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.

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.

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.

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.

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.

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.

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.

Lower gamma globulin level before conditioning is a risk factor for cytomegalovirus antigenemia after pediatric allogeneic stem cell transplantation.

BACKGROUND: Despite the development of early detection methods and new antiviral drugs, cytomegalovirus (CMV) infection remains a persistent and sometimes severe complication of stem cell transplantation (SCT). CMV antigenemia has become widely used for early detection of CMV infection after SCT. PROCEDURE: We retrospectively analyzed risk factors for CMV antigenemia in pediatric patients following allogeneic SCT. We analyzed 74 pediatric patients who received allogeneic SCT at Sapporo Hokuyu Hospital between April 2007 and March 2018 and were alive over three months after SCT. RESULTS: Of the 74 patients, 22 (29.7%) were CMV antigenemia positive. On univariate analyses, many patients with CMV antigenemia tested positive for CMV antibody before SCT (P < 0.001), and had lower gamma globulin levels before conditioning (P = 0.014). Multivariate analysis additionally confirmed that pre-SCT CMV antibody positivity (P < 0.001) and preconditioning gamma globulin levels under 655 mg/dL (P = 0.004) were independent risk factors for post-SCT CMV antigenemia. CONCLUSIONS: These results indicate the importance of assessing gamma globulin levels in pediatric patients prior to SCT.

Long-term outcome of renal function in children after stem cell transplantation measured by estimated glomerular filtration rate.

BACKGROUND: Stem cell transplantation (SCT) outcomes have improved over the last three decades, with many patients being rescued with this treatment. However, improved outcomes have led to issues with long-term sequelae. One of these sequelae in children is renal dysfunction, an index of which is estimated using glomerular filtration rate (eGFR). PROCEDURE: We retrospectively analyzed eGFR in 83 pediatric patients who received SCT. Data from all patients extended up to 12 months or more post SCT. The median follow-up time was 127.7 months (range 12.0-268.8 months). RESULTS: Eighteen patients (21.7%) had low eGFR (<90 ml/min/1.73 m2 ) post SCT. Cumulative incidence of low eGFR was 25.8 ± 2.0%. Nine (10.6%) patients had a low eGFR pre-SCT. However, pre- and post-SCT incidence of low eGFR were not correlated. Meanwhile, only two patients (2.4%) exhibited severe renal dysfunction, with eGFRs < 60 ml/min/1.73 m2 . Independent risk factors for low eGFR were solid tumor and use of fludarabine. Moreover, age at SCT ≥ 7 years was also a long-term post-SCT risk factor for low eGFR in all patients. CONCLUSION: Independent post-SCT long-term risk factors for low eGFR in children were solid tumor and use of fludarabine. Moreover, age at SCT ≥ 7 years was a post-SCT long-term risk factor for low eGFR across all patients.

Ingrown Toenails During Chemotherapy and Stem Cell Transplantation in Children With Hematologic Malignancies and Solid Tumors.

BACKGROUND: At our institution, we noted that children with hematologic malignancies and solid tumors often suffered from ingrown toenails (IGTNs) during hospitalization for chemotherapy and stem cell transplantation. However, only few reports have dealt with IGTNs in the above setting. PROCEDURE: Between August 2007 and July 2017, 180 children who received treatment for hematologic malignancies and solid tumors at our institute were enrolled in this study. Twelve patients with insufficient data and 7 patients with past histories of IGTNs were excluded. A total of 161 patients were analyzed. Median age at admission was 7.9 years (range, 1.0 to 25.4 y), with 92 males and 69 females. Diagnoses were hematologic diseases in 128 patients, including acute lymphoblastic leukemia (ALL) in 75 patients, and solid tumors in 33 patients. RESULTS: A total of 22 patients (13.7%) suffered from IGTNs (or toe paronychia) during hospitalization. Multivariable analysis disclosed a strong correlation between the occurrence of IGTNs and older age (over 9.0 y) and ALL. CONCLUSIONS: Patient-related factors, such as age over 9 years and ALL were associated with IGTNs. This is the first report of a survey on IGTNs in patients with hematologic malignancies and solid tumors hospitalized for chemotherapy and stem cell transplantation.

Early blood stream infection following allogeneic hematopoietic stem cell transplantation is a risk factor for acute grade III-IV GVHD in children and adolescents.

BACKGROUND: Graft-versus-host disease (GVHD) remains a major cause of mortality and morbidity in allogeneic hematopoietic stem cell transplantation (HSCT). In adults, early blood stream infection (BSI) and acute GVHD (AGVHD) have been reported to be related. The impact of BSI on risk for AGVHD, however, has not been assessed in pediatric patients. PROCEDURE: We conducted a retrospective analysis to test the hypothesis that early BSI (before day +30) predisposes allogeneic pediatric transplant patients to severe AGVHD. We analyzed 293 allogeneic HSCT performed at Children's Healthcare of Atlanta between 2005 and 2014 that met eligibility criteria. RESULTS: The cumulative incidence of acute grade III-IV GVHD at 100 days after HSCT was 17.1%. In multivariate analysis, risk for acute grade III-IV GVHD was associated with HLA-mismatched donor (hazard ratio [HR] = 4.870, P < 0.001), and BSI between day 0 and +30 prior to AGVHD (HR = 3.010, P = 0.001). CONCLUSIONS: These results indicate that early BSI appears to be a risk factor for acute grade III-IV GVHD. Further research is needed to determine if the link is causal.

