Prevalence and Risk Factors of Constipation Symptoms among Patients Undergoing Colonoscopy: A Single-Center Cross-Sectional Study.

INTRODUCTION: Constipation is one of the most common gastrointestinal symptoms. It may compromise quality of life and social functioning and result in increased healthcare use and costs. We aimed to evaluate the prevalence and risk factors of constipation symptoms, as well as those of refractory constipation symptoms among patients who underwent colonoscopy. METHODS: Over 4.5 years, patients who underwent colonoscopy and completed questionnaires were analyzed. Patients' symptoms were evaluated using the Gastrointestinal Symptoms Rating Scale. RESULTS: Among 8,621 eligible patients, the prevalence of constipation symptoms was 33.3%. Multivariate analysis revealed female sex (odds ratio [OR] 1.7, P < 0.001), older age (OR 1.3, P < 0.001), cerebral stroke with paralysis (OR 1.7, P = 0.009), chronic renal failure (OR 2.6, P < 0.001), ischemic heart disease (OR 1.3, P = 0.008), diabetes (OR 1.4, P < 0.001), chronic obstructive pulmonary disease (OR 1.5, P = 0.002), benzodiazepine use (OR 1.7, P < 0.001), antiparkinsonian medications use (OR 1.9, P = 0.030), and opioid use (OR 2.1, P = 0.002) as independent risk factors for constipation symptoms. The number of patients taking any medication for constipation was 1,134 (13.2%); however, refractory symptoms of constipation were still present in 61.4% of these patients. Diabetes (OR 1.5, P = 0.028) and irritable bowel syndrome (OR 3.1, P < 0.001) were identified as predictors for refractory constipation symptoms. CONCLUSIONS: Constipation occurred in one-third of patients, and more than half of patients still exhibited refractory symptoms of constipation despite taking laxatives. Multiple medications and concurrent diseases seem to be associated with constipation symptoms.

Continuum of care for maternal and child health and child undernutrition in Angola.

BACKGROUND: Continuum of care (CoC) for maternal and child health provides opportunities for mothers and children to improve their nutritional status, but many children remain undernourished in Angola. This study aimed to assess the achievement level of CoC and examine the association between the CoC achievement level and child nutritional status. METHODS: We used nationally representative data from the Angola 2015-2016 Multiple Indicator and Health Survey. Completion of CoC was defined as achieving at least four antenatal care visits (4 + ANC), delivery with a skilled birth attendant (SBA), child vaccination at birth, child postnatal check within 2 months (PNC), and a series of child vaccinations at 2, 4, 6, 9 and 15 months of child age. We included under 5 years old children who were eligible for child vaccination questionnaires and their mothers. The difference in CoC achievement level among different nutritional status were presented using the Kaplan-Meier method and examined using the Log-Lank test. Additionally, the multivariable logistic regression analysis examined the associations between child nutritional status and CoC achievement levels. RESULTS: The prevalence of child stunting, underweight and wasting was 48.3%, 23.2% and 5.9% respectively. The overall CoC completion level was 1.2%. The level of achieving CoC of mother-child pairs was 62.8% for 4 + ANC, 42.2% for SBA, 23.0% for child vaccination at birth, and 6.7% for PNC, and it continued to decline over 15 months. The Log-Lank test showed that there were significant differences in the CoC achievement level between children with no stunting and those with stunting (p < 0.001), those with no underweight and those with underweight (p < 0.001), those with no wasting and those with wasting (p = 0.003), and those with malnutrition and those with a normal nutritional status (p < 0.001). Achieving 4 + ANC (CoC1), 4 + ANC and SBA (CoC 2), and 4 + ANC, SBA, and child vaccination at birth (CoC 3) were associated with reduction in child stunting and underweight. CONCLUSIONS: The completion of CoC is low in Angola and many children miss their opportunity of nutritional intervention. According to our result, improving care utilization and its continuity could improve child nutritional status.

Landscape of driver mutations and their clinical effects on Down syndrome-related myeloid neoplasms.

Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse, and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group AML-D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival [28.6% vs. 90.5%, P < 0.001; 25.0% vs. 89.5%, P < 0.001] than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS.

Rituximab-combined anthracycline-free chemotherapy in newly diagnosed paediatric and adolescent patients with non-high-risk aggressive mature B cell lymphoma: protocol for a single-arm, open-label, multicentre, phase II study (the Japan Children's Cancer Group Multicentre Trial, JPLSG B-NHL-20).

