Analysis of overweight/obese pediatric patients with acute myeloid leukemia: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study.

The dosage of chemotherapy drugs for overweight/obese children with acute myeloid leukemia (AML) has been empirically reduced based on ideal body weight (BW) in Japan to reduce the risk of adverse events. We investigated the associations between pre-therapeutic body mass index (BMI) and clinical outcomes among children with AML. A total of 280 children were divided into two groups based on the World Health Organization Child Growth Standards: a healthy-weight group (n = 254), and an overweight/obese group (n = 26). If BW exceeded 1.2 times the standard BW of Japanese children, the dosage of chemotherapy drugs was calculated using 1.2 times the standard BW. The dosage of chemotherapy drugs was reduced during at least one chemotherapy cycle in 24 of 26 patients (92.3%) in the overweight/obese group, compared with zero patients in the healthy-weight group. Overall/event-free survival, cumulative incidence of relapse, and treatment-related mortality (TRM) did not differ between the overweight/obese and healthy weight groups. However, the frequency of bacteremia was higher in the overweight/obese group (80.8 vs. 52.4%, P = 0.006). This indicates that TRM may increase when chemotherapy drug dosage is not corrected in overweight/obese patients. Drug reduction is a potential treatment strategy.

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.

Inter-reporter differences in symptom burdens in Japanese children with cancer.

BACKGROUND: Recent studies about inter-reporter differences and patient-reported outcomes (PROs) in childhood cancer from Western countries showed that caregiver proxy reports tend to overestimate symptom burdens in comparison with children's self-reports. However, the results from Western countries may not be generalizable to Asian countries. METHODS: This paper is a secondary analysis of a validation study of the Japanese pediatric version of the Memorial Symptom Assessment Scale including 88 dyads of children aged 7-12 years and 74 dyads of children aged 13-18 years and their caregivers. The study assessed the inter-reporter differences of eight and 31 symptom burdens calculated as symptom scores in children aged 7-12 years and 13-18 years, respectively, and the association between inter-reporter differences and the characteristics of children and caregivers. RESULTS: The majority of children and caregivers scored equally at the dyadic level for almost all symptoms. However, 37.5% of symptoms in children aged 7-12 years and 10.0% of symptoms in children aged 13-18 years showed significant inter-reporter differences, suggesting a general tendency of caregivers to underestimate their children's symptom burden. The caregiver's age was the characteristic most frequently associated with magnitude of inter-reporter differences. CONCLUSIONS: Caregiver proxy reports may be a reliable source of PROs in Japanese children with cancer, as self-reported and caregiver proxy-reported symptom burdens were generally concordant. However, as some significant inter-reporter differences were observed, an effort should be made within the medical community to evaluate the parent-child relationship to minimize inter-reporter differences and achieve better symptom management.

Analysis of non-alcoholic fatty liver disease during induction therapy for B-cell precursor acute lymphoblastic leukemia in children and adolescents.

BACKGROUND: A prospective evaluation of non-alcoholic fatty liver disease (NAFLD) during induction therapy for acute lymphoblastic leukemia (ALL) has not been performed. Herein, we prospectively investigated the frequency, risk factors, and outcomes of NAFLD during induction therapy in children and adolescents with B-cell precursor ALL (BCP-ALL). METHODS: This study enrolled 74 newly diagnosed BCP-ALL cases aged 1 year and older who were admitted to our department between January 2011 and December 2020. Median age was 6.6 years (1.3-17.5 years). Plain computed tomography (CT) of the upper abdomen was performed before induction therapy, and on days 15 and 29 after initiation of induction therapy. Patients with a liver/spleen CT ratio <0.9 were defined as having NAFLD. RESULTS: The frequency of NAFLD was 73%. Patients with NAFLD had a higher rate of hypertriglyceridemia. There was no significant difference in 5-year overall survival and event-free survival (EFS) between patients with and without NAFLD. However, after restricting the target age to 10 years and older, 5-year EFS was significantly higher in patients with NAFLD than in those without (88.5 vs. 42.9%, respectively, P = 0.037). Similarly, 5-year cumulative incidence of relapse (CIR) was significantly lower in patients with NAFLD than in those without it (5-year CIR, 6.3 vs. 57.1%, respectively, P = 0.013). CONCLUSION: Patients with NAFLD exhibit better outcomes including 5-year EFS and CIR. Further studies are necessary.

