Successful treatment of young childhood standard-risk hepatoblastoma with cisplatin monotherapy using a central review system.

BACKGROUND: The JPLT3-S (Japanese Study Group for Pediatric Liver Tumors-3) study, conducted cisplatin (CDDP) monotherapy for young children (<3 years old) with standard-risk hepatoblastoma (HB) using a central review system in Japan. In the previous JPLT2 study, cases with resectable tumors without any annotation factors in the PRETEXT (PRETreatment EXTent of disease) classification (standard-risk HB) showed favorable outcomes with treatment consisting of CDDP and pirarubicin, but showed toxicities and late complications. In the JPLT3-S trial, a less intense regimen consisting of CDDP alone was evaluated. METHODS: Patients who were less than 3 years of age and with PRETEXT I, II, or III HB without any annotation factors (e.g., E1, E1a, E2, E2a, H1, N1, P2, P2a, V3, and V3a) were eligible for inclusion in this study. In this trial, the central radiological and pathological features of all patients were reviewed. The primary outcome was the 3-year progression-free survival (PFS). RESULTS: A total of 38 patients (23 female) were included. The median patient age was 12 months (range: 2-34). Two patients discontinued treatment because of progressive disease, and five patients discontinued treatment for other reasons. The 3-year PFS rate was 93.9% (95% confidence interval [CI]: 86.4%-100%). All 38 patients survived (follow-up period 38-98 months), and the OS rate was 100% (CI: 100). Eighteen of the 38 patients (47.4%) experienced ototoxicity as a late complication. CONCLUSION: CDDP monotherapy regimen is feasible in young patients with localized HB, as classified by a central review.

Usefulness of central radiologic review in clinical trials of children with hepatoblastoma.

BACKGROUND: No previous research papers have reported a comparative survey of local radiologic diagnoses and central review in children with hepatoblastoma. OBJECTIVE: To evaluate the utility of central review of children with hepatoblastoma enrolled in a clinical trial. MATERIALS AND METHODS: The study included 91 children enrolled in a clinical trial conducted by the Japanese Study Group for Pediatric Liver Tumor. We compared the results of the initial pre-treatment extent of tumor (PRETEXT) disease staging performed at local sites with the results obtained on central review to determine the concurrence rates for tumor staging and additional criteria. RESULTS: The concurrence rate for PRETEXT staging was 70%. As the stage increased, the concurrence rate decreased. Using additional criteria, central review identified 143 lesions (157.1%), about 1.8 times higher than the number identified for the local site diagnoses. The additional criterion found most often on central review was "multifocal lesion" (n=19). The concurrence rate for lung metastases was high. However, our central review found many false-positive assertions of hepatic vein lesions, portal vein invasion and extrahepatic lesions among the local site diagnoses. CONCLUSION: In a clinical trial of hepatoblastoma, central review provided a more precise diagnosis than local site diagnoses with respect to severe PRETEXT stages III and IV cases and other cases including hepatic and portal vein invasion. The central review process appears to be effective and essential for improving the quality of clinical trials.

A novel risk stratification model based on the Children's Hepatic Tumours International Collaboration-Hepatoblastoma Stratification and deoxyribonucleic acid methylation analysis for hepatoblastoma.

INTRODUCTION: Hepatoblastoma (HB) is the most common paediatric liver tumour, and epigenetic aberrations may be important in HB development. Recently, the Children's Hepatic Tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) developed risk stratification based on clinicopathological factors. This study aimed to construct a more accurate model by integrating CHIC-HS with molecular factors based on DNA methylation. METHODS: HB tumour specimens (N = 132) from patients treated with the Japanese Pediatric Liver Tumors Group-2 protocol were collected and subjected to methylation analysis by bisulfite pyrosequencing. Associations between methylation status and clinicopathological factors, overall survival (OS), and event-free survival (EFS) were retrospectively analysed. We investigated the effectiveness of the evaluation of methylation status in each CHIC-HS risk group and generated a new risk stratification model. RESULTS: Most specimens (82%) were from post-chemotherapy tissue. Hypermethylation in ≥2 of the four genes (RASSF1A, PARP6, OCIAD2, and MST1R) was significantly associated with poorer OS and EFS. Multivariate analysis indicated that ≥2 methylated genes was an independent prognostic factor (hazard ratios of 6.014 and 3.684 for OS and EFS, respectively). Two or more methylated genes was also associated with poorer OS in the CHIC-very low (VL)-/low (L)-risk and CHIC-intermediate (I) risk groups (3-year OS rates were 83% vs. 98% and 50% vs. 95%, respectively). The 3-year OS rates of the VL/L, I, and high-risk groups in the new stratification model were 98%, 90%, and 62% (vs. CHIC-HS [96%, 82%, and 65%, respectively]), optimising CHIC-HS. CONCLUSIONS: Our proposed stratification system considers individual risk in HB and may improve patient clinical management.

