Usefulness of the one-step technique in functional end-to-end anastomosis for colonic surgery: results of a prospective multicentre cohort study from the Japanese KYCC group.

BACKGROUND: Although functional end-to-end anastomosis (FEEA) using a stapler in the colorectal field has been recognised worldwide, the technique varies by surgeon, and the safety of anastomosis using different techniques is unknown. METHODS: This multicentre prospective observational cohort study was conducted by the KYCC Study Group in Yokohama, Japan, and included patients who underwent colonic resection at seven centres between April 2020 and March 2022. This study compared the incidence of surgery-related abdominal complications (SAC: anastomotic leakage [AL], anastomotic bleeding, intra-abdominal abscess, enteritis, ileus, surgical site infection, and other abdominal complications) between two different methods of FEEA (one-step [OS] method: simultaneous anastomosis and bowel resection; two-step [TS] method: anastomosis after bowel resection). Complications of Clavien-Dindo classification grade 2 or higher were assessed. RESULTS: Among 293 eligible cases, the OS and TS methods were used in 194 (66.2%) and 99 (33.8%) patients, respectively. The baseline characteristics were similar between the groups. The OS method used fewer staplers (three vs. four staplers, p < 0.00001). There were no significant differences in SAC rate between the OS (19.1%) and the TS (16.2%) groups (p = 0.44). The OS group had four cases (2.1%) of AL (two patients; grade 3, two patients; grade 2) while the TS group had one case (1.0%) of grade 2 AL (p = 0.67). Multivariate logistic regression analysis showed that male sex (odds ratio [OR] 3.95; p < 0.00001), an open surgical approach (OR 2.36; p = 0.03), and longer operative duration (OR,2.79; p = 0.002) were independent predictors of complications, whereas the OS method was not an independent predictor (OR 1.17; p = 0.66). CONCLUSIONS: The OS and the TS technique for stapled colonic anastomosis in a FEEA had a similar postoperative complication rate. TRIAL REGISTRATION NUMBER: UMIN000039902 (registration date 23 March 2020).

The prognostic value of 18F-FDG PET/CT taken immediately after completion of radiotherapy for lung cancer treated with concurrent chemoradiotherapy: A pilot study.

PURPOSE: The prognostic value of F-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) taken immediately after completion of radiotherapy in lung cancer patients is not well known. The purpose of this study is to assess the prognostic value of PET/CT taken immediately after completion of radiotherapy in lung cancer patients. MATERIALS AND METHODS: Patients with primary lung cancer planned to undergo concurrent chemoradiotherapy were enrolled. Patients underwent PET/CT scans at 3 time points: before radiotherapy, within 24hours of completing radiotherapy (im-PET/CT), and 2-9 months after radiotherapy (post-PET/CT). Maximum standardized uptake value (SUVmax) was obtained. A post-PET/CT-SUVmax cut-off of 2.5 was determined as radiotherapy success. RESULTS: Nineteen patients were enrolled. im-PET/CT-SUVmax for patients in the high post-PET/CT-SUVmax group was significantly higher than that of the low group (P=0.004). Receiver operator curve analysis indicated that im-PET/CT-SUVmax of 4.35 was an optimal cut-off value to discriminate between the two groups. Multivariable analysis showed that a high im-PET/CT-SUVmax was significantly associated with a high post-PET/CT-SUVmax (P=0.003). CONCLUSION: PET/CT-SUVmax taken immediately following radiotherapy was associated with that evaluated 2-9 months after radiotherapy.

Chronic Basophilic Leukaemia in a Dog.

A 13-year-old neutered female mixed-breed dog with a clinical history of emaciation, inappetence and vomiting for 2 months was presented. Blood tests showed marked leucocytosis with increased neutrophil and basophil count, mild thrombocytosis and anaemia. Seven days after the initial visit, the dog died and was submitted for necropsy examination. Grossly, the bone marrow was red in colour and hepatomegaly and splenomegaly with discolouration were observed. A bone marrow smear showed an increased proportion of basophilic lineage cells. Histologically, the bone marrow showed high cellular density and numerous basophilic lineage cells with a round or segmented nucleus. The cytoplasm contained basophilic granules exhibiting metachromasia on toluidine blue staining. Immunohistochemically, the neoplastic basophils were diffusely positive for vimentin and myeloperoxidase, but negative for CD3, BLA36, CD163, CD204 and c-kit. The immunohistochemical features of neoplastic basophils that had invaded the liver and spleen were similar to those of the basophils in the bone marrow. Based on the clinicopathological and histopathological findings, chronic basophilic leukaemia was diagnosed. The present case study provides insights into the pathological features of chronic basophilic leukaemia in dogs.