Current methods of preventing infectious disease and managing febrile neutropenia in childhood cancer patients: a nationwide survey in Japan.

BACKGROUND: Preventing infection and managing febrile neutropenia (FN) is mandatory for children with cancer undergoing chemotherapy. However, the current situation in Japan is unknown. METHODS: We conducted a nationwide web-based questionnaire survey in 153 institutions treating childhood cancer in Japan. We asked about the type prophylaxis used to prevent infectious disease and manage FN. If patients with childhood cancer were managed by both pediatricians and surgeons at the same institution, we asked both to reply. RESULTS: We received replies from 117 departments at 111 centers: of these, 108 were from pediatricians. Laminar air flow for neutropenic patients, and frequent hand sanitization with ethanol, were widespread. Twenty-eight percent and forty percent of departments performed active surveillance by taking cultures from patients and the environment, respectively, before initiation of chemotherapy. Forty-four percent of departments administered prophylactic intravenous antibiotics according to patient status. Many departments measured serum (1,3)-ß-D glucan, procalcitonin, and aspergillus galactomannan at the onset of FN. Twenty-eight percent of departments used carbapenem as empirical therapy for FN. Some departments used prophylactic granulocyte-colony stimulating factor for acute leukemia. Seventy-two percent of departments used prophylactic immunoglobulin for hypogammaglobinemia caused by chemotherapy. Palivizumab was administered widely for respiratory syncytial virus prophylaxis in immunocompromised infants. CONCLUSION: As a whole, intensive care for infectious prophylaxis or FN is applied in Japan; however, the methods vary among centers, and some are excessive or inadequate. Therefore, it is desirable to conduct clinical trials and establish adequate care protocols for infection in children with cancer in Japan.

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.

Impact of muscle loss in children with hematologic malignancies undergoing allogeneic hematopoietic cell transplantation.

The widespread recognition of the concept of sarcopenia, or muscle loss, has impacted the prognosis of patients undergoing high-intensity treatments. We focused on the effect of muscle loss on the prognosis of pediatric patients with hematologic diseases. A total of 65 patients with hematologic malignancies who underwent allogeneic HCT once were investigated. The change in cross-sectional psoas muscle area (PMA) measured on computed tomography (CT) images was expressed as the muscle loss index (MLI), which was calculated by dividing the pre-HCT PMA by the baseline PMA. In this study, patients with MLI values less than 0.85 were classified into the muscle loss group. Muscle loss was observed in 27 patients (41.5%). Patients who experienced muscle loss were older than those who did not. Muscle loss was an independent predictor of higher non-relapse mortality (NRM) (p = 0.012) and inferior overall survival (OS) (p = 0.045) at 5 years. Multivariate analysis showed that muscle loss was an independent risk factor for higher NRM (p = 0.046), and inferior EFS (p = 0.048). Muscle loss observed pre-HCT may be a predictor of increased NRM, poor OS and EFS in pediatric patients with hematologic malignancies undergoing allogeneic HCT.

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.

Reliability and Validity of the Japanese Pediatric Version of Memorial Symptom Assessment Scale.

CONTEXT: Few instruments in Japanese assess health-related quality of life in pediatric cancer patients. OBJECTIVES: To translate the Memorial Symptom Assessment Scale (MSAS) into Japanese pediatric and proxy versions (MSAS-J 7-12, MSAS-J 13-18, and MSAS-J-Proxy) and assess validity and reliability. METHODS: Phase I comprised forward-backward translation and pilot testing in 13 children and 16 guardians. Phase II consisted of psychometric testing of the three MSAS-J versions in 162 children and 238 guardians. Internal consistency, test-retest reliability, and construct and known-group validity of the MSAS-J were assessed. RESULTS: Cronbach's alpha coefficients for the total and subscale scores were over 0.70, excluding the psychological symptom (PSYCH) subscale score of the MSAS-J 7-12. Most MSAS-J scores significantly inversely correlated with two versions of the Pediatric Quality of Life Inventory. A strong child-guardian correlation was shown in the total and subscale scores (ICC range 0.66-0.83). Kappa estimates showed acceptable child-guardian symptom agreement. MSAS-J 7-12 and proxy differentiated patients according to clinical status. CONCLUSION: MSAS-J is a reliable and valid instrument to assess symptoms among Japanese children with cancer.

