A novel NFKB1 variant in a Japanese pedigree with common variable immunodeficiency.

Recently, heterozygous loss-of-function NFKB1 variants were identified as the primary cause of common variable immunodeficiency (CVID) in the European population. However, pathogenic NFKB1 variants have never been reported in the Japanese population. We present a 29-year-old Japanese woman with CVID. A novel variant, c.136 C > T, p.(Gln46*), was identified in NFKB1. Her mother and daughter carried the same variant, demonstrating the first Japanese pedigree with an NFKB1 pathogenic variant.

Anatomical analysis of ligaments surrounding calcaneocuboid joint; implications for role in foot stability.

PURPOSE: The calcaneocuboid joint is located in the lateral part of the foot and acts as a major stabilizer for the foot. Injuries to this joint often occur in association with ankle or foot injuries and are frequently overlooked, subsequently causing chronic pain or osteoarthritis. However, the relationship between ligaments surrounding the joint and joint instability remains unclear. Therefore, this study aimed to clarify the morphology and position of the ligaments surrounding the calcaneocuboid joint, and to reveal the relationship between the ligament structure. METHODS: The position and morphology of the bifurcate ligament (subdivided into calcaneonavicular and calcaneocuboid ligaments), dorsal calcaneocuboid ligament, lateral calcaneocuboid ligament, long plantar ligament, and short plantar ligament were measured (N = 11 feet in 6 Japanese cadavers). The circumference of the joint was quartered, while the ligament-uncovered area and the estimated cross-sectional area of each ligament were compared between the four sides. Furthermore, the estimated cross-sectional area of each ligament was calculated as an index for the ligament strength. RESULTS: The inferolateral side of the calcaneocuboid joint had the most uncovered area (54.63%) by the ligaments. In addition, the cross-sectional area of the ligaments on the lateral side was considerably smaller than that on the medial side. CONCLUSION: Our results suggest that ligament weakness on the inferolateral side may cause instability of the calcaneocuboid joint, especially after an inversion sprain injury, and may decrease the lateral longitudinal arch function, which results in chronic foot pain.

[Colitis Suggested to be Related to Nivolumab in a Gastric Cancer Patient with a History of Ulcerative Colitis: A Case Report].

We experienced a case in which long-term use of nivolumab in a patient with a history of ulcerative colitis led to disease control of gastric cancer. The case is a 77-year-old man. The patient had a history of ulcerative colitis and remained in remission on mesalazine 1500 mg/d. With continuous monitoring, nivolumab could be continued up to 16 courses, but was withdrawn due to the appearance of diarrhea (grade 1) and bloody stools, which was relieved with prednisolone (PSL) 40 mg/d. After two more courses, diarrhea (grade 3) appeared again, which improved with PSL 60 mg/d and increased dose of mesalazine. It is difficult to distinguish whether colitis that occurs after nivolumab administration is due to relapse exacerbation or irAE. The onset of irAE colitis is often reported within 3 months, and the fact that this patient developed irAE colitis after 8 months, despite having ulcerative colitis, is considered novel. In the future, we hope to accumulate cases so that immune checkpoint inhibitors can be used safely in patients with ulcerative colitis, and to establish appropriate methods for their use.

Age of Adolescent Female Soccer Players at First Ankle Sprain and Menarche.

Objectives: : To provide targeted interventions for the prevention of first ankle sprains, this study determined the prevalence of ankle sprains in female adolescent soccer players and analyzed the correlation between the age at the first occurrence of ankle sprain and the age at menarche. Methods: : The study included 131 female participants from three club teams. The mean age was 13.37 ± 0.96 years. A survey was conducted using a questionnaire that requested information regarding the age at which the first ankle sprain occurred, age at menarche, status of ankle problems, extent to which the ankle joint problem affected playing ability, use of medical facilities or other healthcare facilities for the first or recurrent ankle sprains, and methods used to care for their ankle. Results: Ankle sprains most commonly occurred for the first time at 12 years, followed by the ages of 13, 10, and 11 years. About 25% of participants experienced their first ankle sprain at the age of menarche, 20% at 1 year after menarche, and 16% a year before menarche. The incidence of the first ankle sprain was high in the second and fifth years after starting to play soccer. Medical treatment was rarely received for the second or subsequent injury, although 36% had some sequelae. Conclusions: Adolescent female soccer players were not injured early in their soccer careers. Most players experienced their first ankle sprain at the age of 12 years, which was at or close to the age of menarche.

