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Childhood melanoma is a rare and biologically heterogeneous pediatric malignancy. The differential diagnosis of pediatric melanoma is usually broad, including a wide variety of spindle cell or epithelioid neoplasms. Different molecular alterations affecting the MAPK and PI3K/AKT/mTOR pathways, tumor suppressor genes, and telomerase reactivation have been implicated in melanoma tumorigenesis and progression. Here, we report a novel MED15::ATF1 fusion in a pediatric melanoma with spitzoid features and an aggressive clinical course.

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Introduction: Status asthmaticus (SA) is a cause of many pediatric hospitalizations. This study sought to evaluate how a standardized asthma care pathway (ACP) in the electronic medical record impacted the length of stay (LOS). Methods: An interdisciplinary team internally validated a standardized respiratory score for patients admitted with SA to a 25-bed pediatric intensive care unit (PICU) at a tertiary children's hospital. The respiratory score determined weaning schedules for albuterol and steroid therapies. In addition, pharmacy and information technology staff developed an electronic ACP within our electronic medical record system using best practice alerts. These best practice alerts informed staff to initiate the pathway, wean/escalate treatment, transition to oral steroids, transfer level of care, and complete discharge education. The PICU, stepdown ICU (SD ICU), and acute care units implemented the clinical pathway. Pre- and postintervention metrics were assessed using process control charts and compared using Welch's t tests with a significance level of 0.05. Results: Nine hundred two consecutive patients were analyzed (598 preintervention, 304 postintervention). Order set utilization significantly increased from 68% to 97% (P < 0.001), PICU LOS decreased from 38.4 to 31.1 hours (P = 0.013), and stepdown ICU LOS decreased from 25.7 to 20.9 hours (P = 0.01). Hospital LOS decreased from 59.5 to 50.7 hours (P = 0.003), with cost savings of $1,215,088 for the patient cohort. Conclusions: Implementing a standardized respiratory therapist-driven ACP for children with SA led to significantly increased order set utilization and decreased ICU and hospital LOS. Leveraging information technology and standardized pathways may improve care quality, outcomes, and costs for other common diagnoses.

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Small round cell neoplasms comprise a diverse group of tumors characterized by a primitive/undifferentiated appearance. Although several entities are associated with recurrent gene fusions, many of these neoplasms have not been fully characterized, and novel molecular alterations are being discovered. Here, we report an undifferentiated small round cell neoplasm arising in the anterior mediastinum of a 17-month-old female. The tumor harbored a novel HNRNPM::LEUTX fusion resulting from chromothripsis of chromosome 19, which was identified by whole transcriptome sequencing, but not by targeted sequencing. The structural variations caused by the chromothripsis event also challenged the interpretation of the targeted sequencing findings. This report expands the spectrum of gene partners involved in LEUTX fusions and underscores the value of whole transcriptome sequencing in the diagnostic workup of undifferentiated small round cell tumors. It also highlights the interpretive challenges associated with complex genomic alterations. A careful evidence-based analysis of sequencing data along with histopathologic correlation is essential to ensure correct categorization of fusions.

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Infantile fibrosarcoma is the most common soft-tissue sarcoma in children under the age of 1 yr and is defined molecularly by NTRK fusion proteins. This tumor is known to be locally invasive; however, although rare, metastases can occur. The NTRK fusion acts as a driver for tumor formation, which can be targeted by first- and second-generation TRK inhibitors. Although NTRK gatekeeper mutations have been well-described as mechanisms of resistance to these agents, alternative pathway mutations are rare. Here, we report the case of a patient with infantile fibrosarcoma treated with chemotherapy and TRK inhibition that developed metastatic, progressive disease with multiple acquired mutations, including TP53, SUFU, and an NTRK F617L gatekeeper mutation. Alterations in pathways of SUFU and TP53 have been widely described in the literature in other tumors; however, not yet in infantile fibrosarcoma. Although most patients have a sustained response to TRK inhibitors, a subset will go on to develop mechanisms of resistance that have implications for clinical management, such as in our patient. We hypothesize this constellation of mutations contributed to the patient's aggressive clinical course. Taken together, we report the first case of infantile fibrosarcoma with ETV6::NTRK3 and acquired SUFU, TP53, and NTRK F617L gatekeeper mutation along with detailed clinical course and management. Our report highlights the importance of genomic profiling in recurrent infantile fibrosarcoma to reveal actionable mutations, such as gatekeeper mutations, that can improve patient outcomes.