Increased serum PCSK9, a potential biomarker to screen for periodontitis, and decreased total bilirubin associated with probing depth in a Japanese community survey.

BACKGROUND AND OBJECTIVES: Previous reports suggest that several serum biomarkers play roles in the pathogenesis, inflammatory response, and oxidative stress in periodontitis caused by bacterial infections, linking chronic periodontitis to atherosclerotic vascular disease (ASVD). The aim of this preliminary study was to investigate, in a Japanese cross-sectional community survey, potential serum biomarkers of periodontitis that are associated with ASVD and chronic periodontitis. MATERIAL AND METHODS: The study cohort included a total of 108 male subjects who underwent annual health examinations. Serum biomarkers (high-sensitivity C-reactive protein [hs-CRP], proprotein convertase subtilisin/kexin type 9 [PCSK9], interleukin-6, tumor necrosis factor-α, soluble CD14, myeloperoxidase, matrix metalloproteinase-3, adiponectin, total bilirubin [TBIL], and serum lipids) were analyzed to determine their association (if any) with periodontal parameters. Aortic stiffness was evaluated using the brachial-ankle aortic pulse wave velocity (PWV) index and the cardio-ankle vascular index (CAVI). RESULTS: The concentrations of PCSK9 and hs-CRP were increased (P = .001 and .042, respectively), and the concentration of TBIL was decreased (P = .046), in subjects with periodontal disease (determined as a probing depth of ≥4 mm in at least one site) compared with periodontally healthy subjects. The ratio of low-density lipoprotein cholesterol (LDL-C) to high-density lipoprotein cholesterol and the concentrations of triglycerides, remnant-like particles-cholesterol, and oxidized LDL were elevated in subjects with periodontal disease compared with periodontally healthy subjects (P = .038, .007, .002, and .049, respectively). Multivariate regression analyses indicated that the number of sites with a pocket depth of ≥4 mm was associated with the concentration of PCSK9 and inversely associated with the concentration of TBIL independently (standardized ß = .243, P = .040; standardized ß = -.443, P = .0002; respectively). Analysis of receiver operating characteristic curves of PCSK9 indicated moderate accuracy for predicting the presence of disease sites (probing depth ≥ 4 mm) (area under the curve = 0.740). No significance in the values of PWV and CAVI was observed between subjects with periodontal disease and periodontally healthy subjects. CONCLUSION: In Japanese male subjects, the concentrations of serum PCSK9 and TBIL were correlated with periodontal parameters. Moreover, PCSK9 could be a candidate biomarker for diagnosing chronic periodontitis, and may also have potential to evaluate the risk for periodontitis to cause ASVD. Longitudinal studies of larger populations are necessary to confirm the exact association of periodontitis with increased serum PCSK9 and decreased TBIL.

Effect of the combined use of enamel matrix derivative and atelocollagen sponge scaffold on osteoblastic differentiation of mouse induced pluripotent stem cells in vitro.

BACKGROUND AND OBJECTIVE: Induced pluripotent stem cells (iPSCs) are a candidate cell source in periodontal regenerative therapy. Enamel matrix derivative (EMD) has been shown to regenerate periodontal tissues, and atelocollagen sponge (ACS) is considered a suitable scaffold or carrier for growth factors. This study aimed to investigate the effect of combined use of EMD and an ACS scaffold on cell behaviors and differentiation of mouse iPSCs (miPSCs) in vitro. MATERIAL AND METHODS: Following embryonic body formation from miPSCs, dissociated cells (miPS-EB-derived cells) were seeded onto ACS with or without EMD, and cultured in osteoblast differentiation medium. Scanning electron microscopy and histological analyses were used to assess cell morphology and infiltration within the ACS. Cell viability (metabolism) was determined using an MTS assay, and expression of mRNA of osteoblastic differentiation markers was assessed by quantitative RT -PCR. Alkaline phosphatase (ALP) staining intensity and activity were evaluated. Mineralization was assessed by von Kossa staining, and calcium content was quantitated using the methylxylenol blue method. RESULTS: By 24 hours after seeding, miPS-EB-derived cells in both the EMD and control groups had attached to and infiltrated the ACS scaffold. Scanning electron microscopy images revealed that by day 14, many cytoplasmic protrusions and extracellular deposits, suggestive of calcified matrix, were present in the EMD group. There was a time-dependent increase in cell viability up to day 3, but no difference between groups was observed at any time point. The levels expressed of ALP and osterix genes were significantly higher in the EMD group than in the control group. Expression of runt-related transcription factor 2 was increased in the EMD group compared with the control group on day 7. EMD upregulated the expression of bone sialoprotein and osteopontin on day 14, whereas expression of osteocalcin was lower at all time points. The staining intensity and activity of ALP were higher in the EMD group than in the control group. Mineralization levels and calcium contents were significantly higher in the EMD group throughout the observation period. CONCLUSION: These data suggest that combining ACS with EMD increases levels of osteoblastic differentiation and mineralization in miPS-EB-derived cells, compared with ACS used alone.