INTRODUCTION: Children and adolescents with mature B cell non-Hodgkin lymphoma (B-NHL) are treated with short-intensive chemotherapy. The burden of short-term and long-term toxicity is highly relative to its high cure rate in good-risk patients. Although the addition of rituximab to standard lymphome Malin B (LMB) chemotherapy markedly prolongs event-free survival and overall survival in high-risk patients, the benefit of rituximab in good-risk patients remains to be elucidated. This clinical trial will examine whether the addition of rituximab eliminates anthracyclines in good-risk patients without compromising treatment outcomes. METHODS AND ANALYSIS: We will perform a single-arm, open-label, multicentre phase II study. Low-risk (stage I - completely resected, stage II abdominal) and intermediate-risk (stages I and II - incompletely resected; stage II - resected, other than abdominal; stage III with LDH <2× upper limit of normal) patients with newly diagnosed B-NHL are eligible. Low-risk patients receive two courses of R-COM1P (rituximab, cyclophosphamide, vincristine, methotrexate, prednisolone and intrathecal methotrexate with hydrocortisone), and intermediate-risk patients receive COP (cyclophosphamide, vincristine, prednisolone and intrathecal methotrexate with hydrocortisone) followed by two courses each of R-COM3P and R-CYM (rituximab, cytarabine, methotrexate and intrathecal methotrexate with hydrocortisone). The primary endpoint is a 3-year event-free survival rate in paediatric patients (<18 years) with intermediate-risk disease. 100 patients (10 low-risk and 90 intermediate-risk) will enrol within a 4-year enrolment period and the follow-up period will be 3 years. 108 institutions are participating as of 1 January 2024 (64 university hospitals, 29 general hospitals, 12 children's hospitals and three cancer centres). ETHICS AND DISSEMINATION: This research was approved by the Certified Review Board at NHO Nagoya Medical Center (Nagoya, Japan) on 21 September 2021. Written informed consent is obtained from all patients and/or their guardians. The results of this study will be disseminated through peer-reviewed publications and conference presentations. STUDY REGISTRATION: Japan Registry of Clinical Trials, jRCTs041210104.

Miliary tuberculosis diagnosed by diffuse hepatic uptake on PET/CT and transjugular liver biopsy.

The patient was an 81-year-old man. In his 20s, he had been treated with pharmacotherapy for pulmonary tuberculosis for 1 year. He presented to the Department of Respiratory Medicine with a chief complaint of dyspnea. The possibility of respiratory disease appeared to be low, but hepatic impairment was detected. The patient was thus referred to our department. Though the cause of hepatic impairment was unknown, the soluble interleukin-2 receptor level was elevated, suggesting malignant lymphoma. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) revealed diffuse, homogenous, intense FDG uptake in the entire liver, and transjugular liver biopsy confirmed the diagnosis. Histopathological examination revealed an epithelioid granuloma, and auramine staining was positive for bacilli suggestive of tuberculosis. CT revealed diffuse micronodular shadows in the lung, yielding a diagnosis of miliary tuberculosis. Therefore, the patient was prescribed antituberculosis medication by the Department of Respiratory Medicine. His subsequent clinical course was good. The miliary (hepatic) tuberculosis was typical based on the diffuse, homogenous, intense FDG uptake throughout the liver observed on PET-CT.

Transitional dynamics in oncology clinical trials: evaluating the impact of Clinical Trials Act on cooperative groups.

OBJECTIVE: large-scale multicentre clinical trials conducted by cooperative groups have generated a lot of evidence to establish better standard treatments. The Clinical Trials Act was enforced on 1 April 2018, in Japan, and it has remarkably increased the operational burden on investigators, but its long-term impact on cancer cooperative groups is unknown. METHODS: a survey was conducted across the nine major cooperative groups that constitute the Japan Cancer Trials Network to assess the impact of Clinical Trials Act on the number of newly initiated trials from fiscal year (from 1 April to 31 March) 2017 to 2022 and that of ongoing trials on 1 April in each year from 2018 to 2023. RESULTS: the number of newly initiated trials dropped from 38 trials in fiscal year 2017 to 26 trials in fiscal year 2018, surged to 50 trials in fiscal year 2019, but then gradually decreased to 25 trials by fiscal year 2022. Specified clinical trials decreased from 32 trials in fiscal year 2019 to 12 trials in fiscal year 2022. The number of ongoing trials was 220 trials in 2018, peaked at 245 trials in 2020, but then gradually decreased to 219 trials by 2023. The number of specified clinical trials has been in consistent decline. By April 2023, of the 20 ongoing non-specified clinical trials, nine adhered to Clinical Trials Act and 11 followed the Ethical Guidelines for Medical and Health Research Involving Human Subjects. CONCLUSION: the number of multicentre clinical trials in oncology gradually decreased after the Clinical Trials Act's enforcement, which underscores the need for comprehensive amendment of the Clinical Trials Act to streamline the operational process.

