Clinical characteristics and outcomes of immune-complex membranoproliferative glomerulonephritis and C3 glomerulopathy in Japanese children.

BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) can be divided into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G), which includes dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). These conditions result from abnormalities in different complement pathways and may lead to different prognoses. However, there are limited studies describing the respective clinical courses. METHODS: In this study, Japanese pediatric patients diagnosed with MPGN based on kidney biopsies conducted between February 2002 and December 2022 were reclassified as having IC-MPGN or C3G (DDD or C3GN). We retrospectively analyzed the clinical characteristics and outcomes of these patients. RESULTS: Out of 25 patients with MPGN, three (12.0%) were diagnosed with DDD, 20 (80.0%) with C3GN, and two (8.0%) with IC-MPGN. There were 13 (65.0%) patients and one (33.3%) patient in remission after treatment for C3GN and DDD, respectively, and no patients with IC-MPGN achieved remission. The median follow-up period was 5.3 (2.5-8.9) years, and none of the patients in either group progressed to an estimated glomerular filtration rate < 15 ml/min/1.73 m2. Patients with C3GN presenting mild to moderate proteinuria (n = 8) received a renin-angiotensin system inhibitor (RAS-I) alone, and these patients exhibited a significant decrease in the urinary protein creatinine ratio and a notable increase in serum C3 levels at the last follow-up. CONCLUSIONS: Most patients with MPGN were diagnosed with C3GN. The remission rate for C3GN was high, and no patients developed kidney failure during the approximately 5-year follow-up. Additionally, patients with C3GN with mild to moderate proteinuria had good outcomes with RAS-I alone, but continued vigilance is necessary to determine long-term prognosis.

Nephronophthisis 13 caused by WDR19 variants with pancytopenia: case report.

We present a case of nephronophthisis 13 that resulted from WDR19 variants. The patient, a nine-year-old Japanese boy, had detection of mild proteinuria during a school urine screening. Urinalysis revealed mild proteinuria without hematuria. Blood tests indicated pancytopenia, mild elevation of liver enzymes, and kidney dysfunction. Ultrasound examination disclosed hepatosplenomegaly. Abdominal computed tomography and bone marrow assessments ruled out malignant tumors. Subsequent kidney and liver biopsies suggested nephronophthisis and congenital hepatic fibrosis. Furthermore, comprehensive genetic analysis through next-generation sequencing revealed compound heterozygous variants in WDR19 (NM_025132.4), including the previously reported c.3533G > A, p.(Arg1178Gln), and c.3703G > A, p.(Glu1235Lys) variants, confirming the diagnosis of nephronophthisis 13. There is potential need for liver and kidney transplantation in patients with nephronophthisis and hepatic fibrosis. Early diagnosis is therefore crucial to mitigate delays in treating complications associated with kidney and hepatic insufficiency and to facilitate preparation of transplantation. To achieve early diagnosis of nephronophthisis, it is imperative to consider it as a differential diagnosis when extrarenal symptoms and kidney dysfunction coexist, particularly when mild proteinuria is observed through opportunistic urinalysis. Genetic testing is important because nephronophthisis manifests as diverse symptoms, necessitating an accurate diagnosis. Next-generation sequencing was shown to be invaluable for the genetic diagnosis of nephronophthisis, given the numerous identified causative genes.

Significance of Serum Leucine-rich Alpha-2 Glycoprotein as a Diagnostic Marker in Pediatric Inflammatory Bowel Disease.

Serum leucine-rich alpha-2 glycoprotein (LRG) has been utilized for adult inflammatory bowel disease (IBD); however, its efficacy in pediatric IBD remains unknown. The aim of this study was to compare the diagnostic accuracy of serum LRG for pediatric IBD with that of current inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). This retrospective case-control study included pediatric patients, aged <16 years, who underwent colonoscopy and/or esophagogastroduodenoscopy between April 2017 and March 2022. All eligible patients were divided into two groups: patients with IBD, diagnosed with ulcerative colitis and Crohn's disease, and non-IBD controls. The optimal cut-off value of serum LRG for IBD diagnosis was determined from receiver operating characteristic analysis, and diagnostic accuracy of serum LRG was compared to serum ESR and CRP. A total of 53 patients (24 with IBD and 29 non-IBD controls) met the inclusion criteria. The cut-off value of serum LRG for IBD diagnosis was determined to be 19.5 µg/ml. At this cut-off value, serum LRG had a positive predictive value (PPV) of 0.80 and negative predictive value (NPV) of 0.88. In contrast, PPV and NPV were 0.78 and 0.70 for serum ESR and 0.82 and 0.72 for serum CRP, respectively. Serum LRG can be a potential diagnostic marker for pediatric IBD, with higher diagnostic accuracy than that of the conventional serum markers ESR and CRP.

