival (OS) of 100%. Two patients with tumors ≤ 5 cm were treated with microscopically complete resection only and were alive 1 and 4.2 years after diagnosis. The 5-year EFS and OS for infants with LD were 86% (±11; CI 95%) and 91% (±9; CI 95%), respectively. One patient had metastatic disease (NCOA fusion positive) with primary tumor in head and neck and brain metastases. This patient died despite chemotherapy and delayed resection of the primary tumor due to respiratory failure secondary to cytomegalovirus infection 1.2 years after diagnosis. CONCLUSION: Infants with spindle cell RMS have an excellent prognosis. Multimodal treatment including microscopically complete resection of the tumor is strongly recommended.

Esophageal remodeling in eosinophilic esophagitis: Relationships to luminal captured biomarkers of inflammation and periostin.

BACKGROUND: Esophageal remodeling is a factor in disease progression and symptom severity for patients with eosinophilic esophagitis (EoE). Remodeling can begin early in children, resulting in stricture and food impaction. Detection of esophageal remodeling often depends on endoscopy and is appreciated only in its later stages. OBJECTIVE: We sought to determine whether luminal eosinophil-associated and remodeling proteins captured by the esophageal string test (EST) correlate with measures of esophageal remodeling and biomarkers of the epithelial-mesenchymal transition (EMT). METHODS: Patients with EoE (7-18 years old) were enrolled from 2 pediatric hospitals. Participants performed the EST and underwent endoscopy. Histology, distensibility measured by endoluminal functional lumen imaging probe, and symptoms were assessed. Protein quantitation by ELISA was performed on mucosal biopsy and EST samples. Tissue sections were evaluated for EMT. Outcome measures were summarized, and Spearman ρ was used to assess bivariate correlations. RESULTS: Forty patients (68% male) were enrolled (mean age, 12.5 years). Twenty-four (60%) had active disease (≥15 eosinophils per high-power field). EST-captured eotaxin-3, major basic protein 1, EDN, eosinophil peroxidase, and Charcot-Leyden crystal protein/galectin-10 showed significant correlations with peak eosinophils per high-power field (ρ 0.53-0.68, P < .001). Luminal proteins positively correlated with endoscopic features and markers of EMT, and negatively with esophageal distensibility. Periostin was captured by the EST and correlated with eosinophil density, basal zone hyperplasia, endoscopic appearance, and markers of EMT. CONCLUSION: Luminal markers of esophageal remodeling in addition to biomarkers of eosinophilic inflammation correlate with epithelial and functional remodeling in EoE.

Subsequent malignant neoplasms in the Childhood Cancer Survivor Study: Occurrence of cancer types in which human papillomavirus is an established etiologic risk factor.

BACKGROUND: Human papillomavirus (HPV)-associated subsequent malignant neoplasms (SMNHPV ) in childhood cancer survivors are poorly understood. METHODS: The cumulative risk of SMNHPV was assessed among 24,363 Childhood Cancer Survivor Study participants. Standardized incidence ratios (SIRs) and absolute excess risk were calculated using age-matched, sex-matched, and calendar year rates from the Surveillance, Epidemiology, and End Results program. Poisson regression models identified SMNHPV risk factors, evaluating relative SIRs (rSIR) and 95% confidence intervals (95% CIs). RESULTS: In total, 46 survivors developed an SMNHPV (median age, 31 years [range, 10-56 years]; median time from primary cancer, 21 years [range, 9-35 years]). SMNHPV sites included oropharynx (N = 44), anorectum (N = 6), uterine cervix (N = 2), and vulva (N = 2). The 33-year cumulative incidence was 0.3% (95% CI, 0.2%-0.4%), and the SIR was nearly 3-fold that of the general population (SIR, 2.86; 95% CI, 2.05-4.00). Female survivors were not at increased risk of cervical or vulvar cancers compared with the general population. All survivors had an elevated risk of oropharyngeal SMNHPV (males: SIR, 4.06; 95% CI, 2.37-6.97; females: SIR, 8.44; 95% CI 4.88-14.61) and anorectal SMNHPV (males: SIR, 13.56; 95% CI, 5.09-36.13; females: SIR, 9.15; 95% CI, 2.29-36.61). Males (vs females: rSIR, 1.99; 95% CI, 1.00-3.94); head, neck, and pelvic radiotherapy doses >3000 centigray (vs none: rSIR, 2.35; 95% CI, 1.11-4.97); and cisplatin-equivalent doses >400 mg/m2 (vs none: rSIR, 4.51; 95% CI, 1.78-11.43) were associated with increased SMNHPV SIRs in multivariable analysis. CONCLUSIONS: Childhood cancer survivors are at increased risk for SMN in sites susceptible to HPV-associated malignancies. Further research examining HPV in the etiology of SMN and the promotion of HPV vaccination and surveillance guidelines for SMNHPV in cancer survivors is warranted.

