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Purpose: The "out-of-hours effect," which indicates hospital admittance during weekends or nighttime, has poorer outcomes for patients than for those admitted on weekdays and is widely documented in various medical conditions. However, this effect remains understudied in pediatric trauma cases, including blunt liver and spleen injuries (BLSIs)., Methods: This was a secondary analysis of a nationwide multicenter retrospective study, focusing on pediatric patients with trauma (≤ 16 years old) with BLSI admitted from 2008 to 2019. This study evaluated the association between out-of-hour admissions and outcomes. The primary outcome was the intervention rate and secondary outcomes were 30-day mortality and time from hospital arrival to the first intervention., Results: This study identified 1414 pediatric patients with BLSI. In total, 681 events occurred during the daytime and 733 during the nighttime, with 927 weekday and 487 weekend events. Out-of-hour admissions did not significantly associate with a higher rate of intervention. This association remained after adjusting for five potential confounders and patient clustering within the hospital. In addition, Out-of-hour admissions did not significantly associated with 30-day mortality, or time from hospital arrival to the first intervention., Conclusions: The current study showed no significant difference in treatment strategy and outcomes between weekday and out-of-hour among children with BLSI., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Hyponatremia can occur in the acute phase of any illness through various mechanisms. However, the frequency and severity of hyponatremia are not well known across a broad range of illnesses including medical and surgical diseases and trauma., Methods: The present, retrospective chart review was conducted at Tokyo Metropolitan Children's Medical Center from 2018 to 2019. Included were healthy children aged < 16 years with an acute illness, who were urgently admitted, and had their serum sodium level measured on arrival., Results: In total, 2717 patients were urgently admitted and had their serum sodium level measured. Of these, 1890 were included. Hyponatremia was found in 260 patients (13.8%). The most common hyponatremic disease was type 1 diabetes mellitus (69%) followed by acute infectious encephalopathy (60%), pyogenic arthritis (60%), and Kawasaki disease (51%). Kawasaki disease, seizure, urinary tract infection, acute appendicitis, lower respiratory tract infection, and acute gastroenteritis were associated with a significantly lower serum sodium value than cases of fracture comprising a control group. Conversely, acute bronchial asthma exacerbation (3%), anaphylaxis (0%), intussusception (0%), acute scrotal disease (0%), head injury (1%), and fracture (0%) were very infrequently associated with hyponatremia., Conclusions: The present study determined the frequency and severity of hyponatremia in various, acute, pediatric illnesses, including medical and surgical diseases and trauma. Despite reports of respiratory distress and pain inducing vasopressin secretion, hyponatremia was rarely observed on arrival in patients with acute bronchial asthma exacerbation, anaphylaxis, intussusception, acute scrotal diseases, head injury, or fracture., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Competing Interests: The authors have no funding or conflicts of interest to disclose.

Objectives: Hemorrhagic events are a rare but potentially fatal complication in patients with polycythemia vera (PV)., Methods: We analyzed the characteristics of hemorrhagic events in 267 patients with PV., Results: A median follow-up of 4.8 years revealed that 23 (8.6%) hemorrhagic events occurred. Significantly more hemorrhagic events occurred in younger patients aged below 60 years (n = 72) than in older patients aged 60 years or above (n = 191) (n = 12 [16.7%] vs. n = 11 [5.8%], respectively, P  = 0.012). In univariate analysis among the younger patients, white blood cell (WBC) count ≥ 15 × 10 9 /L (hazard ratio [HR] = 7.746, 95% confidence interval [CI] 2.082-28.830, P  = 0.002), palpable splenomegaly (HR = 5.629, 95% CI 1.193-26.550, P  = 0.029), and JAK2 V617F allele burden ≥ 80% (HR = 22.850, 95% CI 2.885-181.00, P  = 0.003) were associated with an increased risk of hemorrhagic events. In multivariate analysis, JAK2 V617F allele burden ≥ 80% (HR = 9.394, 95% CI 1.046-84.380, P  = 0.046) was a significant risk factor., Conclusions: There is an increased risk of hemorrhagic events after diagnosis in younger PV patients with a high JAK2 V617F allele burden, high WBC count or palpable splenomegaly. It is important to consider treatment options that aim to avoid hemorrhagic events by reducing the JAK2 V617F allele burden in younger PV patients.