Leg and Joint Stiffness of the Supporting Leg during Side-Foot Kicking in Soccer Players with Chronic Ankle Instability.

Soccer players with chronic ankle instability (CAI) may stabilize their supporting leg by the proximal joint to compensate for the ankle instability during kicking motion. This study aimed to investigate the characteristics of leg and joint stiffness of the supporting leg during side-foot kicking in soccer players with CAI. Twenty-four male collegiate-level soccer players with and without CAI participated in this study. The kinematic and kinetic data were obtained using a three-dimensional motion analysis system. Leg stiffness and joint (hip, knee, and ankle) stiffness in the sagittal and frontal planes were calculated and analyzed. The results clarified that soccer players with CAI (0.106 ± 0.053 Nm/°) had greater knee stiffness in knee adduction during the kicking cycle compared to those without CAI (0.066 ± 0.030 Nm/°; p = 0.046), whereas no characteristic differences were observed in knee stiffness in knee flexion and hip and ankle stiffness (p > 0.05). Knee stiffness is believed to occur to compensate for ankle joint instability in the supporting leg. Therefore, adjusting knee stiffness to accommodate ankle joint instability is crucial for maintaining kicking performance. Based on results of this study, it may be important to consider training and exercises focused on joint coordination to improve knee stiffness in soccer players with CAI.

Higher levels of minimal residual disease in peripheral blood than bone marrow before 1st and 2nd relapse/regrowth in a patient with high­risk neuroblastoma: A case report.

More than half of patients with high-risk neuroblastoma (HR-NB) experience relapse/regrowth due to the activation of chemoresistant minimal residual disease (MRD). MRD in patients with HR-NB can be evaluated by quantitating neuroblastoma-associated mRNAs (NB-mRNAs) in bone marrow (BM) and peripheral blood (PB) samples. Although several sets of NB-mRNAs have been shown to possess a prognostic value for MRD in BM samples (BM-MRD), MRD in PB samples (PB-MRD) is considered to be low and difficult to evaluate. The present report describes an HR-NB case presenting higher PB-MRD than BM-MRD before 1st and 2nd relapse/regrowth. A 3-year-old female presented with an abdominal mass, was diagnosed with HR-NB, and treated according to the nationwide standard protocol for HR-NB. Following systemic induction and consolidation therapy with local therapy, the patient achieved complete remission but experienced a 1st relapse/regrowth 6 months after maintenance therapy. The patient partially responded to salvage chemotherapy and anti-GD2 immunotherapy but had a 2nd relapse/regrowth 14 months after the 1st relapse/regrowth. Consecutive PB-MRD and BM-MRD monitoring revealed that PB-MRD was lower than BM-MRD at diagnosis (100 times) and 1st and 2nd relapse/regrowth (1,000 and 3 times) but became higher than BM-MRD before 1st and 2nd relapse/regrowth. The present case highlights that PB-MRD can become higher than BM-MRD before relapse/regrowth of patients with HR-NB.

Muscle Activity Characteristics of the Pronator Teres during Throwing in Baseball Pitchers: A Pilot Study.

The pronator teres muscle is a major dynamic stabilizer of elbow valgus stress during throwing. This study aims to investigate pronator teres muscle activation during breaking ball pitching in baseball pitchers. Twelve male college baseball players with more than eight years of baseball experience were included in this study. A wireless surface electromyography (EMG) system was used to measure the activation of the forearm muscles and record EMG data during fastball and curveball pitching. Peak pronator teres muscle activation during curveball pitching was greater than that during fastball pitching (p = 0.03). There was no difference in the muscle activation of the other forearm muscles (p > 0.05). These results indicate that increased muscle activity in the pronator teres may contribute to stiffness and induce pronator teres syndrome or medial elbow injuries related to the overuse of the pronator teres, especially during curveball pitching. Controlling curveball throws contributes to player coaching and conditioning for the prevention of elbow joint disorders and pronator teres syndrome.

