Comparison of two apheresis systems for granulocyte collection without hydroxyethyl starch.

BACKGROUND AND OBJECTIVES: Granulocyte transfusion (GTX) is a treatment option for severe infections in patients with neutropenia. In previous studies, hydroxyethyl starch (HES) was used to enhance red blood cell sedimentation for granulocyte collection (GC). However, there are safety concerns about HES, and HES is not readily available in some countries. Therefore, we compared the granulocyte counts and GC efficiency achieved by two apheresis systems without HES. MATERIALS AND METHODS: All consecutive GC procedures performed between July 2011 and March 2018 at our hospital were analysed. COBE Spectra was used until 5 February 2016, and Spectra Optia was used afterwards. HES was not used. RESULTS: Twenty-six GC procedures were performed, including 18 performed using COBE Spectra and 8 using Spectra Optia. When Spectra Optia was used, >1 × 1010 neutrophils were collected from seven of the eight (88%) procedures. Although there was no significant difference in the granulocyte yield between COBE Spectra-based and Spectra Optia-based GC procedures, the collection efficiency of Spectra Optia was significantly higher than that of COBE Spectra (p = 0.021). Furthermore, the granulocyte yields of Spectra Optia-based GC tended to be more strongly correlated with the peripheral blood neutrophil count on the day of apheresis than those of COBE Spectra-based GC. CONCLUSION: Our results suggest that Spectra Optia achieves greater GC efficiency than COBE Spectra, even without HES. GTX may be a therapeutic option for severe neutropenia, even in places where HES is not available.

Increased infiltration of CD4+ T cell in the complement deficient lymphedema model.

BACKGROUND: Lymphedema is an intractable disease that can be caused by injury to lymphatic vessels, such as by surgical treatments for cancer. It can lead to impaired joint mobility in the extremities and reduced quality of life. Chronic inflammation due to infiltration of various immune cells in an area of lymphedema is thought to lead to local fibrosis, but the molecular pathogenesis of lymphedema remains unclear. Development of effective therapies requires elucidation of the immunological mechanisms involved in the progression of lymphedema. The complement system is part of the innate immune system which has a central role in the elimination of invading microbes and acts as a scavenger of altered host cells, such as apoptotic and necrotic cells and cellular debris. Complement-targeted therapies have recently been clinically applied to various diseases caused by complement overactivation. In this context, we aimed to determine whether complement activation is involved in the development of lymphedema. RESULTS: Our mouse tail lymphedema models showed increased expression of C3, and that the classical or lectin pathway was locally activated. Complement activation was suggested to be involved in the progression of lymphedema. In comparison of the C3 knockout (KO) mouse lymphedema model and wild-type mice, there was no difference in the degree of edema at three weeks postoperatively, but the C3 KO mice had a significant increase of TUNEL+ necrotic cells and CD4+ T cells. Infiltration of macrophages and granulocytes was not significantly elevated in C3 KO or C5 KO mice compared with in wild-type mice. Impaired opsonization and decreased migration of macrophages and granulocytes due to C3 deficiency should therefore induce the accumulation of dead cells and may lead to increased infiltration of CD4+ T cells. CONCLUSIONS: Vigilance for exacerbation of lymphedema is necessary when surgical treatments have the potential to injure lymphatic vessels in patients undergoing complement-targeted therapies or with complement deficiency. Future studies should aim to elucidate the molecular mechanism of CD4+ T cell infiltration by accumulated dead cells.

HLA-haploidentical peripheral blood stem cell transplantation following reduced-intensity conditioning with very low-dose antithymocyte globulin for relapsed/refractory acute leukemia in pediatric patients: a single-institution retrospective analysis.

