Molecular and clinicopathologic characteristics of CNS embryonal tumors with BRD4::LEUTX fusion.

Central nervous system (CNS) embryonal tumors are a heterogeneous group of high-grade malignancies, and the increasing clinical use of methylation profiling and next-generation sequencing has led to the identification of molecularly distinct subtypes. One proposed tumor type, CNS tumor with BRD4::LEUTX fusion, has been described. As only a few CNS tumors with BRD4::LEUTX fusions have been described, we herein characterize a cohort of 9 such cases (4 new, 5 previously published) to further describe their clinicopathologic and molecular features. We demonstrate that CNS embryonal tumor with BRD4::LEUTX fusion comprises a well-defined methylation class/cluster. We find that patients are young (4 years or younger), with large tumors at variable locations, and frequently with evidence of leptomeningeal/cerebrospinal fluid (CSF) dissemination. Histologically, tumors were highly cellular with high-grade embryonal features. Immunohistochemically, 5/5 cases showed synaptophysin and 4/5 showed OLIG2 expression, thus overlapping with CNS neuroblastoma, FOXR2-activated. DNA copy number profiles were generally flat; however, two tumors had chromosome 1q gains. No recurring genomic changes, besides the presence of the fusion, were found. The LEUTX portion of the fusion transcript was constant in all cases assessed, while the BRD4 portion varied but included a domain with proto-oncogenic activity in all cases. Two patients with clinical follow up available had tumors with excellent response to chemotherapy. Two of our patients were alive without evidence of recurrence or progression after gross total resection and chemotherapy at 16 and 33 months. One patient relapsed, and the last of our four patients died of disease one month after diagnosis. Overall, this case series provides additional evidence for this as a distinct tumor type defined by the presence of a specific fusion as well as a distinct DNA methylation signature. Studies on larger series are required to further characterize these tumors.

From Microcytosis to Macrodiagnosis.

A 12-year-old Hispanic girl presented with fatigue, lightheadedness, and intermittent headaches. She was depressed and appeared pale to her mother. Her examination was unremarkable except for palpebral conjunctival pallor and was otherwise noncontributory. She had a profound hypoproliferative microcytic anemia with low iron level, low transferrin saturation, and a normal ferritin level. The patient experienced improvement in clinical symptoms following transfusion of packed red blood cells and oral iron therapy. At follow-up 2 months later, she presented with similar symptoms and persistent microcytic anemia with low iron levels. Her ferritin level was increased along with markedly elevated C-reactive protein and erythrocyte sedimentation rate. An oral iron challenge demonstrated lack of absorption, and hepcidin level was also significantly elevated. Thorough gastrointestinal and rheumatologic evaluations were performed to search for a source of inflammation. Key components of the patient's social history supplemented by serology, radiographic, and pathologic findings ultimately cinched an unexpected diagnosis.

Project Baby Bear: Rapid precision care incorporating rWGS in 5 California children's hospitals demonstrates improved clinical outcomes and reduced costs of care.

Genetic disorders are a leading contributor to mortality in neonatal and pediatric intensive care units (ICUs). Rapid whole-genome sequencing (rWGS)-based rapid precision medicine (RPM) is an intervention that has demonstrated improved clinical outcomes and reduced costs of care. However, the feasibility of broad clinical deployment has not been established. The objective of this study was to implement RPM based on rWGS and evaluate the clinical and economic impact of this implementation as a first line diagnostic test in the California Medicaid (Medi-Cal) program. Project Baby Bear was a payor funded, prospective, real-world quality improvement project in the regional ICUs of five tertiary care children's hospitals. Participation was limited to acutely ill Medi-Cal beneficiaries who were admitted November 2018 to May 2020, were <1 year old and within one week of hospitalization, or had just developed an abnormal response to therapy. The whole cohort received RPM. There were two prespecified primary outcomes-changes in medical care reported by physicians and changes in the cost of care. The majority of infants were from underserved populations. Of 184 infants enrolled, 74 (40%) received a diagnosis by rWGS that explained their admission in a median time of 3 days. In 58 (32%) affected individuals, rWGS led to changes in medical care. Testing and precision medicine cost $1.7 million and led to $2.2-2.9 million cost savings. rWGS-based RPM had clinical utility and reduced net health care expenditures for infants in regional ICUs. rWGS should be considered early in ICU admission when the underlying etiology is unclear.

