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.

Analysis of bacteremia at first-line antibiotic treatment for febrile neutropenia in children and adolescents: A retrospective, single-center analysis.

BACKGROUND: Control of bacterial and fungal infections is critical to improving outcomes in hematological neoplastic diseases of children and adolescents. In this study, a retrospective analysis of our previous studies on febrile neutropenia was performed to investigate bacteremia. PROCEDURE: From August 2008 to December 2023, five antibiotic studies were performed for febrile and neutropenic pediatric patients who had been treated with chemotherapy, immunosuppressive therapy, or had received stem cell transplantation in the pediatric unit at Sapporo Hokuyu Hospital. The rate of positive blood culture, detected bacteria, and susceptibility of several types of antibiotics in febrile episodes were investigated. RESULTS: Blood culture was positive in 133 of 1604 febrile episodes of 329 patients. Detected bacteria were Gram-positive cocci (61.2 %), Gram-negative bacilli (27.6 %), Gram-negative cocci (0.7 %), and Gram-positive bacilli (10.4 %). The incidence of bacteremia over time showed a decreasing trend with each passing year. In particular, the incidence of bacteremia was around 10 % in 2008-2013, whereas it was often below 5 % after 2020; this decrease was statistically significant. Although almost all detected bacteria and their susceptibilities to antibiotics (piperacillin/tazobactam, meropenem, ceftazidime, and cefozopran) did not change over time, all Escherichia coli detected after 2014 were extended-spectrum ß-lactamase-producing bacteria.

Non-germinal center B-cell subtype of pediatric diffuse large B-cell lymphoma in Japan: A retrospective cohort study.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is classified into two molecular subtypes according to its cell of origin: germinal center B-cell (GCB) subtype and activated B-cell/non-GCB subtype. This latter subtype shows a poorer prognosis in adults. However, in pediatric DLBCL, the prognostic impact of the subtype is yet to be clarified. OBJECTIVES: This study sought to compare the prognosis between GCB and non-GCB DLBCL in a large number of cases in children and adolescents. In addition, this study intended to describe the clinical, immunohistochemical, and cytogenetic characteristics of these two molecular subtypes of DLBCL, and consider differences in the biology, frequency, and prognosis of GCB and non-GCB subtypes in pediatric versus adult DLBCL or in Japanese versus Western pediatric DLBCL patients. DESIGN/METHODS: We selected mature B-cell lymphoma/leukemia patients for whom specimens had been submitted to the central pathology review in Japan between June 2005 and November 2019. We referred the past studies on Asian adult patients and Western pediatric patients to compare with our results. RESULTS: Data were obtained from 199 DLBCL patients. The median age of all patients was 10 years, with 125 patients (62.8%) in the GCB group and 49 (24.6%) in the non-GCB group other than 25 cases whose immunohistochemical data were insufficient. Overall, the percentage of translocation of MYC (1.4%) and BCL6 (6.3%) was lower than in adult and Western pediatric DLBCL cases. The non-GCB group showed a significantly higher proportion of females (44.9%), a higher incidence of stage III disease (38.8%), and B-cell lymphoma 2 (BCL2)-positivity in immunohistochemistry (79.6%) compared to the GCB group; however, no BCL2 rearrangement was observed in both GCB and non-GCB groups. The prognosis did not differ significantly between the GCB and non-GCB groups. CONCLUSION: This study including a large number of non-GCB patients showed the same prognosis between GCB and non-GCB groups and suggested a difference in the biology of pediatric and adolescent DLBCL compared to adult DLBCL as well as between Asian and Western DLBCL.

Clinical Outcomes after One-day or Two-day Intervals in Conditioning Regimens for allo-HCT.

One-day or two-day intervals are generally inserted into scheduled conditioning regimens for allogeneic hematopoietic cell transplantation, primarily due to various social circumstances, such as unexpected natural adversities, abrupt deterioration of patient health, and delays in graft source arrival. We compared the clinical outcomes of patients with interrupted conditioning with those with ordinarily scheduled conditioning. We analyzed 83 patients (children and adolescents) with oncologic disease who underwent myeloablative conditioning with total body irradiation. Overall and event-free survival were similar between the groups ( P =0.955, P =0.908, respectively). Non-relapse mortality and relapse rates were similar between the groups ( P =0.923, P =0.946, respectively). The engraftment rate was not affected by interruption ( P =1.000). In contrast, the incidence of chronic graft-versus-host disease (GVHD) was higher in the interrupted group compared with the scheduled group, although there was no statistical significance (42% vs. 19%, P =0.063). Conditioning interruption was identified to be an independent risk factor for chronic GVHD by multivariate analysis (odds ratio: 3.72; 95% CI: 1.04 to 13.3; P =0.043). In conclusion, apart from the incidence of chronic GVHD, clinical outcomes were not affected by one-day or two-day intervals during conditioning.