Feasibility of Real-Time Central Surgical Review for Patients with Advanced-Stage Hepatoblastoma in the JPLT3 Trial.

In the JPLT3 study, a real-time central surgical reviewing (CSR) system was employed aimed at facilitating early referral of candidates for liver transplantation (LTx) to centers with pediatric LTx services. The expected consequence was surgery, including LTx, conducted at the appropriate time in all cases. This study aimed to review the effect of CSR on institutional surgical decisions in cases enrolled in the JPLT3 study. Real-time CSR was performed in cases in which complex surgeries were expected, using images obtained after two courses of preoperative chemotherapy. Using the cloud-based remote image viewing system, an expert panel consisting of pediatric and transplant surgeons reviewed the images and commented on the expected surgical strategy or the necessity of transferring the patient to a transplant unit. The results were summarized and reported to the treating institutions. A total of 41 reviews were conducted for 35 patients, and 16 cases were evaluated as possible candidates for LTx, with the treating institutions being advised to consult a transplant center. Most of the reviewed cases promptly underwent definitive liver surgeries, including LTx per protocol.

Feasibility of dose-dense cisplatin-based chemotherapy in Japanese children with high-risk hepatoblastoma: Analysis of the JPLT3-H pilot study.

BACKGROUND: The SIOPEL-4 study has demonstrated that dose-dense cisplatin-based chemotherapy dramatically improves outcome in children with high-risk hepatoblastoma in western countries. However, the feasibility and safety of this regimen have not been clarified in Japanese patients. METHODS: A pilot study, JPLT3-H, was designed to evaluate the safety profile of the SIOPEL-4 regimen in Japanese children with newly diagnosed hepatoblastoma with either metastatic disease or low alpha-fetoprotein. RESULTS: A total of 15 patients (three female) were enrolled. Median age was 2 years (range, 0-14). Three patients were PRETEXT II (where PRETEXT is PRETreatment EXTent of disease), six PRETEXT III, and six PRETEXT IV. All patients had lung metastasis, none had low alpha-fetoprotein. Eight patients completed the prescribed treatment, and seven patients discontinued therapy prematurely, four due to progressive disease and three due to causes other than severe toxicity. Grade 4 neutropenia was documented in most patients in preoperative cycles A1-3 (11/15 in A1, 9/11 in A2, and 7/11 in A3) and in all considering all cycles. Grade 3-4 thrombocytopenia and grade 3 anemia were also frequently observed. Patients experienced several episodes of grade 3 febrile neutropenia, but none had grade 4 febrile neutropenia or severe infections. One patient had grade 3 heart failure only in the first cycle. Other grade 3 or 4 toxicities were hypomagnesemia, anorexia, nausea, mucositis, liver enzyme elevation, fever, infection, and fatigue. There were no unexpected severe toxicities. CONCLUSION: The toxicity profile of JPLT3-H was comparable to that of SIOPEL-4. Dose-dense cisplatin-based chemotherapy may be feasible among Japanese patients with high-risk hepatoblastoma.

Genetic and epigenetic basis of hepatoblastoma diversity.

