Allogeneic stem cell transplantation for inherited metabolic disorders: 35 years' experience at a single institution.

Hematopoietic stem cell transplants for inherited metabolic disorders performed at Tokai University Hospital between June 5, 1986, and May 28, 2021, were analyzed and compared between the period before 2007 and the period from 2007 onward based on availability of medical resources. Transplants were performed for 38 patients with mucopolysaccharidosis, 33 with adrenoleukodystrophy, and 16 with another disorder. Before 2007, oral busulfan-based regimens were mainly used. From 2007 onward, intravenous busulfan-based regimens or 4 Gy of thoracoabdominal irradiation (TAI), fludarabine, and melphalan (Mel)/treosulfan were adopted. Between 2002 and 2010, adrenoleukodystrophy was treated with 12 Gy of TAI and Mel. HLA-identical sibling bone marrow was used in 43% of cases before 2007 and 15% from 2007 onward, while alternative donors were selected for other transplants. Overall survival and event-free survival (EFS) before 2007 and from 2007 onward were 76% and 62%, and 97% and 85%, respectively (P = 0.006 and 0.017). Transplant era predicted superior overall survival and EFS, while myeloablative conditioning also predicted EFS. The incidence of primary graft failure decreased from 2007 onward, especially in cord blood transplant when 4 Gy of TAI with 150 mg/m2 fludarabine and 180 mg/m2 Mel or 42 g/m2 treosulfan were used as conditioning.

Subcutaneous Panniculitis-like T Cell Lymphoma Diagnosed with a Slowly Progressive Course: A Case Report.

Panniculitis is an inflammation that occurs in subcutaneous adipose tissue. Panniculitis includes physical panniculitis (e.g., traumatic) and infectious panniculitis (e.g., bacterial, fungal, subcutaneous panniculitis-like T cell lymphoma [SPCTL], etc.). Accurate diagnosis is crucial due to similar clinical presentation of all types of panniculitis. Here, we report a case of SPCTL which was initially diagnosed with traumatic panniculitis. A 15-year-old male patient was admitted to a previous hospital due to a progressively enlarged right flank and inguinal mass after an abdominal bruise. He was initially diagnosed with traumatic panniculitis, but the mass expanded throughout the chest and abdomen accompanied by a fever of over 11 months. Computed tomography (CT) revealed a subcutaneous mass in the anterior chest and abdominal wall. Fludeoxyglucose F18 (FDG) uptake was observed at those lesions using FDG-positron emission tomography (PET). A biopsy of the mass lesion was performed, during which SPCTL was diagnosed based on pathological examination. He was initially treated with prednisolone and cyclosporine A for two weeks. His fever went down, but subcutaneous mass in the chest and abdominal wall persisted. Therefore, he received a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen. After 6 courses of CHOP, CT revealed no disease evidence. He remained in complete remission at 30 months of therapy.

The effect of massage on the plantar flexor muscles during the fixation period in postoperative patients with an ankle fracture.

INTRODUCTION: Ankle fractures are one of the most common lower extremity fractures. After surgery, the ankle joint is often immobilized in a plantar flexion position, and there have been many reported cases of limited ankle joint range of motion. Therefore, the purpose of the present study was to investigate the effect of regular massage interventions on ankle joint range of motion after removal of fixation. METHODS: The massage group comprised 30 patients who had sustained an ankle fracture and had undergone surgical fixation, physical therapy, and massage between November 2020 and March 2022. These subjects received a 3-min massage twice daily, five times a week. The control group consisted of 38 patients who had sustained an ankle fracture between January 2015 and September 2020 and had undergone surgical fixation as well as regular physical therapy. RESULTS: The respective ankle dorsiflexion and plantarflexion ranges of motion after cast removal were 2.50 ± 7.2° and 42.3 ± 7.2° in the massage group and -8.62 ± 2.9° and 34.8 ± 8.3° in the control group. An unpaired t-test showed that the ankle dorsiflexion and plantarflexion ranges of motion in the massage group were significantly greater than those in the control group (p = 0.036 and p < 0.01). CONCLUSIONS: Our results indicate that regular 3-min massage interventions of the plantar flexors could prevent the progression of a range of motion limitations in postoperative patients with an ankle fracture more effectively than regular physical therapy alone.

Efficacy of off-the-shelf bone marrow mesenchymal stem cells for pediatric steroid-refractory acute graft-versus-host disease.