Surfactant protein D inhibits activation of non-small cell lung cancer-associated mutant EGFR and affects clinical outcomes of patients.

Tyrosine kinase inhibitor (TKI)-sensitive and TKI-resistant mutations of epidermal growth factor receptor (EGFR) are associated with lung adenocarcinoma. EGFR mutants were previously shown to exhibit ligand-independent activation. We have previously demonstrated that pulmonary surfactant protein D (SP-D, SFTPD) suppressed wild-type EGFR signaling by blocking ligand binding to EGFR. We herein demonstrate that SFTPD downregulates ligand-independent signaling in cells harboring EGFR mutations such as TKI-sensitive exon 19 deletion (Ex19del) and L858R mutation as well as TKI-resistant T790M mutation, subsequently suppressing cellular growth and motility. Lectin blotting and ligand blotting in lung cancer cell lines suggested that EGFR mutants express oligomannose-type N-glycans and interact with SFTPD directly. Cross-linking assay indicated that SFTPD inhibits ligand-independent dimerization of EGFR mutants. We also demonstrated that SFTPD reduced dimerization-independent phosphorylation of Ex19del and T790M EGFR mutants using point mutations that disrupted the asymmetric dimer interface. It was confirmed that SFTPD augmented the viability-suppressing effects of EGFR-TKIs. Furthermore, retrospective analysis of 121 patients with lung adenocarcinoma to examine associations between serum SFTPD levels and clinical outcome indicated that in TKI-treated patients with lung cancer harboring EGFR mutations, including Ex19del or L858R, high serum SFTPD levels correlated with a lower number of distant metastases and prolonged overall survival and progression-free survival. These findings suggest that SFTPD downregulates both TKI-sensitive and -resistant EGFR mutant signaling, and SFTPD level is correlated with clinical outcome. These findings illustrate the use of serum SFTPD level as a potential marker to estimate the efficacy of EGFR-TKIs.

Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan.

Recent studies revealed that a substantial proportion of patients with high-risk B-cell precursor acute lymphoblastic leukemia (BCP-ALL) harbor fusions involving tyrosine kinase and cytokine receptors, such as ABL1, PDGFRB, JAK2 and CRLF2, which are targeted by tyrosine kinase inhibitors (TKIs). In the present study, transcriptome analysis or multiplex reverse transcriptase-PCR analysis of 373 BCP-ALL patients without recurrent genetic abnormalities identified 29 patients with kinase fusions. Clinically, male predominance (male/female: 22/7), older age at onset (mean age at onset: 8.8 years) and a high white blood cell count at diagnosis (mean: 94 200/µl) reflected the predominance of National Cancer Institute high-risk (NCI-HR) patients (NCI-standard risk/HR: 8/21). Genetic analysis identified three patients with ABL1 rearrangements, eight with PDGFRB rearrangements, two with JAK2 rearrangements, three with IgH-EPOR and one with NCOR1-LYN. Of the 14 patients with CRLF2 rearrangements, two harbored IgH-EPOR and PDGFRB rearrangements. IKZF1 deletion was present in 16 of the 22 patients. The 5-year event-free and overall survival rates were 48.6±9.7% and 73.5±8.6%, respectively. The outcome was not satisfactory without sophisticated minimal residual disease-based stratification. Furthermore, the efficacy of TKIs combined with conventional chemotherapy without allogeneic hematopoietic stem cell transplantation in this cohort should be determined.

Polylactic acid nanosheets in prevention of postoperative intestinal adhesion and their effects on bacterial propagation in an experimental model.

