Index for the appropriate vancomycin dosing in premature neonates and infants.

BACKGROUND: In neonates, vancomycin (VCM) is used to treat Gram-positive bacterial infections. However, VCM blood concentrations are affected by gestational age, bodyweight (BW), and renal function. The initial VCM dose adjustment can therefore be difficult, and few reports have evaluated this issue. In this study, we investigated the factors determining the appropriate VCM dosing schedule in neonates, especially premature infants. METHODS: The VCM dosage and trough concentrations were retrospectively investigated from the initial treatment to maintenance therapy in neonatal intensive care unit patients who underwent therapeutic drug monitoring. We examined the average single-administration VCM dosage during maintenance therapy. We then compared the actual VCM dose with that calculated using an index comprising six items that influence the VCM daily dose (postnatal age, gestational age, BW, serum creatinine level, urine output, and lactate level). RESULTS: Twenty premature infants were included. The average BW of patients at the initial VCM administration was 975 g. During maintenance therapy, the average VCM dose was 8.4 mg/kg, and the median trough concentration was 12.4 µg/mL. When we applied the six-item index, 18 of 20 patients (90%) had concordant results between the actual VCM dosing schedule and the VCM calculated using the index. CONCLUSIONS: The average VCM dose and six-item index can facilitate the transition from the initial VCM dose to an appropriate dose in many cases and contribute to early treatment in low-birthweight infants with more variable BW, distribution volumes, and renal function. In conclusion, our six-item index may help standardize VCM administration in premature infants.

Relationship between amikacin blood concentration and ototoxicity in low birth weight infants.

Amikacin (AMK) is used as empiric therapy for severe infections such as sepsis in low birth weight (LBW) infants. AMK administered once daily (OD) in adults is reported to be therapeutically effective and prevent side effects, however, evidence on AMK administration in LBW infants is limited, with no clear indications of effectiveness. We performed therapeutic drug monitoring analysis of 20 infants treated with AMK OD for severe infections such as bacteremia. Treatment effectiveness was admitted by the patients' medical records, and side effects of renal dysfunction and ototoxicity were investigated. The mean gestational age was 30.4 ± 5 weeks and mean body weight (Bw) was 1280.2 ± 809.8 g. The mean AMK dose was 14.1 ± 2.6 mg/kg and mean administration period was 10.1 ± 4.1 days. Blood concentration was measured 6.3 ± 2.3 days after AMK administration; mean peak and trough concentrations were 29.1 ± 7.5 µg/mL and 7.6 ± 6.9 µg/mL, respectively. Additionally, therapeutic effect was observed in all patients, and no significant change in serum creatinine (CRE) concentration (a marker of renal dysfunction) was observed, suggesting no renal dysfunction. Ototoxicity was observed in 4 patients, 3 of whom had trough concentrations ≥10 µg/mL. When we categorized patients into two groups using a trough cut-off value of 10 µg/mL, no difference in AMK dose was observed. However, there were significant differences in peak concentration, Bw, volume of distribution and CRE. Our findings suggest AMK trough concentration ≥10 µg/mL significantly affects ototoxicity in neonates.

Giant umbilical cord and hypoglycemia in an infant with Proteus syndrome.

Proteus syndrome (PS) is characterized by the progressive, segmental, or patchy overgrowth of the skin, and other tissues. This is the first case report of recurrent severe insulin-independent hypoglycemia in an infant with PS. Somatic p.E17K of AKT1 mutation was confirmed. The patient also had a giant umbilical cord, which has not yet been reported in PS.

Correlation between the Closure Time of Patent Ductus Arteriosus in Preterm Infants and Long-Term Neurodevelopmental Outcome.

In patent ductus arteriosus (PDA) in preterm infants, the relationship between treatment timing and long-term developmental prognosis remains unclear. The purpose of this study was to clarify the relationship between the age in days when ductus arteriosus closure occurred and long-term development. Preterm infants with a birth weight of less than 1500 g who were admitted to our NICU over a period of 9 years (2011-2019) and were diagnosed with PDA were included. A new version of the K-type developmental test for corrected ages of 1.5 and 3 years was used as an index of development. The relationship between the duration of PDA and the developmental index was evaluated using Pearson's correlation coefficient, and multiple regression analysis was performed. Development quotient (DQ) at the ages of 1.5 and 3 years showed a correlation with the PDA closure date and the standard deviation (SD) value of the term birth weight. Multiple regression analysis showed a positive correlation of the DQ at 1.5 and 3 years with the SD value of the term birth weight and a negative correlation with the PDA closure date. In addition, a stronger correlation was found in the "posture/motor" sub-item at 3 years. On the other hand, the analysis including preterm infants without PDA showed that preterm infants with PDA closure on the 6th day or later after birth had a significantly lower 3-year-old DQ than preterm infants with a PDA exposure within 5 days. In conclusion, it is suggested that the decrease in cerebral blood flow due to PDA in preterm infants has an adverse effect on long-term neurodevelopment. Appropriate interventions, including surgical treatment for PDA in preterm infants without delay, ideally within 5 days of birth, may be effective in improving the developmental prognosis.