Hepatoblastoma (HB) is the most common pediatric liver malignancy; however, hereditary predisposition and acquired molecular aberrations related to HB clinicopathological diversity are not well understood. Here, we perform an integrative genomic profiling of 163 pediatric liver tumors (154 HBs and nine hepatocellular carcinomas) based on the data acquired from a cohort study (JPLT-2). The total number of somatic mutations is precious low (0.52/Mb on exonic regions) but correlated with age at diagnosis. Telomerase reverse transcriptase (TERT) promoter mutations are prevalent in the tween HBs, selective in the transitional liver cell tumor (TLCT, > 8 years old). DNA methylation profiling reveals that classical HBs are characterized by the specific hypomethylated enhancers, which are enriched with binding sites for ASCL2, a regulatory transcription factor for definitive endoderm in Wnt-pathway. Prolonged upregulation of ASCL2, as well as fetal-liver-like methylation patterns of IGF2 promoters, suggests their "cell of origin" derived from the premature hepatoblast, similar to intestinal epithelial cells, which are highly proliferative. Systematic molecular profiling of HB is a promising approach for understanding the epigenetic drivers of hepatoblast carcinogenesis and deriving clues for risk stratification.

Outcome and Late Complications of Hepatoblastomas Treated Using the Japanese Study Group for Pediatric Liver Tumor 2 Protocol.

PURPOSE: We report here the outcomes and late effects of the Japanese Study Group for Pediatric Liver Tumors (JPLT)-2 protocol, on the basis of cisplatin-tetrahydropyranyl-adriamycin (CITA) with risk stratification according to the pretreatment extent of disease (PRETEXT) classification for hepatoblastoma (HB). PATIENTS AND METHODS: From 1999 to 2012, 361 patients with untreated HB were enrolled. PRETEXT I/II patients were treated with up-front resection, followed by low-dose CITA (stratum 1) or received low-dose CITA, followed by surgery and postoperative chemotherapy (stratum 2). In the remaining patients, after 2 cycles of CITA, responders received the CITA regimen before resection (stratum 3), and nonresponders were switched to ifosfamide, pirarubicin, etoposide, and carboplatin (ITEC; stratum 4). Intensified chemotherapeutic regimens with autologous hematopoietic stem-cell transplantation (SCT) after resection were an optional treatment for patients with refractory/metastatic disease. RESULTS: The 5-year event-free and overall survival rates of HB patients were 74.2% and 89.9%, respectively, for stratum 1, 84.8% and 90.8%%, respectively, for stratum 2, 71.6% and 85.9%%, respectively, for stratum 3, and 59.1% and 67.3%%, respectively, for stratum 4. The outcomes for CITA responders were significantly better than those for nonresponders, whose outcomes remained poor despite salvage therapy with a second-line ITEC regimen or SCT. The late effects, ototoxicity, cardiotoxicity, and delayed growth, occurred in 61, 18, and 47 patients, respectively. Thirteen secondary malignant neoplasms (SMNs), including 10 leukemia, occurred, correlating with higher exposure to pirarubicin and younger age at diagnosis. CONCLUSION: The JPLT-2 protocol achieved up-front resectability in PRETEXT I/II patients with no annotation factors, and satisfactory survival in patients who were CITA responders in the remaining patients. However, outcomes for CITA nonresponders were unsatisfactory, despite therapy intensification with ITEC regimens and SCT. JPLT-2 had a relatively low incidence of cardiotoxicity but high rates of SMNs.

Registration-directed phase 1/2 trial of irinotecan for pediatric solid tumors.

BACKGROUND: Although irinotecan hydrochloride (IRI) is a promising chemotherapeutic agent for pediatric solid tumors, its indications had been off-label in the USA, EU and Japan. Therefore, we conducted a phase 1/2 trial of IRI monotherapy in a registration-directed setting. METHODS: Children aged 2-18 years with solid tumors who were either refractory to or relapsed after standard chemotherapy were enrolled. Phase 1 was a conventional dose escalation study to determine the dose-limiting toxicity (DLT) and the recommended dose. IRI was given i.v. on days 1, 2, 3 and 8, 9, 10 in up to eight, 21 day cycles. RESULTS: The starting dose (40 mg/m2 /day) was determined to be the recommended dose because the next higher dose level (45 mg/m2 /day) resulted in two cases of DLT. Seventeen children (11 in phase 1 and six in phase 2) with a refractory solid tumor received IRI. Of the 12 patients treated with 40 mg/m2 /day, seven (58.3%) achieved a stable disease condition for >8 weeks. CONCLUSIONS: The RD of IRI in this treatment schedule was 40 mg/m2 /day. IRI did not cause tumor shrinkage but might help to stabilize refractory pediatric solid tumors. Based on the accumulating evidence from international studies of the efficacy of IRI against refractory pediatric solid tumors, the Japanese regulatory authority approved its use for this indication in 2011.