Sirolimus treatment for intractable lymphatic anomalies: an open-label, single-arm, multicenter, prospective trial.

Introduction: Intractable lymphatic anomalies (LAs) include cystic lymphatic malformation (LM; macrocystic, microcystic, or mixed), generalized lymphatic anomaly, and Gorham-Stout disease. LAs can present with severe symptoms and poor prognosis. Thus, prospective studies for treatments are warranted. We conducted a prospective clinical trial of sirolimus for intractable LAs. Methods: This was an open-label, single-arm, multicenter, prospective trial involving five institutions in Japan. All patients with LAs received oral sirolimus once daily, and the dose was adjusted to ensure that the trough concentration remained within 5-15 ng/mL. We prospectively assessed the drug response (response rate for radiological volumetric change in target lesion), performance state, change in respiratory function, visceral impairment (pleural effusion, ascites, bleeding, pain), laboratory examination data, quality of life (QOL), and safety at 12, 24, and 52 weeks of administration. Results: Eleven patients with LAs (9 generalized lymphatic anomaly, 1 cystic LM, 1 Gorham-Stout disease) were treated with sirolimus, of whom 6 (54.5%; 95% confidence interval: 23.4-83.3%) demonstrated a partial response on radiological examination at 52 weeks of administration. No patients achieved a complete response. At 12 and 24 weeks of administration, 8 patients (72.7%) already showed a partial response. However, patients with stable disease showed minor or no reduction after 12 weeks. Adverse events, such as stomatitis, acneiform dermatitis, diarrhea, and fever, were common with sirolimus. Sirolimus was safe and tolerable. Conclusion: Sirolimus can reduce the lymphatic tissue volume in LAs and may lead to improvements in clinical symptoms and QOL.

Patients' perceptions of patient-centered communication with healthcare providers and associated factors in Japan - The INFORM Study 2020.

OBJECTIVE: To describe patients' perceptions of the patient-centeredness of their communication with healthcare providers in Japan, and to examine factors associated with these perceptions. METHODS: We analyzed the cross-sectional data from the INFORM Study 2020, which is a nationwide survey on health information access in Japan. A total of 3605 respondents completed the survey. Our primary outcome was the nine elements of the patient-centered communication scale (PCCS), which was compiled from 2703 respondents (75.0%) reporting at least one provider visit within 12 months. It was rated on a four-point Likert scale: always, usually, sometimes, and never. We used binary logistic regression to examine the association between sociodemographic and health-related variables, and each element of the PCCS. RESULTS: For all elements, the percentage of respondents who agreed that their healthcare providers always communicated in a patient-centered way was low (17-31%). Patients with higher age, higher education, poorer general health status and a larger number of visits to providers in the previous 12 months were more likely to have positive perception. CONCLUSION: Patient-centered communication as reported in a national sample in Japan was low. CLINICAL IMPLICATIONS: Efforts are needed to improve the patient-centeredness of patient-provider communication in Japan to optimize health outcomes.

Associations of individual characteristics and socioeconomic status with heated tobacco product harmfulness perceptions in Japan: A nationwide cross-sectional study (INFORM Study 2020).