A case of pseudo-Bartter/Gitelman syndrome caused by long-term laxative abuse, leading to end-stage kidney disease.

Pseudo-Bartter/Gitelman syndrome (PBS/PGS) is a disorder that presents with hypokalemia and metabolic alkalosis resembling Gitelman syndrome (GS) due to secondary factors, such as lifestyle and /or medicines. Notably, PBS/PGS is more likely to cause renal dysfunction than GS. We report the first case of PBS/PGS due to long-term laxative abuse leading to end-stage kidney disease (ESKD). The patient was a 49-year-old woman with a history of constipation since school, who had used excessive doses of laxatives on her own judgment for nine years at least from 22 years of age. Two years later, blood tests revealed hypokalemia (serum K 3.1 mEq/L), and nine years later, the patient's renal function began to deteriorate (Cr-eGFR 48.7 mL/min/1.73 m2). Since abuse of laxatives was suspected as the cause, it was changed to the proper dosage of laxatives. At 33 years, the patient developed acute kidney injury (AKI), due to a urinary tract infection, and required intensive treatment, including hemodialysis. Although the patient was eventually weaned off dialysis, the renal function did not recover to pre-AKI levels. In suspected GS, comprehensive genetic testing for renal disease-related genes was performed; however, no obvious pathogenic variants were identified. Thereafter, despite decreasing the laxative doses and potassium supplementation, her renal function continued to decline. At 49 years, the patient developed ESKD and was started on maintenance hemodialysis. PBS/PGS is a disease that can lead to ESKD. An early diagnosis of PBS/PGS is crucial to prevent renal function deterioration, and the underlying causes should be removed immediately.

IgA nephropathy in a boy with frequently relapsing nephrotic syndrome.

A Japanese boy developed nephrotic syndrome (NS) and had microscopic hematuria at 8 years old. Renal biopsy was performed. Light microscopy study revealed mesangial proliferation and all immunofluorescent stains (including IgA) were negative, so he was diagnosed with non-IgA diffuse mesangial proliferation (DMP). Complete remission was achieved at 13 days after the initiation of oral prednisolone, and hematuria also disappeared 3 days later, but the patient developed frequently relapsing nephrotic syndrome. Cyclosporine A (CyA) was introduced at 10 years old, and there were no relapses between then and when it was discontinued at 12 years old. A second renal biopsy revealed minimal change without CyA nephrotoxicity. However, there was repeated relapse of NS after discontinuation, so CyA was reintroduced 8 months later, and NS remained in remission thereafter. Microscopic hematuria appeared at 13 years old, however, with gross hematuria appearing at the time of infection. A third renal biopsy revealed mesangial proliferation with IgA-dominant deposition, so the patient was diagnosed with IgA nephropathy. Currently (14 years old), CyA treatment has been discontinued and the patient is undergoing lisinopril therapy for IgA nephropathy, but there are still relapses of NS. To the best of our knowledge, there have been no previous reports of a patient with non-IgA DMP at the onset of NS who had later development of IgA nephropathy. The patient showed non-IgA DMP at the onset, suggesting that NS with non-IgA DMP and IgA nephropathy has some common pathophysiology. Treatment for NS, such as PSL and/or CyA treatment, may suppress the clinical manifestation of late IgA nephropathy.

ACLP Activates Cancer-Associated Fibroblasts and Inhibits CD8+ T-Cell Infiltration in Oral Squamous Cell Carcinoma.