BACKGROUND: Ultrathin films (nanosheets) adhere tightly to organ surfaces but prevent adhesion to other organs. The antiadhesive effect of nanosheets and their effect on bacterial propagation were investigated in a murine intestinal adhesion model. METHODS: Polylactic acid nanosheets (approximately 80 nm thick) were produced. Serosal defects were created by peeling off the intestinal serosa; these were left open or covered with nanosheets or Seprafilm® and the formation of intestinal adhesions was analysed. To examine bacterial propagation, a nanosheet or Seprafilm® was placed on intact murine jejunum followed by Escherichia coli inoculation at the site. RESULTS: Treatment both with nanosheets and with Seprafilm® reduced postoperative intestinal adhesion (mean adhesion score 0·67 for nanosheets, 0·43 for Seprafilm® and 2·87 for no antiadhesive treatment; P < 0·001 for nanosheets or Seprafilm® versus no adhesive treatment). Nanosheet treatment did not affect bacterial propagation in the peritoneal cavity, whereas Seprafilm®-treated mice showed bacterial propagation, leading to increased mortality. CONCLUSION: Nanosheets may be effective novel antiadhesive agents even in the presence of bacterial contamination. Surgical relevance Intra-abdominal adhesions following surgical contamination can trigger postoperative complications and lead to deterioration in long-term quality of life. However, currently there are no effective antiadhesion materials to prevent the formation of adhesions. Treatment with ultrathin nanosheets effectively reduced postoperative intestinal adhesion in an experimental mouse model, and did not affect bacterial propagation in the peritoneal cavity. These nanosheets are potent novel antiadhesive materials that potentially can be applied even in contaminated conditions.

Spectrum of clinical and genetic features of patients with inherited platelet disorder with suspected predisposition to hematological malignancies: a nationwide survey in Japan.

BACKGROUND: Inherited thrombocytopenia (IT) contains several forms of familial thrombocytopenia and some of them have propensity to hematological malignancies. The etiological and genetic features of this heterogeneous syndrome have not yet been elucidated. PATIENTS AND METHODS: We conducted a nationwide survey to collect clinical information and samples from patients with familial thrombocytopenia and/or hematological malignancies in order to obtain a comprehensive understanding of IT. RESULTS: Among the 43 pedigrees with clinical samples, RUNX1 mutations were identified in 8 pedigrees (18.6%). While MYH9 and ANKRD26 mutations were identified in 2 and 1 pedigrees, respectively, no gene mutations were detected in the remaining 32 pedigrees from a panel of previously reported pathogenetic mutations. Clinical data were comparable between FPD/AML and non-FPD/AML probands. CONCLUSIONS: Our study clarified that it is unexpectedly difficult to diagnose FPD/AML based on clinical information alone, and thus, genetic testing is strongly recommended. Our survey also identified some pedigrees with a strong family history of myelodysplastic syndromes of unknown origin. Additionally, there were 14 pedigrees in which three or more members were affected by immune thrombocytopenia (ITP), and a computer-aided simulation suggested that such a distribution almost never happens by coincidence, which implicates a genetic predisposition to ITP.

Optimal MR Plaque Imaging for Cervical Carotid Artery Stenosis in Predicting the Development of Microembolic Signals during Exposure of Carotid Arteries in Endarterectomy: Comparison of 4 T1-Weighted Imaging Techniques.

BACKGROUND AND PURPOSE: Preoperative identification of plaque vulnerability may allow improved risk stratification for patients considered for carotid endarterectomy. The present study aimed to determine which plaque imaging technique, cardiac-gated black-blood fast spin-echo, magnetization-prepared rapid acquisition of gradient echo, source image of 3D time-of-flight MR angiography, or noncardiac-gated spin-echo, most accurately predicts development of microembolic signals during exposure of carotid arteries in carotid endarterectomy. MATERIALS AND METHODS: Eighty patients with ICA stenosis (≥70%) underwent the 4 sequences of preoperative MR plaque imaging of the affected carotid bifurcation and then carotid endarterectomy under transcranial Doppler monitoring of microembolic signals in the ipsilateral middle cerebral artery. The contrast ratio of the carotid plaque was calculated by dividing plaque signal intensity by sternocleidomastoid muscle signal intensity. RESULTS: Microembolic signals during exposure of carotid arteries were detected in 23 patients (29%), 3 of whom developed new neurologic deficits postoperatively. Those deficits remained at 24 hours after surgery in only 1 patient. The area under the receiver operating characteristic curve to discriminate between the presence and absence of microembolic signals during exposure of the carotid arteries was significantly greater with nongated spin-echo than with black-blood fast spin-echo (difference between areas, 0.258; P < .0001), MPRAGE (difference between areas, 0.106; P = .0023), or source image of 3D time-of-flight MR angiography (difference between areas, 0.128; P = .0010). Negative binomial regression showed that in the 23 patients with microembolic signals, the contrast ratio was associated with the number of microembolic signals only in nongated spin-echo (risk ratio, 1.36; 95% confidence interval, 1.01-1.97; P < .001). CONCLUSIONS: Nongated spin-echo may predict the development of microembolic signals during exposure of the carotid arteries in carotid endarterectomy more accurately than other MR plaque imaging techniques.