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Giant focal nodular hyperplasia (GFNH) is rarely seen in children, presenting complex diagnostic and management considerations. Pathognomonic radiographic findings can be absent in this population, and the nuances of pathologic examination are critical. We present a child with a GFNH involving the right side of the liver arising in the background of hepatic steatosis. The details of the diagnosis and therapeutic decisions involved in his treatment are discussed.

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Pulmonary complications are common in children following hematopoietic cell transplantation (HCT) and contribute to their morbidity and mortality. Early diagnosis is essential for management and prevention of progression of lung injury and damage. In many cases, diagnosis can be challenging and may require diagnostic imaging and more invasive testing such as bronchoscopy and lung biopsy. We report the case of a 12-year-old girl who developed recurrent episodes of acute respiratory failure requiring intensive care unit admission in the post-HCT phase and describe the diagnostic and multidisciplinary approach for her management. In addition, we review the diagnostic approach of pulmonary complications post-HCT and highlight the utility and risks of bronchoscopy and lung biopsy in these children.

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Pediatric adrenocortical tumors (ACTs) are rare and heterogeneous. Approximately 50% of children with ACT carry a germline TP53 variant; however, the genetic underpinning of remaining cases has not been elucidated. In patients having germline TP53 variants, loss of maternal chromosome 11 and duplication of the paternal copy [paternal uniparental disomy, (UPD)] occurs early in tumorigenesis and explains the overexpression of IGF2, the hallmark of pediatric ACT. Beckwith-Wiedemann syndrome (BWS) is also associated with overexpression of IGF2 due to disruption of the 11p15 loci, including segmental UPD. Here, we report six children with ACT with wild type TP53 and germline paternal 11p15 UPD. Median age of five girls and one boy was 3.2 years (range 0.5-11 years). Two patients met the criteria for BWS before diagnosis of ACT. However, ACT was the first and only manifestation of paternal 11p15 UPD in four children. Tumor weight ranged from 21.5 g to 550 g. Despite poor prognostic features at presentation, such as pulmonary metastasis, bilateral adrenal involvement, and large tumors, all patients are alive 8-21 years after cancer diagnosis. Our observations suggest that children with ACT and wild type TP53, irrespective of their age, should be screened for germline abnormalities in chromosome 11p15.

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Nuclear protein in testis carcinoma is a rare and highly aggressive carcinoma associated with a 70% mortality rate 1 year from diagnosis and a median survival of only 6.5 months. No established treatment protocol exists, although some success has been achieved using a multimodal approach including early surgical resection and adjuvant chemotherapy and radiation. Prior studies have not demonstrated successful treatment in the absence of upfront surgical resection. We describe the first reported case of a patient with unresectable nuclear protein in testis carcinoma treated successfully with definitive chemotherapy using the Scandinavian Sarcoma Group IX Protocol and concurrent radiation therapy, but without surgical resection.

