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 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.

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.

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.

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.

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.

Risk factors for delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia and lymphoma.

High-dose methotrexate (HD-MTX) therapy is widely used in patients with acute lymphoblastic leukemia (ALL) and lymphoma. However, some patients experience delayed MTX elimination, which requires treatment suspension or dose reduction to avoid organ damage. This single-center retrospective analysis reviewed the clinical data of 88 children with ALL or non-Hodgkin lymphoma who received a total of 269 courses of HD-MTX therapy between April 2008 and April 2019. HD-MTX was defined as MTX administration at 2.0, 3.0, or 5.0 g/m2 over a 24-h period, and delayed MTX elimination was defined as a serum MTX concentration ≥ 1.0 µmol/L at 48 h after the start of HD-MTX. Clinical factors were compared between courses with and without delayed MTX elimination. MTX elimination was delayed in 21 of the 269 courses (7.8%). Multivariate analysis showed that first HD-MTX course (OR 4.04), lower urine volume per BSA on the first day of HD-MTX administration (< 2,675 mL/m2, OR 5.10), higher total bilirubin (> 0.5 mg/dL, OR 5.11), lower eGFR (< 136 mL/min/1.73 m2, OR 3.90), higher dose of MTX(> 3.0 g/m2, OR 10.8), and lower urine volume per BSA on the next day of starting HD-MTX (< 2,107 mL/m2, OR 3.43) were independent risk factors for delayed MTX elimination.

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.

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.

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).

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.

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.

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.

[Risk of Euglycemic Diabetic Ketoacidosis Due to Low-carbohydrate Diet While Taking Empagliflozin: a Case Report].

Empagliflozin reduces blood glucose levels independently of insulin secretion by reducing glucose reabsorption in the proximal renal tubules through inhibition of sodium-glucose cotransporter 2 (SGLT2). Because SGLT2 inhibitors have a different mechanism of action to conventional antidiabetic drugs, recommendations have been issued about the management of specific side effect such as ketoacidosis, urinary tract infection, and genital infection. There have been some reports of SGLT2 inhibitor-associated euglycemic diabetic ketoacidosis (euDKA), but there have been few reports about euDKA in patients with type 2 diabetes using SGLT2 inhibitors while on a low-carbohydrate diet. Here we report a patient who developed euDKA after starting a very low-carbohydrate diet while taking empagliflozin. A 51-year-old man was hospitalized with nausea and vomiting, and investigations revealed metabolic acidosis. euDKA was diagnosed from the information about medications in his drug notebook and a history of eating a low-carbohydrate diet (1900 kcal, consisting of 5.7% carbohydrate, 21.1% protein, 47.3% fat and 25.9% alcohol) for 4 d. The patient improved after infusion of acetated Ringer's solution with 5% glucose and administration of regular insulin. It is necessary for physicians and pharmacists to thoroughly inform patients about the side effects of SGLT2 inhibitors such as ketoacidosis, urinary tract infection, and genital infection. Patients should also be advised about the higher risk of euDKA associated with a low-carbohydrate diet while taking SGLT2 inhibitors.