Effect of periodontal surgery on oral health-related quality of life in patients who have completed initial periodontal therapy.

BACKGROUND AND OBJECTIVE: Patient-centered assessments are particularly important in periodontal treatment in which their concerns may differ from the traditional clinical endpoints. However, information is limited regarding the influence of periodontal surgery on patients' quality of life (QoL). The aim of the present study was to investigate the impact of surgical periodontal therapy on the oral health-related QoL of patients who have received initial periodontal therapy. METHODS: A three-center prospective clinical study design was used, with the study participants comprising patients with moderate to severe periodontitis. Following initial periodontal therapy, the participants received either surgical or non-surgical periodontal treatment. The Oral Health-related Quality of Life Model for Dental Hygiene (OHRQL instrument), was used to assess participants' oral health-related QoL at each periodontal assessment interval: baseline (phase I), after initial therapy (phase II) and after surgery or during supportive periodontal therapy (phase III). RESULTS: Seventy-six patients (26 non-surgery, 50 surgery) completed the third phase of OHRQL assessment and were subjected to data analysis. From phase II to III, an improvement was achieved in all clinical parameters (p < 0.05-0.001) in the surgery group, whereas no such improvement was observed in the non-surgery group. In both groups, a significant difference in total OHRQL score was noted between phases I and III (p < 0.001 for surgery and p < 0.05 for non-surgery). The OHRQL domain scores for pain and eating/chewing function showed a significant improvement between these time points. However, no further significant improvement in OHRQL scores was achieved from phase II to III. CONCLUSION: A significant improvement in oral health-related QoL was noted between phases I and III in the surgery and non-surgery groups. Such improvement was less pronounced in the non-surgery vs. the surgery group. From phase II to III, neither surgery nor non-surgical treatment yielded significant improvement in oral health-related QoL.

Role of mitogen-activated protein kinase pathways in migration of gingival epithelial cells in response to stimulation by cigarette smoke condensate and infection by Porphyromonas gingivalis.

BACKGROUND AND OBJECTIVE: Previous studies have shown that cigarette smoke (CS) and periodontal pathogens could alter wound healing responses of gingival epithelial cells. To elucidate molecular mechanisms leading to these epithelial changes, we studied the signaling pathway involved in the modulation of cell migration by CS condensate (CSC) and the infection by a prominent periodontal pathogen, Porphyromonas gingivalis. MATERIAL AND METHODS: Human gingival epithelial cells (Ca9-22) were treated with CSC or vehicle control for 24 h. Activation of mitogen-activated protein kinases (MAPK) in cells with or without infection by P. gingivalis was assessed by polymerase chain reaction array and immunoblotting using phospho-specific antibodies. Cell migration was assessed using in vitro wound closure model, and specific pharmacologic inhibitors of MAPK pathways were used to characterize further the extent of involvement of the MAPK pathways. RESULTS: Polymerase chain reaction array showed that gene expression of several members of the MAPK, particularly p38 and JNK, was upregulated more than twofold in Ca9-22 cells stimulated with 10 µg/mL CSC. Coincubation with P. gingivalis induced a different pattern of gene expression for MAPK pathways, but it did not suppress the MAPK-related genes upregulated by CSC. A significant phosphorylation of ERK1/2 and p38 was observed in cells stimulated with 10 µg/mL CSC (p < 0.05), whereas coincubation with a higher concentration of CSC (250 µg/mL) evoked no such activation. P. gingivalis infection resulted in a tendency to reduce the phosphorylation of ERK1/2 and p38, which had been enhanced by stimulation with 10 µg/mL CSC. Incubation with ERK1/2 and p38 inhibitors significantly reduced the wound closure of CSC-stimulated cells, by approximately 43% and 46%, respectively (p < 0.05). CONCLUSION: CSC exerts effects on the migration of human gingival epithelial cells through the activation of the MAPK ERK1/2 and p38 signaling pathways. P. gingivalis infection attenuates the CSC-induced migration at least partly by suppressing the phosphorylation of ERK1/2 and p38, but other pathways are likely to be involved in this modulatory process.