Introduction: Temcell is a mesenchymal stem cell (MSC) product approved for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in Japan. However, reports regarding Temcell's efficacy in pediatric patients have been scarce, and the appropriate use of MSC therapy against pediatric SR-aGVHD also remains to be determined. Patients and Methods: We retrospectively assessed a cohort of pediatric patients treated with Temcell for SR-aGVHD following allogeneic hematopoietic transplantation. MSCs were infused intravenously at a dose of 2 × 106 cells/kg according to the manufacturer's instructions. Results: Twelve patients received eighteen cycles of MSC therapy (median age, 10.3 [1.7-17.8] years), with four receiving additional cycles (one cycle: n = 3, three cycles: n = 1). The severity of aGVHD before MSC therapy was grade I-II in three patients and grade III-IV in nine patients (gut stage 3-4, n= 7; liver stage 3-4; n =2). The median number of immunosuppressive therapy regimens received prior to MSC administration was two (range: 1-5). The first MSC cycle displayed the best overall response rate of 83%, including six patients with a complete response (CR) and with a 49% reduction in the mean daily dose of prednisone after eight weeks. The median time to first response was 3.5 days (range: 2-15 days). Two of the four patients who were re-administered MSCs for recurrent or persistent GVHD achieved a CR. The three-year overall survival rate was 69.4%, while the three-year failure free survival (FFS) rate was 22.2%, with a median FFS of 4.9 months. There were no observable side effects of MSC therapy. Conclusions: MSC therapy appears to be an effective and safe treatment for pediatric SR-aGVHD, with a steroid-sparing effect and satisfactory efficacy upon re-administration. Further studies are needed to determine its appropriate combination with additional treatments and the optimal use of re-administration of MSCs.

The acute effect of roller massager on knee joint range of motion and muscle pain in older adults with total knee arthroplasty.

OBJECTIVES: Older adults with total knee arthroplasty (TKA) have a limited range of knee joint motion due to pain and stiffness. A roller massager (RM) has recently been suggested to decrease pain and increase joint range of motion (ROM). Therefore, this study aimed to investigate the acute effect of RM intervention on pain and knee joint ROM in older adults with TKA in the second postoperative week. METHODS: The participants were 23 patients (76.3±5.4 years) who had undergone TKA for knee OA. The degree of pain during the ROM measurements was measured using the visual analog scale before and immediately after the RM intervention. The RM intervention was performed on the thigh's lateral, central, and medial parts for three sets of 60 s using an RM. RESULTS: RM intervention could significantly increase knee flexion ROM (p<0.01, d=0.41, Δchange: 4.1±3.2°) and decrease pain during the knee ROM measurements (p<0.01, d=-0.53, Δchange: -11.9±21.0). CONCLUSIONS: The three sets of 60-s RM intervention significantly increased knee flexion ROM and reduced pain in older adults with TKA in the second postoperative week. These results show that RM intervention is an effective tool for treating stiffness and pain after TKA.

A 1-Week Comprehensive Foam Rolling Intervention Program Can Improve Knee Pain but Not Muscle Function and Range of Motion in Patients with Total Knee Arthroplasty.

We investigate the effect of a 1-week comprehensive foam rolling (FR) intervention program on knee pain, range of motion (ROM), and muscle function in patients with TKA.Thirty patients with TKA were randomly allocated to FR (n = 15) or control (n = 15) groups. The control group received only regular physical therapy. Patients in the FR group performed the FR intervention in addition to their regular physical therapy twice daily from postoperative weeks two to three (60 s × 3 repetitions × 2 times/day × 6 days: total = 2160 s). Pain score, knee flexion and extension ROM, muscle strength, walking function, and balance function were measured before and after the FR intervention. From the second to third postoperative weeks, there were significant improvements in all variables, and the reduction in pain score at stretching was significantly greater in the FR group (-26.0 ± 1.4; p < 0.05) than in the control group (-12.5 ± 1.9). However, there was no significant difference in changes in the other variables except for the pain score at stretching between FR and control groups. A 1-week comprehensive FR intervention program in patients with TKA could reduce pain scores at stretching without a synergistic effect on physical function, i.e., walking speed, balance function, and muscle strength of the knee extensors muscles.

Long-term efficacy and safety profile of splenectomy for pediatric chronic immune thrombocytopenia.

There are few reports of the long-term efficacy of splenectomy in children with immune thrombocytopenia (ITP). In a 33-year period, we performed splenectomies in 23 pediatric patients with ITP at a single institution in Japan. The age at surgery was 5-22 years with a median of 10 years. The follow-up period was 1-141 months with a median of 48 months. Before surgery, we confirmed the presence or absence of the accessory spleen by contrast-enhanced CT scan and we recommended vaccination with pneumococcal vaccine. Four patients underwent laparotomy before 1998, and 19 patients underwent laparoscopic surgery after 1999. Splenectomy showed high efficacy with a partial response rate of 83% and a complete response rate of 74%. Complete response was maintained in 70% of patients until the end of the observation period, and 91% were able to discontinue long-term management drugs such as steroids. No serious complications such as infectious diseases were observed. Although the number of cases here was small, the long-term efficacy and safety of splenectomy makes it a viable option in pediatric ITP despite the existence of newer therapeutic agents. Further research is necessary to compare the long-term efficacy and safety of splenectomy with new therapeutic agents.