We previously showed that upregulation of adipocyte enhancer-binding protein 1 (AEBP1) in vascular endothelial cells promotes tumor angiogenesis. In the present study, we aimed to clarify the role of stromal AEBP1/ACLP expression in oral squamous cell carcinoma (OSCC). Immunohistochemical analysis showed that ACLP is abundantly expressed in cancer-associated fibroblasts (CAFs) in primary OSCC tissues and that upregulated expression of ACLP is associated with disease progression. Analysis using CAFs obtained from surgically resected OSCCs showed that the expression of AEBP1/ACLP in CAFs is upregulated by co-culture with OSCC cells or treatment with TGF-ß1, suggesting cancer-cell-derived TGF-ß1 induces AEBP1/ACLP in CAFs. Collagen gel contraction assays showed that ACLP contributes to the activation of CAFs. In addition, CAF-derived ACLP promotes migration, invasion, and in vivo tumor formation by OSCC cells. Notably, tumor stromal ACLP expression correlated positively with collagen expression and correlated inversely with CD8+ T cell infiltration into primary OSCC tumors. Boyden chamber assays suggested that ACLP in CAFs may attenuate CD8+ T cell migration. Our results suggest that stromal ACLP contributes to the development of OSCCs, and that ACLP is a potential therapeutic target.

Systematic Review of Clinical Characteristics and Genotype-Phenotype Correlation in LAMB2-Associated Disease.

Introduction: Laminin subunit beta-2 (LAMB2)-associated disease, termed Pierson syndrome, presents with congenital nephrotic syndrome, ocular symptoms, and neuromuscular symptoms. In recent years, however, the widespread use of next-generation sequencing (NGS) has helped to discover a variety of phenotypes associated with this disease. Therefore, we conducted this systematic review. Methods: A literature search of patients with LAMB2 variants was conducted, and 110 patients were investigated, including 12 of our patients. For genotype-phenotype correlation analyses, the extracted data were investigated for pathogenic variant types, the severity of nephropathy, and extrarenal symptoms. Survival analyses were also performed for the onset age of end-stage kidney disease (ESKD). Results: Among all patients, 81 (78%) presented with congenital nephrotic syndrome, and 52 (55%) developed ESKD within 12 months. The median age at ESKD onset was 6.0 months. Kidney survival analysis showed that patients with biallelic truncating variants had a significantly earlier progression to ESKD than those with other variants (median age 1.2 months vs. 60.0 months, P < 0.05). Although the laminin N-terminal domain is functionally important in laminin proteins, and variants in the laminin N-terminal domain are said to result in a severe kidney phenotype such as earlier onset age and worse prognosis, there were no significant differences in onset age of nephropathy and progression to ESKD between patients with nontruncating variants located in the laminin N-terminal domain and those with variants located outside this domain. Conclusion: This study revealed a diversity of LAMB2-associated diseases, characteristics of LAMB2 nephropathy, and genotype-phenotype correlations.

Pyruvate kinase deficiency mutant gene carriage in stray cats and rescued cats from animal hoarding in Hokkaido, Japan.

The mutant allele frequency of the Pyruvate kinase (PK) gene has been investigated mostly in pure breed cats. We investigated the PK mutant gene in stray and animal hoarding mongrel cats in Hokkaido, Japan. We also investigated the kinship of individuals carrying the mutant gene. Genotyping was conducted using the previously reported real-time PCR method. Fourteen microsatellite markers were used to identify the parents and offspring of cats carrying the PK mutant gene, and some kinship such as parent-offspring and siblings was observed. Some stray and animal hoarding cats carried the PK mutation gene and that consanguinity was confirmed among these cats indicated that the PK mutation gene was spread by unregulated interbreeding.

Association of Familial Fanconi Syndrome with a Novel GATM Variant.

Fanconi syndrome is a disorder of the proximal renal tubule. Recently, advanced genetic analysis technology has revealed that several genes cause familial Fanconi syndrome. We identified a family with autosomal dominant Fanconi syndrome and chronic kidney disease with a novel glycine amidinotransferase (GATM) variant. Case 1 was a 57-year-old Japanese woman. Her father and two siblings had Fanconi syndrome or chronic kidney disease. She presented to our hospital at the age of 34 years with recurrent glucosuria. Her height and weight were 151 cm and 46.6 kg, respectively. Laboratory tests showed glucosuria, hypophosphatemia, hypouricemia, and normal renal function. Her serum creatinine level gradually increased over the following next two decades, and she developed end-stage renal disease. Case 2, the daughter of Case 1, was a 26-year-old woman. Her height and weight were 151 cm and 37.5 kg, respectively. Glucosuria was detected at the age of 13 years, which led to a referral to our hospital. Urinalysis showed low-molecular-weight proteinuria. She was diagnosed with Fanconi syndrome. At the age of 26 years, she had glucosuria, low-molecular-weight proteinuria, hypouricemia, and normal renal function. Genetic testing of both cases revealed a novel missense variant in GATM. The heterozygous missense variants in GATM have been reported to cause familial Fanconi syndrome, which manifests early in life and progresses to renal glomerular failure by mid-adulthood. The novel GATM variant detected in our cases was suspected to be associated with the development of Fanconi syndrome. GATM variants should be tested in patients with idiopathic Fanconi syndrome.

