Congenital cytomegalovirus infection in a preterm infant with 22q11.2 deletion syndrome and immunological abnormalities.

The 22q11.2 deletion syndrome has many complications; one of them is immunodeficiency. However, the time of onset and the degree of immunodeficiency can vary. We report a case of a preterm infant with congenital cytomegalovirus infection complicated with 22q11.2 deletion syndrome and immunological abnormalities. Ultrasonography revealed pulmonary atresia, ventricular septal defect, major aortopulmonary collateral artery, and thymic hypoplasia. His serum chemistry tests on admission revealed immunoglobulin G, A, and M levels of 1,547 mg/dL, 70 mg/dL, and 274 mg/dL, respectively. A surface antigen analysis of the peripheral lymphocytes using flow cytometry revealed the following: relatively low CD4-positive T-cell levels (18.1%; 1,767/µL), very high CD8-positive T-cell levels (58.9%; 5,751/µL), and CD4/CD8 ratio of 0.31. The level of T-cell receptor excision circles was relatively low at 17.5 copies/µL. After birth, the CD8-positive T-cell level began to gradually decrease, whereas the CD4/CD8 ratio began to increase. Thrombocytopenia, neutropenia, and skin petechiae were observed on admission. However, the condition improved. Treatment for congenital cytomegalovirus infection was not provided due to the absence of viremia. Unfortunately, the patient died suddenly on the 158th day of life, and the cause of death was unknown. To the best of our knowledge, no association between 22q11 deletion syndrome and cCMV has been described in the recent medical literature. According to the calculation, around one newborn infant who have both 22q11 deletion syndrome and cCMV infection will be born each year in Japan. Healthcare providers should pay more attention to this medical situation in the future.

Immediate postnatal prediction of death or bronchopulmonary dysplasia among very preterm and very low birth weight infants based on gradient boosting decision trees algorithm: A nationwide database study in Japan.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) poses a substantial global health burden. Individualized treatment strategies based on early prediction of the development of BPD can mitigate preterm birth complications; however, previously suggested predictive models lack early postnatal applicability. We aimed to develop predictive models for BPD and mortality based on immediate postnatal clinical data. METHODS: Clinical information on very preterm and very low birth weight infants born between 2008 and 2018 was extracted from a nationwide Japanese database. The gradient boosting decision trees (GBDT) algorithm was adopted to predict BPD and mortality, using predictors within the first 6 h postpartum. We assessed the temporal validity and evaluated model adequacy using Shapley additive explanations (SHAP) values. RESULTS: We developed three predictive models using data from 39,488, 39,096, and 40,291 infants to predict "death or BPD," "death or severe BPD," and "death before discharge," respectively. These well-calibrated models achieved areas under the receiver operating characteristic curve of 0.828 (95% CI: 0.828-0.828), 0.873 (0.873-0.873), and 0.887 (0.887-0.888), respectively, outperforming the multivariable logistic regression models. SHAP value analysis identified predictors of BPD, including gestational age, size at birth, male sex, and persistent pulmonary hypertension. In SHAP value-based case clustering, the "death or BPD" prediction model stratified infants by gestational age and persistent pulmonary hypertension, whereas the other models for "death or severe BPD" and "death before discharge" commonly formed clusters of low mortality, extreme prematurity, low Apgar scores, and persistent pulmonary hypertension of the newborn. CONCLUSIONS: GBDT models for predicting BPD and mortality, designed for use within 6 h postpartum, demonstrated superior prognostic performance. SHAP value-based clustering, a data-driven approach, formed clusters of clinical relevance. These findings suggest the efficacy of a GBDT algorithm for the early postnatal prediction of BPD.

Ventriculosubgaleal shunt placement for hydrocephalus in osteogenesis imperfecta with novel compound heterozygous CRTAP variants.