Ropeginterferon alfa-2b (ropegIFN), a new-generation interferon-based agent, has been approved in Japan for patients with polycythemia vera (PV) who are ineligible for or respond inadequately to conventional treatment. However, long-term outcomes with ropegIFN in Japanese patients have not been reported. This extension of a phase 2 study of ropegIFN in Japanese patients with PV aimed to determine its long-term safety/efficacy, and changes over time in JAK2 V617F allele burden. Here, we report data from the phase 2 study and subsequent extension over a period of 36 months. The primary endpoint was the complete hematologic response (CHR) maintenance rate without phlebotomy (hematocrit value < 45% without phlebotomy during the previous 12 weeks, platelet count ≤ 400 × 10 9 /L, and white blood cell count ≤ 10 × 10 9 /L). The CHR maintenance rates were 8/27 (29.6%), 18/27 (66.7%), and 22/27 (81.5%) at 12, 24, and 36 months, respectively. No thrombotic or hemorrhagic events occurred. The median allele burden change from baseline was - 74.8% at 36 months. All patients experienced adverse events; 25/27 (92.6%) experienced adverse drug reactions (ADRs), but no serious ADRs or deaths occurred. This interim analysis demonstrated the safety and efficacy of ropegIFN over 36 months in Japanese patients with PV., Competing Interests: Declarations. Conflict of interest: KK reports honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie G.K., Novartis Pharma K.K., PharmaEssentia Japan KK, Sanofi K.K., and Takeda Pharmaceutical Co., Ltd. YS reports research funding from Astellas Pharma Inc., Incyte Biosciences Japan G.K., Kyowa Kirin Co., Ltd., Ono Pharmaceutical Co., Ltd., and Toyo Kohan Co., Ltd.; grants from Shojunkai Takeuchi Hospital; honoraria from Novartis Pharma K.K.; and participation on a data safety monitoring board or advisory board for Novartis Pharma K.K. AG reports research funding from Bayer Yakuhin, Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., MSD K.K., Nihon Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd.; consulting fees from Alexion Pharmaceuticals, Inc., Chugai Pharmaceutical Co., Ltd., and PharmaEssentia Japan KK; honoraria from Alexion Pharmaceuticals, Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Kyowa Kirin Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Nihon Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Sumitomo Pharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd.; and participation on a data safety monitoring board or advisory board for Alexion Pharmaceuticals, Inc., Chugai Pharmaceutical Co., Ltd., and PharmaEssentia Japan KK. KT reports research funding and consulting fees from Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Otsuka Pharmaceutical Co., Ltd., PharmaEssentia Japan KK, and Takeda Pharmaceutical Co., Ltd.; and honoraria from Alexion Pharmaceuticals, Inc., Kyowa Kirin Co., Ltd., MSD K.K., and Novartis Pharma K.K. M Ichii reports payments for presentations from Novartis Pharmaceuticals and payments for speakers bureaus from Sumitomo Pharma Co., Ltd. TI reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Asahi Kasei Pharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., Novartis Pharma K.K., and PharmaEssentia Japan KK. SS reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie G.K., Amgen K.K., Asahi Kasei Pharma Co., Ltd., Novartis Pharma K.K., and Ono Pharmaceutical Co., Ltd. M Ito reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca K.K., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Incyte Biosciences Japan G.K., Janssen Pharmaceutical K.K., Novartis Pharma K.K., PharmaEssentia Japan KK, and Takeda Pharmaceutical Co., Ltd. OZ is an employee of PharmaEssentia Corporation USA. AQ is an employee of PharmaEssentia Corporation Taiwan. HK is an employee of PharmaEssentia Japan KK. TS is a board member of PharmaEssentia Japan KK. NK reports grants from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Perseus Proteomics Inc., PharmaEssentia Japan KK, and Sumitomo Pharma Co., Ltd.; research funding from Meiji Seika Pharma Co., Ltd. and Takeda Pharmaceutical Co., Ltd.; consulting fees from Japan Tobacco Inc., PharmaEssentia Japan KK, and Torii Pharmaceutical Co., Ltd.; honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis Pharma K.K. and Takeda Pharmaceutical Co., Ltd.; and is a board member of PharmaEssentia Japan KK. KS reports research funding from AbbVie G.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Sumitomo Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd.; honoraria from Novartis Pharma K.K. and Takeda Pharmaceutical Co., Ltd.; and participation on a data safety monitoring board or advisory board for AbbVie G.K., (© 2024. The Author(s).)