CTLA-4 Haploinsufficiency Presenting as Extensive Enteropathy in a Patient With Very Early Onset Inflammatory Bowel Disease.

Patients with very early onset inflammatory bowel disease (VEO-IBD) have a higher incidence of monogenic disease compared to older age groups. Age, alone, is a strong predictor for monogenic disease. We discuss a case of VEO-IBD in which the patient presented with severe and refractory enteropathy, leading to diagnosis of CTLA-4 haploinsufficiency. Genetic workup showed de novo heterozygous deletions of the CTLA-4 and ICOS genes. This case was unique, as the patient did not have the other manifestations commonly present with the disease. We advocate for early and routine genetic workup of VEO-IBD, as patients with monogenic IBD have high morbidity and mortality, if inadequately treated. Our patient did not respond to conventional treatment modalities and required targeted treatment with Abatacept, a CTLA-4 agonist.

Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor.

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.

Myxoid glioneuronal tumor, PDGFRA p.K385-mutant: clinical, radiologic, and histopathologic features.

"Myxoid glioneuronal tumor, PDGFRA p.K385-mutant" is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow-up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports "myxoid glioneuronal tumor, PDGFRA p.K385-mutant" as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.

Clinicopathologic and molecular features of intracranial desmoplastic small round cell tumors.

Desmoplastic small round cell tumors (DSRCTs) are highly aggressive sarcomas that most commonly occur intra-abdominally, and are defined by EWSR1-WT1 gene fusion. Intracranial DSRCTs are exceptionally rare with only seven previously reported fusion-positive cases. Herein, we evaluate the clinical, morphologic, immunohistochemical and molecular features of five additional examples. All patients were male (age range 6-25 years; median 11 years), with four tumors located supratentorially and one within the posterior fossa. The histologic features were highly variable including small cell, embryonal, clear cell, rhabdoid, anaplastic and glioma-like appearances. A prominent desmoplastic stroma was seen in only two cases. The mitotic index ranged from <1 to 12/10 HPF (median 5). While all tumors showed strong desmin positivity, epithelial markers such as EMA, CAM 5.2 and other keratins were strongly positive in only one, focally positive in two and negative in two cases. EWSR1-WT1 gene fusion was present in all cases, with accompanying mutations in the TERT promoter or STAG2 gene in individual cases. Given the significant histologic diversity, in the absence of genetic evaluation these cases could easily be misinterpreted as other entities. Desmin immunostaining is a useful initial screening method for consideration of a DSRCT diagnosis, prompting confirmatory molecular testing. Demonstrating the presence of an EWSR1-WT1 fusion provides a definitive diagnosis of DSRCT. Genome-wide methylation profiles of intracranial DSRCTs matched those of extracranial DSRCTs. Thus, despite the occasionally unusual histologic features and immunoprofile, intracranial DSRCTs likely represent a similar, if not the same, entity as their soft tissue counterpart based on the shared fusion and methylation profiles.

Pediatric ovarian angiosarcoma treated with systemic chemotherapy and cytoreductive surgery with heated intraperitoneal chemotherapy: Case report and review of therapy.

Ovarian angiosarcoma is a rare and aggressive vascular tumor, which has a 5-year overall survival of less than 30% for patients with nonmetastatic disease and almost certain death within 1 year for those with metastasis. Here, we briefly review historical approaches to therapy and present a long-term survivor in the case of an 11-year-old female with metastatic ovarian angiosarcoma. This is the second reported case to utilize heated intraperitoneal chemotherapy in the treatment of this disease. Our patient is currently alive and well 3 years after initial diagnosis, significantly longer than any reported case of advanced-stage ovarian angiosarcoma.

Undifferentiated sarcoma of the orbit with angiomyxoid features.

