Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by large T-cells with strong CD30 and ALK expression. Although ...conventional chemotherapy is effective in most patients, approximately 30% experience a relapse or refractory disease and have a poor prognosis. Several risk factors associated with poor prognosis have been identified in pediatric ALK-positive ALCL. These include morphological patterns with the small cell variant or lymphohistiocytic variant, leukemic presentation, the presence of minimal disseminated disease, or involvement of the central nervous system. Relapsed or refractory ALK-positive ALCL is often resistant to conventional chemotherapy; therefore, salvage therapy is required. In recent years, targeted therapies such as ALK inhibitors and brentuximab vedotin (BV) have been developed. ALK inhibitors block the continuous activation of ALK kinase, a driver mutation that leads to cell proliferation in ALK-positive ALCL. Additionally, BV is an antibody-drug conjugate that targets CD30-positive cells. Both ALK inhibitors and BV have displayed dramatic effects in chemoresistant ALK-positive ALCL. Weekly vinblastine treatment and hematopoietic stem cell transplantation have also been reported to be effective therapies. This article reviews pediatric ALK-positive ALCL, focusing on risk factors and treatment strategies for pediatric patients with relapsed or refractory ALK-positive ALCL.
Purpose
Paediatric high-risk neuroblastoma has poor prognosis despite modern multimodality therapy. This phase I/II study aimed to determine the safety, dose-limiting toxicity (DLT), and efficacy of ...high-dose
131
I-meta-iodobenzylguanidine (
131
I-mIBG) therapy combined with single high-dose chemotherapy (HDC) and haematopoietic stem cell transplantation (HSCT) in high-risk neuroblastoma in Japan.
Methods
Patients received 666 MBq/kg of
131
I-mIBG and single HDC and HSCT from autologous or allogeneic stem cell sources. The primary endpoint was DLT defined as adverse events associated with
131
I-mIBG treatment posing a significant obstacle to subsequent HDC. The secondary endpoints were adverse events/reactions, haematopoietic stem cell engraftment and responses according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) and
123
I-mIBG scintigraphy. Response was evaluated after engraftment.
Results
We enrolled eight patients with high-risk neuroblastoma (six females; six newly diagnosed and two relapsed high-risk neuroblastoma; median age, 4 years; range, 1–10 years). Although all patients had adverse events/reactions after high-dose
131
I-mIBG therapy, we found no DLT. Adverse events and reactions were observed in 100% and 25% patients during single HDC and 100% and 12.5% patients during HSCT, respectively. No Grade 4 complications except myelosuppression occurred during single HDC and HSCT. The response rate according to RECIST 1.1 was observed in 87.5% (7/8) in stable disease and 12.5% (1/8) were not evaluated. Scintigraphic response occurred in 62.5% (5/8) and 37.5% (3/8) patients in complete response and stable disease, respectively.
Conclusion
131
I-mIBG therapy with 666 MBq/kg followed by single HDC and autologous or allogeneic SCT is safe and efficacious in patients with high-risk neuroblastoma and has no DLT.
Trial registration number
jRCTs041180030.
Name of registry
Feasibility of high-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding myeloablative chemotherapy and haematopoietic stem cell transplantation (High-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma).
URL of registry
https://jrct.niph.go.jp/en-latest-detail/jRCTs041180030
.
Date of enrolment of the first participant to the trial
12/01/2018.
Bloom syndrome (BS) is a rare autosomal recessive disorder characterized by genomic instability that leads to various complications, including cancer. Given the low prevalence of BS in Japan, we ...conducted a nationwide survey. We recruited eight patients with BS, three of whom exhibited intellectual disability. The 631delCAA mutation in the BLM gene was detected in 9 out of 16 alleles. To investigate neuronal development in patients with BS, we generated induced pluripotent stem cells derived from one of these patients (BS-iPSCs). We examined the phenotypes of the induced cortical neurons derived from the generated BS-iPSCs using a previously reported protocol; the generated BS-iPSCs showed an approximately 10-times higher frequency of sister-chromatid exchange (SCE) than the control iPSCs. Immunocytochemistry revealed shorter axons and higher proliferative potential in BS-iPSC-derived cortical neurons compared with control iPSCs. To our knowledge, our study is the first to clarify the abnormality of the cortical neuron phenotypes derived from patients with BS. Our findings may help identify the pathogenesis of neuronal differentiation in BS and aid in the development of novel therapeutic agents.