Disease recurrence remains the principal cause of treatment failure after allogeneic hematopoietic stem cell transplantation. Post-transplant maintenance therapy with azacitidine (AZA) is promising to prevent relapse but the outcomes are unsatisfactory in patients at high risk of recurrence. Herein, we evaluated the outcome in patients who received AZA and gemtuzumab ozogamicin (GO), anti-CD33 antibody-calicheamicin conjugate, as post-transplant maintenance therapy. Twenty-eight patients with high-risk hematologic malignancies harboring CD33-positive leukemic blasts received the maintenance therapy. AZA (30 mg/m 2 ) was administered for 7 days, followed by GO (3 mg/m 2 ) on day 8. The maximum number of cycles was 4. At transplant, 21 patients (75.0%) had active disease. Their 2-year overall survival, disease-free survival, relapse, and non-relapse mortality rates were 53.6%, 39.3%, 50.0%, and 10.7%, respectively. Of these patients, those with minimal residual disease at the start of maintenance therapy (n = 9) had a higher recurrence rate (66.7% vs. 42.1% at 2 years, P = 0.069) and shorter disease-free survival (11.1% vs. 52.6% at 2 years, P = 0.003). Post-transplant maintenance therapy with AZA and GO was generally tolerable but more than half of the patients eventually relapsed. Further improvements are needed to prevent relapse after transplantation in patients with high-risk hematologic malignancies., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Persistent COVID-19 is a well recognized issue of concern in patients with hematological malignancies. Such patients are not only at risk of mortality due to the infection itself, but are also at risk of suboptimal malignancy-related outcomes because of delays and terminations of chemotherapy. We report two lymphoma patients with heavily pretreated persistent COVID-19 in which ensitrelvir brought about radical changes in the clinical course leading to rapid remissions. Patient 1 was on ibrutinib treatment for mantle cell lymphoma when he developed COVID-19 pneumonia which was severe and ongoing for 2 months despite therapy with molnupiravir, multiple courses of remdesivir, one course of sotrovimab, tocilizumab, and steroids. Patient 2 was administered R-CHOP therapy for diffuse large B-cell lymphoma when he developed COVID-19 which was ongoing for a month despite treatment with multiple courses of remdesivir and one course of sotrovimab. A 5-day administration of ensitrelvir promptly resolved the persistent COVID-19 accommodated by negative conversions of RT-qPCR tests in both patients within days. Ensitrelvir is a novel COVID-19 therapeutic that accelerates viral clearance through inhibition of the main protease of SARS-CoV-2, 3-chymotrypsin-like protease, which is vital for viral replication. Ensitrelvir is a promising treatment approach for immunocompromised lymphoma patients suffering from persisting and severe COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Furuya, Yasuda, Hiki, Shirane, Yamana, Uchimura, Inano, Takaku, Hamano and Ando.)

Budd-Chiari syndrome (BCS) is a rare vascular disorder characterized by obstruction of hepatic venous outflow, culminating in elevated hepatic and portal venous pressure. BCS is associated with myeloproliferative neoplasms (MPN) in 40% of cases, which is significantly higher than the rate observed in other venous thrombotic conditions, and suggests that MPN may contribute to the etiology of BCS. In particular, the JAK2 V617F mutation has recently attracted substantial attention, given its profound association with thrombogenesis, mechanically implicated through endothelial damage, increased blood cell adhesion, and facilitation of neutrophil extracellular trap formation. A common treatment approach consists of anticoagulation for prevention and treatment of thrombosis, and cytoreductive therapy targeting MPN. However, as no definitive evidence exists for this approach, a bespoke therapeutic strategy tailored to individual patient profiles is required.

Risk-adapted therapy is recommended to prevent major clinical complications, such as thrombo-haemorrhagic events, in patients with essential thrombocythaemia (ET). In this study, we analysed the association between non-driver gene mutations and thrombo-haemorrhagic events in 579 patients with ET. ASXL1 and TP53 mutations were frequently identified in patients with ET complicated by thrombosis (22.7% and 23.1%, respectively), and the DNMT3A mutation was frequently identified in patients who experienced haemorrhage (15.2%). Multivariate analyses of thrombosis-free survival (TFS) revealed that ASXL1 and TP53 mutations are associated with thrombosis (hazard ratio [HR] = 3.140 and 3.752 respectively). Patients harbouring the ASXL1 or TP53 mutation had significantly worse TFS rates than those without mutation (p = 0.002 and p < 0.001 respectively). Furthermore, JAK2V617F-mutated patients with accompanying ASXL1 mutations showed significantly shorter TFS compared with those without ASXL1 mutations (p = 0.003). Multivariate analyses of haemorrhage-free survival (HFS) revealed that the DNMT3A mutation (HR = 2.784) is associated with haemorrhage. DNMT3A-mutated patients showed significantly shorter HFS than those without the mutation (p = 0.026). Non-driver gene mutations should be considered in treatment strategies and may provide important information for personalised treatment approaches., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Objectives: Since MPL mutation is a rare driver gene mutation found in a small number of essential thrombocythemia (ET) patients, the clinical characteristics of patients with MPL mutations and their association with thrombotic events have not yet been elucidated in Japan., Methods: We enrolled 579 Japanese ET patients based on the diagnostic criteria of the WHO classification 2017 and compared clinical characteristics of MPL -mutated patients ( n  = 22; 3.8%) to JAK2 V617F-mutated ( n  = 299; 51.6%), CALR -mutated ( n  = 144; 24.9%), and triple-negative (TN) ( n  = 114; 19.7%) patients., Results: Thrombosis during follow up was observed in 4 out of 22 (18.2%) in the MPL -mutated group, which was the highest among all driver gene mutation groups ( JAK2 V617F-mutated, 8.7%; CALR -mutated, 3.5%; TN,1.8%). The MPL- and JAK2 V617F-mutated groups had worse thrombosis-free survival (TFS) than the CALR -mutated ( p  = 0.043) and TN groups ( p  = 0.006). Univariable analysis revealed that a history of thrombosis was a possible risk factor for thrombosis among MPL -mutated patients (hazard ratio: 9.572, p  = 0.032)., Conclusions: MPL -mutated ET patients should require more intensive management to prevent recurrence of thrombosis.