Survival After Cardiac Laceration From a Gunshot Wound: A Rare Case Report.

In the United States, approximately 48,000 deaths annually are attributed to gunshot wounds, with a notably low survival rate of 24.5% in cases involving cardiac injury. This case report presents a unique instance of a gunshot wound to the heart, where the patient, despite sustaining cardiac damage, maintained stable hemodynamics and underwent successful surgical removal of the bullet from the pericardial cavity. The absence of significant pericardial effusion and the maintenance of stable hemodynamics in this case provide valuable insights into the management of similar traumatic injuries. This report contributes to the existing knowledge on gunshot wound treatment, highlighting the importance of considering bullet retention in the pericardial cavity, even in the absence of substantial pericardial effusion.

Factors associated with the development of epilepsy in very low birth weight infants.

BACKGROUND: The survival rate of very low birth weight (VLBW) infants has recently improved. However, the occurrence of and factors associated with epilepsy in VLBW infants remain unknown. This study aimed to clarify the incidence, characteristics, and factors associated with epilepsy development in VLBW infants. METHODS: All VLBW infants admitted to our hospital between 2012 and 2017 were included in this study. VLBW infants with a follow-up period of <1 year were excluded. Chromosomal abnormalities, brain anomalies, severe intraventricular hemorrhage (IVH), cystic periventricular leukomalacia (PVL), and hypoxic ischemic encephalopathy (HIE) were considered to be risk factors. RESULTS: Epilepsy occurred in 21/526 (4.0%) VLBW infants. Chromosomal abnormalities, brain anomalies, severe IVH, cystic PVL, HIE, neonatal seizures, advanced maternal age, maternal diabetes mellitus, no administration of antenatal corticosteroids, and low Apgar scores at 1 and 5 min were associated with a risk of epilepsy. The median time to epilepsy onset was 8 months (range: 0-59 months), and the onset occurred within 2 years in 15/21 patients (71.4%) and within 4 years in 18/21 patients (85.7%). VLBW infants with risk factors developed epilepsy earlier and at a significantly higher rate than those without risk factors. Among infants who had risk factors and who developed epilepsy, 86.7% did so within 2 years of age, compared to 33.3% of those who developed epilepsy but did not have risk factors. CONCLUSION: These findings regarding factors associated with a risk of development of epilepsy and temporal feature of epilepsy may contribute to the development of monitoring and treatment protocols for epilepsy in VLBW infants.

Concomitant left atrial appendage closure during left ventricular assist device surgery can reduce ischaemic cerebrovascular accidents.

OBJECTIVES: It remains unknown if the left atrial appendage closure (LAAC) at the time of left ventricular assist device (LVAD) surgery can reduce ischaemic cerebrovascular accidents. METHODS: Consecutive 310 patients who underwent LVAD surgery with HeartMate II or 3 between January 2012 and November 2021 were included in this study. The cohort was divided into 2 groups: patients with LAAC (group A) and without LAAC (group B). We compared the clinical outcomes including the incidence of cerebrovascular accident between 2 groups. RESULTS: Ninety-eight patients were included in group A, and 212 patients in group B. There were no significant differences between 2 groups in age, preoperative CHADS2 score and history of atrial fibrillation. In-hospital mortality did not differ significantly between the 2 groups (group A: 7.1%, group B: 12.3%, P = 0.16). Thirty-seven patients (11.9%) experienced ischaemic cerebrovascular accident (5 patients in group A and 32 patients in group B). The cumulative incidence from ischaemic cerebrovascular accidents in group A (5.3% at 12 months and 5.3% at 36 months) was significantly lower than that in group B (8.2% at 12 months and 16.8% at 36 months; P = 0.017). In a multivariable competing risk analysis, LAAC was associated with reducing ischaemic cerebrovascular accidents (hazard ratio 0.38, 95% confidence interval 0.15-0.97, P = 0.043). CONCLUSIONS: Concomitant LAAC in LVAD surgery can reduce ischaemic cerebrovascular accidents without increasing perioperative mortality and complications.