The role of pulmonary metastasectomy for hepatoblastoma in children with metastasis at diagnosis: Results from the JPLT-2 study.

BACKGROUND/PURPOSE: The purpose of this study was to clarify the role of pulmonary metastasectomy in hepatoblastomas with lung metastasis at diagnosis. We reviewed cases enrolled in the JPLT-2 study. METHODS: A total of 360 cases with hepatoblastoma were enrolled. The clinical courses and outcome of 60 cases with pulmonary metastasis at diagnosis were reviewed, focusing on metastasectomy. RESULTS: Induction chemotherapy resulted in eradication of nodules in 26, residual nodules in 33, and early treatment-related death in one. Of the 33 cases with residual nodules, 11 underwent complete resection of the lung lesions, and among these, progression was reported in five. Complete resection of the liver tumor was not achieved in two of these. Three underwent incomplete resection of lung nodules, eventually leading to progression. Twelve cases with incomplete or no liver tumor resection progressed regardless of the status of lung lesions. Contrarily, among patients who underwent complete resection of the liver tumor, half were cured without metastasectomy. CONCLUSIONS: Metastasectomy for residual pulmonary nodules after induction chemotherapy is effective provided that the liver tumor could be completely resected. TYPE OF STUDY: Prospective Cohort Study. LEVEL OF EVIDENCE: Level II.

Resectability and tumor response after preoperative chemotherapy in hepatoblastoma treated by the Japanese Study Group for Pediatric Liver Tumor (JPLT)-2 protocol.

BACKGROUND/PURPOSE: We aimed to clarify whether surgical resectability and tumor response after preoperative chemotherapy (preCTx) represented prognostic factors for patients with hepatoblastoma (HBL) in the JPLT-2 study (1999-2012). METHODS: Patients (N=342) with HBL who underwent preCTx were eligible. PRETEXT, CHIC risk stratification (standard [SR], intermediate [IR] and high risk [HR]) at diagnosis, POST-TEXT, and tumor resectability were evaluated by imaging. Tumor response was classified into responders (CR or PR) and nonresponders (NC or PD) according to RECIST criteria. RESULTS: There were 7 PRETEXT I, 106 II, 143 III, and 86 IV, including 71 metastatic HBLs. In POST-TEXT, 12 PRETEXT II, 42 III, and 58 IV were down-staged. The 5-year EFS/OS rates of 198 SR, 73 IR, and 71 HR-HBLs were 82/94%, 49/64%, and 28/34%, respectively. In 198 SR, 154 of 160 responders and 24 of 38 nonresponders survived event-free (P<0.01). In 73 IR, 12 of 24 whose tumors remained unresectable experienced recurrence, 9 of whom were nonresponders (P<0.01). In 71 HR, chemoresponders and tumor resectability after preCTx correlated with favorable outcomes (P<0.05). CONCLUSIONS: Evaluation of response and tumor resectability after preCTx is useful for predicting prognosis in HBLs. To improve outcomes, we should reconsider surgical procedures according to resectability and chemoresponsiveness. LEVEL OF EVIDENCE: Level II.

Residual disease detected by multidimensional flow cytometry shows prognostic significance in childhood acute myeloid leukemia with intermediate cytogenetics and negative FLT3-ITD: a report from the Tokyo Children's Cancer Study Group.

Residual disease (RD) after induction chemotherapy may predict clinical outcome in acute myeloid leukemia (AML). In the present study, we investigated the prognostic significance of RD detected by multidimensional flow cytometry (MDF) among 34 children treated for AML in a clinical trial (JPLSG AML-05) in Japan. Bone marrow samples were analyzed at the points of the end of the first induction course (BMA-1) and second induction course (BMA-2) by MDF. RD was evaluated by detecting the immature cells showing abnormal antigen expression pattern; CD34(+), CD15(+), CD7(+). Thirteen (39.4 %) of 34 patients at BMA-1 and 8 (27.6 %) of 34 at BMA-2 had RD levels ≥0.1 %. There was no significant difference in 3y-EFS and 3y-OS between patients with RD levels ≥0.1 % and those with RD levels <0.1 % (53.8 versus 70.0 %, P = 0.30 and 50.0 versus 66.7 %, P = 0.27, respectively). However, IR cytogenetics and negative FLT3-ITD patients with RD levels ≥0.1 % exhibited significantly lower 3y-EFS and 3y-OS than those with RD levels <0.1 % (33.3 versus 83.3 %, P = 0.02 and 20.0 versus 76.9 %, P = 0.005, respectively). Our study suggests that RD shows prognostic relevance in pediatric patients with IR cytogenetics and negative FLT3-ITD AML.

