Changes in cell morphology and function induced by the NRAS Q61R mutation in lymphatic endothelial cells.

Recently, a low-level somatic mutation in the NRAS gene (c.182 A > G, Q61R) was identified in various specimens from patients with kaposiform lymphangiomatosis. However, it is unknown how these low-frequency mutated cells can affect the characterization and surrounding environment of their lesions. To understand the pathogenesis and association of these gene abnormalities, we established NRASQ61R mutated lymphatic endothelial cells transfected with lentivirus vector and undertook morphological and functional characterization, protein expression profiling, and metabolome analysis. NRASQ61R human dermal lymphatic endothelial cells showed poor tube formation, a low proliferation rate, and high migration ability, with an increase in the ratio of mutated cells. An analysis of signaling pathways showed inactivation of the PIK3/AKT/mTOR pathway and hyperactivation of the RAS/MAPK/ERK pathway, which was improved by MAPK kinase (MEK) inhibitor treatment. This study shows the theoretical circumstances induced in vitro by NRASQ61R-mutated cells in the affected lesions of kaposiform lymphangiomatosis patients.

Highly sensitive detection of Epstein-Barr virus-infected cells by EBER flow FISH.

When Epstein-Barr virus (EBV) infection is suspected, identification of infected cells is important to understand the pathogenesis, determinine the treatment strategy, and predict the prognosis. We used the PrimeFlow™ RNA Assay Kit with a probe to detect EBV-encoded small RNAs (EBERs) and multiple surface markers, to identify EBV-infected cells by flow cytometry. We analyzed a total of 24 patients [11 with chronic active EBV disease (CAEBV), 3 with hydroa vacciniforme lymphoproliferative disorder, 2 with X-linked lymphoproliferative disease type 1 (XLP1), 2 with EBV-associated hemophagocytic lymphohistiocytosis, and 6 with posttransplant lymphoproliferative disorder (PTLD)]. We compared infected cells using conventional quantitative PCR methods and confirmed that infected cell types were identical in most patients. Patients with CAEBV had widespread infection in T and NK cells, but a small amount of B cells were also infected, and infection in patients with XLP1 and PTLD was not limited to B cells. EBV-associated diseases are believed to be complex pathologies caused by EBV infecting a variety of cells other than B cells. We also demonstrated that infected cells were positive for HLA-DR in patients with CAEBV. EBER flow FISH can identify EBV-infected cells with high sensitivity and is useful for elucidating the pathogenesis.

Sirolimus monotherapy for Kasabach-Merritt phenomenon in a neonate; Case report.

INTRODUCTION AND IMPORTANCE: The Kasabach-Merritt Phenomenon (KMP), characterized by thrombocytopenia and consumptive coagulopathy due to endothelial cell growth in the infantile vascular tumor kaposiform hemangioendothelioma, presents a therapeutic challenge. This case highlights the novel use of sirolimus in a neonate, an approach less explored in this age group. CASE PRESENTATION: A female neonate presented with a right anterior chest mass, progressing to respiratory distress and congestive heart failure. Diagnosed with KMP, she exhibited low platelet count and coagulation abnormalities. Treatment with sirolimus (0.06 mg/day) led to mass reduction, improved bleeding, and a stable tumor after 12 months, without side effects. This case contrasts with existing literature advocating for combination therapy or higher sirolimus concentrations for effective treatment. Yet, our patient achieved favorable outcomes with low-dose monotherapy, suggesting a potentially safer approach in neonates with immature hepatic and renal metabolism. CLINICAL DISCUSSION: This case demonstrates the efficacy of low-dose sirolimus monotherapy in treating KMP in a neonate, challenging current preferences for combination therapies or higher doses. It emphasizes the need for further research into age-specific treatment protocols in KMP, considering the unique metabolic profiles of neonates and infants. CONCLUSION: Sirolimus has demonstrated potential in treating KMP in pediatric patients. While initial results are promising, determining optimal dosages and trough concentrations, especially in neonates and infants, remains essential.

Sirolimus treatment for intractable lymphatic anomalies: an open-label, single-arm, multicenter, prospective trial.