Osteogenesis imperfecta is characterized by frequent fractures, bone deformities, and other systemic symptoms. Severe osteogenesis imperfecta may progress to hydrocephalus; however, treatment strategies for this complication remain unclear. Here, we describe severe osteogenesis imperfecta in an infant with symptomatic hydrocephalus treated with ventriculosubgaleal shunt placement. Targeted next-generation sequencing revealed novel compound heterozygous CRTAP variants, i.e., NM_006371.5, c.241 G > T, p.(Glu81*) and NM_006371.5, c.923-2_932del. We suggest that ventriculosubgaleal shunt placement is an effective and safe treatment for hydrocephalus in patients with severe osteogenesis imperfecta.

Prolonged renal function impairment in infants born during the peri-viable period: A retrospective longitudinal cohort study.

BACKGROUND: The number of infants born during the peri-viable period who survive has been increasing. AIM: To clarify renal function in infants from the time of birth during the peri-viable period until their due date. STUDY DESIGN: This retrospective cohort study was conducted at a single center. SUBJECTS: We reviewed the data of infants born at ≤28 weeks of gestation between 2018 and 2022 at our hospital. The infants were divided into the following groups: born at 22-24 weeks vs. 25-28 weeks (appropriate-for-gestational age [AGA] infants), and AGA infants vs. small-for-gestational age (SGA) infants (born at 22-28 weeks). OUTCOME MEASURES: We compared the perinatal data and renal function of the infants from birth until their due date. RESULTS: Eighty-one infants were included. Their serum creatinine, fractional excretion of sodium, and urine glucose levels were high or positive soon after birth but gradually improved. The urine albumin level was significantly higher among AGA infants born at 22-24 weeks, even at term equivalent age, than among those born at 25-28 weeks. CONCLUSIONS: Persistent renal insufficiency was observed even around the term equivalent age in peri-viable infants. Follow-up data collected after the neonatal period should be investigated in these infants.

Assessment of patients' characteristics associated with the efficacy and safety of oral valganciclovir treatment for infants with symptomatic congenital cytomegalovirus disease.

INTRODUCTION: Insurance coverage for oral valganciclovir (VGCV) began in Japan in April 2023 on the basis of results, including our clinical trials for symptomatic congenital cytomegalovirus (CMV) disease. The VGCV treatment is available throughout Japan, so clinicians must consider the likelihood of hearing improvement and the possibility of neutropenia before dosing. MATERIALS AND METHODS: We performed a substudy of an investigator-initiated, single-arm, prospective, multicenter, clinical trial in which 24 infants with symptomatic congenital CMV disease were orally administered 16 mg/kg VGCV twice daily for 6 months as an intervention. We examined the infants' baseline characteristics associated with improved hearing impairment or a severely reduced neutrophil count. RESULTS: Of the 24 patients, 4 had normal hearing on assessment of their ear with the best hearing. Hearing impairment improved in 14 patients and did not respond to VGCV treatment in 6 patients at the 6-month hearing assessment. CMV DNA levels in plasma at baseline were higher in patients in whom hearing did not respond to treatment. A neutrophil count <500/mm3 occurred in 5 (21%) patients for the first 6 weeks and in 8 (33%) patients for the first 6 months. A neutrophil count at screening and the lowest neutrophil count over the 6 months showed the highest correlation (r = 0.477, p = 0.019). CONCLUSIONS: Infants with a low plasma viral load at screening tend to have an improvement in hearing impairment. Clinicians should be aware of neutropenia during VGCV treatment particularly in patients with a low neutrophil count during screening.

Prognostic impact of peripheral blood WT1 mRNA dynamics in patients with acute myeloid leukemia treated with venetoclax combination therapy.