IntroductionIn Japan, heated tobacco products (HTPs) are promoted by the tobacco industry as reduced-risk tobacco products despite the lack of evidence for this claim. This study determined the distribution of HTP-harmfulness perception and identify the explanatory factors associated with the perception of HTP as less harmful than conventional cigarettes.MethodsA nationwide cross-sectional survey was conducted with Japanese people aged 20 years or older (INFORM Study 2020) using a self-administered questionnaire. We performed descriptive analysis and weighted logistic regression analysis to examine the relationship between explanatory factors (e.g., individual characteristics, socioeconomic status, and trusted sources of cancer information) and the perception of HTPs as less harmful.ResultsAmong 3,420 participants (response rate: 35.2%), the proportions of those who perceived HTPs as less harmful were 40.3% and 18.3% for users and non-users of tobacco, respectively. For participants aged 20-39 years, the proportion were 49.9% and 30.4%, respectively. Among 1,160 non-tobacco users who were familiar with HTPs, male, aged under 39 years, and had lower education were associated with the perception of HTPs as less harmful. Trusted sources of cancer information were not associated with the perception of HTPs as less harmful.ConclusionsThis study showed that, among non-tobacco users, being male, aged under 39 years, and lower education were associated with a perception of HTPs as less harmful. Public health stakeholders should provide the latest evidence about HTP harmfulness in their daily practice, and strengthen the regulations on HTP marketing directed at both tobacco- and non-tobacco users.

TBI, etoposide, and cyclophosphamide conditioning for intermediate-risk relapsed childhood acute lymphoblastic leukemia.

BACKGROUND: In children with intermediate-risk relapsed acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) has markedly improved the outcome of patients with an unsatisfactory minimal residual disease (MRD) response. Total body irradiation (TBI), etoposide (ETP), and cyclophosphamide (CY) have been shown to be equivalent to or better than TBI + ETP for conditioning, so we hypothesized that even greater survival could be achieved due to recent advances in HSCT and supportive care. PROCEDURE: We prospectively analyzed the efficacy and safety of allo-HSCT with a unified conditioning regimen of TBI + ETP + CY in children with intermediate-risk relapsed ALL, based on MRD in the bone marrow after induction, from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-R08-II nationwide cohort (UMIN000002025). RESULTS: Twenty patients with post-induction MRD ≥ 10-3 and two not evaluated for MRD underwent allo-HSCT. Engraftment was confirmed in all patients, and no transplantation-related mortality was observed. The 3-year event-free survival and overall survival rates after transplantation were 86.4% ± 7.3% and 95.5% ± 4.4%, respectively. CONCLUSION: Allo-HSCT based on post-induction MRD with TBI + ETP + CY conditioning was feasible in Japanese children with intermediate-risk relapsed ALL.

Characteristics and prognosis of patients with COVID-19 and hematological diseases in Japan: a cross-sectional study.

The Japanese Society of Hematology performed an observational cross-sectional study to clarify the morbidity, prognosis, and prognostic factors in patients with COVID-19 with hematological diseases (HDs) in Japan. The study included patients with HDs who enrolled in our epidemiological survey and had a COVID-19 diagnosis and a verified outcome of up to 2 months. The primary endpoints were characteristics and short-term prognosis of COVID-19 in patients with HDs. A total of 367 patients from 68 institutes were enrolled over 1 year, and the collected data were analyzed. The median follow-up among survivors was 73 days (range, 1-639 days). The 60-day overall survival (OS) rate was 86.6%. In the multivariate analysis, albumin ≤ 3.3 g/dL and a need for oxygen were independently associated with inferior 60-day OS rates (hazard ratio [HR] 4.026, 95% confidence interval (CI) 1.954-8.294 and HR 14.55, 95% CI 3.378-62.64, respectively), whereas 60-day survival was significantly greater in patients with benign rather than malignant disease (HR 0.095, 95% CI 0.012-0.750). Together, these data suggest that intensive treatment may be necessary for patients with COVID-19 with malignant HDs who have low albumin levels and require oxygen at the time of diagnosis.

Talc slurry pleurodesis in patients with secondary intractable pneumothorax: A phase 2 study.

