Severe cytokine release syndrome in a patient receiving PD‐1‐directed therapy

Cytokine release syndrome (CRS) is a phenomenon of immune hyperactivation described in the setting of cellular and bispecific T‐cell engaging immunotherapy. Checkpoint blockade using anti‐programmed cell death 1 (anti‐PD‐1) inhibitors is an approach to antitumor immune system stimulation. A 29‐year‐old female with alveolar soft part sarcoma developed severe CRS after treatment with anti‐PD‐1 therapy. CRS was characterized by high fevers, encephalopathy, hypotension, hypoxia, hepatic dysfunction, and evidence of coagulopathy, and resolved after infusion of the interleukin‐6 inhibitor tocilizumab and corticosteroids.     

Low Frequency of Programmed Death Ligand 1 Expression in Pediatric Cancers

Programmed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) pathway blockade has become a promising therapeutic target in adult cancers. We evaluated PD‐L1 expression and tumor‐infiltrating CD8⁺ T cells in formalin‐fixed, paraffin‐embedded tumor specimens from 53 untreated pediatric patients with eight cancer types: neuroblastoma, extracranial malignant germ cell tumor, hepatoblastoma, germinoma, medulloblastoma, renal tumor, rhabdomyosarcoma, and atypical teratoid/rhabdoid tumor. One rhabdomyosarcoma with the shortest survival exhibited membranous PD‐L1 expression and germinoma contained abundant tumor‐infiltrating CD8⁺ T cells and PD‐L1‐positive macrophages. The PD‐1/PD‐L1 pathway tended to be inactive in pediatric cancers.     

PD‐1 inhibition in congenital pigment synthesizing metastatic melanoma

A newborn female child was born with a congenital pigment synthesizing melanoma of the scalp. Further workup revealed metastatic disease within the liver, lungs, and left tibia. Whole exome sequencing was performed on multiple samples that revealed one somatic mutation, lysine methyltransferase 2C (KMT2C), at low allelic frequency but no v‐Raf murine sarcoma viral oncogene homolog B (BRAF), NF‐1 mutation. Programmed death ligand 1 was moderately expressed. Treatment was initiated with the programmed cell death protein 1 inhibitor nivolumab. The patient tolerated this treatment well with minimal toxicity. She is now over a year out from initial diagnosis, continuing on nivolumab, with stable disease.     

Association of neonatal hyperbilirubinemia with uridine diphosphate‐glucuronosyltransferase 1A1 gene polymorphisms: Meta‐analysis

Background: Recent reports have suggested that genetic factors, including mutations in the coding region or promoter of uridine diphosphate‐glucuronosyltransferase 1A1 (UGT1A1) may increase the risk of development of neonatal hyperbilirubinemia, but the relationship has not been evaluated on systematic review or meta‐analysis. Methods: A meta‐analysis of observational studies reporting effect estimates and 95% confidence intervals (95%CI) was conducted on the association between UGT1A1 polymorphisms and neonatal hyperbilirubinemia. Results: A total of 27 eligible studies were identified. In total, 17 studies focused on the association of neonatal hyperbilirubinemia with UGT1A1 Gly71Arg polymorphisms, which indicated that these polymorphisms were associated with an increased risk of neonatal hyperbilirubinemia (A/A+G/A vs G/G: odds ratio [OR], 2.70; P= 0.00; 95%CI: 2.22–3.29; I²= 0.0%; P_{heterogeneity}= 0.55). Subgroup analyses by ethnicity validated this correlation in Asian, but not in Caucasian, populations (OR, 1.74; P= 0.10; 95%CI: 0.90–3.35; I²= 0.00%; P_{heterogeneity}= 0.67). Furthermore, 18 studies focused on the association of neonatal hyperbilirubinemia with UGT1A1 TATA promoter polymorphisms. These studies concluded that TATA promoter variants were not associated with an increased risk of neonatal hyperbilirubinemia (7/7 + 6/7 vs 6/6: OR, 1.13; P= 0.23; 95%CI: 0.93–1.37; I²= 80.0%; P_{heterogeneity}= 0.00). Conclusion: UGT1A1 Gly71Arg polymorphisms are a risk factor for developing neonatal hyperbilirubinemia in Asian, but not Caucasian, subjects. UGT1A1 TATA promoter polymorphisms were not associated with an increased risk of neonatal hyperbilirubinemia in Asian subjects, but results from the Caucasian population were conflicting and require further epidemiological investigation.     

Current human T‐cell lymphotropic virus type 1 mother‐to‐child transmission prevention status in Kagoshima

The aim of this study was to assess the current human T‐cell lymphotropic virus type 1 (HTLV‐I) mother‐to‐child transmission (MTCT) prevention system in Kagoshima Prefecture. We investigated the rate of carrier pregnant women from obstetrics facilities in Kagoshima by mail in 2012 and compared our results with previous study results. We interviewed carrier pregnant women about their choices for infant nutrition, and we interviewed midwives about the follow‐up system. In 2012, 8719 screening tests were performed, covering 58.1% of all pregnant women in Kagoshima; the rate of carrier pregnant women was 1.3%. Of 59 carriers, 39 chose short‐term breast‐feeding. The HTLV‐I carrier rate among pregnant women in Kagoshima has declined. The current HTLV‐I MTCT prevention system in Kagoshima is effective, but not sufficient. To bring the nutrition methods to completion, various types of support are needed. Further studies will elucidate many unsolved problems concerning MTCT.     