Introduction: Intractable lymphatic anomalies (LAs) include cystic lymphatic malformation (LM; macrocystic, microcystic, or mixed), generalized lymphatic anomaly, and Gorham-Stout disease. LAs can present with severe symptoms and poor prognosis. Thus, prospective studies for treatments are warranted. We conducted a prospective clinical trial of sirolimus for intractable LAs. Methods: This was an open-label, single-arm, multicenter, prospective trial involving five institutions in Japan. All patients with LAs received oral sirolimus once daily, and the dose was adjusted to ensure that the trough concentration remained within 5-15 ng/mL. We prospectively assessed the drug response (response rate for radiological volumetric change in target lesion), performance state, change in respiratory function, visceral impairment (pleural effusion, ascites, bleeding, pain), laboratory examination data, quality of life (QOL), and safety at 12, 24, and 52 weeks of administration. Results: Eleven patients with LAs (9 generalized lymphatic anomaly, 1 cystic LM, 1 Gorham-Stout disease) were treated with sirolimus, of whom 6 (54.5%; 95% confidence interval: 23.4-83.3%) demonstrated a partial response on radiological examination at 52 weeks of administration. No patients achieved a complete response. At 12 and 24 weeks of administration, 8 patients (72.7%) already showed a partial response. However, patients with stable disease showed minor or no reduction after 12 weeks. Adverse events, such as stomatitis, acneiform dermatitis, diarrhea, and fever, were common with sirolimus. Sirolimus was safe and tolerable. Conclusion: Sirolimus can reduce the lymphatic tissue volume in LAs and may lead to improvements in clinical symptoms and QOL.

Two Pediatric Patients with Acute Acquired Comitant Esotropia as the First Symptom of Brainstem Tumor: A Case Report.

Introduction: Acute acquired comitant esotropia (AACE) is an acquired strabismus with uncrossed sudden-onset diplopia due to esodeviation, comitant esotropia without accommodation factor, or paretic eye movement. The diagnosis of AACE entails differentiation from incomitant esotropia caused by abnormalities in the central nervous system. We present 2 pediatric patients with AACE as the first symptom of brainstem tumor. Case Presentation: The 2 patients were aware of their diplopia and had no other neurological abnormalities. There were no special findings in the anterior segment, ocular media, or fundus. Esotropia with a difference of no more than 10Δ between distant and near fixations was observed. Eye movements were normal, and Hess red-green test under prism neutralization did not reveal abduction restriction. The presumed cause of AACE in both patients was excessive use of digital displays, and brain magnetic resonance imaging (MRI) was performed to confirm the absence of neurological abnormality. Using MRI, a definitive diagnosis of AACE was made based on comitant esotropia associated with diffuse median glioma and medullary pilocytic astrocytoma without abducens nerve palsy. Conclusion: Although the incidence of AACE caused by brainstem tumors may be low, it is necessary to perform head imaging to confirm etiology. Furthermore, Hess red-green test under prism neutralization is considered important for the differentiation of abducens nerve palsy.

Solid pseudopapillary neoplasm in a woman presenting with acute pancreatitis: a case report and review of literature.

Solid pseudopapillary neoplasm (SPN) is a rare pancreatic tumor that typically affects young women in the body and tail of the pancreas. SPN is often asymptomatic in the early stages, so it is initially discovered as a large tumor. In this report, we experienced a case of a relatively small SPN discovered in the setting of acute pancreatitis. Because there have been few reports of SPN being discovered in the situation like our case, we report this case based on a review of the literature.

Detection of transient abnormal myelopoiesis blasts in a liver biopsy specimen by double-immunostaining for full-length GATA1 and CD42b.

BACKGROUND: Transient abnormal myelopoiesis (TAM) is characterized by leukocytosis with increased circulating megakaryoblasts that harbor N-terminal truncating mutations in the GATA1 gene. Approximately 10% of affected patients experience early death. OBSERVATIONS: A 2-month-old boy with Down syndrome was diagnosed with TAM and followed without treatment. Although the blasts in the peripheral blood disappeared, liver failure progressed. A pathological examination revealed liver fibrosis, and double-immunostaining for full-length GATA1 and CD42b identified megakaryocytes with a GATA1 mutation. CONCLUSIONS: This simple and cost-effective method can be applied in routine practice to detect TAM blasts during assessment in a TAM crisis.

A Case of Multifocal Lymphangioendotheliomatosis With Thrombocytopenia and Changes in Coagulopathy.

Multifocal lymphangioendotheliomatosis with thrombocytopenia is a rare disease characterized by progressive multiple vascular lesions and is accompanied by thrombocytopenia. The precise diagnosis of this disease is frequently difficult because of the heterogeneity of the clinical symptoms. We report a case of a male infant who presented with severe thrombocytopenia induced by local inflammation. In addition, enlargement of the extremities with soft tissue and bone involvement without gastrointestinal bleeding was observed. The thrombocytopenia resolved after a combination therapy of sirolimus and prednisolone. Our finding that plasma angiopoietin-2 concentrations reflected the disease status suggests its utility as a biomarker of Multifocal lymphangioendotheliomatosis with thrombocytopenia.