Aim: Capnography is recommended for use in procedural sedation and analgesia (PSA); however, limited studies assess its impact on recovery time. We investigated the association between capnography and the recovery time of PSA in the emergency department (ED)., Methods: This study was a secondary analysis of a multicenter PSA patient registry including eight hospitals in Japan. We included all patients who received PSA in the ED between May 2017 and May 2021 and divided the patients into capnography and no-capnography groups. The primary outcome was recovery time, defined as the time from the end of the procedure to the cessation of monitoring. The log-rank test and multivariable analysis using clustering for institutions were performed., Results: Of the 1265 screened patients, 943 patients who received PSA were enrolled and categorized into the capnography ( n  = 150, 16%) and no-capnography ( n  = 793, 84%) groups. The median recovery time was 40 (interquartile range [IQR]: 25-63) min in the capnography group and 30 (IQR: 14-55) min in the no-capnography group. In the log-rank test, the recovery time was significantly longer in the capnography group ( p  = 0.03) than in the no-capnography group. In the multivariable analysis, recovery time did not differ between the two groups (adjusted hazard ratio, 0.95; 95% confidence interval, 0.77-1.17; p  = 0.61)., Conclusion: In this secondary analysis of the multicenter registry of PSA in Japan, capnography use did not associate with shorter recovery time in the ED., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Background: Palliative care provided to patients with heart failure (HF) are reported to be inadequate. Herein, we examined the impact of the recently introduced financial incentive scheme for team-based palliative care for patients with HF in acute care hospitals in Japan., Methods: Using a nationwide inpatient database, we identified patients aged ≥65 years with HF who had died between April 2015 and March 2021. Interrupted time-series analyses were used to compare practice patterns in end-of-life care (symptom management and invasive medical procedures within one week before death) before and after the financial incentive scheme issuance in April 2018., Results: Overall, 53,857 patients in 835 hospitals were eligible. The adoption of the financial incentive was 1.10 to 1.22% after the introduction. There were upward pre-trends in opioid use (+0.11% per month; 95% confidence interval [CI], 0.06 to 0.15) and antidepressant use (+0.06% per month; 95% CI, 0.04 to 0.09). Opioid use showed a downward slope change during the post-period (-0.07% change in trend; 95% CI, -0.13 to -0.01). Intensive care unit stay showed a downward pre-trend (-0.09% per month; 95% CI, -0.14 to -0.04) and upward slope changes during the post-period (+0.12% change in trend; 95% CI, 0.04 to 0.19). Invasive mechanical ventilation showed downward slope changes during the post-period (-0.11% change in trend; 95% CI, -0.18 to -0.04)., Conclusions: The financial incentive scheme for team-based palliative care was rarely adopted and not associated with changes in end-of-life care. Further multifaceted strategies to promote palliative care for HF are warranted., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare disease, which presents with features of myelodysplastic syndromes with ring sideroblasts and essential thrombocythemia, as well as anemia and marked thrombocytosis. SF3B1 and JAK2 mutations are often found in patients, and are associated with their specific clinical features. This study was a retrospective analysis of 34 Japanese patients with MDS/MPN-RS-T. Median age at diagnosis was 77 (range, 51-88) years, and patients had anemia (median hemoglobin: 9.0 g/dL) and thrombocytosis (median platelet count: 642 × 109/L). Median overall survival was 70 (95% confidence interval: 68-not applicable) months during the median follow-up period of 26 (range: 0-91) months. A JAK2V617F mutation was detected in 46.2% (n = 12) of analyzed patients (n = 26), while an SF3B1 mutation was detected in 87.5% (n = 7) of analyzed patients (n = 8). Like those with myelodysplastic syndromes or myeloproliferative neoplasms, patients often received erythropoiesis-stimulating agents and aspirin to improve anemia and prevent thrombosis. This study, which was the largest to describe the real-world characteristics of Japanese patients with MDS/MPN-RS-T, showed that the patients had similar characteristics to those in western countries., (© 2023. Japanese Society of Hematology.)

Objectives: Branchial cleft cysts (BCCs) are common in daily practice, however, BCC patients suffer aesthetic problems due to postoperative scars on visible parts after surgery. To analyze the feasibility, surgical outcomes and possible risks and complications encountered during a facelift procedure for patients with BCC., Methods: This retrospective analysis examined patients who had undergone surgery for branchial cleft cyst using a facelift procedure (n = 16) or conventional transcervical resection (n = 20) at our institutes between April 2015 and August 2021., Results: There was no significant difference between the groups that underwent the facelift procedure or conventional transcervical resection as to the average size of the cysts, operating time, bleeding, drain out, or recurrence. None of the patients needed to switch from the facelift procedure to conventional transcervical resection. In all the patients in the facelift procedure group, postoperative scars were fully concealed by the auricle and hair. However, four patients in the facelift procedure group experienced a transient auricular complication after surgery., Conclusion: The facelift procedure provides adequate visualization, workspace and excellent cosmetic results in suitably selected cases with BCC., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier B.V.)

