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.

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.

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.

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.

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.

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.

Cubic coil system composed of three sets of cubic triple coils to produce wide area 0.66% uniform magnetic field in any direction.

A cubic coil system, which combines three sets of cubic triple square coils orthogonal to each other, is proposed, constructed, and tested. This coil system can generate a 0.66% (=±0.33%) uniform magnetic field in any direction over a large region of ∼2 m, although there is some ripple. This system has the advantages of easy assembly, self-standing, and easy access to internal instruments. In one set of cubic triple square coils, the outer two square coils form a cube, and the middle square coil is located at the center of the cube. The number of turns in the center square coil is proposed to be 0.6 times that of the outer square coil.

Natto (fermented soybeans)-induced anaphylaxis in a surfer with the possibility of sensitization to poly(γ-glutamic acid) from cutaneous exposure to jellyfish sting: a case report.

BACKGROUND: We report a case of anaphylaxis induced by natto (fermented soybeans) allergy that occurred following dermal sensitization from a jellyfish sting. CASE PRESENTATION: A 49-year-old male presented to the emergency room complaining of an acute onset of erythema with pruritis that appeared while he was surfing. Given that his heart rate dropped to ~ 40 bpm without a decline in blood pressure or oxygen saturation, we suspected anaphylaxis and administered 0.5 mg of adrenaline intramuscularly. Immediately after the muscular adrenaline injection, his heart rate recovered to ~ 60-70 bpm. CONCLUSIONS: The major allergen that induces natto allergy is poly(γ-glutamic acid) (PGA), which is present in its mucilage. Given that PGA is also produced by jellyfish tentacles, it can be inferred that the PGA sensitization occurred via dermal exposure to jellyfish PGA. This is an example of a food allergy induced by animal stings. As PGA is a high-molecular-weight polymer, natto allergy, despite being IgE-mediated, often presents with late-onset anaphylaxis, which typically develops half a day after digestion. PGA has a wide range of applications in pharmaceuticals, cosmetics, and foods. Patients may develop allergic symptoms and experience repeated anaphylaxis with no known cause. Therefore, it is important to obtain a detailed medical history and individually instruct patients suspected of being allergic to PGA to avoid PGA-containing products.

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.

Central Nervous System Adverse Reactions to Amantadine Intoxication: A Case Report and Analysis of JADER.

BACKGROUND/AIM: A few case reports of central nervous system (CNS) symptoms caused by amantadine intoxication have been published, detailing various types of symptoms and differing times to onset. We encountered a patient who developed CNS symptoms with amantadine. This prompted us to investigate the types, time to onset, and outcome of CNS adverse reactions to amantadine by analyzing data from a pharmacovigilance database. PATIENTS AND METHODS: The patient was evaluated at Chutoen General Hospital, Shizuoka, Japan. Analysis was performed using the Japanese Adverse Drug Event Report (JADER) database. RESULTS: In our case, the amantadine blood concentration was 4,042 ng/ml, i.e., in the toxic range. The time to onset was 26 days for dyskinesia and 90 days for depressed level of consciousness. Symptoms resolved when amantadine was discontinued. The JADER database contained 974 cases of adverse reactions to amantadine. The most frequently reported CNS adverse reaction was hallucination, with a reporting odds ratio of 64.28 (95% confidence interval=52.67-78.46). Positive signals were detected for all CNS adverse reactions. For all CNS reactions, clinical outcomes were poor in a comparatively low percentage of cases. Most CNS reactions occurred soon after administration of amantadine, usually within approximately one month. CONCLUSION: Because most CNS adverse reactions to amantadine usually occur within approximately one month of initiating treatment, healthcare providers should exercise heightened vigilance in monitoring patients for such reactions during this period.

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.

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.