Prognostic factors of children and adolescents with T-cell acute lymphoblastic leukemia after allogeneic transplantation.

Acute lymphoblastic leukemia (ALL) is the most common cancer during childhood, and some high-risk patients with ALL require hematopoietic stem cell transplantation (HSCT). Mainly due to small patient numbers, studies focusing specifically on children and adolescents with T-cell ALL (T-ALL) are limited. Using a nationwide registry, we retrospectively analyzed data from patients under 20 years old who underwent their first HSCT for T-ALL between 2000 and 2018. As a result, total 484 patients were included, and their median follow-up period was 6.9 years after HSCT for survivors. While patients receiving HSCT at first complete remission (CR) showed relatively good 5-year leukemia free survival (5yLFS, 73.5%), once relapse occurred, their prognosis was much worse (44.4%) even if they attained second remission again (p < 0.001). Among patients receiving HSCT at CR1, grade II-IV acute graft versus host disease was associated with worse overall and LFS than grade 0-I (5yLFS 69.5% vs. 82.1%, p = 0.026) mainly due to high non-relapse mortality. Among those patients, patients receiving related bone marrow transplantation, unrelated bone marrow transplantation, or unrelated cord blood transplantation showed similar survival (5yLFS, 73.2%, 76.3%, and 77.0%, respectively). For patients undergoing cord blood transplantation at CR1, total-body irradiation-based myeloablative conditioning was associated with better 5yLFS than other conditioning regimens (85.4% vs. 62.2%, p = 0.044), as it reduced the risk of relapse. These results indicate that relapsed patients have much less chance of cure, and that identifying patients who require HSCT for cure and offering them HSCT with optimal settings during CR1 are crucial for children and adolescents with T-ALL.

Analysis of long-term renal function in patients with malignant solid tumors: Retrospective analysis using the estimated glomerular filtration rate.

BACKGROUND: Childhood cancer survivors are at an increased risk of impaired renal function. The aim of the present study was to assess the frequency of and risk factors for long-term renal dysfunction in patients with solid tumors using the estimated glomerular filtration rate (eGFR). METHODS: We retrospectively evaluated eGFR in 52 patients with solid tumors (25 females, 27 males) who received chemotherapy and were regularly followed up in our institute. Decreased eGFR was defined as <90 ml/min/1.73 m2 . Cases under treatment and of death were excluded. RESULTS: Median age at the diagnosis of the primary disease was 2.4 years (range, 0.0-23.9 years) and the median follow-up period was 98.4 months (range, 14.4-231.6 months). The mean cumulative incidence of decreased eGFR was 24.7 ± 2.2%. Multivariate analysis showed that decreased eGFR correlated with an older age at diagnosis (≥2.3 years) (hazard ratio 7.330, p = 0.018). CONCLUSION: Although previous studies have indicated that the risk of long-term nephrotoxicity is higher in patients treated at a younger age, the present study showed that patients treated at an older age were at an increased risk of decreased eGFR.

Early reconstitution of lymphocytes after allogenic hematopoietic stem cell transplantation affects chronic graft-versus-host disease.

BACKGROUND: Lymphocyte reconstitution after hematopoietic stem cell transplantation (HSCT) is important for the prevention of infections, as well as for the reduction of recurrence, by its graft versus tumor effect. However, these lymphocytes may also play a role in the development of graft-versus-host disease (GVHD). Few studies have investigated the association between lymphocyte reconstitution and clinical outcomes after HSCT. METHODS: This issue was investigated by retrospectively analyzing pediatric patients who received their first allogeneic-HSCT using a newly developed parameter, the LD-index, which evaluates both the intensity and duration of lymphopenia. A total of 101 patients underwent allo-HSCT from April 2007 to August 2019 in our hospital. Excluding patients who died before lymphocyte recovery or underwent multiple HSCT, 78 patients were analyzed for associations between the LD-index with various factors relating to HSCT. RESULTS: A significantly high association was observed between a low LD-index and the incidence of chronic GVHD (P = 0.0019). Analysis of predictive factors for chronic GVHD was carried out using univariate analysis. Lower LD-index, donor source and duration of lymphopenia were found to be significant factors associated with chronic GVHD. Multivariate analysis, however, only identified an association between a lower LD-index and an increased incidence of chronic GVHD (P = 0.00081). CONCLUSIONS: Early reconstitution of lymphocytes after allo-HSCT is associated with a higher incidence of chronic GVHD.