Mortality and morbidity in primarily resected hepatoblastomas in Japan: Experience of the JPLT (Japanese Study Group for Pediatric Liver Tumor) trials.

BACKGROUND: In the Japanese Study Group for Pediatric Liver Tumor (JPLT) protocols (JPLT-1 and 2) for evaluating the cure rate of risk-stratified hepatoblastoma, primary resection was permitted in PRETEXT I and II cases, followed by postoperative chemotherapy. METHODS: In approximately 500 enrolled cases, resection was performed as the initial treatment in 60 cases, including all 18 PRETEXT I, 30 PRETEXT II, and 12 ruptured cases. The clinical features, surgical procedures, complications, and survival rates were compared in these three groups. RESULTS: All 18 PRETEXT I cases underwent complete resection by lobectomy or segmentectomy (n=14) or nonanatomical partial hepatectomy (NPH) (n=4). The 30 PRETEXT II cases underwent primary resection by right or left lobectomy (n=16), NPH (n=10), or other procedures (n=4). Of these 30 cases, operational death occurred in 1 newborn, and recurrence occurred in 7 cases (14.6%), including 6 NPH cases and 4 older cases (aged >3years). Of the 12 ruptured cases, 7 (58.3%) showed recurrence. Event-free survival rates at 5years in the 3 groups were 88%, 70%, and 32%, respectively. CONCLUSIONS: Primary resection for PRETEXT I or II HB cases should be performed by anatomical resection according to strict surgical guidelines. More intensified chemotherapy is required for primary resected cases whose tumors have ruptured.

Support for school reentry and relationships between children with cancer, peers, and teachers.

BACKGROUND: Returning to school after a cancer diagnosis can be socially challenging for children with cancer. This study investigated the form of support for school reentry and the associations with social support from peers and teachers. METHODS: This was a multicenter cross-sectional study. Children with cancer and their guardians completed questionnaires. Their guardians also underwent a semi-structured interview to describe the background of support for school reentry. RESULTS: Thirty-nine children with cancer and guardian dyads completed questionnaires and three guardians underwent semi-structured interview. Peer visits and their understanding of hospital experiences and how to interact with children were related to social support from peers. Teachers' understanding of physical appearance, academic performance, hospital experience and of how to interact with children was related to social support from peers. Teachers' understanding of diagnosis/treatment, academic performance and their status as the liaison between doctors/nurses in hospitals and teachers in local schools were also related to social support from teachers. Furthermore, children with cancer were also encouraged to establish supportive relationships with peers and teachers as a result of school reentry support that (i) helped children to feel that they are still members of the local school; (ii) improved peer and teacher understanding of the long-term recovery process of children with cancer; and (iii) facilitated the children's own awareness that they are fighting the disease. CONCLUSIONS: The multidisciplinary team consisting of the children with cancer, their families, doctors, nurses and teachers in the local school need to communicate with peers regarding positive experiences of fighting, and overcoming, severe disease.

Relapsed acute lymphoblastic leukemia with unusual multiple bone invasions: A case report.

The present study describes a unique pediatric case with multiple bone invasions of acute lymphoblastic leukemia (ALL) during remission. An eight-year-old male with a history of ALL was admitted complaining of intermittent and migrating pain in the limb 2 years following complete remission. Magnetic resonance imaging and whole-body positron emission tomography with 18F-fluorodeoxyglucose revealed abnormal multifocal involvement in the bones and corresponding soft tissues. Repeated bone marrow (BM) aspiration indicated normal cellular marrow without leukemic cells, and marked leukemic cell infiltration in different sections of the ilium, respectively. These findings suggested isolated bone relapse, and it is probable that systematic BM relapse occurred as a consequence.