Impact of prophylactic donor heart tricuspid valve annuloplasty on outcomes in heart transplantation.

BACKGROUND: Tricuspid regurgitation(TR) following heart transplantation could adversely affect clinical outcomes. In an effort to reduce the incidence of TR, prophylactic donor heart tricuspid valve annuloplasty has been performed during heart transplantation in our institution. We assessed early and long-term outcomes. METHODS: Between August 2011 and August 2021, 349 patients who underwent prophylactic tricuspid valve annuloplasty were included. Tricuspid valve annuloplasty was performed using the DeVega annuloplasty technique. The clinical outcomes of the interests included complete atrioventricular block requiring pacemaker implantation, the occurrence of significant TR(defined as moderate or greater), and survival. Long-term survival was compared in patients with and without significant TR using the Kaplan-Meier method. The Cox proportional hazards regression with time-dependent covariate analysis was used to see if significant TR affected the long-term survival. RESULTS: There was one patient(0.3%) who required pacemaker implantation for complete atrioventricular block. No patients developed tricuspid valve stenosis that required intervention. Significant TR developed in 31 patients(8.9%) during the follow-up period. The survival rate of patients who developed significant TR was significantly lower than that of those who did not(log rank < 0.01). Significant TR was associated with the long-term mortality(HR2.92, 95%CI 1.47-5.82, p < 0.01). CONCLUSIONS: Prophylactic donor heart tricuspid valve annuloplasty has the potential to reduce the occurrence of significant TR and can be performed safely. The significant TR that developed in patients with prophylactic annuloplasty negatively affected survival and was an independent predictor of long-term mortality.

An unusual case of type IIIB endoleak after repeat thoracic endovascular aortic repair at acute-angled arch: A case of fabric tear by bare-metal stent.

We report a case of an unusual case of type IIIB endoleaks after repeat thoracic endovascular aortic repair that was not visualized on computed tomography, first diagnosed during open conversion surgery, and successfully treated. A 69-year-old man had undergone repeat thoracic endovascular aortic repair for an enlarged thoracic aortic aneurysm six months before. His repeat computed tomography showed an acutely enlarged aneurysm, which had expanded from 80 to 96 mm in diameter, without any endoleaks. A type IIIB endoleak resulted from a small tear in fabric caused by a bare-metal stent of the previous endograft. The tip of the bare-metal of smaller outer endograft had penetrated a fabric portion of the inner larger endograft. The aneurysmal sac pressure was 58/46 mmHg, compared with a systemic pressure of 79/35 mmHg. The endografts were explanted and replaced with a vascular graft.

Volvulus of the stomach and wandering spleen after repair of congenital diaphragmatic hernia: unexpected manifestations in a neonate.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is sometimes associated with complications involving herniation of intrathoracic organs, which further increase mortality rate. We encountered a case of postoperative gastric and splenic volvulus shortly after left CDH repair in a female neonate who was treated with gastropexy. CASE PRESENTATION: At 39 weeks gestation, a female patient with left Bochdalek CDH was delivered (birth weight: 3748 g, Apgar score: 3/4). The patient was provided ventilator support with nitric oxide. After pulmonary hypertension improved, CDH repair was performed via the abdominal approach on day 7. The stomach, small intestine, large intestine, and spleen were herniated through a diaphragmatic defect of 4 × 2 cm. Although the diaphragm was directly closed, it was tight and the reconstructed diaphragm "dome" was shallow, restricting space for the spleen and stomach. Nonetheless, the spleen was positioned in the left upper abdomen and the stomach was positioned medially. The postoperative course was complicated by organo-axial gastric volvulus, and laparotomy was performed on day 14. In addition to the gastric volvulus, we confirmed a wandering splenic volvulus. The spleen was easily detorted and returned to the left upper abdomen. However, the patient experienced relapse of gastric volvulus without splenic volvulus. Gastropexy was performed electively on day 47. Postoperatively, the patient could be fed orally, and the patient's development was satisfactory 6 years after surgery. CONCLUSIONS: The cause of these rare complications appeared to be tight direct diaphragmatic closure, which reduced space for the spleen and stomach beneath the left diaphragm.

PTPN11 c.853T>C (p.Phe285Leu) mutation in Noonan syndrome with chylothorax.