Characteristics of genetic alterations of peripheral T-cell lymphoma in childhood including identification of novel fusion genes: the Japan Children's Cancer Group (JCCG).

Peripheral T-cell lymphoma (PTCL) is a group of heterogeneous non-Hodgkin lymphomas showing a mature T-cell or natural killer cell phenotype, but its molecular abnormalities in paediatric patients remain unclear. By employing next-generation sequencing and multiplex ligation-dependent probe amplification of tumour samples from 26 patients, we identified somatic alterations in paediatric PTCL including Epstein-Barr virus (EBV)-negative (EBV- ) and EBV-positive (EBV+ ) patients. As recurrent mutational targets for PTCL, we identified several previously unreported genes, including TNS1, ZFHX3, LRP2, NCOA2 and HOXA1, as well as genes previously reported in adult patients, e.g. TET2, CDKN2A, STAT3 and TP53. However, for other reported mutations, VAV1-related abnormalities were absent and mutations of NRAS, GATA3 and JAK3 showed a low frequency in our cohort. Concerning the association of EBV infection, two novel fusion genes: STAG2-AFF2 and ITPR2-FSTL4, and deletion and alteration of CDKN2A/2B, LMO1 and HOXA1 were identified in EBV- PTCL, but not in EBV+ PTCL. Conversely, alterations of PCDHGA4, ADAR, CUL9 and TP53 were identified only in EBV+ PTCL. Our observations suggest a clear difference in the molecular mechanism of onset between paediatric and adult PTCL and a difference in the characteristics of genetic alterations between EBV- and EBV+ paediatric PTCL.

Comparison of myelosuppression using the D-index between children and adolescents/young adults with acute lymphoblastic leukemia during induction chemotherapy.

BACKGROUND: Adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) are more likely to have chemotherapy-related complications than children. In addition, several reports have shown that infections account for most of the therapy-related mortality during cancer treatment in AYAs. Thus, we hypothesized that chemotherapy-induced myelosuppression is more severe in AYAs than in children, and the state of neutropenia was compared between children and AYAs using the D-index, a numerical value calculated from the duration and depth of neutropenia. PROCEDURE: This study retrospectively analyzed 95 patients newly diagnosed with ALL at our institution between 2007 and 2019. Of these, 81 were children (<15 years old) and 14 were AYAs (≥15 years old). The D-index and duration of neutropenia during induction chemotherapy for ALL were compared between children and AYAs. RESULTS: The median D-index of children was significantly higher than that of AYAs (8187 vs 6446, respectively, P = .017). Moreover, the median duration of neutropenia was also significantly longer in children than in AYAs (24.0 days vs 11.5 days, respectively, P = .007). CONCLUSION: Contrary to our expectations, myelosuppressive toxicity during induction chemotherapy for ALL was more severe in children than in AYAs.

Paranasal sinusitis at the initiation of chemotherapy is a risk factor for invasive fungal disease in children and adolescents with cancer.

BACKGROUND: The impact of paranasal sinusitis on the clinical outcome of patients with cancer remains unknown. The aim of this study was to determine whether paranasal sinusitis at the initiation of chemotherapy (SAI) affects the development of infectious complications in children and adolescents with cancer. METHODS: A retrospective cohort analysis of patients aged 0-20 years with cancer who received chemotherapy was performed. SAI was defined as the presence of a fluid level or mucosal swelling or total opacity on sinus computed tomography examination before the initiation of chemotherapy. The primary outcome measures were the incidence of bacteremia, septic shock, and invasive fungal disease (IFD, including proven, probable, and possible cases). RESULTS: SAI was observed in 57 (44%) of 130 enrolled patients. There were no significant differences in age, sex, and disease distribution between the patients with SAI (SAI group) and those without (non-SAI group). There was no significant difference in the 1-year cumulative incidence of bacteremia or septic shock after treatment initiation between the two groups (bacteremia, SAI group 33% vs. non-SAI group 35%, P = 0.53; septic shock, SAI group 4% vs. non-SAI group 4%, P = 0.87). The 1-year cumulative incidence of IFD was higher in the SAI group than in the non-SAI group (22% vs. 6%, P = 0.012). Cumulative incidence analysis after inverse probability of treatment weighting adjustment showed that the SAI group was more likely to develop IFD (HR: 3.5, 95% CI: 1.1-11.2, P = 0.033). CONCLUSIONS: Our findings suggest that patients with SAI may be at higher risk for IFD during chemotherapy.