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PURPOSE: To assess the ability of older-adult hearing-impaired (OHI) listeners to identify verbal expressions of emotions, and to evaluate whether hearing-aid (HA) use improves identification performance in those listeners. METHODS: Twenty-nine OHI listeners, who were experienced bilateral-HA users, participated in the study. They listened to a 20-sentence-long speech passage rendered with six different emotional expressions ("happiness", "pleasant surprise", "sadness", "anger", "fear", and "neutral"). The task was to identify the emotion portrayed in each version of the passage. Listeners completed the task twice in random order, once unaided, and once wearing their own bilateral HAs. Seventeen young-adult normal-hearing (YNH) listeners were also tested unaided as controls. RESULTS: Most YNH listeners (89.2%) correctly identified emotions compared to just over half of the OHI listeners (58.7%). Within the OHI group, verbal emotion identification was significantly correlated with age, but not with audibility-related factors. The number of OHI listeners who were able to correctly identify the different emotions did not significantly change when HAs were worn (54.8%). CONCLUSION: In line with previous investigations using shorter speech stimuli, there were clear age differences in the recognition of verbal emotions, with OHI listeners showing a significant reduction in unaided verbal-emotion identification performance that progressively declined with age across older adulthood. Rehabilitation through HAs did not provide compensation for the impaired ability to perceive emotions carried by speech sounds.

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PURPOSE: The aim of this study was to determine a reliable and efficient set of acoustic parameters of the human voice able to estimate individuals' mental load level. Implementing detection methods and real-time analysis of mental load is a major challenge for monitoring and enhancing human task performance, especially during high-risk activities (e.g., flying aircraft). METHOD: The voices of 32 participants were recorded during a cognitive task featuring word list recall. The difficulty of the task was manipulated by varying the number of words in each list (i.e., between 1 and 7, corresponding to 7 mental load conditions). Evoked pupillary response, known to be a useful proxy of mental load, was recorded simultaneously with speech to attest variations in mental load level during the experimental task. RESULTS: Classic features (fundamental frequency, its standard deviation, number of periods) and original features (frequency modulation and short-term variation in digital amplitude length) of the acoustic signals were predictive of memory load condition. They varied significantly according to the number of words to recall, specifically beyond a threshold of 3-5 words to recall, that is, when memory performance started to decline. CONCLUSIONS: Some acoustic parameters of the human voice could be an appropriate and efficient means for detecting mental load levels.

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PURPOSE: The authors investigated the relationship between the intelligibility and comprehension of speech presented in babble noise. METHOD: Forty participants listened to French imperative sentences (commands for moving objects) in a multitalker babble background for which intensity was experimentally controlled. Participants were instructed to transcribe what they heard and obey the commands in an interactive environment set up for this purpose. The former test provided intelligibility scores and the latter provided comprehension scores. RESULTS: Collected data revealed a globally weak correlation between intelligibility and comprehension scores (r = .35, p < .001). The discrepancy tended to grow as noise level increased. An analysis of standard deviations showed that variability in comprehension scores increased linearly with noise level, whereas higher variability in intelligibility scores was found for moderate noise level conditions. CONCLUSION: These results support the hypothesis that intelligibility scores are poor predictors of listeners' comprehension in real communication situations. Intelligibility and comprehension scores appear to provide different insights, the first measure being centered on speech signal transfer and the second on communicative performance. Both theoretical and practical implications for the use of speech intelligibility tests as indicators of speakers' performances are discussed.

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Congenital infantile fibrosarcoma is a rare soft tissue malignancy that occurs in both axial and extremity locations. We report a case of this tumor arising from the left colon in a newborn presenting with an intrauterine perforation and meconium peritonitis.

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Birth depression unresponsive to conventional resuscitative measures merits careful consideration. The case of a term infant with primary respiratory failure at birth despite extensive intervention is presented. Postmortem examination revealed bilateral pulmonary artery thrombi, which underscores the importance of careful exploration of possible pathogenetic mechanisms.

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We report a 3-year-old boy with a malignant triton tumor (MTT) involving the left masticator space with local invasion and regional lymph node metastasis. Family history and detection of a novel germline TP53 mutation confirmed his diagnosis of Li Fraumeni syndrome (LFS). MTT has not been previously described in association with LFS. This case along with a comprehensive review of the literature, illustrate the importance of both somatic and germline TP53 mutations in the pathogenesis MTT. The tumor could not be resected and he was successfully treated with intensive induction chemotherapy, irradiation, and high-dose chemotherapy with autologous stem cell transplantation.