Multicenter observational study comparing sedation/analgesia protocols for laser photocoagulation treatment of retinopathy of prematurity.

OBJECTIVE: The aim of this study was to identify the best sedation/analgesia protocol for laser photocoagulation (PC) of retinopathy of prematurity (ROP). STUDY DESIGN: This multicenter observational study included five hospitals, each using a specific sedation/analgesia protocol: local anesthesia with oxybuprocaine hydrochloride (Group L); intravenous pentazocine (Group P); intravenous fentanyl (Group F); air, oxygen and sevoflurane (AOS) inhalation (Group I). The groups were compared for pain responses, vital signs and adverse events. RESULTS: Heart rates and systemic blood pressures were elevated by PC in Groups L and P and Groups L, P and F, respectively. Moreover, poor analgesic efficacy was recognized in Groups L, P and F. In contrast, Group I experienced hypothermia, enteral feeding intolerance and apnea more frequently. CONCLUSION: From the viewpoint of sedation/pain relief, AOS anesthesia should be the best protocol. However, considering all the various factors together, the most reasonable one can be varied based on the patient's condition and hospital.

Cigarette smoke condensate modulates migration of human gingival epithelial cells and their interactions with Porphyromonas gingivalis.

BACKGROUND AND OBJECTIVE: Epithelial cells are recognized as the first line of defense against bacterial infection and environmental harmful stimuli such as cigarette smoke (CS). Although previous studies explored the effects of nicotine on host cells, mechanisms by which CS affects cellular functions remain uncertain. The present study investigated the effects of CS condensate (CSC) on in vitro wound closure of gingival epithelial cells and their potential interactions with a major periodontal pathogen, Porphyromonas gingivalis. MATERIAL AND METHODS: Human gingival epithelial cells (Ca9-22) were treated with CSC for 24 h. Cell proliferation was determined using a WST-1 assay. Cell migration was assessed using a wound closure model. The expression of integrins was analyzed by confocal scanning laser microscopy and real-time PCR. Intracellular invasion of P. gingivalis was evaluated by confocal scanning laser microscopy and an antibiotic protection assay. RESULTS: Low concentrations (1-10 µg/mL) of CSC showed no significant effect on cell proliferation. CSC demonstrated dual effects on epithelial wound closure of Ca9-22 cells: high concentrations (i.e. 250 µg/mL) significantly inhibited the wound closure whereas low concentrations (i.e. 10 µg/mL) promoted it (p < 0.01). CSC induced distinct changes in cytoskeleton. When CSC-exposed cells were infected with P. gingivalis for 2 h, a significant inhibition of wound closure was observed concurrent with a decrease in integrin α3 expression near the wound area. A significantly increased P. gingivalis invasion into Ca9-22 was observed when exposed to low concentrations of CSC. CONCLUSION: Low concentrations of CSC increased invasion of human gingival epithelial cells by P. gingivalis and induced changes in cytoskeleton and integrin expression, thereby modulating the cell migration.

Early use of allogeneic hematopoietic stem cell transplantation for infants with MLL gene-rearrangement-positive acute lymphoblastic leukemia.

Sixty-two infants with MLL gene-rearrangement-positive acute lymphoblastic leukemia (MLL-r ALL) were treated with the MLL03 protocol of the Japanese Pediatric Leukemia/Lymphoma Study Group: short-course intensive chemotherapy followed by early allogeneic hematopoietic stem cell transplantation (HSCT) within 4 months of the initial induction. The 4-year event-free survival and overall survival rates were 43.2% (95% confidence interval (CI)=30.7-55.1%) and 67.2% (53.8-77.4%), respectively. A univariate analysis showed younger age (<90 days at diagnosis), central nervous system disease and poor response to initial prednisolone therapy significantly associated with poor prognosis (P<0.05). In a multivariate analysis, younger age at diagnosis tended to be associated with poor outcome (hazard ratio=1.969; 95% CI=0.903-4.291; P=0.088). Although the strategy of early use of HSCT effectively prevented early relapse and was feasible for infants with MLL-r ALL, the fact that substantial number of patients still relapsed even though transplanted in their first remission indicates the limited efficacy of allogeneic HSCT for infants with MLL-r ALL. Considering the risk of severe late effects, indications for HSCT should be restricted to specific subgroups with poor risk factors. An alternative approach incorporating molecular-targeted drugs should be established.