Spindle cell sarcoma with KIAA1549-BRAF resembling infantile fibrosarcoma morphologically: A case report and literature review.

Infantile fibrosarcoma (IFS) commonly harbors ETS variant transcription factor 6 (ETV6)-neurotrophic receptor tyrosine kinase 3 (NTRK3) fusion. However, the recent accessibility to clinical next-generation sequencing (NGS) has revealed ETV6-NTRK3 negative spindle cell sarcomas resembling IFS morphologically, involving NTRK1/2, MET, RET and BRAF. The present report describes a pediatric case of spindle cell sarcoma with KIAA1549-BRAF resembling IFS morphologically. A 20-month-old female patient was referred to Kobe Children's Hospital (Kobe, Japan) for the treatment of intrathoracic spindle cell sarcoma. Pathologically, the intrathoracic tumor cells were composed of spindle cells with focal hemagiopericytomatous pattern. In immunohistochemistry analysis, the intrathoracic tumor cells focally expressed desmin and WT-1 and were negative for pan-tropomyosin receptor kinase (TRK), S-100 and CD34. Fluorescence in situ hybridization analysis for ETV6 and capicua transcriptional repressor revealed negative split signals. Although the patient was initially diagnosed with IFS morphologically, KIAA1549-BRAF fusion transcript was detected by comprehensive genomic profiling with NGS using intrathoracic tumor tissues and confirmed by reverse transcription-PCR. Chemotherapy induced a reduction in the tumor size. At present, the patient is alive with the disease and has been receiving therapy for 8 months since the initiation of chemotherapy. Review of BRAF-altered spindle cell sarcomas resembling IFS morphologically revealed the inconsistency in immunohistochemical expression patterns and the diversity of BRAF fusion genes and mutations. Therefore, the elucidation of genomic profiling by NGS may assist in making an appropriate diagnosis and selecting novel alternative therapies in ETV6-NTRK3-negative spindle cell sarcomas resembling IFS morphologically.

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.

Minimal residual disease detected by droplet digital PCR in peripheral blood stem cell grafts has a prognostic impact on high-risk neuroblastoma patients.

More than half of high-risk neuroblastoma (NB) patients have experienced relapse due to the activation of chemoresistant minimal residual disease (MRD) even though they are treated by high-dose chemotherapy with autologous peripheral blood stem cell (PBSC) transplantation. Although MRD in high-risk NB patients can be evaluated by quantitative PCR with several sets of neuroblastoma-associated mRNAs (NB-mRNAs), the prognostic significance of MRD in PBSC grafts (PBSC-MRD) is unclear. In the present study, we collected 20 PBSC grafts from 20 high-risk NB patients and evaluated PBSC-MRD detected by droplet digital PCR (ddPCR) with 7NB-mRNAs (CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNA). PBSC-MRD in 11 relapsed patients was significantly higher than that in 9 non-relapsed patients. Patients with a higher PBSC-MRD had a lower 3-year event-free survival (P = 0.0148). The present study suggests that PBSC-MRD detected by ddPCR with 7NB-mRNAs has a prognostic impact on high-risk NB patients.

Biomechanical Characteristics of the Support Leg During Side-Foot Kicking in Soccer Players With Chronic Ankle Instability.