Successful combination chemotherapy involving clofarabine, cyclophosphamide, and etoposide for pediatric relapsed acute myeloid leukemia: A case report.

Limited salvage chemotherapies are available for relapsed/refractory acute myeloid leukemia. Herein, we described successful reinduction chemotherapy, involving a combination of clofarabine, cyclophosphamide, and etoposide, in a 12-year-old male with relapsed acute myeloid leukemia prior to allogeneic bone marrow transplantation from his father. Although treatment with a combination of fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin, and gemtuzumab ozogamicin had no positive effects, the aforementioned clofarabine-based chemotherapy induced complete remission and allowed the transplantation to go ahead. The abovementioned regimen may be useful for induction chemotherapy prior to hematopoietic stem cell transplantation for refractory/relapsed acute myeloid leukemia.

Anticoagulation treatment and prophylactic edoxaban for cerebral sinus venous thrombosis in an adolescent with acute lymphoblastic leukemia.

Pediatric acute lymphoblastic leukemia regimens include large L-asparaginase dosages and steroids, which are associated with an increased risk of venous thromboemboli in adolescents and young adults. Herein, we report the case of an 18-year-old male with acute lymphoblastic leukemia, who was treated with the pediatric regimen, in which edoxaban was employed as a prophylaxis against cerebral sinus venous thrombosis. The event happened on day 20 of induction therapy, when brain magnetic resonance imaging demonstrated a cerebral sinus venous thrombosis in the superior sagittal sinus. Anticoagulation therapy was initiated, and the patient's symptoms disappeared 3 days later. The induction therapy was restarted after an interruption of 16 days, and the consolidation therapies, which included L-asparaginase and steroids, were completed. Edoxaban was administered as a prophylaxis during the consolidation therapy. There were no further adverse events. Edoxaban could be an effective prophylaxis for coagulation complications in adolescents and young adults with acute lymphoblastic leukemia.

Successful Treatment of Pediatric Refractory/Relapsed AML with KIR-Ligand-Mismatched Cord Blood Transplant after FLAG-IDA Reinduction Therapy with or without the GO Regimen.

Prognosis in pediatric patients with refractory/relapsed acute myeloid leukemia (AML) is grim, and there is no standard treatment for such patients. Combined treatment with intensive chemotherapy and gemtuzumab ozogamicin (GO), a monoclonal anti-CD33 antibody conjugated with calicheamicin, is useful as reinduction therapy in refractory/relapsed AML. Here, we describe three cases of pediatric refractory/relapsed AML that were successfully managed with FLAG-IDA (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin), with or without GO, as reinduction therapy before a KIR-ligand-mismatched cord blood transplant. This strategy relies on the fact that killer cell immunoglobulin-like receptors (KIR) on cord blood natural killer (NK) cells recognize human leukocyte antigen (HLA) class I alleles, and that donor KIR-ligand incompatibility may be associated with lower incidence of relapse and improved survival in AML, as cells that lack these inhibitory HLA ligands can activate NK cells. All three patients are currently alive and have been disease-free for 24-65 months, although one patient developed severe sinusoidal obstructive syndrome (SOS). Thus, our strategy can result in excellent outcomes in pediatric patients with refractory/relapsed AML.

Gastric antral vascular ectasia in a pediatric patient with neuroblastoma who underwent tandem stem cell transplantation.

Gastric antral vascular ectasia (GAVE) is an angiodysplastic disorder, which causes severe and prolonged gastric bleeding. Although GAVE has been described in adult patients treated with hematopoietic stem cell transplantation (HSCT), a few cases involving pediatric patients have also been reported. A 5-year-old boy with neuroblastoma (NB) developed severe hematemesis after undergoing tandem HSCT, i.e. autologous peripheral blood stem cell transplantation (auto-PBSCT), followed by allogeneic cord blood transplantation (allo-CBT). The patient suffered oral feeding difficulties because of the effects of chemotherapy and an unbalanced diet. Intravenous Busulfan (ivBU) was used as a conditioning regimen for the auto-PBSCT. The diagnosis of GAVE was made based on endoscopy of the upper gastrointestinal tract on day 31 after the allo-CBT. Argon plasma coagulation (APC) was performed twice, and the complete resolution of GAVE was confirmed by an endoscopic re-evaluation, conducted on day 87. GAVE in this case might have been associated with ivBU treatment. Atrophy of the gastric mucosa due to loss of appetite might also have contributed to GAVE. NB was treated using high-doses of alkylating agents, such as BU. Such treatment can cause significant mucositis of the oral cavity as well as vascular lesions and is associated with GAVE. Therefore, GAVE should be considered when gastrointestinal bleeding occurs in NB patients treated with HSCT. APC might be effective against HSCT-GAVE.

