Epithelioid neoplasm of the spinal cord in a child with spinal muscular atrophy treated with onasemnogene abeparvovec.

Spinal muscular atrophy is an autosomal recessive disease resulting in motor neuron degeneration and progressive life-limiting motor deficits when untreated. Onasemnogene abeparvovec is an adeno-associated virus serotype 9-based gene therapy that improves survival, motor function, and motor milestone achievement in symptomatic and presymptomatic patients. Although the adeno-associated virus genome is maintained as an episome, theoretical risk of tumorigenicity persists should genomic insertion occur. We present the case of a 16-month-old male with spinal muscular atrophy who was diagnosed with an epithelioid neoplasm of the spinal cord approximately 14 months after receiving onasemnogene abeparvovec. In situ hybridization analysis detected an onasemnogene abeparvovec nucleic acid signal broadly distributed in many but not all tumor cells. Integration site analysis on patient formalin-fixed, paraffin-embedded tumor samples failed to detect high-confidence integration sites of onasemnogene abeparvovec. The finding was considered inconclusive because of limited remaining tissue/DNA input. The improved life expectancy resulting from innovative spinal muscular atrophy therapies, including onasemnogene abeparvovec, has created an opportunity to analyze the long-term adverse events and durability of these therapies as well as identify potential disease associations that were previously unrecognized because of the premature death of these patients.

Orbital cellulitis with panophthalmitis and scleral necrosis - a case report.

BACKGROUND: Orbital cellulitis is common in young children and is often secondary to coexisting sinus disease. Coexisting orbital cellulitis and panophthalmitis is a rare clinical event and usually occurs secondary to trauma or from an endogenous source. CASE PRESENTATION: A febrile 2-year-old male presented with periorbital inflammation and exudative retinal detachment. Imaging showed acute sinusitis and extensive orbital cellulitis. Because of progressive scleral thinning, the patient underwent enucleation. CONCLUSION: We present a case of concurrent orbital cellulitis, panophthalmitis, and scleral necrosis in an immunocompetent pediatric patient. Timely intervention is important to prevent life threatening complications with the rare occurrence of coexistent orbital cellulitis and panophthalmitis.

PLAG1 Immunohistochemical Staining Is a Surrogate Marker for PLAG1 Fusions in Lipoblastomas.

BACKGROUND: The hallmark of lipoblastoma is a PLAG1 fusion. PLAG1 protein overexpression has been reported in sporadic PLAG1-rearranged lipoblastomas. METHODS: We evaluated the utility of PLAG1 immunohistochemical staining (IHC) in 34 pediatric lipomatous tumors, correlating the results with histology and conventional cytogenetics, FISH and/or next generation sequencing (NGS) results. RESULTS: The study included 24 lipoblastomas, divided into 2 groups designated as "Lipoblastoma 1" with both lipoblastoma histology and PLAG1 rearrangement (n = 16) and "Lipoblastoma 2" with lipoblastoma histology but without PLAG1 cytogenetic rearrangement (n = 8), and 10 lipomas with neither lipoblastoma histology nor a PLAG1 rearrangement. Using the presence of a fusion as the "gold standard" for diagnosing lipoblastoma (Lipoblastoma 1), the sensitivity of PLAG1 IHC was 94%. Using histologic features alone (Lipoblastoma 1 + 2), the sensitivity was 96%. Specificity, as defined by the ability to distinguish lipoma from lipoblastoma, was 100%, as there were no false positives in the lipoma group. CONCLUSIONS: Cytogenetics/molecular testing is expensive and may not be ideal for detecting PLAG1 fusions because PLAG1 fusions are often cytogenetically cryptic and NGS panels may not include all partner genes. PLAG1 IHC is an inexpensive surrogate marker of PLAG1 fusions and may be useful in distinguishing lipoblastomas from lipomas.

Antiplatelet Agents in Sepsis-Putting it all together: A Call to Action.

How to cite this article: Tiwari NR, Chaudhari KS, Sharma R, Haas KP, Sharma VR. Antiplatelet Agents in Sepsis-Putting it all together: A Call to Action. Indian J Crit Care Med 2020;24(6):483-484.

Berunda Polypeptides: Biheaded Rapamycin Carriers for Subcutaneous Treatment of Autoimmune Dry Eye Disease.