Prognostic significance of leukopenia in childhood acute lymphoblastic leukemia.

Chemotherapy-induced leukopenia has been shown to be associated with the outcomes of several types of cancer, but the association with childhood acute lymphoblastic leukemia (ALL) remains unknown. To elucidate the association of chemotherapy-induced leukopenia with the clinical outcome of childhood ALL, retrospective analysis was performed on 19 child patients with ALL treated according to the ALL-BFM 95 high-risk (HR) protocol. The mean minimum leukocyte count over the first three courses of the consolidation phase was used as the measure of hematological toxicity and ranged between 200 and 1,167/µl. The risk of relapse was significantly higher in patients with a mean minimum leukocyte count above the median of 433/µl (hazard ratio, 6.61; P=0.047). In conclusion, chemotherapy-induced leukopenia was found to correlate with relapse-free survival in childhood HR ALL. Dose escalation based on hematologic toxicity must be prospectively studied.

The effect of the order of total body irradiation and chemotherapy on graft-versus-host disease.

BACKGROUND: Graft-versus-host disease (GVHD) is one of the most important complications in allogeneic hematopoietic stem cell transplantation. Intensity of conditioning regimen is one of the risk factors, which is associated with acute GVHD, and some studies have shown that alteration of the administration order from busulfan to cyclophosphamide to cyclophosphamide to busulfan could decrease cytokine levels and organ toxicity. METHODS: To investigate whether the order of total body irradiation (TBI) and chemotherapy is associated with the incidence of GVHD, we reviewed the charts of 124 consecutive hematopoietic stem cell transplantation, which was performed in Saitama Children's Medical Centre and University of Tokyo Hospital between 1995 and 2010. RESULTS: TBI performed before chemotherapy (TBI-CT) showed an increased risk for grades II to IV acute GVHD (61.6±7.8%) compared with the TBI performed after chemotherapy (CT-TBI) (42.8±7.2%) (P=0.048), whereas the incidence of grades III and IV GVHD were similar between TBI-CT and CT-TBI. Multivariate analysis showed that TBI-CT was associated with a higher risk of grades II to IV acute GVHD. However, overall survival probability of TBI-CT cohort was similar to that of CT-TBI cohort. CONCLUSIONS: Our results provided a novel risk factor for acute GVHD, which can be easily controlled by the physician.

Cancer-specific health-related quality of life in children with brain tumors.

PURPOSE: To understand the influence of disease and treatment on the health-related quality of life (HRQOL) of children with brain tumors, compared to the HRQOL of children with other cancers, from the viewpoints of children and parents. METHODS: A total of 133 children aged 5-18 years and 165 parents of children aged 2-18 completed questionnaires of the Pediatric Quality of Life Inventory Cancer Module (Pain and Hurt, Nausea, Procedural Anxiety, Treatment Anxiety, Worry, Cognitive Problems, Perceived Physical Appearance, and Communication scales); higher scores indicate a better HRQOL. The Cancer Module scores, weighted by age and treatment status, were compared to those obtained in a previous study of children with other cancers (mostly leukemia). RESULTS: The weighted mean scores for Pain and Hurt (effect size d = 0.26) and Nausea (d = 0.23) from child reports and the scores for Nausea (d = 0.28) from parent reports were higher for children with brain tumors than scores for children with other cancers. The scores for Procedural Anxiety (d = -0.22) and Treatment Anxiety (d = -0.32) from parent reports were lower for parents of children with brain tumors than the scores for parents of children with other cancers. The child-reported Pain and Hurt score of the Cancer Module was higher (d = 0.29) and in less agreement (intraclass correlation coefficient = 0.43) with scores from the Brain Tumor Module, indicating that assessments completed with the Cancer Module misesteem pain and hurt problems in children with brain tumors. CONCLUSIONS: The profiles of cancer-specific HRQOL in children with brain tumors differ from those of children with other cancers; we therefore suggest that these children receive specific psychological support.

Two cases of bacteremia caused by Leptotrichia trevisanii in patients with febrile neutropenia.