Prophylactic recombinant thrombomodulin treatment prevents hepatic sinusoidal obstruction syndrome in high-risk pediatric patients that undergo hematopoietic stem cell transplants.

Hepatic SOS is a potentially life-threatening complication of conditioning for allogeneic HSCT. rTM is a new drug for treating DIC. We report our experience of the use of rTM as a prophylaxis against SOS in high-risk pediatric patients that underwent HSCT. We evaluated the cases of 19 pediatric hematology and oncology patients who underwent HSCT at our institution between 2007 and 2016. The patients who received HSCT after 2012 (n = 8) were treated with rTM as a prophylaxis against SOS together with UDCA and LMWH, whereas the others (n = 11) were only treated with UDCA and LMWH. Although SOS occurred by post-HSCT day 35 in 3 (27%) patients in the control group, SOS was not seen in the rTM group. Two of the former three patients suffered severe SOS, and one died of the condition. The mean peak level of PAI-1 (a marker of endothelial damage) was significantly lower in the rTM group. rTM appears to be a safe prophylaxis for SOS. The present findings suggest that prophylactic rTM after HSCT might help to prevent SOS.

[Initial presentation of lymphoblastic crisis in a pediatric chronic myelogenous leukemia patient].

A 9-year-old girl was referred to our hospital because of facial palsy. Both physical and blood examination revealed hepatosplenomegaly and leukocytosis, respectively. A bone marrow examination demonstrated marked hypercellularity involving myeloblasts and lymphoblasts. Based on these results, we suspected mixed phenotype acute leukemia. However, her leukemic blasts expressed B-cell antigens, and a chromosomal analysis of her bone marrow cells revealed the following karyotype: 46, XX, t (9;22) (q34;q11.2). All her neutrophils were positive for the breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 fusion protein. Based on these findings, she was diagnosed with a lymphoblastic crisis of chronic myelogenous leukemia (CML). Combined chemotherapy, involving imatinib, resulted in complete molecular remission. She received cord blood transplant (CBT) during the first complete remission; she is alive and has not suffered a relapse since two years after the CBT. The sudden onset of a blastic crisis in pediatric CML is rare, and it may be difficult to distinguish such cases from de novo Ph-positive leukemia. For diagnostic purposes, it is essential to consider a patient's clinical course and blood test results.

Wiskott-Aldrich syndrome that was initially diagnosed as immune thrombocytopenic purpura secondary to a cytomegalovirus infection.

Wiskott-Aldrich syndrome is a rare X-linked recessive disease resulting from variations in the WAS gene. Wiskott-Aldrich syndrome is sometimes difficult to differentiate from immune thrombocytopenic purpura. A 2-month-old boy was admitted to our hospital for purpura and thrombocytopenia. His mean platelet volume was reported to be normal. Treatment with intravenous immunoglobulins failed to improve the patient's platelet count. Subsequently, an acute cytomegalovirus infection was confirmed by serological testing and antigenemia. The patient was diagnosed with immune thrombocytopenic purpura secondary to a cytomegalovirus infection. However, based on the patient's clinical course and the refractoriness of his condition, Wiskott-Aldrich syndrome was strongly suspected. Through direct sequencing of the genomic DNA of the Wiskott-Aldrich syndrome protein (WASP) gene, we identified a novel missense mutation in exon 3 of the patient's WASP gene (c. 343 C>T, p. H115T), and the patient was diagnosed with Wiskott-Aldrich syndrome at 3 months after onset. Children with Wiskott-Aldrich syndrome are often initially diagnosed with immune thrombocytopenic purpura, which can lead to inappropriate treatment and delays to life-saving definitive therapy. Our findings imply that Wiskott-Aldrich syndrome should be considered as a differential diagnosis in cases of refractory immune thrombocytopenic purpura combined with a cytomegalovirus infection.

Successful low-dose radiotherapy treatment for Kasabach-Merritt syndrome.

Kasabach-Merritt syndrome (KMS) is characterized by hemangioma associated with life-threatening thrombocytopenia, and is a consumptive coagulopathy. Although treatments available include corticosteroids, α-interferon, vincristine, and surgery, response may be unsatisfactory, and the mortality rate remains at approximately 30%. Although radiotherapy has been used effectively for KMS, it may cause growth retardation and secondary malignancy. We report a case of KMS in which hemangioma of the left thigh was successfully treated with low-dose radiotherapy (6 Gy in six fractions, weekly) after failure of corticosteroid therapy. No significant late effects due to the radiotherapy were noted at 5 year follow up. Thus, low-dose radiotherapy remains an important treatment method for KMS when patients fail to respond to other treatments.