The prognosis of relapsed/refractory (R/R) pediatric acute leukemia is extremely poor. We retrospectively reviewed 20 consecutive pediatric patients with R/R acute leukemia who underwent a first HLA-haploidentical peripheral blood stem cell transplantation following reduced-intensity conditioning (haplo-RIC-PBSCT) with very low-dose antithymocyte globulin (ATG) between 2012 and 2019. Of these 20 patients, 7 patients had acute lymphoblastic leukemia, and 13 had acute myeloid leukemia. At the time of haplo-RIC-PBSCT, 15 patients had active disease. The median follow-up duration for survivors was 56 months (range 22-108 months). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus, short-term methotrexate, methylprednisolone, and ATG 1.25 mg/kg on day-2. The 2-year cumulative incidence of transplant-related mortality and relapse were 5.0% [95% confidence interval (CI) 0.7-30.5%)] and 57.8% (95% CI 37.4-79.6%), respectively. Among the 20 patients, 16 (80.0%) developed grade III-IV acute GVHD, and 2 developed severe chronic GVHD. The 2-year event-free survival and overall survival rates were 40.0% (95% CI 19.3-60.0%) and 50.0% (95% CI 27.1-69.2%), respectively. Although the sample size is small, the survival outcomes of the present study are encouraging.

Hematopoietic Cell Transplantation Rescues Inflammatory Bowel Disease and Dysbiosis of Gut Microbiota in XIAP Deficiency.

BACKGROUND: X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn error of immunity that is often associated with refractory inflammatory bowel disease (IBD). The natural course of XIAP deficiency is typically associated with poor prognosis, and hematopoietic cell transplantation (HCT) is the only curative treatment. OBJECTIVE: To study (1) the effect of HCT on patients with XIAP deficiency undergoing HCT, (2) the status of XIAP deficiency-associated IBD after HCT, and (3) the gut microbiota of XIAP deficiency-associated IBD before and after HCT. METHODS: A nationwide survey of patients with XIAP deficiency was conducted. A spreadsheet questionnaire was collected from the physicians. Feces samples collected from the patients before and after HCT and their healthy family members were analyzed. RESULTS: Twenty-six patients with XIAP deficiency underwent HCT by the end of March 2020, and 22 patients (84.6%) survived. All the survivors underwent a fludarabine-based reduced-intensity condition regimen. Acute graft-versus-host disease was observed in 17 patients (65.4%). Nineteen patients experienced refractory IBD before undergoing HCT. IBD improved remarkably after HCT. After HCT, the colonoscopic and pathological symptoms were restored to normal, and the pediatric ulcerative colitis activity index improved significantly. Gut microbiota indicated dysbiosis before HCT; however, it was improved to resemble that of the healthy family members after HCT. CONCLUSIONS: This study revealed that HCT has a favorable outcome for XIAP deficiency. HCT rescues gut inflammation and dysbiosis in patients with XIAP deficiency.

Candida guilliermondii-induced chorioretinitis in a patient with eating disorder.

Candidemia is a life-threatening fungal infection among patients undergoing long-term intravenous catheterization, hematopoietic stem cell transplantation, or immunosuppressive therapy, as well as patients with severe immunodeficiency or cancer. Endophthalmitis is a rare but severe form of ocular inflammation caused by infection of the intraocular cavity, which can lead to irreversible visual loss if not treated properly and promptly. The initial manifestation typically involves chorioretinitis, which requires early diagnosis and appropriate treatment. Candida guilliermondii is a non-Candida albicans yeast species; its frequency of detection in Japan has increased in recent years, and many drug-resistant and less-chorioretinitis-related strains are known. Here, we describe a 17-year-old girl with an eating disorder who exhibited chorioretinitis because of catheter-related bloodstream infection (CRBSI) caused by C. guilliermondii. The patient was hospitalized with severe weight loss, and she was presumed to develop candidemia because of immunosuppression during central parenteral nutrition therapy with a peripherally inserted central catheter. After onset of CRBSI, the catheter was immediately removed. Antifungal therapy was modified following fundus examination, fungal species confirmation, and drug sensitivity confirmation; thus, the patient recovered without long-term complications. To the best of our knowledge, this is the first report of C. guilliermondii-induced chorioretinitis in a patient with an eating disorder. Prolonged malnutrition and immunosuppression during nutritional therapy create a risk of candidemia in patients with eating disorders. After the onset of CRBSI, early administration and appropriate use of antifungal agents, with respect to specific ocular complications, are important for reduction of both mortality and ocular complications.