Recent advances in molecular and genetic approaches have identified a number of genes responsible for Noonan syndrome (NS). However, there has been limited analysis of the genotype-phenotype correlation of NS patients. Here, we report the case of a Japanese patient with NS possessing a c.853T>C (p.Phe285Leu) mutation in the gene encoding protein-tyrosine phosphatase, nonreceptor-type 11 (PTPN11). To clarify genotype-phenotype correlations, the accumulation of data on the clinical course of patients with genetically confirmed NS is important. We summarized the cases with mutations at PTPN11 position 285 and found that c854T>C (p.Phe285Ser) is the most common mutation at this position. In these reports, although little is mentioned about the genotype-phenotype correlation, two patients with NS possessing the PTPN11 c854T>C (p.Phe285Ser) mutation accompanied by chylothorax are described. There is still a lack of detailed information about the phenotype associated with the c.853T>C (p.Phe285Leu) mutation observed in this case. More research is needed to better understand these cases.

Giant pulmonary bulla causing respiratory compromise in a very low-birthweight infant.

Acquired cystic lung disease in premature infants is a serious respiratory complication, and pulmonary interstitial emphysema (PIE) has been widely reported. We report a rare case of giant pulmonary bulla in an infant treated with bullectomy where chest computed tomography was useful in directing treatment.

Evaluation of nephrotoxicity and ototoxicity following amikacin administration once daily or every 48 hours in neonates.

The purpose of this study was to evaluate the effects of once daily (OD) or every 48 hours (every-48-h) administration of amikacin (AMK) on renal function and ototoxicity in neonates. We investigated the frequency of nephrotoxicity and ototoxicity in neonates who received AMK OD or every-48-h from April 2015 to March 2021 and underwent dose evaluation by therapeutic drug monitoring (TDM). In addition, the relationships among birth weight, gestational age, AMK peak and trough values, total duration of AMK administration, and total AMK dose were examined separately for nephrotoxicity and ototoxicity. AMK was administered OD in 38 patients and every-48-h in 62 patients. Nephrotoxicity was observed in 8 patients on OD versus 36 patients on every-48-h administration (P < .001), and ototoxicity was observed in 2 patients on OD versus 12 patients on every-48-h administration (P = .192). For nephrotoxicity, only the trough value was relevant (P = .007). In terms of ototoxicity, there were no influencing factors. The risk of nephrotoxicity was higher with every-48-h AMK administration than with OD AMK administration, with nephrotoxicity depending on the trough value. However, compared with OD, the every-48-h group had lower body weight and possibly poorer original renal function. In addition, ototoxicity did not differ by administration method. Based on these results, every-48-h administration of AMK can be used as safely as OD by performing TDM and preventing high concentrations.

The benchmark analysis of gastric, colorectal and rectal cancer pathways: toward establishing standardized clinical pathway in the cancer care.

Most clinical pathways in treating cancers in Japan are based on individual physician's personal experiences rather than on an empirical analysis of clinical data such as benchmark comparison with other hospitals. Therefore, these pathways are far from being standardized. By comparing detailed clinical data from five cancer centers, we have observed various differences among hospitals. By conducting benchmark analyses, providing detailed feedback to the participating hospitals and by repeating the benchmark a year later, we strive to develop more standardized clinical pathways for the treatment of cancers. The Cancer Quality Initiative was launched in 2007 by five cancer centers. Using diagnosis procedure combination data, the member hospitals benchmarked their pre-operative and post-operative length of stays, the duration of antibiotics administrations and the post-operative fasting duration for gastric, colon and rectal cancers. The benchmark was conducted by disclosing hospital identities and performed using 2007 and 2008 data. In the 2007 benchmark, substantial differences were shown among five hospitals in the treatment of gastric, colon and rectal cancers. After providing the 2007 results to the participating hospitals and organizing several brainstorming discussions, significant improvements were observed in the 2008 data study. The benchmark analysis of clinical data is extremely useful in promoting more standardized care and, thus in improving the quality of cancer treatment in Japan. By repeating the benchmark analyses, we can offer truly clinical evidence-based higher quality standardized cancer treatment to our patients.

Safety of high doses of Propionibacterium freudenreichii ET-3 culture in healthy adult subjects.