The USFDA-approved immunosuppressive drug rapamycin (Rapa), despite its potency, is limited by poor bioavailability and a narrow therapeutic index. In this study, we sought to improve bioavailability of Rapa with subcutaneous (SC) administration and to test its therapeutic feasibility and practicality in a murine model of Sjögren's syndrome (SS), a systemic autoimmune disease with no approved therapies. To improve its therapeutic index, we formulated Rapa with a carrier termed FAF, a fusion of the human cytosolic FK506-binding protein 12 (FKBP12) and an elastin-like polypeptide (ELP). The resulting 97 kDa FAF (i) has minimal burst release, (ii) is "humanized", (iii) is biodegradable, (iv) solubilizes two Rapa per FAF, and (v) avoids organic solvents or amphiphilic carriers. Demonstrating high stability, FAF remained soluble and monodisperse with a hydrodynamic radius of 8 nm at physiological temperature. A complete pharmacokinetic (PK) analysis of FAF revealed that the bioavailability of SC FAF was 60%, with significantly higher blood concentration during the elimination phase compared to IV FAF. The plasma concentration of Rapa delivered by FAF was 8-fold higher with a significantly increased plasma-to-whole blood ratio relative to free Rapa, 24 h after injection. To evaluate therapeutic effects, FAF-Rapa was administered SC every other day for 2 weeks to male non-obese diabetic (NOD) mice, which develop an SS-like autoimmune-mediated lacrimal gland (LG) inflammation and other characteristic features of SS. Both FAF-Rapa and free Rapa exhibited immunomodulatory effects by significantly suppressing lymphocytic infiltration, gene expression of IFN-γ, MHC II, type I collagen and IL-12a, and cathepsin S (CTSS) activity in LG compared to controls. Serum chemistry and histopathological analyses in major organs revealed no apparent toxicity of FAF-Rapa. Given its improved PK and equipotent therapeutic efficacy compared to free Rapa, FAF-Rapa is of further interest for systemic treatments for autoimmune diseases like SS.

Unusual radiological and histological presentation of a diffuse leptomeningeal glioneuronal tumor (DLGNT) in a 13-year-old girl.

Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are newly recognized as an entity in the 2016 revision of the WHO Classification of tumors of the central nervous system. They typically present as diffuse leptomeningeal infiltrates along the neuraxis with focal and superficial involvement of the parenchyma. Here, we report a DLGNT with unusual radiological and histological features. A 13-year-old girl presented with scoliosis and back pain. Magnetic resonance imaging demonstrated a syrinx from C2 to T11 and an intramedullary mass from T6 to T9-10. No leptomeningeal involvement was recognized. Histological examination of the gross total resection specimen revealed a low-grade neuroepithelial neoplasm predominantly infiltrating the spinal cord and only focally involving the leptomeninges. Chromosome microarray identified co-deletion of the short arm of chromosome 1 and the long arm of chromosome 19 as well as fusion of the KIAA1549 and BRAF genes. Next-generation sequencing demonstrated wild-type alleles at the mutational hotspots of IDH1 (R132) and IDH2 (R140 and R172). In contrast to most reported DLGNTs, the tumor described in this manuscript was characterized by a predominant parenchymal component and only minor leptomeningeal involvement both radiographically and histologically. Our case, therefore, expands the spectrum of radiological and histopathological features of this new entity. It also highlights the critical role of molecular genetic testing in establishing the diagnosis of DLGNT in unusual cases.

Recurrent subependymoma of fourth ventricle with unusual atypical histological features: A case report.

Subependymoma is a rare subtype of benign ependymal neoplasm with distinct histological features. Anaplastic transformation has not yet been reported in this tumor to date. We present here a very unusual case of a 62-year-old woman with recurrent subependymoma of the fourth ventricle with multiple atypical histological features. Histologically, the resected recurrent tumor showed characteristic small cell clusters and nests of ependymal cells with an interspersed gliofibrillary matrix as seen in a classic subependymoma. In addition, there were very unusual histological features, including multiple areas of necrosis, microvascular proliferation, thrombosed blood vessels, and scattered mitotic figures. No coexisting ependymoma component of higher World Health Organization (WHO) grade was present. Immunohistochemically, MIB-1 labeling index was high, with up to 15% in the highest areas. Review of this patient's initial tumor, which was resected 6 years prior to recurrence, demonstrated features of a typical classic subependymoma without atypical features or a secondary tumor component. Subependymomas are known to be low-grade tumors and are usually cured if completely excised. The tumor presented here is unique in that several atypical pathological features were found in an otherwise typical subependymoma. Our case may represent anaplastic transformation of subependymoma, although no such examples have been reported to date.