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A 7-year-old boy presented with a 1-year history of back pain radiating to his left scapula and arm, with tenderness to palpation over the area. Laboratory studies were unremarkable. Computed tomographic scan showed a mixed lytic and sclerotic process at the T5-T6 level of the vertebral column in continuity with an adjacent paravertebral soft tissue mass. Nuclear medicine scan demonstrated increased uptake in the T5 vertebral body. Histology revealed invasive squamous cell carcinoma infiltrating mature, gliotic neural tissue, with areas of necrosis and prominent perivascular space involvement. Associated vertebral fragments showed bone destruction, reactive bone formation, and fibrosis. By immunohistochemistry, the carcinoma cells were positive for cytokeratin AE1/AE3, cytokeratin 5/6, EMA, and MIC-2 (membranous staining). The mature neural tissue was positive for GFAP; immature neural elements were not identified. Based on morphologic, immunohistochemical, and clinical features, this lesion was diagnosed as invasive squamous cell carcinoma arising within an intravertebral and paravertebral teratoma.

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Synovial sarcomas are highly malignant tumors of soft tissue which are characterized by the t(X;18) resulting in SYT-SSX fusion transcript production. Diagnosis of these tumors based on histology can be challenging, particularly when minimal biopsy specimens are presented to the pathologist. Demonstration by molecular methods of SYT-SSX transcripts is a useful adjunct for diagnosis in these situations. We have developed an assay, which combines one-step RT-multiplex PCR with capillary electrophoresis to detect and genotype the SYT-SSX transcripts from synovial sarcomas. Small amplicons from chimeric transcripts as well as GAPD transcripts are differentially labeled with fluorophores, allowing detection and size discrimination by capillary electrophoresis. In a study of 32 formalin-fixed soft tissue tumor specimens, the assay detected chimeric transcripts from 17/22 (77%) synovial sarcomas. All five assay negative specimens yielded no intact RNA as evidenced by lack of a GAPD amplicon. Chimeric transcripts were not detected in 9/9 malignant peripheral nerve sheath tumors or 1/1 epithelioid sarcoma. Representative amplicons were sequenced and confirmed the genotype results obtained by capillary electrophoresis. One-step RT-multiplex PCR combined with capillary electrophoresis is a rapid and accurate method for the detection and genotypic classification of SYT-SSX transcripts from fixed tissue specimens.

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We describe the clinical, radiologic, and pathologic features of primary bone anaplastic large cell lymphoma (ALCL) in 3 boys. Radiologic imaging showed lytic lesions involving sacrum, femur, or rib. Bone was the only site of disease in 2 cases; an associated partial lymph node was involved in case 3. Differential diagnoses included osteomyelitis and small round cell tumors of childhood, particularly Ewing sarcoma. Preoperatively, ALCL was not a diagnostic consideration in any case. Two cases showed classic large pleomorphic cells; 1 showed a composite pattern with a distinct small cell component and the more typical large cell type. Neoplastic cells in all cases showed strong CD30 and anaplastic lymphoma kinase expression with relatively weak epithelial membrane antigen positivity. Cytotoxic granule protein was expressed in 2 cases. All cases showed unusually strong expression of neuron-specific enolase (NSE). Two patients were disease-free at last follow-up (15 months and 11 years); 1 patient died of disseminated disease within a year of diagnosis. ALCL should be considered a diagnostic possibility when evaluating neoplastic bone lesions in children. Although expression of NSE in ALCL has not been emphasized in the literature, it is worth noting because it may pose a diagnostic pitfall.

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Angiomyolipoma is a tumor of the kidney and, more rarely, the liver, which histologically consists of smooth muscle cells, adipose cells, and abnormal blood vessels in varying proportions. This tumor is generally benign and resection is curative, but here the authors present the case of a 14-year-old girl with an unusual primary hepatic angiomyolipoma that recurred following resection and behaved aggressively. Despite stabilization with a number of novel therapies, the child ultimately died of progressive disease.

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