We present two cases of bacteremia caused by Leptotrichia trevisanii: a 12-year-old girl with recurrent myeloid leukemia of the mandible and a 66-year-old man with esophageal carcinoma. As this filamentous bacillus showed indefinite Gram staining and the identification based on biochemical enzymatic reactions was not definitive, identification required 16s rRNA analysis. For this organism, drug sensitivity testing showed susceptiblity to each ß-lactam antibiotics and clindamycin, but resistance to fluoroquinolone and erythromycin. This filamentous bacillus needs careful identification and appropriate antibiotic treatment.

Factors influencing self- and parent-reporting health-related quality of life in children with brain tumors.

PURPOSE: Health-related quality of life (HRQOL) is not only a degree of health but also reflects patient perceptions and expectations of health. For children with brain tumors, better understanding of HRQOL requires the use of complementary reports from parents and interviewer-administered reports for children. Here, we aimed to test whether or not the trait anxiety of children and the psychological distress of their parents influence children's and parents' responses to HRQOL questionnaires, and whether or not the report-administration method for children influences children's responses to HRQOL questionnaires. METHODS: One hundred and thirty-four children aged 5-18 with brain tumors and one of their parents completed the Pediatric Quality of Life Inventory(™) (PedsQL(™)) Brain Tumor Module questionnaires. In addition, the children also completed the State-Trait Anxiety Inventory for Children (STAIC), and the parents also completed the Kessler-10 (K10) and health and sociodemographic characteristics questionnaires. The child questionnaires were administered either by the child (self-administered) or an interviewer. Rater-dependent perceptions about HRQOL were derived from the subscales scores of the PedsQL(™) Brain Tumor Module using structural equation modeling based on a multitrait-multimethod model. The STAIC trait-anxiety score, K10 score, report-administration method, and other health and sociodemographic factors related to each child's or parent's perceptions were identified through multiple linear regression analyses of the questionnaire responses. We used a path analysis to estimate the change in a PedsQL(™) child-reported score that occurs when interviewer-administration changes the child's perception about HRQOL. RESULTS: Surveys for 89 children were self-administered while those for 45 were interviewer-administered. The perceptions of the children and parents were calculated by fitting data to the model (chi-squared P = 0.087, normed fit index = 0.932, comparative fit index = 0.978, standardized root mean squared residual = 0.053, and root mean square error of approximation = 0.054). The children's perception of HRQOL was affected by their STAIC trait-anxiety score (b = -0.43, 95% CI [-0.60, -0.25]). The parent's perception was affected by their child's treatment status (b = 0.26, 95% CI [0.09, 0.43]), the parent's K10 score (b = -0.21, 95% CI [-0.37, -0.04]), and by education level (b = 0.17, 95% CI [0.00, 0.34]). The change in the child-reported PedsQL(™) score in relation to the method of administration ranged from -1.1 (95% CI: -3.5, 1.3) on the procedural anxiety subscale to -2.5 (95% CI: -7.6, 2.6) on the movement and balance subscale. CONCLUSION: Child-reporting of HRQOL is little influenced by the method of administration. Children's perception about HRQOL tended to be influenced by their trait anxiety, while parents' perception was influenced by their psychological distress, academic background, and their child's treatment status.

Early occurrence of nephrotic syndrome associated with cord blood stem cell transplantation.

Nephrotic syndrome (NS) associated with hematopoietic stem cell transplantation (HSCT) is usually related to chronic graft-versus-host disease (GVHD) and invariably occurs later than 100 days after transplantation. Here, we report the case of a 6-year-old boy who presented with NS only 61 days after cord blood stem cell transplantation (CBSCT). At 4 years old he was diagnosed with acute lymphoblastic leukemia and underwent bone marrow transplantation. Six months later, a recurrence was noted in the thymus, which required CBSCT at the age of 6. Acute GVHD and hemophagocytic syndrome occurred on day +13 and day +15, respectively, and were successfully treated with tacrolimus and a steroid. After tacrolimus was switched from intravenous infusion to oral administration, NS occurred on day +61. Complete remission was achieved in 3 weeks by resuming steroid treatment. Dry erythema with pigmentation and elevation of Th2 cytokine level suggest that NS in this case was also related to chronic GVHD. To our knowledge, this is the earliest occurrence of NS after HSCT. Hematologists and nephrologists should be aware that this condition may occur even in early periods after HSCT.