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.

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.

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.

Proinflammatory Cytokine Secretion in a Patient With Recurrent Neuroblastoma Related to the Onset of Malignancy-associated Hemophagocytic Lymphohistiocytosis.

The onset of malignancy-associated hemophagocytic lymphohistiocytosis (M-HLH) may be associated with the secretion of proinflammatory cytokines from malignant cells. We here report a patient with recurrent neuroblastoma who developed hemophagocytic lymphohistiocytosis after surgery for brain metastases and relapsed after chemotherapy. The neuroblastoma cells in the recurrent tumor were positive for tumor necrosis factor-α and interleukin-6, whereas the primary site was negative. The secretion of proinflammatory cytokines from neuroblastoma cells may have been related to the pathogenesis of M-HLH in our patients. We should pay attention to possible development of M-HLH when treating advanced neuroblastoma.

Immunologic Effects of Sirolimus in Patients With Vascular Anomalies.

Emerging data have suggested that sirolimus may be a treatment option for complicated vascular anomalies (VAs). The present study aimed to investigate the immunologic effects of sirolimus treatment for 6 months in patients with VAs. Blood samples obtained from the patients enrolled in 2 multicenter studies to investigate the efficacy of sirolimus for VAs before and after sirolimus treatment for 6 months were used. Data for total white blood cell count, absolute lymphocyte count, serum immunoglobulins (Igs) levels (IgG, IgA, IgM), lymphocyte proliferation assays with mitogens including phytohemagglutinin and concanavalin A, and flow cytometric analysis of lymphocyte subsets were evaluated. A total of 18 patients with VAs receiving sirolimus treatment were included in the study. Comparisons of white blood cell, absolute lymphocyte count, IgG, IgA, IgM, and reaction rates of phytohemagglutinin and concanavalin A revealed no significant differences before and after treatment. No significant differences were observed in the absolute counts of lymphocyte subtypes before and after treatment, except for regulatory T-cell counts, which were significantly decreased after treatment. Severe infections were not observed during sirolimus treatment. The immunologic parameters assessed in the present study were hardly affected by sirolimus treatment for 6 months in patients with VAs.

Patterns of bilateral agenesis of maxillary third molars and agenesis of other teeth.

The purpose of this study was to investigate the patterns of bilateral agenesis of maxillary third molars and other tooth agenesis in Japanese orthodontic patients. A group of 262 subjects with bilateral agenesis of maxillary third molars (group A) was divided into three subgroups: group 1A consisting of 114 subjects without agenesis of mandibular third molars; group 2A, 31 subjects with unilateral agenesis of mandibular third molars; and group 3A, 117 subjects with agenesis of all third molars. As controls, 926 other subjects without third molar agenesis were selected (group C). Panoramic radiographs were mainly used to examine for tooth agenesis. The Chi square test and odds ratio were used to make statistical comparisons. The prevalence rates of agenesis of maxillary lateral incisors, mandibular incisors and maxillary and mandibular second premolars, and bilateral agenesis of maxillary lateral incisors and second premolars were significantly higher in any one of the third molar agenesis groups than in the control group. Characteristically, no significant increase in occurrence of bilateral agenesis of mandibular second premolars was demonstrated by the subjects with bilateral agenesis of maxillary third molars. Irrespective of whether unilateral or bilateral agenesis of mandibular third molars is present or not, the Japanese orthodontic patients with bilateral agenesis of maxillary third molars exhibited a significantly increased occurrence of unilateral or bilateral agenesis of maxillary lateral incisors, mandibular incisors and maxillary and mandibular second premolars, except for bilateral agenesis of mandibular incisors and second premolars.

Short-term treatment effects of the quad-helix appliance on dentofacial morphology of hyperdivergent patients.

OBJECTIVES: The purpose of this study was to evaluate the effects of shor-term expansion treatment using the quad-helix appliance on dentofacial morphology in orthodontic patients presenting with a hyperdivergent facial pattern. METHODS: The treatment group consisted of 40 patients with a hyperdivergent facial pattern, who were treated for maxillary incisor crowding with a quad-helix appliance during the mixed dentition period. Lateral cephalograms taken at the start (TO) and end (TI) of the treatment were obtained as a course of care. A similar number of patients, who possessed the same type of facial pattern and who remained untreated, were assigned to a control group. Two consecutive lateral cephalograms of each untreated patient were taken at the same time points as TO and T1. All cephalograms were traced, analysed and compared between the two groups. RESULTS: The treatment changes as a result of the quad-helix appliance were expressed in an upward rotation of the mandible [2.34°] and distal tipping and impeded mesial movement of the maxillary first molars. Significant differences were evident between the treatment and control groups. CONCLUSION: Quad-helix appliance treatment can be appropriate for significantly decreasing the mandibular plane angle in hyperdivergent patients presenting with moderate maxillary incisor crowding and a positive overjet and overbite.

Association between third molar agenesis patterns and agenesis of other teeth in a Japanese orthodontic population.

The purpose of this study was to investigate the patterns of third molar agenesis and incidence of agenesis of other permanent teeth in a Japanese orthodontic patient group. A total of 417 Japanese subjects (134 males and 283 females) with agenesis of one or more third molars were divided into four groups according to the agenesis pattern, and 874 other Japanese subjects (302 males and 572 females) without third molar agenesis were assigned to a control group. Panoramic radiographs and medical and dental records were used to examine for tooth agenesis. The Chi-square test and odds ratio were used to make statistical comparisons. The prevalence of third molar agenesis worked out at 32.3% with no statistically significant gender difference. A high prevalence rate of agenesis of third molars, unilateral or bilateral, could be considered characteristic of the Japanese orthodontic population. Significant increases in occurrence of oligodontia, and unilateral or bilateral agenesis of other teeth, including maxillary lateral incisors and maxillary and mandibular second premolars, were observed in all or almost all of the third molar agenesis groups, compared with the controls. A significantly increased prevalence rate of mandibular lateral incisor agenesis was observed in almost all of the third molar agenesis groups. The Japanese patients with third molar agenesis had a significantly increased occurrence of oligodontia, and unilateral or bilateral agenesis of maxillary and mandibular lateral incisors and second premolars, except for bilateral agenesis of mandibular lateral incisors.

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.

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.

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.

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.

Patterns of tooth agenesis in Japanese subjects with bilateral agenesis of mandibular second premolars.

The aim of this study was to explore the patterns of tooth agenesis in Japanese orthodontic patients with bilateral agenesis of mandibular second premolars. A total of 80 Japanese orthodontic patients with 2 congenitally missing mandibular second premolars were selected as the subjects of this study (experimental group). Another 80 individuals without bilateral agenesis of mandibular second premolars were collected for comparison (control group). The 2 groups were matched with regard to sex. Radiographs, dental casts and records of medical and/or dental treatment were used to identify tooth agenesis. The Chi-square test, odds ratio, and test for equality were used to make statistical comparisons. The prevalence rates of other types of tooth agenesis were significantly higher in the experimental group than in the control group. The occurrence of agenesis of maxillary and mandibular lateral incisors and third molars, and maxillary second premolars was also significantly higher in the experimental group than in the control group. Significantly increased prevalence rates of symmetrical tooth agenesis, with third molars included, and oligodontia were observed in the experimental group. Japanese subjects with bilateral agenesis of mandibular second premolars are at significantly high risk of agenesis of other types of permanent teeth, symmetrical tooth agenesis and oligodontia.

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.

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.

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.

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.