Is the appendix a good organ to diagnose total colonic aganglionosis?

PURPOSE: The use of the appendix for diagnosis of Total Colonic Aganglionosis (TCA) remains controversial. This study aimed to categorize the presence of ganglion cells in the appendix and determine its reliability as a histological specimen for the diagnosis of TCA. METHODS: This was a combined retrospective and prospective study. Permanent histological specimens of normal appendices removed during appendectomy for malrotation or falsely presumed appendicitis, and from patients with short segment Hirschsprung's disease (HD) or TCA were included. Permanent specimens of the appendix tip from Malone procedures were prospectively collected. All specimens were independently reviewed by two experienced pathologists in a standardized manner to assess for the presence of ganglion cells. RESULTS: A total of 112 appendices were evaluated. Nine came from patients with a diagnosis of TCA, and five from patients with HD. Ganglion cells were present in all specimens from patients with diagnoses other than TCA and were absent in all specimens from patients with TCA. CONCLUSION: In the correct clinical setting, the absence of ganglion cells in the appendix can allow for a reliable diagnosis of TCA.

Short NK- and Naïve T-Cell Telomere Length Is Associated with Thyroid Cancer in Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Study.

BACKGROUND: Survivors of childhood cancer are at risk for therapy-related subsequent malignant neoplasms (SMN), including thyroid SMN. Telomere length (TL) is associated with cancer risk, but the relationship between TL and SMN risk among survivors is less clear. METHODS: We conducted a nested, matched case-control study of radiation-exposed 15-year+ adult survivors of childhood cancer with thyroid SMN (cases) and without SMN (controls). Forty-six cases were matched to 46 controls by primary diagnosis, chemotherapy (yes/no), radiation field, and follow-up duration. Lymphocyte TL (LTL) was measured by telomere flow-FISH cytometry using blood samples banked at a mean of 38.9 years (cases), 39.2 years (controls). Genetic variation in telomere genes was assessed by whole genome sequencing. Point estimates for LTL <10th percentile were determined for cases and controls. RESULTS: Cases had shorter median LTL than controls in three out of four leukocyte subsets. Cases were more likely to have NK cell LTL <10th percentile (P = 0.01), and 2.8-fold more likely to have naïve T-cell LTL <10th percentile than controls (CI, 1.07-8.78). Five out of 15 cases with a rare indel or missense variant had naïve T-cell LTL <10th percentile, compared with one out of eight controls. CONCLUSIONS: Long-term survivors have shorter than expected LTL, a finding that is more pronounced among survivors with thyroid SMN. IMPACT: The long-term impact of childhood cancer treatment on immune function is poorly understood. Our findings support immune function studies in larger survivor cohorts to assess long-term deficits in adaptive and innate immunity that may underlie SMN risk.

Polygenic Risk Score Improves Risk Stratification and Prediction of Subsequent Thyroid Cancer after Childhood Cancer.

BACKGROUND: Subsequent thyroid cancer (STC) is one of the most common malignancies in childhood cancer survivors. We aimed to evaluate the polygenic contributions to STC risk and potential utility in improving risk prediction. METHODS: A polygenic risk score (PRS) was calculated from 12 independent SNPs associated with thyroid cancer risk in the general population. Associations between PRS and STC risk were evaluated among survivors from St. Jude Lifetime Cohort (SJLIFE) and were replicated in survivors from Childhood Cancer Survivor Study (CCSS). A risk prediction model integrating the PRS and clinical factors, initially developed in SJLIFE, and its performance were validated in CCSS. RESULTS: Among 2,370 SJLIFE survivors with a median follow-up of 28.8 [interquartile range (IQR) = 21.9-36.1] years, 65 (2.7%) developed STC. Among them, the standardized PRS was associated with an increased rate of STC [relative rate (RR) = 1.57; 95% confidence interval (CI) = 1.24-1.98; P < 0.001]. Similar associations were replicated in 6,416 CCSS survivors, among whom 121 (1.9%) developed STC during median follow-up of 28.9 (IQR = 22.6-34.6) years (RR = 1.52; 95% CI = 1.25-1.83; P < 0.001). A risk prediction model integrating the PRS with clinical factors showed better performance than the model considering only clinical factors in SJLIFE (P = 0.004, AUC = 83.2% vs. 82.1%, at age 40), which was further validated in CCSS (P = 0.010, AUC = 72.9% vs. 70.6%). CONCLUSIONS: Integration of the PRS with clinical factors provided a statistically significant improvement in risk prediction of STC, although the magnitude of improvement was modest. IMPACT: PRS improves risk stratification and prediction of STC, suggesting its potential utility for optimizing screening strategies in survivorship care.