Background: Chronic ankle instability (CAI) in soccer players can increase the risk of recurrent ankle varus sprains and damage the articular surface of the ankle joint, thus increasing the risk of osteoarthritis. It is important to understand the biomechanical characteristics of the support leg during kicking in soccer players with CAI. Purpose/Hypothesis: The purpose of this study was to clarify the kinematics of the kicking motion of soccer players with CAI. It was hypothesized that at the point before ball contact when the support leg makes flat-foot contact with the ground, soccer players with CAI will land with ankle inversion in the support leg during a side-foot kick compared with players without CAI. Study Design: Controlled laboratory study. Methods: The study cohort included 19 male college soccer players (mean age, 20.5 ± 0.9 years) with greater than 8 years of soccer experience who were recruited from August 2019 to March 2020. Of these athletes, 10 had CAI and 9 had no CAI in the support leg, as diagnosed according to the Cumberland Ankle Instability Tool. Kinematic data for the trunk, hip, knee, and foot of the support leg during a side-foot kick were obtained using a 3-dimensional, motion-analysis system. The Mann-Whitney U test or Student t test was selected to identify differences in variables between the CAI and non-CAI groups. Results: There were no significant differences in physical characteristics between the CAI and non-CAI groups. At the point when the support leg made flat-foot contact with the ground, the players with CAI had more eversion of the hindfoot with respect to the tibia (-28.3° ± 12.1° vs -13.9° ± 14.2°; P = .03), a more varus alignment of the knee (26.0° ± 10.7° vs 13.7° ± 10.5°; P = .03), and a lower arch height index (0.210 ± 0.161 vs 0.233 ± 0.214; P = .046) compared with non-CAI players. Conclusion: Significant differences between players with and without CAI were seen in the support leg kinematics at flat-foot contact with the ground during the kicking cycle. Clinical Relevance: The biomechanical alignment of the support leg during a side-foot kick in players with CAI may reflect a subconscious attempt to avoid inversion of the foot and further ankle sprains.

A retrospective survey of patients who discontinued participation in the JPLSG HLH-2004 clinical trial.

Although clinical trials have reported an improvement in the prognosis of hemophagocytic lymphohistiocytosis (HLH), current treatment outcomes are unsatisfactory, especially in severe cases. Most clinical trial patients with severe disease discontinue participation due to complications associated with HLH or treatment-related toxicity. A retrospective survey of patients who discontinued participation in the JPLSG HLH-2004 clinical trial was conducted to review the detailed course of these cases to optimize HLH treatment and supportive care. Findings in these patients were compared with those of 45 patients who completed the protocol treatment. The 3 year overall survival rate of patients who completed treatment was 86.7%, versus 50.7% for those who did not complete treatment. Incidence of serious adverse events, such as infections, coagulopathy, and posterior reversible encephalopathy syndrome, during the initial 8 weeks of treatment was much higher in patients who did not complete treatment than in patients who completed treatment. To improve overall outcomes of patients with HLH, it is important to not only optimize HLH-directed therapy but also provide appropriate supportive care.

Preemptive hematopoietic cell transplantation for asymptomatic patients with X-linked lymphoproliferative syndrome type 1.

Few reports have examined whether prophylactic allogeneic hematopoietic cell transplantation (HCT) for X-linked lymphoproliferative syndrome type 1 (XLP1) improves the prognosis. We compared the prognosis of symptomatic probands and affected siblings in the same family. Twenty-two cases (10 probands and 12 affected siblings) in Japan, the United Kingdom, and the United States were analyzed. The overall survival (OS) rate at 5 years after diagnosis was 70.0% in probands and 91.7% in affected siblings (p = 0.0789). The prognosis of patients who developed symptoms of XLP1 before HCT and those who did not was also compared. The 5-year probability of OS from the time of diagnosis in asymptomatic patients (100%) was significantly better than that in symptomatic patients (66.7%). These results suggested that early HCT as soon as the diagnosis is made improves the prognosis in asymptomatic XLP1 patients.

Multivariate analysis of the impact of weather and air pollution on emergency department visits for unprovoked seizure among children: A retrospective clinical observational study.