Risk-adapted therapy is recommended to prevent thrombosis in essential thrombocythemia (ET) patients. An advanced age, a history of thrombosis, and the presence of the JAK2V617F mutation are well-defined risk factors for thrombosis in ET; however, the impact of cardiovascular risk (CVR) factors on thrombosis in ET remains elusive. Therefore, we herein investigated the impact of CVR factors on thrombosis in 580 ET patients who met the 2017 World Health Organization Classification diagnostic criteria. A univariate analysis identified hypertriglyceridemia and multiple CVR factors as strong risk factors for thrombosis (hazard ratio [HR] 3.530, 95% confidence interval [CI] 1.630-7.643, P = 0.001 and HR 3.368, 95% CI 1.284-8.833, P = 0.014, respectively) and hyper-LDL cholesterolemia as a potential risk factor (HR 2.191, 95% CI 0.966-4.971, P = 0.061). A multivariate analysis revealed that hypertriglyceridemia was an independent risk factor for thrombosis (HR 3.364, 95% CI 1.541-7.346, P = 0.002). Furthermore, poor thrombosis-free survival was observed in patients with a serum triglyceride level ≥ 1.2 mmol/L (HR = 2.592, P = 0.026 vs. < 1.2 mmol/L) or two or more CVR factors (P = 0.011 vs. no CVR factors and P = 0.005 vs. one CVR factor). These results revealed the impact of CVR factors on thrombosis in ET. Since CVR factors are manageable, lifestyle interventions, such as the control of serum triglyceride levels, may effectively prevent thrombosis in ET patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: A proportion of patients with polycythemia vera (PV) and essential thrombocythemia (ET) harbor non-driver mutations associated with poor prognosis. In this study, we analyzed the frequency of non-driver mutations in a large Japanese PV and ET cohort. Furthermore, we studied the relationship of these mutations and prognosis in Japanese patients., Methods: We enrolled 843 Japanese patients with PV or ET. Non-driver mutations were analyzed by target resequencing using next-generation sequencing. The association of the mutations with the prognosis was estimated using multivariable logistic regression analysis and log-rank test., Results: Non-driver mutations were detected in 31.1% and 24.5% patients with PV and ET, respectively. Among them, ASXL1 mutations were identified as a risk factor for leukemic/myelofibrotic transformation in PV and ET patients (hazard ratio: 4.68, p = .006). The higher-risk groups of the mutation-enhanced international prognostic system (MIPSS)-PV and MIPSS-ET incorporating non-driver mutations exhibited significantly shorter overall survival compared with the low-risk group (p < .001)., Conclusions: These results implicate the importance of studying non-driver mutations for predicting the prognosis and survival of Japanese PV and ET patients., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Patients with eosinophilic chronic rhinosinusitis (ECRS) respond poorly to many treatment modalities. Overproduction of periostin in the nasal mucosa is reported to contribute to polyp formation. This study examined periostin levels in patients with ECRS in comparison with levels in patients with non-ECRS., Methods: Fifty-nine patients with chronic rhinosinusitis were grouped into those with ECRS and those with non-ECRS. We compared the relationships between peripheral blood eosinophil level, serum periostin level, histopathological findings, clinical and laboratory findings, nose findings, diagnostic score of the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis Study, and postoperative recurrence of nasal polyps in each group., Results: In the ECRS group, a positive correlation was found between peripheral blood eosinophil level and serum periostin level (r s  = 0.49, P < 0.01: Spearman's rank correlation coefficient). ROC curve analysis was used to evaluate the serum periostin level that could predict postoperative recurrence of nasal polyps in the ECRS group: the area under the curve (AUC) was 0.95, sensitivity was 92%, and specificity was 100%; the serum periostin cutoff value for postoperative recurrence of nasal polyps was 130 ng/ml. In ROC curve analysis to evaluate peripheral blood eosinophil level, the AUC was 0.73, sensitivity was 69.2%, and specificity was 85.0%; the cutoff value was 8.8%., Conclusions: periostin was implicated in the pathophysiology of ECRS. Periostin shown to be a more useful biomarker than eosinophils in ECRS. Periostin was shown to likely be an important biomarker for pathological severity of ECRS and postoperative recurrence of nasal polyps., (Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: Acquired erythrocytosis can be classified into polycythemia vera (PV) and non-neoplastic erythrocytosis (NNE). The vast majority of PV patients harbor JAK2 mutations, but differentiating JAK2 mutation-negative PV from NNE is challenging due to a lack of definitive molecular markers., Methods: We studied the clinical features of 121 patients with erythrocytosis of which 47 (38.8%) were JAK2 mutation-positive and also fulfilled the diagnostic criteria for PV, and 67 (55.4%) JAK2 mutation-negative erythrocytosis patients who were diagnosed as NNE. Diagnosis was strictly based on driver mutation analysis and central pathology review., Results: No JAK2 mutation-negative PV patients were found in our cohort. The NNE group showed significantly younger (p < 0.01) age with higher frequency of smoking (p < 0.001), alcohol consumption (p < 0.001), and diabetes mellitus (p < 0.05), whereas the PV group (n = 47) showed significantly higher white blood cell count, platelet count, and lactate dehydrogenase (p < 0.001). Although serum erythropoietin (EPO) levels were significantly higher in NNE compared to PV (p < 0.001), approximately 40% of the NNE patients had EPO levels below the lower range of normal, fulfilling a minor diagnostic criterion of PV and raising the possibility of PV misdiagnosis., Conclusion: Low EPO levels in JAK2 mutation-negative erythrocytosis may not be a reliable diagnostic criterion for distinguishing PV from NNE., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: Current guidelines for essential thrombocythemia (ET) patients recommend different treatment approaches based on thrombosis risk stratification models. However, these recommendations may not be applicable to some patients under real clinical settings. Therefore, we carried out a retrospective real-world validation study., Methods: Thrombosis-free survival (TFS) was compared between treatment naïve ET patients receiving different treatment approaches. ET patients were stratified by three representative risk models, the conventional, the International Prognostic Score for thrombosis in ET (IPSET-thrombosis), and revised IPSET-thrombosis. Treatment decisions were largely made by individual physicians, taking into account patient preferences and backgrounds., Results: A total of 179 ET patients were included, and thrombotic events were observed in 26 patients. TFS was significantly longer in high-risk patients of all risk models receiving a combination of cytoreductive therapy (CRT) and antiplatelet therapy (APT) compared to CRT alone. Similar results were seen in intermediate-risk patients stratified by IPSET-thrombosis. In contrast, in very low- and low-risk patients of all risk models, TFS was not affected by addition of CRT, indicating that observation or APT alone is an appropriate treatment approach for these patients., Conclusion: We demonstrate that current guidelines provide optimal treatment approaches for Japanese ET patients under real-world clinical settings.