A survey of hypercalciuria during chemotherapy in acute lymphoblastic leukemia.

BACKGROUND: Urolithiasis is an extremely rare complication in childhood acute lymphoblastic leukemia (ALL), and some reports have implicated corticosteroids during chemotherapy as a risk factor for it. However, only a few reports have analyzed urinary electrolytes in this context. METHODS: We retrospectively analyzed 55 patients with ALL who underwent chemotherapy between October 2007 and January 2019. Their median age was 9.3 years (range, 0.3-24.0 years) with 30 males and 25 females. Lineages were B-cell precursor ALL (BCP-ALL) in 42 patients, T-cell in nine and others in four patients. All patients received chemotherapy based on the Berlin-Frankfurt-Münster regimen. RESULTS: Forty-nine out of the 55 ALL patients exhibited hypercalciuria at least once during chemotherapy. Moreover, 36 patients with BCP-ALL, who were receiving identical Berlin-Frankfurt-Münster-based regimens, exhibited significantly high urinary calcium excretion immediately following high-dose glucocorticoid administration. Among the 55 ALL patients, urolithiasis was observed in one patient, a 6-year-old boy with BCP-ALL who developed urolithiasis at reinduction chemotherapy just after cessation of high-dose dexamethasone administration. CONCLUSIONS: Nearly 90% of the ALL patients studied developed hypercalciuria during chemotherapy in strong association with corticosteroid administration.

Efficacy of liposomal amphotericin against febrile neutropenia in pediatric patients receiving prophylactic voriconazole.

BACKGROUND: The risk factors for invasive fungal infection have gradually become evident for pediatric patients with hematological diseases. Here we analyze the efficacy of liposomal amphotericin (L-AMB) for pediatric patients with febrile neutropenia using prophylactic voriconazole (VRCZ). METHOD: We administered L-AMB (2.5 mg/kg/day) in patients with febrile neutropenia who were receiving prophylactic VRCZ (10 mg/kg/day, orally) and were resistant to second-line antibiotics therapy. Thirteen patients (5 males, 8 females) with 19 febrile neutropenia episodes were targeted in this analysis. The median age of the patients was 14 years (range, 1-19 years). Eighteen out of 19 episodes occurred in patients with acute myeloid leukemia, with the remaining episode occurring in a patient with acute unclassified leukemia. RESULTS: The median period from start of L-AMB administration to resolution of fever was 4 days (1-27 days). In 15 out of 19 episodes, fever resolved within 5 days from commencement of L-AMB administration. Using criteria proposed by T. J. Walsh et al., the success rate of L-AMB for febrile neutropenia was 89.5% in this study. CONCLUSIONS: Although the sample size of our study was small, the extremely high efficacy of L-AMB warrants its administration in patients with febrile neutropenia who are receiving VRCZ.

Clinical utility of target capture-based panel sequencing in hematological malignancies: A multicenter feasibility study.

Although next-generation sequencing-based panel testing is well practiced in the field of cancer medicine for the identification of target molecules in solid tumors, the clinical utility and clinical issues surrounding panel testing in hematological malignancies have yet to be fully evaluated. We conducted a multicenter prospective clinical sequencing study to verify the feasibility of a panel test for hematological tumors, including acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, and diffuse large B-cell lymphoma. Out of 96 eligible patients, 79 patients (82%) showed potentially actionable findings, based on the clinical sequencing assays. We identified that genetic alterations with a strong clinical significance were found at a higher frequency in terms of diagnosis (n = 60; 63%) and prognosis (n = 61; 64%) than in terms of therapy (n = 8; 8%). Three patients who harbored a germline mutation in either DDX41 (n = 2) or BRCA2 (n = 1) were provided with genetic counseling. At 6 mo after sequencing, clinical actions based on the diagnostic (n = 5) or prognostic (n = 3) findings were reported, but no patients were enrolled in a clinical trial or received targeted therapies based on the sequencing results. These results suggest that panel testing for hematological malignancies would be feasible given the availability of useful diagnostic and prognostic information. This study is registered with the UMIN Clinical Trial Registry (UMIN000029879, multiple myeloma; UMIN000031343, adult acute myeloid leukemia; UMIN000033144, diffuse large B-cell lymphoma; and UMIN000034243, childhood leukemia).