BACKGROUND: Wilms' tumor gene 1 (WT1) mRNA quantification is a useful marker of measurable residual disease in acute myeloid leukemia (AML). However, whether monitoring the WT1 mRNA levels may predict the outcome of venetoclax (VEN) combination therapy in AML is not reported. This study aims to elucidate whether WT1 mRNA dynamics could predict long-term prognosis. METHODS: 33 patients with untreated or relapsed/refractory AML evaluated for peripheral blood WT1 dynamics in VEN combination therapy were analyzed. RESULTS: The median age was 73 years (range 39-87). Azacitidine was combined with VEN in 91% of patients. Overall, the median overall survival (OS) was 334 days (95% CI 210-482), and the complete remission (CR) plus CR with incomplete hematologic recovery rate was 59%. A 1-log reduction of WT1 mRNA values by the end of cycle 2 of treatment was associated with significantly better OS and event-free survival (EFS) (median OS 482 days vs. 237 days, p = 0.049; median EFS 270 days vs. 125 days, p = 0.02). The negativity of post-treatment WT1 mRNA value during the treatment was associated with significantly better OS and EFS (median OS 482 days vs. 256 days, p = 0.02; median EFS not reached vs. 150 days, p = 0.005). Multivariate analysis confirmed the significance of these two parameters as strong EFS predictors (HR 0.26, p = 0.024 and HR 0.15, p = 0.013, respectively). The increase in WT1 mRNA values was correlated with relapse. CONCLUSION: This study demonstrates that WT1 mRNA dynamics can be a useful marker for assessing long-term prognosis of VEN combination therapy for AML.

Proctoring System Enables Safe Induction of Robotic Gastrectomy: Short-term Outcomes of the First 10 Cases.

BACKGROUND/AIM: The Japan Society of Endoscopic Surgery (JSES) proctoring system was established to prevent serious pancreatic pressure injuries in Japan in 2019. To safely perform robotic gastrectomy (RG) in our hospital, which has no experience in robotic surgery, we conducted a clinical trial with the support of this proctoring system. PATIENTS AND METHODS: The present study was a single-center clinical prospective study. The primary endpoint was morbidity determined using Clavien-Dindo classification (C-D) Grade IIIa or higher. RESULTS: Ten patients, seven males and three females, were recruited in this study. RG was performed under the proctoring system of the JSES in the initial six cases and was completed independently for the remaining four patients. We successfully performed the initial ten cases without C-D classification grade IIIa or higher morbidities. CONCLUSION: This study underscores the significance of a proctoring system for introducing RG to facilities with limited experience in robotic surgery. Despite some limitations, this study demonstrated successful outcomes in the initial ten cases, emphasizing the benefits for both surgeons and patients. This study provides valuable insights into the safety of RG in small institutions and calls for further research in this area.

[Successful cord blood transplantation for refractory gamma-delta hepatosplenic T-cell lymphoma developed during treatment of Crohn's disease].

The patient was a 21-year-old man who had been diagnosed with Crohn's disease and received infliximab and azathioprine six years earlier. He was admitted with fever and fatigue. Peripheral blood examination showed LDH 2,473 U/l and thrombocytopenia, and contrast-enhanced computed tomography (CT) showed hepatosplenomegaly. Bone marrow biopsy and liver biopsy showed CD4+CD56+TCRγδ＋CD8- atypical cells, leading to a diagnosis of hepatosplenic T-cell lymphoma (HSTCL). The patient was refractory to CHOP and DA-EPOCH, and therefore received cord blood transplantation with myeloablative conditioning. CT showed reduced in hepatosplenomegaly and peripheral blood examination showed LDH 165 U/l and plt 180,000/µl, so the patient was discharged on day117. HSTCL is a tumor of immature γδT cells with a Vδ1 mutation in the spleen, and immunodeficiency has been implicated in its pathogenesis. Patients with inflammatory bowel disease treated with azathioprine are known to have an increased risk of lymphoproliferative disease. In this case, use of immunosuppressive drugs for Crohn's disease may have caused malignant transformation of γδ cells in the intestinal epithelium. Although the patient was refractory to chemotherapy, he was able to achieve remission with early cord blood transplantation and long-term survival is expected.

An interlaboratory study on the detection method for Escherichia albertii in food using real time PCR assay and selective agars.