BACKGROUND: Secondary pneumothorax, which occurs most commonly in the elderly, is caused by underlying diseases. Cardiac dysfunction and other organ inefficiencies may render surgical repair impossible. Such non-operative and poor-risk cases are targets for pleurodesis, which involves the instillation of chemicals or irritants to the thoracic cavity through injection, bronchoscopic bronchial occlusion, or other procedures. Sterile graded talc has been used for pleurodesis mainly in Europe and the United States; however, only a few studies and case series investigating this topic have been published. This study evaluates the efficacy and safety of talc slurry pleurodesis. METHODS: Patients with inoperable secondary intractable pneumothorax, who were not candidates for surgical repair, were recruited. Four grams of sterilized talc was suspended in 50 mL of physiological saline and injected through a tube into the pleural cavity. Additional 50 mL of saline was subsequently injected through the same channel to clean the residual saline in the injection tube. Another additional talc instillation was allowed to control persistent air leakage. The primary endpoint was the proportion of drainage tube removal within 30 days after talc pleurodesis. RESULTS: Thirty-one patients were included in this study. In 23 out of 28 patients, the drainage tube could be removed within 30 days of talc instillation (82.1 %, 95 % CI = 63.1-93.9), exceeding the threshold of 36.0 % (p < 0.0001). The most common event was pain (11/28 patients, 39.3 %). CONCLUSIONS: Talc slurry pleurodesis is effective for intractable secondary pneumothorax, with minor side effects.

Allogeneic Hematopoietic Cell Transplantation for Juvenile Myelomonocytic Leukemia with a Busulfan, Fludarabine, and Melphalan Regimen: JPLSG JMML-11.

Juvenile myelomonocytic leukemia (JMML), which is classified as a myelodysplastic/myeloproliferative neoplasm, is a rare hematologic malignancy of childhood. Most patients with JMML require allogeneic hematopoietic cell transplantation (HCT) as a curative therapy. A Japanese retrospective analysis demonstrated favorable outcomes for a busulfan (BU) + fludarabine (FLU) + melphalan (MEL) regimen, with an overall survival (OS) of 72% and an event-free survival (EFS) of 53%. To further validate the efficacy and safety of this regimen, the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) conducted a nationwide prospective study, JMML-11. Between July 2011 and June 2017, 28 patients with newly diagnosed JMML were enrolled in JMML11. Low-dose chemotherapy for tumor control before HCT was recommended, and patients treated with AML-type chemotherapy and azacitidine were excluded. The conditioning regimen comprised i.v. BU, 16 doses administered every 6 h, with dose adjustment based on pharmacokinetic (PK) studies on days -11 to -8; FLU, 30 mg/m2/day or 1 mg/kg/day for patients <10 kg or age <1 year on days -7 to -4; and MEL, 90 mg/m2/day or 3 mg/kg/day for patients <10 kg or <1 year on days -3 to -2. The donor was selected by the physician in charge. A family donor was available for 7 patients (3 HLA-matched siblings, 3 HLA-1-antigen mismatched parents, and 1 haploidentical father). Overall, 21 patients received grafts from unrelated donors, including 8 HLA-matched donors and 13 HLA-mismatched donors. The graft source was related bone marrow (BM) for 7 patients, unrelated BM for 14 patients, and unrelated cord blood for 7 patients. Neutrophil engraftment was achieved in 21 of 28 patients (75%), with a median of 20.5 days (range, 11 to 39 days) after transplantation. The 3-year OS, 3-year EFS, 3-year relapse rate, and 3-year transplantation-related mortality were 63% (95% confidence interval [CI], 42% to 78%), 52% (95% CI, 32% to 69%), 18% (95% CI, 6% to 34%), and 21% (95% CI, 9% to 38%), respectively. WBC count before the conditioning regimen (≥7.0 × 109/L) was significantly associated with inferior EFS and OS. Body surface area ≥.5 m2, spleen size <4 cm before conditioning, and HLA-matched unrelated BM donors were significantly associated with better OS. Adverse effects related to the conditioning regimen included febrile neutropenia (86%), diarrhea (39%), hypoxemia (21%), and mucositis (18%). BU-associated toxicity, including sinusoidal obstruction syndrome (SOS) and thrombotic microangiopathy (TMA), occurred in 7 patients (25%; SOS, n = 6; TMA, n = 2). Retrospective analysis of PK data after the first BU dose in 23 patients, including 6 with SOS and 17 without SOS, did not show significant differences between groups. The JMML-11 study confirms the positive results of previous retrospective analyses. BU+FLU+MEL might become a standard conditioning regimen for patients with JMML.

Trust in Mass Media as Sources of Cancer Information: Findings from a Nationally Representative Cross-Sectional Survey in Japan.