Glucose‐6‐phosphate dehydrogenase deficiency in internationally adopted children

There are conflicting guidelines about screening of internationally adopted children for glucose‐6‐phosphate dehydrogenase (G6PD) deficiency, a common genetic disorder. In a multi‐ethnic population of 2,169 internationally adopted children, we found that the prevalence of G6PD deficiency was 1.6% overall and 2.2% in males. Prevalence differed by country or region of origin, ranging from 0 to 13% overall and 0 to 22% in males. The prevalence in females was 1%. A diagnosis of G6PD deficiency informs the treatment of malaria and enables education and counseling to prevent morbidity and mortality from G6PD deficiency. Screening for G6PD deficiency should be strongly considered for internationally adopted children.     

Elastase, α1‐proteinase inhibitor,and interleukin‐8 in pre‐dialyzed and hemodialyzed patients with chronic kidney disease

Background: Neutrophil elastase in complex with α₁‐proteinase inhibitor (NE‐α₁PI) and interleukin (IL)‐8 may serve as indicators of neutrophil activation and inflammatory stage. The aim of the study was to evaluate NE‐α₁PI, α₁‐PI, and IL‐8 levels in the blood of patients with chronic kidney disease (CKD) undergoing hemodialysis (HD) or conservatively treated (CT). The influence of a single HD session on the investigated parameters was also assessed. Methods: Blood samples were obtained from two groups of hemodialyzed patients (children/young adults [group HD1, n= 8] and adults [group HD2, n= 13]), as well as 13 CT patients and a group of healthy subjects. The proteins were measured using enzyme‐linked immunosorbent assay or radial immunodiffusion. Results: There were no significant differences in NE‐α₁PI, α₁‐PI, and IL‐8 concentrations between the HD1 and HD2 patients. The levels of NE‐α₁PI were considerably higher than normal in both groups of HD patients (before and after the HD session) and in the CT patients. Higher titers of NE‐α₁PI (P < 0.05) and α₁‐PI (P < 0.01) were obtained in the adults during the course of HD. Increased NE‐α₁PI was positively correlated with α₁‐PI. The serum concentration of IL‐8 was significantly higher in the HD2 patients before and after dialysis than in the controls. Conclusions: The data indicate that in CKD patients, neutrophils are highly activated both in the pre‐dialyzed period and on regular HD. Contact with the dialysis membrane during HD causes a significant increase in blood NE‐α₁PI and α₁‐PI in adults, but not in children/young adults. NE‐α₁PI seems to be a much better indicator of an inflammatory state in CKD patients than free α₁‐PI or IL‐8.     

Therapeutic response of metastatic angiomatoid fibrous histiocytoma carrying EWSR1‐CREB1 fusion to the interleukin‐6 receptor antibody tocilizumab

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that has been associated with EWSR1‐CREB1 gene fusion. Outcome in patients with unresectable distant metastases is generally fatal. Interleukin‐6 (IL‐6) secretion has been described in tumors with EWSR1‐CREB1 fusion, and may promote tumor growth due to autocrine stimulation. Tocilizumab is an IL‐6 receptor antibody that has potential benefit as a targeted therapy in refractory neoplasms with IL‐6 secretion. We describe a child with metastatic AFH with EWSR1‐CREB1 fusion and elevated IL‐6 whose disease progressed during treatment with traditional chemotherapeutic agents, but improved after targeted therapy with tocilizumab.     

A 5‐HT2A/2C receptor agonist, 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane,mitigates developmental neurotoxicity of ethanol to serotonergic neurons

Prenatal ethanol exposure causes the reduction of serotonergic (5‐HTergic) neurons in the midbrain raphe nuclei. In the present study, we examined whether an activation of signaling via 5‐HT_2A and 5‐HT_2C receptors during the fetal period is able to prevent the reduction of 5‐HTergic neurons induced by prenatal ethanol exposure. Pregnant Sprague–Dawley rats were given a liquid diet containing 2.5 to 5.0% (w/v) ethanol on gestational days (GDs) 10 to 20 (Et). As a pair‐fed control, other pregnant rats were fed the same liquid diet except that the ethanol was replaced by isocaloric sucrose (Pf). Each Et and Pf group was subdivided into two groups; one of the groups was treated with 1 mg/kg (i.p.) of 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI), an agonist for 5‐HT_2A/2C receptors, during GDs 13 to 19 (Et‐DOI or Pf‐DOI), and another was injected with saline vehicle only (Et‐Sal or Pf‐Sal). Their fetuses were removed by cesarean section on GD 19 or 20, and fetal brains were collected. An immunohistological examination of 5‐HTergic neurons in the fetuses on embryonic day 20 using an antibody against tryptophan hydroxylase revealed that the number of 5‐HTergic neurons in the midbrain raphe nuclei was significantly reduced in the Et‐Sal fetuses compared to that of the Pf‐Sal and Pf‐DOI fetuses, whereas there were no significant differences between Et‐DOI and each Pf control. Thus, we concluded that the reduction of 5‐HTergic neurons that resulted in prenatal ethanol exposure could be alleviated by the enhancement of signaling via 5‐HT_2A/2C receptors during the fetal period.     

Challenges in genetic counseling because of intra‐familial phenotypic variation of oral‐facial‐digital syndrome type 1

Oral‐facial‐digital syndrome type 1 (OFD1; MIM 311200) is characterized by multiple anomalies of the oral cavity, face and digits. We report a family with OFD1, where two female siblings and their mother shared the same mutation of the responsible gene (OFD1) c.1193_1196delAATC. Phenotypic variability was observed among them; the mother showed minimal features of OFD1, whereas her two daughters showed partial features and the full spectrum of OFD1, respectively. Thus, OFD1 was suspected only after a health check‐up during pregnancy of the second patient showing fetal brain anomaly and maternal polycystic kidney. For these reasons, there was a delay in the recognition of OFD1 in this family. Patients with OFD1 show phenotypic variability, which poses challenges for genetic counseling.