Three-Dimensional Ultrasound Imaging of Retinoblastoma and Its Correlation With Pathology.

BACKGROUND AND OBJECTIVE: Monitoring the response of retinoblastoma to globe-salvaging therapies is based on subjective assessments of changes determined by fundoscopy, ultrasound, and optical coherence tomography. Advances in organ-preserving therapies have increased the need for objective, quantitative estimates of tumor response to treatment. Primary tumor volume is a metric that can be objectively determined as a surrogate measure of treatment response. PATIENTS AND METHODS: We evaluated the correlation of objective, quantitative estimates of tumor volume made with two-dimensional (2D) and three-dimensional (3D) ultrasound with gold standard pathological tumor volumes derived by analysis of enucleation specimens. RESULTS: Twelve eyes in 12 patients undergoing primary enucleation were evaluated by 2D and 3D ultrasound during ophthalmic examination under anesthesia prior to enucleation. 2D- and 3D-ultra-sound measurements of tumor volume were both strongly correlated with pathological estimates of tumor volume (r = 0.69, P = 0.018; and r = 0.66, P = 0.027, respectively). CONCLUSIONS: 2D- and 3D-ultrasound measurements of retinoblastoma primary tumor volume are highly correlated with pathological estimates. 3D measurements are easy to perform with volumetric probes and consider the irregular morphology of the tumor. Further study should be undertaken to evaluate the performance of these metrics as surrogate markers of tumor response to treatment. [Ophthalmic Surg Lasers Imaging Retina 2024;55:136-140.].

Amniotic Membrane Augmentation for Enucleation After Chemotherapy in Retinoblastoma.

PURPOSE: To describe amniotic membrane augmentation for enucleation after chemotherapy in retinoblastoma. METHODS: This was a retrospective study of patients with retinoblastoma who underwent enucleation. The study also evaluated the utility of amniotic membrane grafting in enucleation after chemotherapy in eyes with retinoblastoma. RESULTS: In this study, 110 eyes of 107 patients were analyzed, and 49 patients had previous systemic chemotherapy, 13 eyes had previous intra-arterial chemotherapy, and 7 eyes had external beam radiation. Amniotic graft was used in 8 eyes (5 following IAC, 2 following systemic chemotherapy, and 1 after both). After IAC, 3 of 7 eyes without amniotic graft had implant exposure compared to 0 of 6 eyes with amniotic graft (P = .05). Pathological examination of the conjunctiva after intra-arterial chemotherapy showed goblet cell hypoplasia that hinders wound healing. CONCLUSIONS: Amniotic membrane augmentation improves wound integrity in patients with retinoblastoma, especially following intra-arterial chemotherapy. [J Pediatr Ophthalmol Strabismus. 20XX;X(X):XXX-XXX.].

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy-Associated Hepatitis.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an inborn error of immunity, resulting from variation in the autoimmune regulator gene (AIRE). Pathogenic variants in the AIRE gene result in autoimmunity typically involving endocrine organs with nonendocrine organs less commonly affected. Hepatitis associated with APECED has emerged as a potentially fatal complication with higher reported prevalence in the Americas. We describe a case of a 3-year-old boy presenting with hepatitis from APECED without classical clinical diagnostic criteria. This case highlights the importance of APECED in the evaluation of hepatitis given response to immunomodulator treatment and risk of fulminate liver failure.

BRAF Immunohistochemical Studies of Pediatric Conjunctival Lesions.

PURPOSE: The purpose of this study was to analyze the prevalence of an activating mutation in the B-Raf proto-oncogene (BRAF) V600E immunoreactivity in pediatric conjunctival lesions. METHODS: This retrospective case-control study included 32 pediatric patients who underwent surgical excision of conjunctival lesions between Jan 2019 and May 2022. The collected data included demographic data, clinical features, and histopathologic characteristics of the lesion, including BRAF V600E positivity. The Student t test and the Fisher exact test were used to determine the significance of the associations between clinical variables and BRAF positivity. RESULTS: BRAF immunoreactivity was positive in 11/32 lesions (34%). Age at diagnosis did not correlate with BRAF positivity, with a mean age at diagnosis of 131.7 months for patients with BRAF+ lesions and 134.7 months for those with BRAF- lesions (P > 0.1). No clinical or pathological features were found to be significantly correlated with BRAF positivity, although there was a trend toward BRAF positivity in the presence of cysts (P = 0.072). CONCLUSIONS: BRAF reactivity was present in approximately one-third of pediatric conjunctival nevi but does not correlate significantly with unique clinical or histopathological features.