Successful treatment of steroid-dependent gastrointestinal acute graft-versus-host disease with mesenchymal stromal cells administered more than 100 days after allo-HCT.

Administration of mesenchymal stromal cells (MSCs) represents a promising therapy for steroid-resistant acute graft-versus-host disease (aGVHD). However, its efficacy in pediatric patients with steroid-dependent aGVHD remains unclear, given the paucity of studies performed in children. In addition, the duration between the onset of aGVHD and MSC therapy is reportedly critical; a delay in MSC administration negatively impacts overall survival and response rate. Herein, we describe a case of a 14-year-old girl with steroid-dependent aGVHD who was successfully treated with MSCs following a prolonged duration from aGVHD diagnosis. The patient was diagnosed with T-cell lymphoblastic leukemia with central nervous system involvement and underwent cord blood transplantation (CBT). She developed severe gastrointestinal aGVHD on day +14 after CBT and was treated with a steroid; however, her aGVHD was repeatedly exacerbated upon tapering the steroid, later complicated by diabetic ketoacidosis. We eventually implemented MSC therapy for steroid-dependent aGVHD on day +109 after CBT. She rapidly responded to therapy, and her aGVHD was ameliorated even with steroid tapering. This case exemplifies the potential role of MSCs in treating pediatric patients with steroid-dependent aGVHD or late aGVHD.

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.

Analysis of antibiotics discontinuation during bone marrow suppression in childhood, adolescent and young adult patients with febrile neutropenia.

BACKGROUND: Antibiotics have been widely and efficaciously used for febrile neutropenia in pediatric patients. However, reports are scant regarding the risk factors for recurrent fever after discontinuation of antibiotics in a neutropenic state. Here, we investigated these factors using data from our previously reported randomized study regarding meropenem and piperacillin/tazobactam for pediatric patients with febrile neutropenia. PROCEDURE: We analyzed a total of 170 febrile episodes where first line antibiotic treatment was effective and discontinued before neutrophil recovery. RESULTS: Recurrent fever was observed in 31 episodes (18%). The median interval from antibiotics discontinuation to recurrent fever was 5 days (0-27 days). Risk factors for recurrent fever were: incomplete remission of original disease; and high white blood cell count, neutrophil count, and C reactive protein levels at start of antibiotics. Moreover, lower neutrophil count at discontinuation of antibiotics, duration of neutropenia, and onset day of febrile neutropenia from start of neutropenia were also risk factors of recurrent fever. In multivariate analysis, neutrophil count at discontinuation of antibiotics <0.011 × 109/L, neutrophil count at start of antibiotics ≥0.061 × 109/L, febrile onset following <1 day after onset of neutropenia, and incomplete remission of original disease were independent risk factors for recurrent fever. CONCLUSIONS: Discontinuation of antibiotics while pediatric patients were still neutropenic was almost safe. However, physicians should note the risk factors of recurrent fever.

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.

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.

Meropenem versus piperacillin/tazobactam for febrile neutropenia in pediatric patients: efficacy of piperacillin/tazobactam as a 1-h drip infusion four times a day.

Although survival of children with hematological diseases and cancer has increased dramatically, febrile neutropenia (FN) is a frequently observed complication and is sometimes life-threatening in pediatric cancer patients. A prospective, randomized study was performed to clarify the usefulness of meropenem (MEPM) and piperacillin/tazobactam (PIPC/TAZ) for pediatric patients with FN. Ninety-nine patients with 394 episodes were randomly assigned to receive MEPM or PIPC/TAZ. MEPM was administered at 120 mg/kg/day as a 1-h drip infusion 3 times a day. On the other hand, PIPC/TAZ was administered at 360 mg/kg/day as a 1-h drip infusion 4 times a day. MEPM was effective in 69.5% of the 200 episodes, and PIPC/TAZ was effective in 77.2% of the 193 episodes. Compared with our previous study of MEPM 120 mg/kg/day as a 1-h drip infusion 3 times a day versus PIPC/TAZ 337.5 mg/kg/day as a 1-h drip infusion 3 times a day, the success rate of the MEPM group was not different. However, the success rate of the PIPC/TAZ group was higher than in the previous study (p = 0.001). In particular, the success rate in patients ≥ 15 years of age was improved in the PIPC/TAZ group of the present study compared with the previous study (p = 0.005).

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.