Effects of Atezolizumab and Bevacizumab on Adrenal Gland Metastasis of Hepatocellular Carcinoma: A Case Report and Review of Literature.

Regarding the prognosis of cases with advanced-stage hepatocellular carcinoma (HCC), a recent clinical study showed that the immune checkpoint inhibitors atezolizumab plus bevacizumab have superior efficacy to sorafenib. However, only a few reports have focused on their effects on extrahepatic metastases. We herein report a case of HCC in a 59-year-old man with intrahepatic lesions treated successfully by hepatic arterial chemoembolization, radiotherapy, and sorafenib; the extrahepatic lesion in the adrenal gland was treated by atezolizumab plus bevacizumab. The patient showed a tumor-free condition for one year. We have summarized the clinical course and reviewed the literature to underscore the efficacy of atezolizumab plus bevacizumab for treating extrahepatic lesions of HCC.

A rare pediatric case of McCune-Albright syndrome with acute visual disturbance: Case report.

RATIONALE: McCune-Albright syndrome (MAS) is a rare disorder characterized by clinical findings, which includes fibrous dysplasia (FD). FD is a benign tumor that leads to increased rates of bone fracture. In some MAS cases with FD, facial deformities, severe pain, and orbital neuropathies are complicated. Aneurysmal bone cyst (ABC) is a benign bone tumor and rare complication of FD. PATIENT CONCERNS: A 9-year-old boy was admitted to our hospital because of acute visual disturbance. DIAGNOSIS AND INTERVENTIONS: The patient was clinically diagnosed as ABC complicated with MAS, and he underwent surgery. OUTCOMES: After the surgery, his sight became normal. Recurrence of ABC and visual disturbance was not observed in 3 years. Genetic analysis of a tissue sample from the ABC lesion by next-generation sequencing revealed a somatic activating GNAS mutation. LESSONS: To the best of our knowledge, this is the first case report of MAS causing optic neuropathy complicated with ABC. ABC complicated with MAS is extremely rare, but it should be considered as a possible diagnosis in patients with acute visual loss and facial swelling. In addition, our case had OAS, which is an uncommon syndrome and a rare complication in ABC with MAS, and rapid decompression of the ABC was effective in improving the patient's eyesight.

Effectiveness of different coils for endovascular coiling for intractable hepatic encephalopathy caused by a portosystemic shunt.

BACKGROUND: Interventional radiology (IVR), including balloon-occluded retrograde transvenous obliteration (BRTO) and percutaneous transhepatic obliteration (PTO), is performed for patients with intractable hepatic encephalopathy (HE). However, information on the appropriate coil for endovascular coiling for preventing recanalization is lacking. This study aimed to compare the different types of coils for endovascular coiling used in BRTO and PTO for cases of intractable HE. METHODS: This retrospective study included patients who underwent endovascular coiling with BRTO or PTO for HE caused by portosystemic shunts. The number of coils required for complete occlusion was compared among bare, fiber, and hydrogel-coated coils, and the expansion types that close the gap between and inside the hydrogel-coated coils were also compared. RESULTS: Of 38 patients (age range, 30-86 years), 16 and 22 underwent BRTO and PTO, respectively, using bare (19 patients), fiber (8 patients), and hydrogel-coated coils (10 patients; external expansion type, 4; internal expansion type, 6). No significant differences in the size of portosystemic shunts were observed according to the type of coil. The mean number of coils required for complete occlusion varied (bare coils, 19.32; fiber coils, 18.11; hydrogel-coated coils, 10.70). Significantly fewer coils were required for endovascular coiling with hydrogel-coated coils. In the internal expansion type, a mean of 8.5 coils was required for occlusion. CONCLUSIONS: In some patients who underwent portal vein embolization, complete occlusion was not achieved with the scheduled type of coil because of slight expansion of blood vessels due to coil pressure. The findings suggested that hydrogel-coated coils were effective in endovascular coiling for HE caused by a portosystemic shunt, and internal expansion-type hydrogel-coated coils may be effective for the first-line procedure.

Poorly Differentiated Chordoma of the Clivus With Loss of SMARCB1 Expression in a Pediatric Patient: A Case Report.