BACKGROUND: An unprovoked seizure is a seizure or a cluster of seizures occurring within 24 h in a patient older than 1 month of age without precipitating factors. Recent studies have reported that extrinsic factors, such as meteorological conditions and air pollutants, may be important in seizure occurrence. Thus, this study aimed to examine the association between the number of visits to the emergency department (ED) by children for nighttime unprovoked seizures and exposure to multi-faceted factors, such as meteorological conditions and air pollution. METHODS: We conducted a clinical observational analysis and reviewed consecutive patients younger than 16 years of age who visited the primary ED center in Kobe City, Japan, during nighttime (7:30 p.m.-7:00 a.m.) between January 1, 2011 and December 31, 2015. We investigated the effects of meteorological factors and air pollutants on the number of patients with unprovoked seizures using multivariate analysis of Poisson regression estimates. RESULTS: In total, 151,119 children visited the ED, out of which 97 patients presented with unprovoked seizures. The mean age of the patients was 4.7 years (range, 1 month to 15.3 years), and 54.6% of them were boys. The total number of patients with unprovoked seizures showed no significant changes with the seasons; however, there were dominant peaks during the fall and fewer visits during the summer. The multivariate analysis of Poisson regression estimates revealed a significant positive relationship between the number of patients presenting with unprovoked seizures and precipitation (+1 patient/87 mm; p = 0.03) and methane (+1 patient/0.14 ppm; p = 0.03) levels and a negative relationship between the number of patients presenting with unprovoked seizures and nitrogen dioxide level (-1 patient/0.02 ppm; p = 0.04). CONCLUSIONS: The present study is the first to evaluate the association between the number of children who presented to the ED with nighttime unprovoked seizures and environmental factors after controlling for confounding factors.

[Side Effect Management in the Early Stages of Cabozantinib Administration].

In 2 patients with postoperative lung metastases from renal cell carcinoma, we administered cabozantinib at a starting dose of 40 mg. The side effects were proteinuria(Grade 2), hand-foot syndrome(Grade 2), and hypertension(Grade 3), which subsided following dose reduction and drug suspension. We believe that a low starting dose of cabozantinib might be a suitable regimen for advanced renal cell carcinoma.

Contribution of Lower Extremity Joints on Energy Absorption during Soft Landing.

Soft landing after jumping is associated with the prevention of lower extremity injuries during sports activities in terms of the energy absorption mechanisms. In this study, the contribution of lower extremity joints during soft landing was investigated. Subjects comprised 20 healthy females. Kinetics and kinematics data were obtained during drop vertical jumps using a three-dimensional motion analysis system. Negative mechanical work values in the lower extremity joints were calculated during landing. A multiple regression analysis was performed to determine which lower extremity joints contributed more in achieving soft landing. The means of mechanical work of the hip, knee, and ankle in the sagittal plane were -0.30 ± 0.17, -0.62 ± 0.31, and -1.03 ± 0.22 J/kg, respectively. Results showed that negative mechanical work in the hip and knee is effective in achieving soft landing. These findings indicate that energy absorption in the hip and knee joints might be an important factor in achieving soft landing, whereas that in the ankle has a negative effect. Therefore, when improving soft landing techniques, we should consider energy absorption in the hip and knee via eccentric activation of the hip and knee extensors during landing.

Evaluation of the relationship between history of lower back pain and asymmetrical trunk range of motion.

BACKGROUND: Low back pain (LBP) is a common complaint and preventive measures should be considered immediately. In addition, asymmetrical trunk motion, which occurs due to repetitive motion upon performing daily activities, may be one of the biomechanical factors to cause LBP. OBJECTIVE: To investigate the characteristics of asymmetrical trunk motion in women with a history of LBP. METHODS: Thirty-four women were dichotomously categorized into either the LBP or non-LBP group. Trunk active range of motion (RoM) upon sitting and standing were measured via a three-dimensional motion analysis system. Each RoM and rotation and side-flexion asymmetries were calculated and an unpaired t-tests were used to identify differences between each group. RESULTS: Trunk rotation asymmetry upon sitting and standing position in LBP group was significantly greater than that in non-LBP group. Furthermore, trunk rotation angle upon sitting in LBP group was significantly larger than that in non-LBP group. CONCLUSIONS: The limited RoM and asymmetry of trunk rotation may be due to imposed repetitive mechanical stress on habitual excessive motion, including most asymmetrical movements. Our findings indicated that a small trunk rotation angle and asymmetrical trunk rotation may be useful parameters to predict LBP onset or other musculoskeletal conditions of the trunk.