The effect of graft-versus-host disease on outcomes after allogeneic stem cell transplantation for refractory lymphoblastic lymphoma in children and young adults.

BACKGROUND: Patients with relapsed or refractory lymphoblastic lymphoma (LBL) have a poor prognosis. The efficacy of allogeneic blood stem cell transplantation for treatment of this disease remains unclear in terms of transplantation-related toxicity. Acute and chronic graft-versus-host diseases (GVHD) are both harmful to patients after allogeneic transplantation, but may have some positive effects through a substitute graft-versus-lymphoma effect. METHODS: To investigate the effect of GVHD on the survival of patients with refractory LBL, we retrospectively studied the outcomes of 213 patients with LBL who underwent first allogeneic stem cell transplantation before the age of 18 years, between 1990 and 2015 in Japan. RESULTS: The five-year overall survival (OS) and event-free survival rates after stem cell transplantation were 50.3% (95% confidence interval [CI], 43.2-56.9) and 47.8% (95% CI, 40.8-54.4), respectively. In univariate landmark analyses, the probability of OS was significantly better in patients with aGVHD than in those without (P = 0.002, five-year OS 58.1% vs 39.0%). The probability of OS was also better in patients with cGVHD than in those without (P = 0.036, five-year OS 72.2% vs 54.7%). Multivariate analysis demonstrated that only aGVHD was associated with better OS (hazard ratio, 0.63; 95% CI, 0.42-0.94, P = 0.024). Progression and recurrence statuses at SCT were associated with poor prognosis. The patients with grade II aGVHD showed the best prognosis (five-year OS: 65.6%). CONCLUSION: Our results suggest that the occurrence of aGVHD may be associated with better outcomes in patients with relapsed/refractory LBL who undergo allogeneic transplantation.

Peripherally Inserted Central Venous Catheter for Pediatric and Young Adult Patients With Hematologic and Malignant Diseases.

BACKGROUND: Long-term venous access is essential when treating malignant diseases. As an alternative to conventional central venous catheters, peripherally inserted central venous catheter (PICC) are now widely used. The aim of this study is to evaluate the safety, efficacy, and reliability of PICCs in comparison with previous reports, and to describe significant complications associated with their use. PATIENTS AND METHODS: From June 2009 to November 2017, PICCs were inserted 258 times in a total of 160 pediatric and young adult patients at our institution. We retrospectively evaluated our data regarding catheter life, a note of caution during insertion, reasons for removal, infection, and other notable complications. RESULTS: The 258 PICCs were placed for a total of 30,901 catheter-days with a median catheter life of 102 days ranging from 2 to 471 days. The most suitable vein for the insertion was a basilic vein. The insertion depth from the cubital fossa to the point of the lower third superior vena cava was found to have a strong correlation with body surface area. Suspected catheter infection requiring catheter removal was observed 30 times (0.97/1000 catheter-days) and catheter-related bloodstream infection was observed 2 times (0.06/1000 catheter-days). All the responsible pathogens were Staphylococcus epidermidis. As notable complications, fibrin sheath formation were seen in 4 patients and catheter tip migration to the thorax in 1 patient. CONCLUSIONS: Our data suggest that PICC is safe and effective in pediatric and young adult patients receiving long-term treatment. However, clinicians should be aware of the possible complications during PICC use.

Autologous Stem Cell Transplantation for Children With Renal Tumors, and Adults With Wilms Tumor: Retrospective Analysis of the Japanese Transplant Registry Unified Management Program.

BACKGROUND: Almost all pediatric patients with renal tumors are diagnosed with nephroblastoma (Wilms tumor), clear cell sarcoma, or malignant rhabdoid tumor. The choice of treatment is important for relapsed and refractory patients with nephroblastoma. Furthermore, clear cell sarcoma of the kidney (CCSK) and malignant rhabdoid tumor of the kidney (MRTK) have a poor prognosis compared with nephroblastoma. Thus, stem cell transplantation (SCT) is sometimes selected to treat these tumors. PATIENTS AND METHODS: The authors targeted a total of 84 patients with nephroblastoma, CCSK, and MRTK who underwent a first autologous SCT between 1992 and 2014, and were registered in the Japanese Transplant Registry Unified Management Program system. The authors retrospectively analyzed the SCT data for survival rate. RESULTS: Five-year overall survival rates for nephroblastoma, CCSK, and MRTK were 72.4%±6.3%, 46.8%±13.8%, and 36.4%±14.5%, respectively. The event-free survival rates at 5 years were 64.9%±6.7%, 35.7%±12.8%, and 27.3%±13.4%, respectively. The relapse rates at 5 years were 25.3%±11.4%, 46.2%±28.4%, and 60.0%±43.1%, respectively. CONCLUSION: Although the survival rate for nephroblastoma was relatively high, those of CCSK and MRTK were poor.