A 7-month-old female infant developed a grade 3 un-differentiated sarcoma with angiomyxoid features of the right orbit. The tumor expanded rapidly 2 months after an initial sub-total resection and extended posteriorly toward the right cavernous sinus. After treatment with ifosphamide, doxorubicin, and proton beam radiation, there was no discernible residual tumor 20 months after starting chemotherapy.

Placental and fetal findings in intrauterine Candida lusitaniae infection following in vitro fertilization and embryo transfer.

Intrauterine infection with non- albicans Candida species is rare but can be catastrophic to the fetus. A subset of intrauterine infections with non- albicans Candida species has occurred in women who have undergone in vitro fertilization and embryo transfer (IVF-ET). We report a case of a 33-year-old healthy woman, pregnant with triplets by in vitro fertilization, who experienced preterm premature rupture of membranes of fetus A at 16 weeks' gestation and subsequently developed oligohydramnios in all 3 fetuses. Following elective pregnancy termination, microscopic examination and molecular analysis demonstrated Candida lusitaniae chorioamnionitis and pneumonia in all 3 fetuses associated with granulomatous inflammation. Our case is only the 2nd report of C. lusitaniae chorioamnionitis and should raise awareness that C. lusitaniae intrauterine infection is associated with IVF-ET. We also show here that C. lusitaniae can cause granulomatous intraplacental inflammation and intrauterine pneumonia.

Fulminant Clostridium difficile toxic megacolon in a pediatric heart transplant recipient.

CD can be a cause of diarrhea in pediatric heart transplant recipients. Fulminant colitis can develop in immunocompromised patients with CD and progress to toxic megacolon. We report a case of a 10-yr-old girl who developed CD diarrhea and subsequently fulminant colitis with clinical signs and symptoms of abdominal compartment syndrome. She was taken to the operating room emergently and found to have toxic megacolon. She underwent a sub-total abdominal colectomy and end-ileostomy, and made a rapid recovery. Rapid recognition of the severity of the disease in the post-operative transplant patient is imperative as abdominal compartment syndrome may develop requiring surgical management. In pediatric heart transplant patients with diarrhea, we recommend a heightened clinical awareness with aggressive treatment given the risk of progression to fulminant CD and toxic megacolon.

Serous borderline tumor of the fallopian tube in a patient with Klippel-Trenaunay syndrome.

We describe a case of a 3-year-old girl with Klippel-Trenaunay syndrome who presented with an enlarging abdominal mass caused by a serous borderline tumor of the fallopian tube. This case is notable for the rarity of this neoplasm in a premenarchal patient as well as the association with this syndrome. We briefly review these entities and the significance of malignancy in Klippel-Trenaunay syndrome.

Fine needle aspiration cytology of adrenocortical oncocytic neoplasm: a case report.

BACKGROUND: Adrenocortical oncocytic neoplasms (AONs) are rare tumors that typically show marked nuclear pleomorphism and eosinophilic cytoplasm and are highly cellular on fine needle aspiration (FNA) smears. These features, worrisome in conventional adrenocortical tumors, are not necessarily signs of malignancy in AONs. CASE: A 64-year-old woman presented with 3 months of abdominal pressure. Computed tomography showed a 10-cm, solid, left adrenal mass and a 21-cm complex cystic mass in the pelvis. FNA of the adrenal mass showed hypercellular smears with dyscohesive cells having pleomorphic nuclei and abundant, granular cytoplasm. The lesion was initially interpreted as malignant. Resection of the adrenal mass demonstrated an AON without definite malignant features. The pelvic mass revealed bilateral ovarian cellular fibromas. Seventeen months of postoperative follow-up were uneventful. CONCLUSION: On FNA, cells from an AON can be hypercellular and cytologically atypical, which can be pitfalls for a malignant diagnosis. Our case is the first reported in which an AON presented with ovarian cellular fibromas. To our knowledge, there is no association between the 2 lesions. We review criteria to classify benign vs. malignant AONs and discuss the literature on this topic.

Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) arising on the extremities.