Long-term outcome of combination therapy with corticosteroids, mizoribine and RAS inhibitors as initial therapy for severe childhood IgA vasculitis with nephritis.

BACKGROUND: Patients with severe IgA vasculitis with nephritis (IgAVN) typically receive aggressive therapy as an initial approach. We have consistently performed combination therapy including corticosteroids and immunosuppressants as initial therapy for severe IgAVN over a 20-year-plus period, with only minor changes to the treatment protocol. This study seeks to reveal the efficacy of combination therapy for severe IgAVN. METHODS: We retrospectively studied 50 Japanese children diagnosed between 1996 and 2019 with clinicopathologically severe IgAVN who were defined as ISKDC classification grade IIIb-V and/or serum albumin < 2.5 g/dL. RESULTS: The median age at the onset of IgAVN was 8.0 years (IQR: 6.0-10.0). At biopsy, 44% of patients had nephrotic syndrome and 14% had kidney dysfunction. All patients were treated with combination therapy after biopsy. Abnormal proteinuria resolved after initial therapy in all 50 patients. However, eight patients (16%) had recurrence of proteinuria. Abnormal proteinuria was again resolved in three of these patients with additional treatment. At the last follow-up (median 59.5 months; IQR, 26.2-84.2), the median urine protein-to-creatine ratio was 0.08 g/gCr (IQR, 0.05-0.15), and only one patient had kidney dysfunction. CONCLUSIONS: Combination therapy provided good kidney outcomes for Japanese children with severe IgAVN. Even including recurrent cases, the degree of proteinuria was slight, and kidney function was good at the last follow-up. A higher resolution version of the Graphical abstract is available as Supplementary information.

All reported non-canonical splice site variants in GLA cause aberrant splicing.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by insufficient α-galactosidase A (GLA) activity resulting from variants in the GLA gene, which leads to glycosphingolipid accumulation and life-threatening, multi-organ complications. Approximately 50 variants have been reported that cause splicing abnormalities in GLA. Most were found within canonical splice sites, which are highly conserved GT and AG splice acceptor and donor dinucleotides, whereas one-third were located outside canonical splice sites, making it difficult to interpret their pathogenicity. In this study, we aimed to investigate the genetic pathogenicity of variants located in non-canonical splice sites within the GLA gene. METHODS: 13 variants, including four deep intronic variants, were selected from the Human Gene Variant Database Professional. We performed an in vitro splicing assay to identify splicing abnormalities in the variants. RESULTS: All candidate non-canonical splice site variants in GLA caused aberrant splicing. Additionally, all but one variant was protein-truncating. The four deep intronic variants generated abnormal transcripts, including a cryptic exon, as well as normal transcripts, with the proportion of each differing in a cell-specific manner. CONCLUSIONS: Validation of splicing effects using an in vitro splicing assay is useful for confirming pathogenicity and determining associations with clinical phenotypes.

Corrigendum to "Detecting MUC1 Variants in Patients Clinicopathologically Diagnosed With Having Autosomal Dominant Tubulointerstitial Kidney Disease"Kidney International Reports, Volume 7, Issue 4, April 2022, Pages 857-866.

[This corrects the article DOI: 10.1016/j.ekir.2021.12.037.].

Loss of viral genome with altered immune microenvironment during tumour progression of Epstein-Barr virus-associated gastric carcinoma.