Propionibacterium freudenreichii ET-3 (7025) culture, a cell-free product of whey fermentation by P. freudenreichii ET-3, has been shown to promote the growth of Bifidobacteria through the action of 1,4-dihydroxy-2-naphthoic acid (DHNA). Here we report the results of two clinical studies designed to evaluate the safety of high doses of P. freudenreichii ET-3 culture medium. Study 1 had a randomized, double-blind, crossover design. Ten healthy male and four healthy female subjects received 45 tablets of either P. freudenreichii ET-3 culture medium (total daily intake of 3g solid content and 283.5µg of DHNA; active group) or placebo (unfermented product) during two 1-week supplementation periods separated by a 4-week washout period. In Study 2, 11 healthy men took four tablets of P. freudenreichii ET-3 culture medium per day (total daily intake of 0.267g solid content and 22.5µg of DHNA) for a period of 13weeks. In both studies, hematological, clinical chemistry, and urinary parameters were measured before and after each supplementation period and gastrointestinal symptoms were assessed by questionnaire. In Study 1, there were no statistically significant differences between placebo and active supplementation periods in any measured parameter and the incidence of gastrointestinal symptoms were similar between groups. In Study 2, total protein, white blood cell count, hemoglobin, and mean corpuscular hemoglobin concentration decreased significantly from baseline and mean corpuscular volume and urine pH increased from baseline. The changes in hematological parameters were deemed not to be due to P. freudenreichii ET-3 culture medium supplementation given that all parameters remained within normal ranges and were not consistent with any clinically meaningful effect.

Factors affecting psychosocial development of very low birth weight infants at 18 and 36 months of age.

AIM: To identify relationships between neonatal factors including conditions and treatments, nurturing environment, and psychosocial development of children born at very low birth weight (VLBW). METHODS: In this longitudinal study, the medical records of 113 VLBW infants were examined, and the children were then followed up at 18 and 36 months of age. Their developmental quotient (DQ) was assessed using the Kyoto Scale of Psychological Development (KSPD), and their parents were asked about their own health, financial situation, education, and family support. Pearson's correlation and stepwise multiple regression analyses were used to explore relationships between DQ, potentially significant predictors on the KSPD, and nurturing environment. RESULTS: DQ at 18 months was associated with the following neonatal factors: mechanical ventilation days (ß = -.241, p = .020), Apgar score at 5 min (ß = .278, p = .005), periventricular leukomalacia (ß = -.218, p = .006), and treatment for retinopathy of prematurity (ß = -.171, p = .048) (adjusted R2 = .32). DQ at 36 months was associated with the following neonatal and parenting factors: mechanical ventilation days (ß = -.354, p < .001), periventricular leukomalacia (ß = -.207, p = .009), sex (ß = -.199, p = .011), mother's educational background (ß = -.304, p < .001), mother's health status (ß = -.159, p = .042) (adjusted R2 = .35). CONCLUSIONS: These findings suggest that in addition to neonatal clinical parameters including conditions and treatments, the nurturing environment after discharge from the neonatal intensive care unit influences the psychosocial development of VLBW infants.

The effect of fibroblast growth factor 7 on human dental pulp stem cells for differentiation to AQP5-positive and αSMA-positive cells in vitro and in vivo.

OBJECTIVES: Transplantation of stem cells into wounds has become popular in regeneration therapies. As stem cells for transplantation, human dental pulp stem cells (hDPSCs) are known to be pluripotent cells that are relatively easy to collect from the pulp of deciduous or wisdom teeth. The purpose of this study was to investigate whether hDPSCs treated with fibroblast growth factor 7 (FGF7) would contribute to the regeneration of wounded rat submandibular glands (SMGs). MATERIALS AND METHODS: In in vitro studies, hDPSCs were treated with or without FGF7 and mRNA expression levels were examined at days 3, 7 and 14 using qRT-PCR. The target genes analyzed were BMI1 as an undifferentiated marker, AQP5 as an acinar cell marker, CK19 as a ductal epithelial cell marker, αSMA as a myoepithelial cell marker and VIMENTIN as a fibroblast marker. In in vivo studies, hDPSCs treated with or without FGF7 for 14 days were mixed with type I collagen gels and were transplanted into wounded rat SMGs. Hematoxylin-Eosin and immunohistochemical staining were performed at days 3 and 7, and the numbers of positive cells were counted. The primary antibodies used were against BMI1, AQP5, αSMA, PanCK and VIMENTIN. RESULTS: In the in vitro studies, mRNA levels of BMI1 were decreased and αSMA were increased at days 3, 7 and 14, while AQP5 was increased at day 14 in the FGF7 group. In the in vivo studies, the proliferation of hDPSCs and cell islands was observed at day 7 in the FGF7 group. Few BMI1-positive cells were observed, while numbers of AQP5-positive and αSMA-positive cells were increased at days 3 and 7 in the FGF7 group. Moreover, cell islands were AQP5-positive. CONCLUSION: These results suggest that FGF7-treated hDPSCs differentiate into AQP5-positive and αSMA-positive cells. Moreover, AQP5-positive cell aggregations were formed.