Hepatic Inflammatory Myofibroblastic Tumor Detected in the Fetal Period That Caused an Oncologic Emergency.

A huge abdominal cystic lesion with ascites was detected in a male neonate at 31 weeks of gestation. Increasing ascites and the appearance of subcutaneous edema were detected, which caused fetal hydrops. The patient was delivered by emergency cesarean section at 33 weeks of gestation. The birth weight was 2,407 g, and the Apgar score was 8/9 points (1-/5-min values). Breathing at birth was stable, but the patient presented with remarkable abdominal distention due to the ascites. Later, the patient presented with tachypnea, and breathing gradually worsened, so an emergency operation was performed. There were no intraoperative findings within the small intestine, but there was a large amount of ascites and a cystic mass arising from the liver. The patient's breathing and circulation dynamics could only be stabilized by ascites removal, so only a tumor biopsy was performed. The pathological findings led to the diagnosis of an inflammatory myofibroblastic tumor, and steroids were administered early after surgery for the purpose of an anti-inflammatory effect and tumor shrinkage. The abdominal distention was alleviated, and blood examinations showed a reduced inflammatory response. There was no apparent shrinkage of the tumor, however; thus, radical surgical treatment was performed on day 24. The postoperative course was uneventful, so the patient was discharged on day 36. Seven years after the operation there has been no recurrence or distant metastasis.

Serum high mobility group box protein 1 (HMGB1) levels reflect clinical features of childhood hemophagocytic lymphohistiocytosis.

PURPOSE: Hemophagocytic lymphohistiocytosis (HLH) is a potentially lethal hyperinflammatory disorder. For further understanding of the pathogenesis of HLH, we examined serum levels of high mobility group box protein 1 (HMGB1) in children with HLH. PATIENTS AND METHODS: Serum HMGB1 levels were measured in 28 patients with HLH and 6 normal controls using a quantitative enzyme-linked immunosorbent assay. The patients were 21 boys and 7 girls, aged from 10 days to 21 years, with a median age of 8.5 years. The underlying conditions of HLH were infection-associated HLH in 18 patients, malignancy-associated HLH in 7 patients, and genetic HLH in 3 patients. The relations between serum HMGB1 levels and clinical symptoms and laboratory parameters were analyzed. RESULTS: Serum HMGB1 levels were significantly higher in patients with HLH than in normal controls (median, 6.5 ng/mL, interquartile range, 4.25-13.1). The serial serum HMGB1 levels in one patient fell to reflect the disease activity. Serum HMGB1 levels were significantly higher in patients with disseminated intravascular coagulation (DIC) than in patients without DIC (p<0.001) and were also significantly higher in patients with central nervous system (CNS) complications than in patients without CNS complications (p<0.01). Serum HMGB1 levels were positively correlated with aspartate aminotransferase (rs =0.48, p<0.01, Spearman's rank correlation coefficient) and negatively correlated with fibrinogen (rs = -0.475, p=0.011) and hemoglobin (rs = -0.465, p=0.013). CONCLUSION: Serum HMGB1 levels reflect clinical features of childhood HLH. HMGB1 is a potential mediator involved in the pathogenesis and determining the clinical findings of HLH.

Acute Lymphoblastic Leukemia Presenting as Fanconi Syndrome.