Epstein-Barr virus (EBV) is one of the major drivers of gastric carcinogenesis. EBV infection is established before tumour initiation and is generally maintained throughout tumour development; however, the significance of EBV in tumour maintenance and progression remains to be elucidated. Here, we report eight cases of EBV-associated gastric carcinoma (EBVaGC) with intratumoural heterogenous expression of EBV-encoded small RNA (EBER), a highly expressed latent gene of EBV, and demonstrate clinicopathological characteristics of these rare cases. By performing detailed histological assessment of EBER-positive and -negative components of each case, detection of EBV genome in tumour cells by fluorescence in situ hybridisation, TP73 methylation analysis, whole exome sequencing, and targeted gene panel sequencing, we identified tumours in two patients to be collision tumours of different origins. In the other six patients, some genetic/epigenetic alterations were shared between EBER-positive and -negative components, suggesting that EBV was eliminated from tumour cells during progression. Interestingly, in both tumour types, programmed death ligand 1 and intratumoural infiltration of CD8+ T lymphocytes were lower in EBER-negative than in EBER-positive components, suggesting an immunogenic role of EBV. To the best of our knowledge, this study is the first to demonstrate the detailed histological features and genetic/epigenetic alterations in EBVaGC with heterogenous EBER expression; the loss of EBV may benefit tumour progression and immune evasion and might be clinically important for selecting treatment strategies for such cancers. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Numerical Study on Effect of Contact and Interfacial Resistance on Thermal Conductivity of Dispersed Composites.

A series of finite element analyses were conducted to clarify the effect of contact and interfacial resistance between constituents on effective thermal conductivities of dispersed composites. Equally dispersed fillers in FCC (face-centered cubic) and BCC (body-centered cubic) material systems were extracted from cyclic microstructures as unit cell models. In addition to spherical fillers, a polyhedron called the Wigner-Seitz cell that can realize a fully packed microstructure was chosen as the shape of the filler to investigate the effect of contact between the high volumetric fraction of fillers. The effective thermal conductivities of the resulting composites were calculated based on the FEA results and compared to the theoretical results for various volume fractions of the fillers including the maximum packing fraction. The following conclusions were obtained from the present study: 1. The effect of the contact depending on the shape and configuration of the fillers has more of a significant influence on the effective thermal conductivity than the influence of the increase in the volume fraction of the fillers. 2. When the contact occurred, the effective thermal conductivity became more than double that without contact. 3. Interfacial thermal resistance must be less than the order of 10-4 m2 K/W to obtain improvement in the effective thermal conductivity by compounding the fillers.

CXCL12 is expressed by skeletal muscle cells in tongue oral squamous cell carcinoma.

BACKGROUND: The CXCL12/CXCR4 axis plays a pivotal role in the progression of various malignancies, including oral squamous cell carcinoma (OSCC). In this study, we aimed to clarify the biological and clinical significance of CXCL12 in the tumor microenvironment of OSCCs. METHODS: Publicly available single-cell RNA-sequencing (RNA-seq) datasets were used to analyze CXCL12 expression in head and neck squamous cell carcinomas (HNSCC). Immunohistochemical analysis of CXCL12, α-smooth muscle antigen (α-SMA), fibroblast activation protein (FAP) and CD8 was performed in a series of 47 surgically resected primary tongue OSCCs. Human skeletal muscle cells were co-cultured with or without OSCC cells, after which CXCL12 expression was analyzed using quantitative reverse-transcription PCR. RESULTS: Analysis of the RNA-seq data suggested CXCL12 is abundantly expressed in stromal cells within HNSCC tissue. Immunohistochemical analysis showed that in grade 1 primary OSCCs, CXCL12 is expressed in both tumor cells and muscle cells. By contrast, grade 3 tumors were characterized by disruption of muscle structure and reduced CXCL12 expression. Quantitative analysis of CXCL12-positive areas within tumors revealed that reduced CXCL12 expression correlated with poorer overall survival. Levels of CXCL12 expression tended to inversely correlate α-SMA expression and positively correlate with infiltration by CD8+ lymphocytes, though these relations did not reach statistical significance. CXCL12 was significantly upregulated in muscle cells co-cultured with OSCC cells. CONCLUSION: Our results suggest that tongue OSCC cells activate CXCL12 expression in muscle cells, which may contribute to tumor progression. However, CXCL12 is reduced in advanced OSCCs due to muscle tissue destruction.