Trust is a major factor in effective public dissemination and use of relevant health information to guide important health decisions. To examine mass media as a communication channel for delivering cancer information among Japanese adults, we identified the level of trust in various types of mass media as sources of cancer information, and examined factors associated with trust, including exposure to mass media, sociodemographic factors, and cancer history. Data were analyzed for 3,109 Japanese adults who responded to a nationally representative cross-sectional mail survey. Data included trust in cancer information sources, sociodemographic variables, cancer history, and exposure to mass media. Logistic regression analysis was used. The prevalence of high trust in cancer information sources was highest for physicians (94.7%). Among mass media, Internet (47.2%) was the most trusted source of cancer-related information, followed by television (44.3%), newspapers/magazines (42.7%), and radio (32.7%). The high-exposure group for newspapers (AOR = 1.28, 95%CI = 1.07-1.54) was more likely to trust newspapers. Similarly, high-exposure groups for radio (1.22, 1.02-1.45), Internet (1.21, 1.01-1.45), and television (1.30, 1.10-1.53) were positively associated with trust in each media type. Although trust in mass media was lower than trust in physicians, the study found that a large group of respondents had high levels of trust in mass media sources. Trust in cancer information from each mass media type was mainly related to the level of exposure to each mass media type. Developing health communication strategies using mass media may be effective for disseminating relevant cancer information in Japan.

Rituximab with standard LMB chemotherapy in pediatric high-risk mature B-cell non-Hodgkin lymphoma: A report from the JPLSG B-NHL14 trial.

BACKGROUND: The benefit of adding rituximab to standard lymphomes malins B (LMB) chemotherapy for children with high-risk mature B-cell non-Hodgkin lymphoma (B-NHL) has previously been demonstrated in an international randomized phase III trial, to which the Japanese Pediatric Leukemia/Lymphoma Study Group could not participate. METHODS: To evaluate the efficacy and safety of rituximab in combination with LMB chemotherapy in Japanese patients, we conducted a single-arm multicenter trial. RESULTS: In this study, 45 patients were enrolled between April 2016 and September 2018. A total of 33 (73.3%), 5 (11.1%), and 6 (13.3%) patients had Burkitt lymphoma/leukemia, diffuse large B-cell lymphoma, and aggressive mature B-NHL, not otherwise specified, respectively. Ten (22.2%) and 21 (46.7%) patients had central nervous system disease and leukemic disease, respectively. The median follow-up period was 47.5 months. Three-year event-free survival and overall survival were 97.7% (95% confidence interval, 84.9-99.7) and 100%, respectively. The only event was relapse, which occurred in a patient with diffuse large B-cell lymphoma. Seven patients (15.6%) developed Grade 4 or higher non-hematologic adverse events. Febrile neutropenia was the most frequent Grade 3 or higher adverse event after the pre-phase treatment, with a frequency of 54.5%. CONCLUSION: The efficacy and safety of rituximab in combination with LMB chemotherapy in children with high-risk mature B-NHL was observed in Japan.

Mechanical stress-induced FGF-2 promotes proliferation and consequently induces osteoblast differentiation in mesenchymal stem cells.

Mechanical stimuli serve as crucial regulators of bone mass, promoting bone formation. However, the molecular mechanisms governing how mesenchymal stem cells (MSCs) respond to mechanical cues during their differentiation into osteogenic cells remain elusive. In this study, we found that cyclic stretching enhances MSC proliferation but does not increase the expression of osteoblast-related genes. We further revealed that this proliferative effect is mediated by fibroblast growth factor 2 (FGF-2), synthesized by MSCs in response to mechanical stress. Cell proliferation induced by cyclic stretching was inhibited upon the addition of either U0126, an inhibitor of mitogen-activated protein kinase kinase (MEK), or early growth response 1 (EGR1)-targeting small-hairpin RNA (shRNA), indicating the involvement of the extracellular signal-regulated kinase (ERK)/EGR1 signaling pathway. Osteoblast differentiation, evaluated through ALP activity, osteoblast-related gene expression, and mineralization, was stimulated by recombinant human FGF-2 (rhFGF-2) when applied during the proliferation phase, but not when applied during the differentiation stage alone. Our results suggest that FGF-2 indirectly promotes osteoblast differentiation as a downstream effect of stimulating cell proliferation. For the first time, we demonstrate that cyclic stretching induces MSCs to produce FGF-2, which in turn encourages cell proliferation through an autocrine/paracrine mechanism, consequently leading to osteoblast differentiation.