Acute lymphoblastic leukemia (ALL) presenting as Fanconi syndrome (FS) is extremely rare. Here, we report a case of ALL presenting as bilateral nephromegaly following FS. A 2-year-old girl was unexpectedly diagnosed with bilateral nephromegaly. After 2 weeks, she developed general fatigue, thirst, and polyuria. Laboratory examinations revealed renal tubular acidosis, hypokalemia, hypophosphatemia, and aminoaciduria, and FS was diagnosed. Replacement of bicarbonate and potassium did not improve her condition. Two weeks after the onset of FS, leukemic cells appeared on a peripheral blood smear, and the patient was diagnosed with precursor B-cell ALL presenting as nephromegaly and FS. Chemotherapy brought about a prompt resolution of acidosis and electrolyte abnormalities, without renal dysfunction. The patient remains well 4 years after the onset of the disease. Although extremely rare, FS should be recognized as one of the emerging renal complications of ALL.

Efficacy of Paclitaxel in a Patient with Inoperable Pulmonary Vein Leiomyosarcoma.

Pulmonary vein leiomyosarcoma is extremely rare and has a poor prognosis. Surgical resection with a wide margin seems to offer the only chance of cure. The role of adjuvant therapy is controversial, and the exact efficacy of chemotherapy has not been observed. In this report, we present an 18-year-old male patient with pulmonary vein leiomyosarcoma in whom the use of paclitaxel (PAX) proved to be effective. Because the tumor originated from the left superior pulmonary vein and diffused into the left atrial wall and the junction of the right superior pulmonary vein and left atrium, the en bloc excision of the tumor was impossible. The first-line chemotherapy, including ifosfamide, doxorubicin, and dacarbazine, in conjugation with radiation therapy could not demonstrate any effect on the tumor size. However, the following PAX-containing regimen provided complete regression of the tumor. After PAX-based high-dose chemotherapy with autologous peripheral blood stem cell transplantation, the patient showed complete remission for 2 years. Although he suffered metastatic recurrences and died 4 years after the onset of symptoms, our patient's clinical course clearly reveals the efficacy of PAX.

Hematopoietic Stem Cell Transplantation for XIAP Deficiency in Japan.

BACKGROUND: X-linked inhibitor of apoptosis protein (XIAP) deficiency is a rare immunodeficiency that is characterized by recurrent hemophagocytic lymphohistiocytosis (HLH) and splenomegaly and sometimes associated with refractory inflammatory bowel disease (IBD). Although hematopoietic stem cell transplantation (HSCT) is the only curative therapy, the outcomes of HSCT for XIAP deficiency remain unsatisfactory compared with those for SLAM-associated protein deficiency and familial HLH. AIM: To investigate the outcomes and adverse events of HSCT for patients with XIAP deficiency, a national survey was conducted. METHODS: A spreadsheet questionnaire was sent to physicians who had provided HSCT treatment for patients with XIAP deficiency in Japan. RESULTS: Up to the end of September 2016, 10 patients with XIAP deficiency had undergone HSCT in Japan, 9 of whom (90%) had survived. All surviving patients had received a fludarabine-based reduced intensity conditioning (RIC) regimen. Although 5 patients developed post-HSCT HLH, 4 of them survived after etoposide administration. In addition, the IBD associated with XIAP deficiency improved remarkably after HSCT in all affected cases. CONCLUSION: The RIC regimen and HLH control might be important factors for successful HSCT outcomes, with improved IBD, in patients with XIAP deficiency.

Novel Therapeutic Strategies for Delirium in Patients With Cancer: A Preliminary Study.

To compare the efficacy of antipsychotics (APs) for delirium treatment in patients with cancer, 27 patients treated with 1 of the 4 APs, haloperidol (HPD), risperidone (RIS), olanzapine (OLZ), and quetiapine (QTP), were divided into 2 groups: long half-life (T1/2; HPD, RIS, and OLZ) versus short T1/2 (QTP) or the multiacting receptor-targeted APs (MARTAs; OLZ and QTP) versus the non-MARTA (HPD and RIS). The symptom severity was evaluated by the memorial delirium rating scale (MDAS) on days 0, 3, and 7 following intervention. Significant improvements in total MDAS scores were found in all groups on day 3. However, on day 7, only the short T1/2 group and MARTA group showed significant improvement. Consideration of an AP's pharmacological properties may be helpful for improving the outcomes of pharmacological delirium intervention in patients with cancer.