Aberrant splicing caused by exonic single nucleotide variants positioned 2nd or 3rd to the last nucleotide in the COL4A5 gene.

BACKGROUND AND OBJECTIVES: The evident genotype-phenotype correlation shown by the X-linked Alport syndrome warrants the assessment of the impact of identified gene variants on aberrant splicing. We previously reported that single nucleotide variants (SNVs) in the last nucleotide of exons in COL4A5 cause aberrant splicing. It is known that the nucleotides located 2nd and 3rd to the last nucleotides of exons can also play an essential role in the first step of the splicing process. In this study, we aimed to investigate whether SNVs positioned 2nd or 3rd to the last nucleotide of exons in COL4A5 resulted in aberrant splicing. METHODS: We selected eight candidate variants: six from the Human Gene Variant Database Professional and two from our cohort. We performed an in-vitro splicing assay and reverse transcription-polymerase chain reaction (RT-PCR) for messenger RNA obtained from patients, if available. RESULTS: The candidate variants were initially classified into the following groups: three nonsense, two missense, and three synonymous variants. Splicing assays and RT-PCR for messenger RNA revealed that six of the eight variants caused aberrant splicing. Four variants, initially classified as non-truncating variants, were found to be truncating ones, which usually show relatively more severe phenotypes. CONCLUSION: We revealed that exonic SNVs positioned 2nd or 3rd to the last nucleotide of exons in the COL4A5 were responsible for aberrant splicing. The results of our study suggest that attention should be paid when interpreting the pathogenicity of exonic SNVs near the 5' splice site.

Clinical and pathological investigation of oligomeganephronia.

BACKGROUND: Oligomeganephronia (OMN) is a rare congenital anomaly involving the kidney and urinary tract, characterized by decreased number and compensatory hypertrophy of the nephron. It is caused by abnormal kidney development during the embryonic period, especially in patients with low birth weight; however, the actual etiology and clinical features remain unknown. We aim to reveal the clinical and pathological characteristics, treatment, and outcome. METHODS: Ten patients diagnosed with OMN between 2013 and 2020 were retrospectively investigated. The data were presented as the median ± interquartile range, and statistical significance was set at p < 0.05. RESULTS: The age at diagnosis was 14.1 years, the male-to-female ratio was 6:4, and only four cases were born with low birth weight. The estimated glomerular filtration rate (eGFR) was 62.2 mL/min/1.73 m2. The glomerulus diameter of OMN patients was significantly larger (217 vs. 154 µm, p < 0.001) in OMN patients, and the number of glomeruli of OMN patients was lower (0.89 vs. 2.05/mm2, p < 0.001) than the control group. Eight of the ten cases were identified by urinary screening. Nine patients were treated with renin-angiotensin system (RAS) inhibitors, following which proteinuria successfully decreased or disappeared. Their median eGFR was also stable, 53.3 mL/min/1.73 m2. CONCLUSIONS: As few symptoms can lead to OMN discovery, most patients were found during urine screening at school. Kidney dysfunction was observed in all patients at the time of kidney biopsy. Proteinuria has been significantly reduced and the decline rate of eGFR might be improved by RAS inhibitors. "A higher resolution version of the Graphical abstract is available as Supplementary information".

[Hemophagocytic lymphohistiocytosis following mRNA-1273 COVID-19 vaccination].

A 34-year-old man with no medical history presented with fever 4 days after receiving the first dose of mRNA-1273 coronavirus disease 2019 (COVID-19) vaccine. He had no prior clinical evidence of severe acute respiratory syndrome coronavirus 2 infection and was negative for serial polymerase chain reaction testing. Ten days after vaccination, he was referred to our hospital because of no response to antibiotics and the emergence of neutropenia, thrombocytopenia, and liver dysfunction. Blood tests also showed elevated serum ferritin and plasma soluble interleukin-2 receptors. Serological and PCR testing excluded active infections of cytomegalovirus, Epstein-Barr virus, and hepatitis viruses. Blood culture yielded no growth. Computed tomography revealed mild hepatosplenomegaly and porta hepatis lymphadenopathy but no focus on infection. Bone marrow aspiration demonstrated hemophagocytosis but no infiltrating lymphoma cells. Immediately, 2-mg/kg intravenous methylprednisolone was commenced based on the presumptive diagnosis of hemophagocytic lymphohistiocytosis (HLH), leading to the rapid and durable improvement of his symptoms and laboratory data. Later, without other causes triggering hemophagocytosis, and with the close link between vaccination and disease onset, the final diagnosis of vaccination-induced secondary HLH was made. HLH after COVID-19 vaccination, though extremely rare, can occur regardless of the vaccine type. Therefore, clinicians should recognize and deal with this occasionally fatal adverse event.