Background: The etiology of POEMS syndrome and its associated polyneuropathy have not been fully elucidated. The clinical picture of POEMS-associated polyneuropathy and nutritional polyneuropathy due to vitamin B6 (VB6) deficiency are strikingly similar, both being typically sensorimotor, symmetrical, stocking and glove distribution, and more severe in the lower extremities., Case Presentation: We report two consecutive POEMS patients with VB6 deficiency who showed unusual rapid and drastic recovery of polyneuropathies within 6-8 weeks after oral VB6 supplementation. Case 1 was supplemented with VB6 from time of autologous stem cell transplantation. Polyneuropathy began to improve within one week, and he became walker-free and could walk unaided with a cane within 6 weeks. Case 2 was supplemented with VB6 from time of stem cell harvest, and he became cane-free and his gait almost normalized within two months. Nerve conduction studies were also confirmatory of neurologic recovery in both cases., Conclusions: Objective physical improvement of POEMS-associated polyneuropathy has been reported to typically require approximately a year after autologous stem cell transplantation, and together with our observations of VB6 deficiency and supplementations leading to accelerated recoveries of polyneuropathy, VB6 deficiency most probably contributes to POEMS-associated polyneuropathy. VB6 acts as a coenzyme in approximately 150 biochemical reactions. VB6 has been reported to inhibit the hypoxia-inducible factor/vascular endothelial growth factor (VEGF) pathway, and VEGF levels are known to corollate with disease activity of POEMS syndrome. Therefore, VB6 deficiency may contribute not only to POEMS-associated polyneuropathy, but also to the etiology of POEMS syndrome itself.

Objectives: Plunging ranula intruding into the cervical region is rare and a standard therapy has not yet been consolidated. This paper investigates the outcomes and side effects of OK-432 treatment in patients with a ranula extending into the cervical region., Methods: The study design and setting consisted of a planned data collection at Tohoku Medical and Pharmaceutical University and Fukase Clinic. Eight patients with ranula extending into the cervical region received OK-432 treatment between January 2016 and February 2019. OK-432 treatment was performed for patients with ranula extending into the cervical region., Results: In all patients, a total shrinkage and marked reduction in lesions were observed without local scars or deformations after OK-432 treatment. Complications were local swelling and mild fever (37.5-38.5 °C), which lasted a few days in half of the patients., Conclusions: OK-432 treatment is straightforward, secure, and efficacious and can be substituted for surgery in the treatment of ranula extending into the cervical region.

The concept of allogeneic cell therapy was first presented over 60 years ago with hematopoietic stem cell transplantation. However, complications such as graft versus host disease (GVHD) and regimen-related toxicities remained as major obstacles. To maximize the effect of graft versus leukemia, while minimizing the effect of GVHD, donor lymphocyte infusion was utilized. This idea, which was used against viral infections, postulated that adoptive transfer of virus-specific cytotoxic T lymphocytes could reconstitute specific immunity and eliminate virus infected cells and led to the idea of banking third party cytotoxic T cells (CTLs). T cell exhaustion sometimes became a problem and difficulty arose in creating robust CTLs. However, the introduction of induced pluripotent stem cells (iPSCs) lessens such problems, and by using iPSC technology, unlimited numbers of allogeneic rejuvenated CTLs with robust and proliferative cytotoxic activity can be created. Despite this revolutionary concept, several concerns still exist, such as immunorejection by recipient cells and safety issues of gene editing. In this review, we describe approaches to a feasible "off-the-shelf" therapy that can be distributed rapidly worldwide. We also offer perspectives on the future of allogeneic cell cancer immunotherapy.