Escherichia albertii is an emerging enteropathogen. Although E. albertii-specific detection and isolation methods have been developed, their efficiency on food samples have not yet been systematically studied. To establish a series of effective methods for detecting E. albertii in food, an interlaboratory study was conducted in 11 laboratories using enrichment with modified E. coli broth supplemented with cefixime and tellurite (CT-mEC), real-time PCR assay, and plating on four kinds of selective agars. This study focused on the detection efficiency of an E. albertii-specific real-time PCR assay (EA-rtPCR) and plating on deoxycholate hydrogen sulfide lactose agar (DHL), MacConkey agar (MAC), DHL supplemented with rhamnose and xylose (RX-DHL), and MAC supplemented with rhamnose and xylose (RX-MAC). Chicken and bean sprout samples were inoculated with E. albertii either at 17.7 CFU/25 g (low inoculation level) or 88.5 CFU/25 g (high inoculation level), and uninoculated samples were used as controls. The sensitivity of EA-rtPCR was 1.000 for chicken and bean sprout samples inoculated with E. albertii at low and high inoculation levels. The Ct values of bean sprout samples were higher than those of the chicken samples. Analysis of microbial distribution by 16S rRNA gene amplicon sequencing in enriched cultures of bean sprout samples showed that approximately >96 % of the population comprised unidentified genus of family Enterobacteriaceae and genus Acinetobacter in samples which E. albertii was not isolated. The sensitivity of the plating methods for chicken and bean sprout samples inoculated with a high inoculation level of E. albertii was 1.000 and 0.848-0.970, respectively. The sensitivity of the plating methods for chicken and bean sprout samples inoculated with a low inoculation level of E. albertii was 0.939-1.000 and 0.515-0.727, respectively. The E. albertii-positive rate in all colonies isolated in this study was 89-90 % in RX-DHL and RX-MAC, and 64 and 44 % in DHL and MAC, respectively. Therefore, the sensitivity of RX-supplemented agar was higher than that of the agars without these sugars. Using a combination of enrichment in CT-mEC and E. albertii isolation on selective agars supplemented with RX, E. albertii at an inoculation level of over 17.5 CFU/25 g of food was detected with a sensitivity of 1.000 and 0.667-0.727 in chicken and bean sprouts, respectively. Therefore, screening for E. albertii-specific genes using EA-rtPCR followed by isolation with RX-DHL or RX-MAC is an efficient method for E. albertii detection in food.

The importance of designing a protector for a preterm and low birth weight infant with ectopia cordis.

Ectopia cordis is a rare condition with expected low survival rate based on past studies. We encountered a case of a preterm and low birth weight infant with ectopia cordis. When the infant cried, the prolapse of the heart, liver, and intestinal tract worsened. A pressure-applying protector was used to protect the organs and reduce the prolapse. Upon application, the infant's tachypnea and desaturation worsened. Fluoroscopic examination suggested that the pressure from the prolapsed regions was impeding pulmonary expansion and negatively affecting circulation. It is essential to carefully design a protector that accommodates the infant's growth.

Geographical distribution of antimicrobial exposure among very preterm and very low birth weight infants: A nationwide database study in Japan.

OBJECTIVES: To examine spatial effects in neonatal care, we conducted a retrospective cohort study to investigate the geographical distribution of antimicrobial exposure among very preterm and very low birth weight infants in Japan. STUDY DESIGN: We utilized a nationwide claims database in Japan to extract prescriptions of injectable antimicrobials for 41,423 very preterm and very low birth weight infants admitted within the first two days of life from April 2010 to March 2021. We identified frequently prescribed antimicrobials, revealed early neonatal exposure and neonatal exposure to each antimicrobial agent by 47 prefectures in Japan, and evaluated their spatial autocorrelation using global and local Moran's I statistics. We then scrutinized regional disparities in antimicrobial drug prescriptions. RESULTS: The top 10 antimicrobials prescribed to very preterm and very low birth weight infants in Japan were ampicillin, amikacin, gentamicin, cefotaxime, fluconazole, ampicillin combination, micafungin, cefmetazole, cefazolin, and vancomycin. We identified northern cold spots for fluconazole exposure and southern hot spots for ampicillin, amikacin, gentamicin, and cefmetazole exposure. Geographical heterogeneity in the selection of antibacterial and antimycotic agents was observed. CONCLUSION: Our study revealed the geographical distribution of antimicrobial exposure among very preterm and very low birth weight infants in Japan, thus disclosing its spatial effects. Further research addressing the spatial effects of neonatal care is needed to understand how drug exposure affects the outcomes of preterm infants.