Successful Treatment of Mediastinal γδ T-Cell Lymphoblastic Lymphoma in a 3-Year-Old Girl by Allogeneic Cord Blood Transplantation.

A 3-year-old girl presenting with a huge mediastinal tumor and massive pleural effusion, was diagnosed with stage III γδ T-cell lymphoblastic lymphoma (γδ T-LBL) by flow cytometry of effusion cells. Four courses of chemotherapy achieved complete remission, and 5/6 HLA allele-matched cord blood transplantation was performed with success. The patient remains in first complete remission >16 months after transplantation. γδ T-LBL is very rare, especially that of mediastinal origin, and is acknowledged as having an extremely poor clinical outcome. The present case study is the first to report the successful treatment of mediastinal γδ T-LBL in a toddler.

African American Race Is a Newly Identified Risk Factor for Postengraftment Blood Stream Infections in Pediatric Allogeneic Blood and Marrow Transplantation.

Blood stream infections (BSI) are a major source of morbidity and mortality both in allogeneic blood and marrow transplant (BMT) recipients. Various risk factors for BSI in BMT have been identified. The impact of race and cytomegalovirus (CMV) viremia, a common complication after engraftment, however, has not been rigorously assessed. This is important because both CMV infection and ganciclovir, the mainstay of pre-emptive therapy, have myelosuppressive and immunosuppressive effects. We conducted a retrospective analysis to test the hypothesis that race and CMV viremia predispose allogeneic BMT patients to postengraftment BSI. We analyzed 278 allogeneic BMT performed at Children's Healthcare of Atlanta between January 1, 2005 and December 31, 2014 that met eligibility criteria. We performed a multivariate analysis to estimate the effect of CMV viremia on risk for BSI in the postengraftment period (days +30 to 100). Risk for BSI was associated with CMV viremia (hazard ratio [HR], 3.34; 95% confidence interval [CI], 1.51 to 7.36; P = .003); grade III and IV acute graft-versus-host disease (HR, 3.28; 95% CI, 1.55 to 6.92; P = .002), and African American race (HR, 2.22; 95% CI, 1.09 to 4.51; P = .027). The results of our study highlight the importance of a novel risk factor for postengraftment BSI, not previously considered-African American race.

A prospective randomized trial comparing piperacillin/tazobactam with meropenem as empirical antibiotic treatment of febrile neutropenic children and adolescents with hematologic and malignant disorders.

BACKGROUND: This randomized prospective study was designed to assess whether piperacillin/tazobactam (PIPC/TAZ) is as effective as meropenem (MEPM) as a first-line antibiotic treatment for febrile neutropenia (FN). PROCEDURE: FN episodes were randomly assigned to receive either PIPC/TAZ (337.5 mg/kg per day in three doses, 1-hr DIV, maximum 13.5 g per day) or MEPM (120 mg/kg per day in three doses, 1-hr DIV, maximum 3 g per day). Clinical responses were evaluated 120 hr after the DIV. RESULTS: A total of 434 febrile episodes in 105 patients (42 females and 63 males) with a median age of 8 years (range 0-25) were included in this trial. Blood cultures were positive in 47 out of the 434 episodes (10.8%). Regarding responses to the treatment, success rates between the PIPC/TAZ and MEPM groups were similar (62.4 vs. 65.9%, P = 0.484), even if patients were restricted to those with bacteremia (26.1 vs 37.5%, P = 0.534). Mortality rates did not significantly differ between the two groups (0.8 vs. 0%, P = 0.500). CONCLUSION: Both PIPC/TAZ and MEPM appeared to be equally efficacious and safe. Carbapenems are now broadly used to treat FN; however, this may increase the prevalence of drug-resistant bacteria. In this regard, the treatment using PIPC/TAZ for FN is more beneficial.

Extrarenal Nephroblastoma of the Retroperitoneal Space in Children: A Case Report and Review of the Literature.

Extrarenal nephroblastoma (ERNB) is a rare disease. We report a case of ERNB in a 4-year-old boy complaining of abdominal pain and vomiting. Imaging showed a retroperitoneal mass and left hydronephrosis. The mass was completely removed by surgery. The pathologic diagnosis was ERNB with favorable histology. Postoperative chemotherapy was administered for 24 weeks with actinomycin D, vincristine, and doxorubicin. No signs of recurrence were found for the next 3 years. We consider 53 reports of ERNB and our own. Median age at diagnosis was 42 months. The most common site is the retroperitoneal space (44.4%), followed by the uterus (14.8%).