Immunosuppressive therapies, including antithymocyte globulin and cyclosporine (CsA), are used for the treatment of aplastic anemia, but they reportedly cause lymphoproliferative diseases. Here, we report two cases of aplastic anemia in which diffuse large B-cell lymphoma developed during treatment with CsA. In both the cases, CsA was discontinued and combination therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisolone) plus the thrombopoietin receptor agonist eltrombopag was initiated. Furthermore, supportive care, including blood transfusion and granulocyte colony-stimulating factor, was provided. After six or eight courses of R-CHOP therapy, a complete metabolic response was achieved without serious adverse events. These cases illustrate the safety of combining R-CHOP with eltrombopag therapy in patients at a high risk of severe pancytopenia.

Background: The present study aimed to assess the appropriate oxygen saturation target in patients with pediatric respiratory diseases by lowering the oxygen saturation target from SpO 2 94% to 90%. No previous study has explored appropriate oxygen saturation targets in respiratory diseases other than bronchiolitis., Methods: The present, prospective, single-arm intervention trial enrolled pediatric inpatients with bronchiolitis, bronchitis, pneumonia, and asthma. The oxygen saturation target was lowered from SpO 2 94% to 90% after the patients' general condition improved. The patients continued to be observed for 12 h after achieving SpO 2 94%. The duration from the first cut-off point (SpO 2 90% for 12 h without oxygen) to the second cut-off point (SpO 2 94% for 12 h) was then evaluated., Results: In total, 248 patients completed the study. Patients with bronchiolitis, bronchitis, pneumonia, and asthma had an interval between the two cut-off points of 23.9, 15.5, 19.1, and 13.8 h, respectively, (mean 17.2 h; 95% confidence interval 15.0-19.5)., Conclusions: In generally healthy children, setting the oxygen saturation target at SpO 2 90% after confirming improvement in their general condition was safe. The time required for increasing SpO 2 from 90% to 94% was longest in the patients with bronchiolitis., (© 2022 Japan Pediatric Society.)

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Objectives: End-of-life cancer care is important; however, data on hospitalization and costs for older patients have been lacking. We aimed to examine quality indicators and costs for older patients in Japan., Methods: Using the Diagnosis Procedure Combination database, a national database of acute-care hospitals in Japan, we retrospectively collected data on cancer decedents aged ≥65 years. We evaluated the quality indicators (hospitalizations, length of stay in the hospital, emergency hospitalizations, emergency hospitalizations using an ambulance, intensive care unit [ICU] admissions, length of stay in the ICU, interval between last chemotherapy use and death, and chemotherapy within 14 days before death) and hospitalization costs at 30, 90 and 180 days before death. We compared the outcomes across age groups (65-74, 75-84 and ≥ 85 years)., Results: Between January 2011 and March 2015, we identified 369 616 cancer decedents. From 180 to 30 days before death, there were increases in emergency hospitalizations, emergency hospitalizations using an ambulance, and the mean costs per hospital day. Overall, 16.7% of patients receiving chemotherapy last received this treatment on the day before death or the day of death. Costs decreased with increasing age. The group aged ≥85 years had the shortest hospital and ICU stays and the lowest multiple hospitalizations, ICU admissions, chemotherapy within 14 days before death, and costs., Conclusions: Many older adult patients had emergency hospitalizations and received chemotherapy just prior to death, and there is room for improvement in appropriate end-of-life care. Oldest old patients consumed relatively few medical resources., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Trio-next generation sequencing is useful to identify undiagnosed inherited diseases. We have attended a patient with trigenic ADH5 / ALDH2 / ADGRV1 pathogenic variants, which caused two distinct diseases, myelodysplastic syndrome and Usher syndrome. Whole genome sequencing of peripheral blood from the patient and his parents were applied to identify disease-causing genes. Sanger sequencing was performed to validate the identified ADH5 / ALDH2 / ADGRV1 variants. Our results identified disease-associated variants in ADGRV1 (disease inheritance autosomal recessive) and in ADH5 (disease inheritance also autosomal recessive) and a variant in ALDH2 (disease inheritance autosomal dominant). Although the variants identified in ADH5 and ALDH2 have been reported, their co-existence in association with disease-causing variation in a third gene has not. They broaden the spectrum of ADGRV1 in Usher syndrome. Findings on next generation sequencing guided rapid and accurate diagnosis, resulting in patient-tailored therapeutic intervention., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)

Competing Interests: Competing interests: None declared.