Poorly differentiated chordoma (PDC) is a rare, aggressive subtype of chordoma. A two-year-old girl presented with cervical pain, limb paralysis and respiratory failure. Magnetic resonance imaging and positron emission tomography-computed tomography revealed a tumor compressing the pons at the clivus and osteoblastic metastatic lesions of the left upper arm and right iliac bone. Her tumors shrank substantially after treatment with chemotherapy and proton beam therapy. Our initial diagnosis was an atypical teratoma/rhabdoid tumor, but final diagnosis of PDC was made on the basis of the immunohistochemical expression of brachyury. In addition, the detection of SMARCB1/INI1 mutation confirmed the diagnosis of PDC.

A Sporadic Pediatric Case of Huge Intracranial Supratentorial Desmoid-type Fibromatosis.

Desmoid-type fibromatosis (DTF) is a rare locally aggressive soft tissue neoplasm without metastatic potential. Here, we report a very rare sporadic case of an intracranial supratentorial extradural DTF measuring 82 mm in a 1-year-old girl, that recurred twice following surgery over the course of 16 months, requiring two other surgeries. In three surgeries, we resected a huge tumor with the dura which was thought to be tumor origin and removed this tumor infiltrated the frontal skull base by drilling widely. Furthermore, we treated the tumor invading the bone flap using liquid nitrogen for 20 minutes, and subsequently used it to perform a cranioplasty. This tumor has not recurred for past 8 months. DTF invading the skull base is prone to recurrence, and liquid nitrogen treatment is considered to be effective in pediatric patients, who need cranioplasty with tumor-infiltrating autologous bone flaps.

Characterization of kaposiform lymphangiomatosis tissue-derived cells.

BACKGROUND: Kaposiform lymphangiomatosis (KLA) is a recently characterized systemic lymphatic anomaly. Activation of RAS/MAPK and PI3K/AKT/mTOR pathways may affect KLA pathogenesis, but the cellular basis of KLA is unclear. Abnormal-spindle endothelial cells that express lymphatic endothelial cell (LEC) markers are characteristic of KLA histopathology. This study evaluated patient-derived KLA cells to establish their morphological and biological characteristics. PROCEDURE: We established cell lines from primary KLA tissues of two patients with KLA and examined their morphological and functional characteristics, messenger RNA and protein expression profiles, gene mutations, and responses to inhibitors of the RAS/MAPK and PI3K/AKT/mTOR pathways. RESULTS: Both KLA cell lines showed spindle-shaped morphology, stained positive for podoplanin (PDPN), and exhibited impaired tube-formation properties. They expressed LEC marker PDPN and mesenchymal stem cell markers (CD90, CD105) in the absence of endothelial cell markers (CD34, CD31, VWF), per real-time polymerase chain reaction. Both mTOR inhibitor rapamycin and MEK inhibitor trametinib inhibited growth of the two cell lines. A NRAS p.Q61R variant was found in one of two independent KLA tissue samples, but not in the KLA cells (per targeted next-generation sequencing); and KLA cells with this variant had elevated AKT phosphorylation levels. ERK phosphorylation levels were undetectable in both KLA cell lines. CONCLUSIONS: Inhibition of the RAS/MAPK and PI3K/AKT/mTOR pathways may represent potential therapeutic targets in KLA. These patient-derived KLA cell lines will be useful research tools to elucidate KLA etiology, and could pave the way for basic, translational, and preclinical studies of this disease.

Validation of measurement scores for evaluating vascular anomaly skin lesions.

Vascular anomalies comprise a heterogeneous group of disorders caused by abnormal proliferation or development of vascular and/or lymphatic vessels. Vascular anomalies present with various symptoms and complications, but no standardized methods evaluate their severity, and to measure treatment outcomes is difficult. To assess the responsiveness of measurement scores for evaluating vascular anomaly skin lesions, we conducted a validation study to compare these measurement scores with patients' objective data. In this study, data were collected from treated and untreated patients. Skin lesions were photographed at baseline and after a follow-up period of 3-6 months. The volume of skin lesions, the degree of red or purple coloration, and color tone were measured objectively. Two external dermatologists evaluated patients' photographs and determined scores, which represented criteria for improvements in skin lesions (size and color) and 6-point Physician Global Assessment scores. The correlation between these scores and patients' objective data (lesion volume and color) was assessed to validate the scores. Twenty-three cases of vascular anomaly (seven vascular tumors, five lymphatic malformations, three venous malformations, and eight lymphatic-venous malformations) were examined. Scores for improvements in vascular anomaly skin lesions (size and color) correlated with a change in lesion volume, the degree of red or purple coloration, color tone score, and 6-point Physician Global Assessment score. Our findings suggest that these measurement scores are responsive to changes in vascular anomaly skin lesions after observation.