Neonatal Acute Megakaryoblastic Leukemia Presenting with Leukemia Cutis and Multiple Intracranial Lesions Successfully Treated with Unrelated Cord Blood Transplantation.

Neonatal acute megakaryoblastic leukemia (AMKL) without Down syndrome (DS) is an extremely rare disorder. We report of a one-day-old male infant without DS who developed AMKL with leukemia cutis and right facial nerve palsy. Magnetic resonance imaging of the patient's brain revealed multiple intracranial tumors. A biopsy specimen of the skin lesion was suggestive of AMKL, but the bone marrow leukemic cells were less than 5% of the marrow nucleated cells. The skin and intracranial lesions had spontaneously regressed within one and a half months, but the patient's anemia and thrombocytopenia gradually worsened and the leukemic cells in the bone marrow gradually increased to more than 20% of the nucleated cells. In addition, multiple intracranial lesions reappeared at 72 days of life. We diagnosed the patient with AMKL, and chemotherapy followed by unrelated cord blood transplantation after a reduced-intensity conditioning regimen resulted in sustained complete remission. At present, the patient is well, and he has demonstrated normal development for five years.

Intravenous immunoglobulin preparations promote apoptosis in lipopolysaccharide-stimulated neutrophils via an oxygen-dependent pathway in vitro.

Since prolonged survival of activated neutrophils has an autotoxic potential, neutrophil apoptosis plays an important role in the rapid resolution of inflammation. Intravenous immunoglobulin (IVIG) preparations, which are beneficial therapeutic agents for the treatment of autoimmune diseases and systemic inflammatory diseases, have been reported to induce apoptosis of lymphocytes and endothelial cells in vitro. In the present study, we investigated whether IVIG may induce apoptosis of neutrophils cultured in vitro. After neutrophils prestimulated with or without lipopolysaccharide (LPS) were cultured in the presence or absence of IVIG, the number of apoptotic cells, intracellular H2O2 and GSH were measured by a flow cytometer. IVIG induced apoptosis of LPS-stimulated neutrophils dose dependently, but not in unstimulated neutrophils. Although anti-Fas monoclonal antibodies (mAbs) had no effect on the IVIG-induced apoptosis in the LPS-stimulated neutrophils, anti-Fc gamma receptor (Fc gammaR) II- and III-blocking mAbs significantly inhibited the IVIG-induced apoptosis. IVIG increased the production of intracellular H2O2, while it decreased the production of GSH, in the LPS-stimulated neutrophils. Furthermore, a specific NADPH oxidase inhibitor and anti-oxidants inhibited the IVIG-induced neutrophil apoptosis. Therefore, these findings indicate that IVIG preparations induce apoptosis of LPS-stimulated neutrophils and suggest that the IVIG-induced apoptosis may be mediated by an oxygen-dependent pathway via Fc gammaRII and III.

Intravenous immunoglobulin therapy induces neutrophil apoptosis in Kawasaki disease.

To investigate the effect of high-dose intravenous immunoglobulin (IVIg) on neutrophil apoptosis in Kawasaki disease (KD), we studied the in vitro spontaneous and IVIg-induced apoptosis of neutrophils by analyzing a proportion of annexin V-positive cells and cells with fragmented DNA. The mean number of peripheral neutrophils in the post-IVIg phase decreased significantly (P < 0.01) compared with that in the pre-IVIg phase. The mean proportion of spontaneous apoptotic neutrophils in the post-IVIg phase was significantly higher (P < 0.01) than that in the pre-IVIg phase, and there was a significantly positive correlation (P < 0.01) with the reduction ratio of the circulating neutrophil counts from the pre-IVIg through the post-IVIg phases. IVIg induced a dose-dependent increase in the proportion of apoptotic neutrophils in the pre-IVIg phase. As a result, the present study demonstrated a novel action in which high-dose IVIg therapy decreased the number of circulating neutrophils by accelerating their apoptosis in KD.