We report the case of a 58-year-old woman with multiple myeloma who relapsed after the first autologous peripheral blood stem cell transplantation. She was refractory to new drugs and underwent a haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HSCT) by administering post-transplantation cyclophosphamide (PTCy) after the second autologous peripheral blood stem cell transplantation. Neutrophil and platelet engraftment were achieved on days 22 and 55, respectively. Grade II cutaneous acute graft-versus-host disease was observed, which was resolved by systemic steroid treatment. Post-transplant bone marrow examination confirmed donor chimerism replacement and immunophenotypic complete response, and the patient is alive and disease-free. Although haplo-HSCT using PTCy for multiple myeloma has not been reported in Japan, it could be performed safely. Here, we report our results with literature review.

A 53-year-old woman had been diagnosed with rheumatoid arthritis (RA) in X-6. She was started on methotrexate (MTX) in X-1. She developed a cough, and chest computed tomography showed abnormalities. In X, MTX was discontinued, but the cough persisted. A lung biopsy revealed a diagnosis of nodular sclerosis classic Hodgkin lymphoma (CHL-NS). She was considered to have "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" (OIIA-LPD), MTX-associated Hodgkin lymphoma (MTX-HL). She received six courses of brentuximab vedotin (BV) in addition to AVD (BV+AVD). A complete metabolic response was obtained, and the RA went into remission. This is the fourth reported case of BV+AVD for MTX-HL.

Bone turnover markers (BTMs) are useful parameters for assessing fracture risk and unlike bone mineral density (BMD), can be measured at any institution. However, BTM values have not been established in patients post-allogeneic hematopoietic stem cell transplantation (allo-HSCT). We investigated the practicality of BTMs in patients who underwent allo-HSCT by measuring levels of the serum bone resorption marker, tartrate-resistant acid phosphatase-5b (TRACP-5b), and the bone formation marker, bone-specific alkaline phosphatase (BAP), together with BMD, 1 month before and 6 months after allo-HSCT. Patients were classified into either the alendronate group (n = 14) if alendronate treatment (35 mg orally per week) was administered before allo-HSCT or within 1 month after allo-HSCT, or the control group (n = 16), in which patients did not receive alendronate treatment. Despite the high frequency of corticosteroids users in the alendronate group (71.4 vs. 18.9%; p < 0.01), the mean percentage changes in BMD at the lumbar spine (- 2.9 vs. - 3.1%; p = 0.44) and femoral neck (- 3.2 vs. - 4.1%; p = 1.00), TRACP-5b levels (- 4.8 vs. 9.9%; p = 0.45), and BAP levels (6.9 vs. 1.0%; p = 0.85) during 6 months did not differ significantly between the alendronate and control groups. Additionally, the percentage changes in BMD at the lumbar spine were negatively associated with the TRACP-5b levels 6 months after allo-HSCT (p = 0.03, r = 0.40). Our results indicate the possible effectiveness of alendronate treatment in allo-HSCT patients. BTM levels could be useful to monitor the BMD changes.

There have been many reports regarding tyrosine kinase inhibitor (TKI) administration to prevent relapse following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). However, there are no commonly accepted standards for the choice of TKIs. We retrospectively analyzed the clinical features of Ph+ALL patients who received TKIs after allo-HSCT at our institution. The prophylactic administration of TKIs (pro) occurred in eight patients, and six patients received preemptive TKI administration (pre). The median follow-up period after allo-HSCT was 1,427 (range, 161-2,428) days in the pro group and 773.5 (range, 156-2,243) days in the pre group. Only one patient with non-hematological complete remission before allo-HSCT relapsed among the patients in the pro group. In the pre group, four patients treated with only TKIs achieved negativity of minimal residual disease. The 2-year overall survival rate after allo-HSCT was 85.7% in the pro group and 100% in the pre group. We used lower doses of TKIs compared with previous reports and this analysis shows that the dose is safe and effective as the treatment.

Objective Little information is available about the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with secondary myelofibrosis from essential thrombocythemia (ET) and polycythemia vera (PV). A nationwide retrospective study of the outcome of HSCT for post-ET and post-PV myelofibrosis was conducted in Japan. Patients and Methods Clinical data for patients with post-ET (n=29) and post-PV (n=9) myelofibrosis who had received first allogeneic HSCT were extracted from the Transplant Registry Unified Management Program, which is a registry of the outcomes of HSCT in Japan. Results Five patients died without neutrophil recovery within 60 days after transplantation. The incidence of neutrophil recovery was significantly lower in umbilical cord blood (UCB) transplantation than in related donor transplantation (40% vs. 92%, p=0.010). The 1-year non-relapse mortality for post-ET and post-PV myelofibrosis was 35% and 27%, respectively (p=0.972). No patient or transplantation characteristics were associated with non-relapse mortality. The 4-year overall survival for post-ET and post-PV myelofibrosis was 46% and 65%, respectively (p=0.362). A univariate analysis identified UCB transplantation (vs. related donor, p=0.017) and ≥10 times red blood cell transfusions before transplantation (vs. <10 times, p=0.037) as predictive of a lower overall survival. Conclusion Allogeneic HSCT provides a long-term survival for at least some patients with post-ET and post-PV myelofibrosis. Further studies with more patients are required to determine the best alternative donor.