Pediatric Giant Cell Glioblastoma Presenting with Intracranial Dissemination at Diagnosis: A Case Report.

Giant cell glioblastoma (GCG) is a rare subtype of glioblastoma multiforme (GBM), and it often occurs in younger patients; however, its onset in children is extremely noticeable. A 7-year-old girl presented with a headache and restlessness. A giant tumor that was 7 cm in diameter was found by magnetic resonance imaging (MRI) in the left frontal lobe with intracranial dissemination. Because the tumor had extended to the lateral ventricles and occluded the foramen of Monro causing hydrocephalus, she underwent ventricular drainage and neuro-endoscopic biopsy from the left posterior horn of the lateral ventricle. The initial pathological diagnosis was an atypical teratoid/rhabdoid tumor (AT/RT). When the dissemination subsided after the first chemotherapy with vincristine, doxorubicin, and cyclophosphamide, she underwent the first tumor resection via a left frontal transcortical approach. After surgery, the second chemotherapy with ifosfamide, cisplatin, and etoposide was not effective for the residual tumor and intracranial dissemination. The second surgery via a transcallosal approach achieved nearly total resection leading to an improvement of the hydrocephalus. The definitive pathological diagnosis was GCG. Despite chemo-radiation therapy, the dissemination in the basal cistern reappeared and the hydrocephalus worsened. She was obliged to receive a ventriculo-peritoneal (VP) shunt and palliative care at home; however, her poor condition prevented her discharge. Ten months after admission, she died of tumor progression. The peritoneal dissemination was demonstrated by cytology of ascites. In conclusion, although unusual, pediatric GCG may be disseminated at diagnosis, in which case both tumor and hydrocephalus control need to be considered.

A pediatric case of anaplastic astrocytoma with a gliomatosis cerebri; the growth pattern and changes in serum VEGF-121 levels after bevacizumab treatment.

Gliomatosis cerebri (GC) is a rare diffusely infiltrating glial neoplasm that carries a poor prognosis. Because tumors are undetectable in most patients at early-stage of the onset, a useful diagnostic method is expected. We compared serum vascular endothelial growth factor (VEGF)-121 levels in patients with GC or glioblastoma and controls. VEGF-121 levels were significantly higher in one patient with GC and patients with glioblastoma than in controls. VEGF-121 levels decreased in a patient with GC after bevacizumab-based therapy. Thus, VEGF-121 may be useful for diagnosing GC, its disease-monitoring and understanding its etiology.

Changes in the Body Composition and Nutritional Status after Long-term Rifaximin Therapy for Hyperammonemia in Japanese Patients with Hepatic Encephalopathy.

Objective Rifaximin has become available for treating hyperammonemia in patients with hepatic encephalopathy. This study analyzed the changes in the body composition and nutritional status after long-term rifaximin therapy. Methods Twenty-one patients who underwent rifaximin therapy at 1,200 mg/day for more than 24 weeks were evaluated for the changes in the controlling nutritional status (CONUT) scores for the nutritional assessment, albumin-bilirubin (ALBI) scores for the liver function assessment, and skeletal muscle index (SMI) for the body composition assessment. Results There were 17 men and 4 women, with a mean age of 67.14±8.32 years. Eleven cases had a portosystemic shunt (52.3%), and 10 had hepatocellular carcinoma (47.6%). The Child-Pugh class was A in 9 cases (42.9%), B in 9 cases (42.9%), and C in 3 cases (14.2%). The blood ammonia levels in the rifaximin group improved significantly upon rifaximin therapy, from 124.76±28.68 µg/dL at baseline to 47.00±14.43 µg/dL after 2 weeks (p<0.001) and 49.81±15.02 µg/dL after 24 weeks (p<0.001). The CONUT scores improved significantly during rifaximin therapy, from 6.47±3.25 at baseline to 3.33±2.65 after 24 weeks (p=0.0007). The ALBI scores also improved significantly from -0.39±1.89 at baseline to -2.20±0.55 after 24 weeks (p=0.0002). The SMI scores showed that the body composition had been maintained in response to rifaximin therapy (50.20±7.67 at baseline and 51.29±7.62 after 24 weeks). Conclusion Rifaximin administration for hepatic encephalopathy improved the CONUT and ALBI scores. It may have a secondary effect on the improvement in the nutritional status and hepatic reserve.