Development and evaluation of a rapid one-step high sensitivity real-time quantitative PCR system for minor BCR-ABL (e1a2) test in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL).

OBJECTIVE: Minimal residual disease assessment of BCR-ABL messenger ribonucleic acid levels is crucial in Philadelphia chromosome-positive acute lymphoblastic leukemia for prognosis and treatment planning. However, accurately quantifying minor BCR-ABL transcripts, which comprise 70% of Philadelphia chromosome-positive acute lymphoblastic leukemia cases, lacks a national-approved method. METHODS: We developed the "Otsuka" minor BCR-ABLmessenger ribonucleic acid assay kit with exceptional precision (0.00151%). Minor BCR-ABL messenger ribonucleic acid levels were analyzed in 175 adults, 36 children with acute lymphoblastic leukemia and 25 healthy individuals to evaluate the kit's performance. RESULTS: The "Otsuka" kit showed high concordance with a commonly used chimeric gene screening method, indicating reliable detection of positive cases. Quantitative results demonstrated a robust correlation with both a laboratory-developed test and a diagnostic research product. The "Otsuka" kit performs comparably or even surpass to conventional products, providing valuable insights into Philadelphia chromosome-positive acute lymphoblastic leukemia pathology. CONCLUSIONS: The 'Otsuka" minor BCR-ABL messenger ribonucleic acid assay kit exhibits excellent performance in quantifying minor BCR-ABL transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia patients. Our results align well with established screening methods and show a strong correlation with laboratory-developed tests and diagnostic research products. The "Otsuka" kit holds great promise as a valuable tool for understanding Philadelphia chromosome-positive acute lymphoblastic leukemia pathology and guiding effective treatment strategies.

Appropriate concentration setting for the intraoperative administration of indocyanine green for fluorescence imaging to identify the sentinel lymph node in early gastric cancer: a clinical pilot study.

PURPOSE: Some prospective trials have demonstrated the feasibility of sentinel node (SN) biopsy in gastric cancer (GC) surgery. This study aimed to identify the appropriate concentration settings for the intraoperative injection of indocyanine green (ICG) for SN biopsy. METHODS: Before the clinical studies, porcine model experiments explored the optimal concentration of ICG injected intraoperatively. Next, nine GC patients were enrolled in the clinical research. ICG (0.5 ml) was injected intraoperatively into four quadrants of the submucosa around the tumor at various concentrations (0.5, 0.25, and 0.1 mg/ml). The lymphatic basin dissection method was applied to the ICG-positive lymphatic areas. The number and location of the lymphatic basins and positive nodes were recorded intraoperatively. RESULTS: In the porcine model, the visibility gradually became clear at an ICG concentration higher than 0.1 mg/ml. In the clinical study, the average number of detected lymphatic basins was 3.3, 1.7, and 1.7, respectively. The mean number of detected SNs was 14.7, 6.7, and 4.0, respectively. CONCLUSION: To improve the reproducibility of SN biopsy, it is essential to prepare the correct concentration setting of ICG. Under current conditions in which ICG is injected intraoperatively, a 0.1 mg/ml concentration setting of ICG may be necessary and sufficient for SN identification.

[Sustaining molecular response with very low dose ponatinib and further response after hemodialysis initiation in a patient with chronic myeloid leukemia].

A 46-year-old man was diagnosed with chronic myeloid leukemia (CML) in chronic phase. He was treated with imatinib, nilotinib, and dasatinib, but failed to achieve a complete cytogenetic response (CCyR). After tyrosine kinase inhibitor therapy, F317L BCR-ABL1 kinase domain mutation was detected. At age 66, the patient started ponatinib (PON) at 45 mg/day, and achieved CCyR within three months. Subsequently, PON was tapered to 15 mg once weekly due to arterial-occlusive events. PON was discontinued after a 3-year deep molecular response (≥ MR4.5). However, the patient lost MR4.0 within two months, and PON (15 mg once weekly) was restarted. He achieved MR4.0 again within one month, and then a deeper molecular response (MR5.0) after starting dialysis therapy at the same PON dose. The trough value of PON (15 mg once weekly) was 5.8 ng/ml, which suppressed F317L mutation in the CML clone. Currently, the patient is 77 years old and is sustaining MR5.0. Chronic renal failure may cause hyperabsorption and metabolic retardation in patients receiving PON. Initiation of hemodialysis may improve homeostasis resulting in enhanced anti-tumor immunity against CML.