Late-onset circulatory dysfunction after thyroid hormone treatment in an extremely low birth weight infant.

Late-onset circulatory dysfunction (LCD) is a phenomenon specific to premature infants and is characterized by sudden onset of hyponatremia, hypotension, oliguria and non-physiological weight gain, without an obvious cause, in premature infants after stabilization of circulation and respiration. The cause of LCD is not clear, but adrenal insufficiency in premature infants is a severe syndrome because steroid replacement therapy is often essential to treat the symptoms. We report a rare case of a premature infant who developed an LCD crisis the day after thyroxine replacement therapy. The female infant was born at 25 weeks of gestational age, weighing 672 g, and appeared to have hypothyroidism, with free T4 of 0.19 ng/dl and elevated TSH levels of 26.3 microIU/ml at Day 14. She developed an LCD crisis the day after starting thyroxine treatment. She received steroid replacement therapy for 4 weeks and her adrenal function progressively recovered. She also needed thyroxine supplementation for 13 weeks, which maintained her thyroid function as euthyroid. Because she exhibited cortisol insufficiency and thyroid hormone insufficiency, the antecedent thyroid hormone replacement may be responsible for the onset of LCD. We must consider monitoring adrenal function when starting thyroxine therapy in premature infants with hypothyroxinemia.

[Chronic graft-versus-host disease with multiple serositis after bone marrow transplantation from non-inherited maternal antigen-complementary sibling donor].

We report a patient who developed multiple serositis during chronic graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation from a non-inherited maternal antigen (NIMA) -complementary sibling donor. The patient was a 9-year-old boy with myelodysplastic syndrome, who urgently underwent bone marrow transplantation from his NIMA-complementary HLA two-locus-mismatched sister following graft failure of cord blood transplantation. Engraftment was successfully confirmed and no acute GVHD developed. After withdrawal of tacrolimus to prevent recurrent viral infection, he developed pleural effusion, ascites and edema approximately 6 months after transplantation. His clinical symptoms were resolved by methylprednisolone pulse therapy, but he subsequently progressed to develop pericardial effusion, pneumothorax and truncal panniculitis. Pleural and pericardial effusion contained numerous lymphocytes, which gradually subsided with continuous drainage. His symptoms were thereafter controlled by the addition of mycophenolate mofetil (MMF) administration, and his current performance status is almost perfect by the administration of prednisolone (5 mg/day) and MMF at 6 years after transplantation. Although multiple serositis associated with GVHD is known to have a poor prognosis, the multiple symptoms of this patient improved gradually, probably owing to a lack of acute GVHD and the effect of MMF.

Fms-like tyrosine kinase 3 ligand stimulation induces MLL-rearranged leukemia cells into quiescence resistant to antileukemic agents.

Fms-like tyrosine kinase 3 (FLT3) is highly expressed in acute lymphoblastic leukemia with the mixed-lineage leukemia (MLL) gene rearrangement refractory to chemotherapy. We examined the biological effect of FLT3-ligand (FL) on 18 B-precursor leukemic cell lines with variable karyotypic abnormalities, and found that nine of nine MLL-rearranged cell lines with wild-type FLT3, in contrast to other leukemic cell lines, are significantly inhibited in their proliferation in a dose-dependent manner by FL. This inhibition was due to induction of the G0-G1 arrest. A marked up-regulation of p27 by suppression of its protein degradation and an abrogation of constitutive signal transducers and activators of transcription 5 phosphorylation were revealed in arrested leukemia cells after FL stimulation. Importantly, FL treatment rendered not only cell lines but also primary leukemia cells with MLL rearrangement resistant to chemotherapeutic agents. MLL-rearranged leukemia cells adhering to the bone marrow stromal cell line, which expresses FL as the membrane-bound form, were induced to quiescent state resistant to chemotherapeutic agents, but their chemosensitivity was significantly restored in the presence of neutralizing anti-FL antibody. The FL/FLT3 interaction between leukemia cells and bone marrow stromal cells expressing FL at high levels should contribute, at least in part, to persistent minimal-residual disease of MLL-rearranged leukemia in bone marrow.