Limited correlation between tumor markers and minimal residual disease detected by seven neuroblastoma-associated mRNAs in high-risk neuroblastoma patients.

Vanillylmandelic acid (VMA), homovanillic acid (HVA), neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) are classical tumor markers and are used as standard clinical evaluations for patients with neuroblastoma (NB). Minimal residual disease (MRD) can be monitored by quantifying several sets of NB-associated mRNAs in the bone marrow (BM) and peripheral blood (PB) of patients with NB. Although MRD in BM and PB has been revealed to be a strong prognostic factor that is independent of standard clinical evaluations, its interrelation with tumor markers remains uncharacterized. The present study determined the levels of tumor markers (VMA, HVA, NSE and LDH) and MRD (BM-MRD and PB-MRD) in 133 pairs of concurrently collected BM, PB and urine samples from 19 patients with high-risk NB. The patients were evaluated during the entire course of treatment, which included 10 diagnoses, 32 treatments, 36 post-treatment, 9 relapses and 46 post-relapse sample pairs. The level of BM-MRD and PB-MRD was determined by quantifying 7 NB-mRNAs (collapsin response mediator protein 1, dopamine beta-hydroxylase, dopa decarboxylase, growth-associated protein 43, ISL LIM homeobox 1, pairedlike homeobox 2b and tyrosine hydroxylase) using droplet digital PCR. In overall sample pairs, tumor markers (VMA, HVA, NSE and LDH) demonstrated weak but significant correlations (P<0.011) with BM-MRD and PB-MRD. In subgroups according to each patient evaluation, the degree of correlation between tumor markers and MRD became stronger in patients with adrenal gland tumors, BM metastasis at diagnosis and relapse/regrowth compared with overall sample pairs. In contrast, tumor markers demonstrated variable correlations with MRD in subgroups according to each sample evaluation (BM infiltration at sampling, collection time point and disease status). The results suggested that tumor markers may demonstrate limited correlation with MRD in patients with high-risk NB.

Minimal residual disease in high-risk neuroblastoma shows a dynamic and disease burden-dependent correlation between bone marrow and peripheral blood.

Neuroblastoma (NB) is the most common extracranial solid tumor in children and originates from sympathoadrenal or Schwann cell precursors derived from neural crest. These neural crest derivatives also constitute the hematopoietic and mesenchymal stem cells in bone marrow (BM) that is the most frequent site of NB metastasis and relapse. In NB patients, NB cells have been pathologically detected in BM and peripheral blood (PB), and minimal residual disease (MRD) in BM and PB (BM-MRD and PB-MRD) can be monitored by quantitating several sets of NB-associated mRNAs (NB-mRNAs). Although previous studies have shown varying degrees of correlation between BM-MRD and PB-MRD, the underlying factors and/or mechanisms remains unknown. In the present study, we determined the levels of BM-MRD and PB-MRD by quantitating seven NB-mRNAs in 133 pairs of concurrently collected BM and PB samples from 19 high-risk NB patients with clinical disease evaluation, and examined their correlation in overall and subgroups of sample pairs. The levels of BM-MRD and PB-MRD were moderately (r = 0.418, p < 0.001) correlated with each other in overall sample pairs. The correlation became strong (r = 0.725, p < 0.001), weak (r = 0.284, p = 0.008), and insignificant (p = 0.194) in progression, stable, and remission subgroups of sample pairs, respectively. It also became stronger in subgroups of sample pairs with poor treatment responses and poor prognostic factors. Present study suggests that MRD in high-risk NB shows a dynamic and disease burden-dependent correlation between BM and PB.