BACKGROUND: Epithelioid hemangioma (EH) is a benign vascular proliferation usually accompanied by a mixed inflammatory infiltrate. METHODS: Skin biopsy specimens from four patients with EH on the extremities were studied. Architecture, extent of vascular proliferation and the presence of epithelioid endothelial cells were evaluated. The features of the inflammatory infiltrate were also assessed, including the distribution, depth, predominant cell type, presence of germinal centers, and distribution and number of CD30+ cells. RESULTS: All cases showed the typical lobular pattern of small vessels centered about a 'feeder' vessel. Larger vessels were lined by epithelioid endothelial cells. The mixed inflammatory infiltrate was nodular, perivascular and periadnexal. Germinal centers were seen in two cases. Large activated CD30+ lymphocytes were seen in all cases. CONCLUSIONS: EH can lead to diagnostic confusion with cutaneous lymphoma and other entities, especially when its mixed inflammatory infiltrate predominates over its vascular component and contains large activated CD30+ lymphocytes. Awareness that the presence of CD30+ activated lymphocytes is not specific for lymphoma and recognition of the vascular component is critical for proper diagnosis of EH.

Cutaneous xanthogranulomas, hepatosplenomegaly, anemia, and thrombocytopenia as presenting signs of juvenile myelomonocytic leukemia.

The development of xanthogranulomas has been linked to hematologic malignancies in children and adults, based on a number of reports in the literature. In children, a specific association between juvenile xanthogranuloma, neurofibromatosis 1, and juvenile myelomonocytic leukemia has been described. We report a case of a 9-month-old child, without a known diagnosis of neurofibromatosis 1, who presented with hepatosplenomegaly, anemia, thrombocytopenia, and multiple cutaneous nodules, which were confirmed to be juvenile xanthogranulomas upon biopsy. A concurrent work-up showed that the child had juvenile myelomonocytic leukemia. Although cutaneous juvenile xanthogranulomas are benign lesions, in several reported cases they have been shown to herald leukemia. This association between xanthogranulomas and hematologic malignancy is poorly understood. Juvenile xanthogranulomas have a number of morphologic variants and clinical presentations that can be confused with the cutaneous lesions of Langerhans cell histiocytosis and dermatofibroma. Recognition of the broad clinicopathologic spectrum of juvenile xanthogranulomas is critical for proper diagnosis.

Detecting ongoing intimate partner violence in the emergency department using a simple 4-question screen: the OVAT.

We wanted to prospectively evaluate the use of a brief screening tool for ongoing intimate partner violence (IPV), the OVAT, and to validate this tool against the present Index of Spouse Abuse (ISA). The design was a prospective survey during randomized 4-hour shifts in an urban emergency department setting. The scale consists of four questions developed based on our previous work. The ISA was compared as the gold standard for detection of present (ongoing) IPV. Of 362 eligible patients presenting during 75 randomized 4-hour shifts, 306 (85%) completed the study. The prevalence of ongoing IPV using the OVAT was 31% (95% CI 26% to 36%). For the ISA, the prevalence was 20% (95% CI 16% to 25%). Compared with the ISA, the sensitivity of the OVAT in detecting ongoing IPV was 86%, specificity 83%, negative predictive value 96%, positive predictive value 56%, with an accuracy of 84%. In conclusion, four brief questions can detect ongoing IPV to aid in identifying the victim.

Development of a screen for ongoing intimate partner violence.

A five-question Ongoing Abuse Screen (OAS) was developed to evaluate ongoing intimate partner violence. Our hypothesis was that the OAS was more accurate and more likely to reflect ongoing intimate partner violence than the AAS when compared to the Index of Spouse Abuse (ISA). The survey included the ISA, the OAS, and the AAS. During the busiest emergency department hours, a sampling of 856 patients completed all aspects of the survey tool. Comparisons were made between the two scales and the ISA. The accuracy, positive predictive value, and positive likelihood ratio were 84%, 58%, and 6.0 for the OAS and 59%, 33%, and 2.0 for the AAS. The OAS was more accurate, had a better positive predictive value, and was three times more likely to detect victims of ongoing intimate partner violence than the AAS. Because the OAS was still not accurate enough, we developed a new screen, based on the ISA, titled the Ongoing Violence Assessment Tool (OVAT).