Management of bronchopulmonary dysplasia in Japan: A nationwide survey.

BACKGROUND: The incidence of bronchopulmonary dysplasia (BPD) and respiratory management practices for extremely low birth weight infants (ELBWIs) widely vary among institutions and countries. AIMS: To clarify the variation and characteristics of the current practices of Japanese neonatologists managing patients with BPD. STUDY DESIGN: Questionnaire-based survey. PARTICIPANTS: Level II and III perinatal centers certified by the Japan Society of Perinatal and Neonatal Medicine. OUTCOME MEASURES: Policies of the neonatal intensive care units (NICUs) regarding respiratory care and medications for BPD prevention and treatment. RESULTS: A total of 76 % of facilities (207/274) responded to our survey. The response rates of level III and II facilities were 91 % (102/112) and 35 % (105/296), respectively. INtubation-SURfactant-Extubation and Less Invasive Surfactant Administration methods were performed in 23 % (47/206) and 1 % (3/206) of facilities, respectively. For the prophylactic purpose, systemic and inhaled steroids were administered "frequently" or "occasionally" in 14 % (28/205) and 42 % (86/204) of NICUs, respectively. For the therapeutic purpose, systemic and inhaled steroids were administered "frequently" or "occasionally" in 84 % (171/204) and 29 % (59/204) of NICUs, respectively. Approximately half of the NICUs (99/202) used volume-targeted ventilation (VTV) "frequently" or "occasionally" in progressing BPD. High-frequency oscillation ventilation (HFOV) was used for progressing BPD "frequently" and "occasionally" in 89 % (180/202) of the facilities. CONCLUSIONS: Our study provided an overview and characteristics of BPD management in Japan in recent years. Noninvasive approaches with surfactant administration remain not widely used in Japan. HFOV is a widely accepted management for progressing BPD.

Clinical Course of a Rare Epstein-Barr Virus-Associated Smooth Muscle Tumor and Its Genomic Analysis.

Epstein-Barr virus (EBV) can rarely induce smooth muscle tumors (SMTs). A 20-year-old female patient underwent kidney transplantation for renal failure. Since then, she has been treated with immunosuppressants, including a calcineurin inhibitor, tacrolimus, and prednisolone, owing to the immunological rejection. Three years later, she developed large liver tumors (diameter >5 cm) and multiple small lung tumors that were identified as EBV-SMTs based on the results of liver biopsy/histopathology. No intervention was performed except for the addition of a mammalian target of the rapamycin inhibitor, everolimus, which inhibits both immune reaction and SMT growth. Finally, after 8 years, the transplanted kidney became nonfunctional, and immunosuppressant administration became unnecessary as urinary dialysis was started. Under these circumstances, SMT growth was observed despite the absence of immunosuppressant administration. Three months after the cessation of the immunosuppressants, EBV-SMTs in the liver and lungs shrank slightly. To the best of our knowledge, this is the first report on the genomic profile of this rare tumor. The clinical course of our patient indicates that EBV can induce SMTs, and immunological suppression of EBV may inhibit the activity of these tumors.

[Next treatment for TKI-resistant CML].

Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML) in the chronic phase. However, only 50-60% of patients stay on the same TKI for 5 years, and the long-term progression-free survival rate is significantly reduced if an early molecular response is not achieved. Possible mechanisms of therapeutic resistance against BCR::ABL1 dependent clones include point mutations in the ABL1 kinase domain, BCR::ABL1 splicing variants, BCR::ABL1 overexpression, and altered pharmacokinetics by the ABC transporter. Ponatinib, the most potent inhibitor among TKIs, and the STAMP inhibitor asciminib are important drugs for overcoming BCR::ABL1-dependent resistance.