Verification of blood volume for blood culture and detection rate in pediatrics.

PURPOSE: This study was conducted to estimate the blood culture volume that should be collected from pediatric patients to improve diagnostic abilities. METHODS: Blood cultures from neonates and children aged up to 18 years were collected and the volume was measured for over a 1-year period. During the intervention period, examiners were instructed to draw 3 mL of blood for culture, if possible. The pre-intervention period was from June 1 to August 31, 2016. The post-intervention period was from September 1, 2016, to May 30, 2017. The rate of positive detections was calculated and compared between pre and post-intervention periods. RESULTS: We collected 1352 samples and measured 1327 bottles. During the pre-intervention period, 340 cases were collected with a median blood volume of 1.64 mL; 9 cases (2.7%) were true-positive. During the intervention period, 1012 cases were ordered with a median blood volume of 2.41 mL; 19 cases (1.9%) were true-positive. After intervention, blood volume was increased significantly (p < 0.01). However, there was no significant difference in the rate of positive detections during the study periods (p = 0.254). CONCLUSIONS: In the pediatric clinical setting in a Japanese municipal hospital, the positive detection rate did not improve even when the collected blood volume was increased. One milliliter of blood volume may be adequate for the pediatric bottle in children.

A Multicenter, Open-label, Clinical Trial to Assess the Effectiveness and Safety of Allogeneic Hematopoietic Stem Cell Transplantation Using Reduced-intensity Conditioning in Relapsed/refractory Anaplastic Large-cell Lymphoma in Children.

No standard treatment for relapsed or refractory anaplastic large-cell lymphoma (ALCL) has been established. This study is a multicenter, open-label trial to examine the effectiveness and safety of transplantation with reduced-intensity conditioning (RIC) for patients under 20 years old with relapsed or refractory ALCL. We defined RIC as the administration of fludarabine (30 mg/m2/day) for five days plus melphalan (70 mg/m2/day) for two days and total body irradiation at 4 Gy, followed by allogeneic hematopoietic stem cell transplantation.

A deep intronic mutation of c.1166-285 T > G in SLC46A1 is shared by four unrelated Japanese patients with hereditary folate malabsorption (HFM).

Hereditary folate malabsorption (HFM) is an autosomal recessive disease caused by mutations in SLC46A1 encoding the proton-coupled folate transporter (PCFT). HFM patients present with various clinical features including megaloblastic anemia, thrombocytopenia, combined immunodeficiency and neurodevelopmental disorders. In this study, we report the same deep intronic mutation of c.1166-285 T > G shared by four unrelated Japanese patients with HFM. This mutation was shown to generate a cryptic splice donor site for a 168-bp insertion of intron 3 sequences, leading to premature termination in the middle of this insertion. This mutation could be a founder mutation in the Japanese population, but also could be a hot-spot and could be present in undiagnosed HFM patients worldwide because of the difficulty to detect this mutation.

Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients.

Fanconi anemia is a rare recessive disease characterized by multiple congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancies. It results from mutations in one of the 22 known FANC genes. The number of Japanese Fanconi anemia patients with a defined genetic diagnosis was relatively limited. In this study, we reveal the genetic subtyping and the characteristics of mutated FANC genes in Japan and clarify the genotype-phenotype correlations. We studied 117 Japanese patients and successfully subtyped 97% of the cases. FANCA and FANCG pathogenic variants accounted for the disease in 58% and 25% of Fanconi anemia patients, respectively. We identified one FANCA and two FANCG hot spot mutations, which are found at low percentages (0.04-0.1%) in the whole-genome reference panel of 3,554 Japanese individuals (Tohoku Medical Megabank). FANCB was the third most common complementation group and only one FANCC case was identified in our series. Based on the data from the Tohoku Medical Megabank, we estimate that approximately 2.6% of Japanese are carriers of disease-causing FANC gene variants, excluding missense mutations. This is the largest series of subtyped Japanese Fanconi anemia patients to date and the results will be useful for future clinical management.