COVID-19 and thrombotic microangiopathies.

Severe COVID-19 can manifest as multiorgan dysfunction with pulmonary involvement being the most common and prominent. As more reports emerge in the literature, it appears that an exaggerated immune response in the form of unfettered complement activation and a cytokine storm may be a key driver of the widespread organ injury seen in this disease. In addition, these patients are also known to be hypercoagulable with a high rate of thrombosis and a higher-than-expected failure rate of anticoagulation. While macrovascular thrombosis is common in these individuals, the frequent finding of extensive microvascular thromboses in several series and case reports, raises the possibility of thrombotic microangiopathy (TMA) as being a contributing factor in the thrombotic and multi-organ complications of the disease. If this is correct, rapidly identifying a TMA and treating the underlying pathophysiology may allow for better outcomes in these critically ill patients. To further explore this, we reviewed the published literature on COVID-19, looking for reports describing TMA-like presentations. We summarize our findings here along with a discussion about presentation, pathophysiology, and a suggested treatment algorithm.

How Have Nutrition Practices in the ICU Changed in the Last Decade (2011-2020): A Scoping Review.

Malnutrition is more prevalent in the critically ill than ambulatory patients due to a variety of factors. Strategies employed in the optimization of nutrition practices rely largely on the review of published literature and guidelines. While the last decade was marked by some landmark large randomized controlled trials taking place and some high-quality systematic reviews, it still has left us with many unanswered questions. The evidence generated by these trials can, to a good extent, extrapolate to the developed countries. However, its implementation in developing and third-world countries needs further elaboration and logistical considerations. With this scoping review, we attempt to provide insights into the landmark developments in the decade 2011-2020. Solutions to employ and implement the results of these developments and ways for their corroboration into a larger population are also discussed.

Clinicopathologic Characteristics of Late Acute Antibody-mediated Rejection in Pediatric Liver Transplantation.

BACKGROUND: An early and accurate diagnosis of liver antibody-mediated rejection (AMR) followed by timely intervention is important for clinical management but remains challenging. The aim of this study was to assess the clinicopathologic characteristics and outcomes of late acute AMR in pediatric liver transplantation recipients. METHODS: We performed a retrospective review of 739 ABO-identical/compatible allograft liver biopsies from 199 pediatric transplantation recipients. RESULTS: Based on Banff 2016 AMR criteria, 3 recipients fulfilled the criteria for definite for late acute AMR, 2 met the criteria for suspicious for AMR, and 2 were indeterminate for AMR. We further assessed the clinicopathologic characteristics of these 7 patients. All 7 patients had at least 1 biopsy with a histopathologic pattern compatible with acute AMR. Additionally, we observed accompanied moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury in all 7 patients; periportal/perivenular hepatocyte necrosis was seen in 6 of 7 patients; and arteritis was seen in 3 of 7 patients. In each case, microvascular C4d deposition was present in at least 1 biopsy. Posttransplant donor specific anti-HLA antibodies were detected in 5 patients. Two of 7 patients were retransplanted, and 2 died after developing refractory AMR. The remaining 5 patients were alive with stable graft function at a median follow-up of 4.1 years. CONCLUSIONS: Our data suggest that acute AMR in pediatric liver grafts is rare, can develop late, and may be associated with graft loss or patient death. The recurrent histopathologic findings of moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury are features that appear unique to pediatric acute AMR of liver grafts.

Anticoagulation in COVID - 19: An Update.

The novel coronavirus disease, 2019 (COVID - 19) evolved as an unprecedented pandemic. The severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2) infection has been associated with significantly deranged coagulation parameters and increased incidence of thrombotic events. Deranged coagulation parameters, such as D-dimers and fibrin degradation products, can indicate a poor prognosis, and their measurement will help stratify the patients according to the disease severity, need of intensive care unit admission, and prediction of the clinical course. Gaps in understanding the natural history of the disease cause difficulties in tailoring therapies and optimizing the management of patients. Lack of specific treatment further complicates this situation. While thrombotic events can cause significant morbidity and mortality in patients, a focused approach to the prevention and treatment of venous thromboembolism (VTE) can, to a great extent, decrease the disease burden caused by thrombotic diseases. Pharmacological prophylactic anticoagulants and mechanical therapies such as pneumatic compression devices can help prevent venous thromboembolism and other thrombotic events. Thrombotic events due to COVID-19, their prevention and management, are the focus of this paper, with the prospect of providing insights into this relatively unexplored area.