Head and neck small-cell carcinoma: A multicenter study of 39 cases from 10 institutions.

Objective: Basal information of head and neck small-cell carcinoma (HNSmCC) including epidemiology, primary site, treatment, and prognosis remains sparse due to its rarity. We report here a multicenter retrospective study on the diagnosis, treatment, and outcomes of patients with HNSmCC. Materials and methods: This study involved 47 patients with HNSmCC from 10 participating institutions. Eight patients were excluded for whom no pathological specimens were available (n = 2) and for discrepant central pathological judgements (n = 6). The remaining 39 patients were processed for data analysis. Results: As pretreatment examinations, computed tomography (CT) was performed for the brain (n = 8), neck (n = 39), and chest (n = 32), magnetic resonance imaging (MRI) for the brain (n = 4) and neck (n = 23), positron emission tomography-CT (PET-CT) in 23 patients, bone scintigraphy in 4, neck ultrasonography in 9, and tumor markers in 25. Primary sites were oral cavity (n = 1), nasal cavity/paranasal sinuses (n = 16), nasopharynx (n = 2), oropharynx (n = 4), hypopharynx (n = 2), larynx (n = 6), salivary gland (n = 3), thyroid (n = 2), and others (n = 3). Stages were II/III/IV-A/IV-B/IV-C/Not determined = 3/5/16/6/5/4; stage IV comprised 69%. No patient had brain metastases. First-line treatments were divided into 3 groups: the chemoradiotherapy (CRT) group (n = 27), non-CRT group (n = 8), and best supportive care group (n = 4). The CRT group included concurrent CRT (CCRT) (n = 17), chemotherapy (Chemo) followed by radiotherapy (RT) (n = 5), and surgery (Surg) followed by CCRT (n = 5). The non-CRT group included Surg followed by RT (n = 2), Surg followed by Chemo (n = 1), RT alone (n = 2), and Chemo alone (n = 3). The 1-year/2-year overall survival (OS) of all 39 patients was 65.3/53.3%. The 1-year OS of the CRT group (77.6%) was significantly better compared with the non-CRT group (31.3%). There were no significant differences in adverse events between the CCRT group (n = 22) and the Chemo without concurrent RT group (n = 9). Conclusion: Neck and chest CT, neck MRI, and PET-CT would be necessary and sufficient examinations in the diagnostic set up for HNSmCC. CCRT may be recommended as the first-line treatment. The 1-year/2-year OS was 65.3%/53.3%. This study would provide basal data for a proposing the diagnostic and treatment algorithms for HNSmCC.

Impact after the Change from Voluntary to Universal Oral Rotavirus Vaccination on Consecutive Emergency Department Visits for Acute Gastroenteritis among Children in Kobe City, Japan (2016-2022).

Rotavirus (RV) is the leading cause of acute gastroenteritis (AGE), particularly in infants. In 2006, the high efficacy of oral RV vaccines (RVVs, RotarixTM and RotaTeqTM) was demonstrated. Voluntary RVV started in Japan in 2011, and in October 2020 were launched as universal oral RVVs in Japan. However, the impact of changes from voluntary to universal RVVs has not been studied in a primary emergency medical center in Japan. We investigated changes in the number of pediatric patients with AGE after introducing universal RVVs in our center. A clinical database of consecutive patients aged <16 who presented to Kobe Children's Primary Emergency Medical Center between 1 April 2016 and 30 June 2022 was reviewed. After implementing universal RVVs, fewer children presented with RV-associated AGE (the reduction of proportion of the patients in 2022 was −61.7% (all ages), −57.9% (<1 years), −67.8% (1−<3 years), and −61.4% (3−<5 years) compared to 2019). A similar decrease in those of age who were not covered by the universal RVV was observed. There was a significant decline in the number of patients with AGE during the RV season who presented to the emergency department after implementing universal RVVs.