The development of hematopoietic stem cell (HSCs) gene therapy for DNA repair disorders, such as Fanconi anemia and Bloom syndrome, is challenging because of the induction of HSCs apoptosis by ...cytokine stimulation. Although the Baboon envelope pseudotyped lentiviral vector (BaEV-Rless-LV) has been reported as a non-stimulatory gene transfer tool, the virus titer of BaEV-Rless-LV is too low for use in clinical applications. Transfected 293 T cells with helper plasmids, including the BaEV-Rless plasmid, showed morphological changes, such as syncytium formation and detachment. To establish a novel protocol for producing a high titer of BaEV-Rless-LV, we optimized three aspects of a basic virus production protocol by focusing on modifying culture conditions and the use of reagents: the virus titer increased 3-fold when the amount of BaEV-Rless plasmid was increased 1.2-fold; the highest titer was obtained when the viral supernatant was harvested at 48-h post-transfection, despite complete syncytium formation and detachment of the 293 T cells; and the use of poly-L-lysine-coated culture plates to enhance the adhesion and proliferation of 293 T cells and prevent detachment doubled the titer. Collectively, our novel protocol resulted in a 10-fold titer increase compared to the basic protocol and may be useful in clinical applications for treating DNA repair disorders.
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•Hematopoietic stem cell gene therapy for DNA repair disorders is challenging.•BaEV-Rless pseudotyped lentiviral vector could solve the issue by cytokine depletion.•Although the titer is too low, novel virus production protocol is needed.•We modified protocol focusing on syncytium and detachment of transfected 293 T cells.•Our novel protocol resulted in a 10-fold titer increase compared to basic protocol.
Acute leukemia is typically diagnosed from presenting features related to hematological symptoms, but certain patients present with prominent musculoskeletal pain without signs of hematological ...abnormality. We reviewed the medical records of 58 children diagnosed with acute lymphoblastic leukemia (ALL) at our hospital to evaluate initial features. Forty six of these patients had hematological symptoms, anemia, or hemorrhage (Group H), while 12 patients had prominent musculoskeletal pain without hematological symptoms (Group P). Diagnosis of leukemia took significantly more time for those 12 patients (Group H, 17.1 days; Group P, 48.5 days). In three of the 12 patients in Group P, localized abnormal imaging findings and unremarkable blood test results led to initial diagnoses of chronic recurrent multifocal osteomyelitis, bone fracture, and septic osteomyelitis. However, 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) revealed multiple intense bone foci or systemic bone marrow uptake, leading to the diagnosis of ALL. A review of 18F-FDG-PET results from 23 patients with ALL who underwent a PET scan (Group H,
n
= 15; Group P,
n
= 8) showed multiple bone foci or systemic bone marrow uptake in all cases. In conclusion, lack of hematological symptoms in ALL patients can delay diagnosis, and 18F-FDG-PET is useful for diagnosing leukemia in such cases.
Abstract
Objective
To investigate the clinical significance of serum IL-18 levels for the diagnosis of systemic JIA (s-JIA) and to predict the disease course of s-JIA.
Methods
Overall, 116 patients ...with s-JIA, 151 with other diseases and 20 healthy controls were analysed. Serum IL-18 levels were measured longitudinally in 41 patients with s-JIA from active phase through remission phase. Serum IL-18 levels were quantified via enzyme-linked immunosorbent assay and the results were compared with clinical features and the disease course of s-JIA.
Results
The serum IL-18 level cut-off value for differentiation of s-JIA from other diseases was 4800 pg/ml. In patients with a monocyclic course, serum IL-18 levels steadily decreased during the inactive phase and low levels were sustained during remission. In contrast, in patients with a chronic course, elevated serum IL-18 levels were sustained even during the inactive phase. In patients with a polycyclic course, serum IL-18 levels were elevated during disease flares and normalized during the inactive phase. The serum IL-18 level cut-off value for diagnosis of remission in s-JIA was 595 pg/ml,
Conclusion
Serum IL-18 levels of >4800 pg/ml may be useful for differentiating between s-JIA and other diseases. Monitoring of serum IL-18 levels might be useful for predicting the disease course and assessing remission in s-JIA.
Bloom syndrome patients often develop severe gastrointestinal symptoms mainly caused by gastric tumors due to DNA repair disorder. Here, we report 31‐year‐old Bloom syndrome patient suffering ...persistent abdominal pain due to refractory gastroduodenal ulcers which required gastroduodenectomy. Various causes should be considered, and the accumulation of their reports is warranted.
We report a patient with Bloom syndrome who had refractory gastroduodenal ulcers requiring gastroduodenectomy. Since gastroduodenal ulcers with Bloom syndrome have not been reported so far, it was challenging to diagnose with her. As the complications of Bloom syndrome are diverse, the accumulation of their case reports is warranted.
Background
The rate of renal involvement in pediatric acute lymphoblastic leukemia (ALL) at diagnosis varies between reports because renal involvement is diagnosed on renal size larger than ...aged‐matched standards on conventional modalities. We propose a new method for precise renal involvement detection using 3‐D enhanced computed tomography (CT) reconstruction.
Methods
Twenty‐five children with ALL were evaluated utilizing 3‐D enhanced CT reconstruction to measure renal volume before and after induction therapy, renal mass lesions and renal axis at diagnosis. Renal involvement was defined as a marked decrease of renal volume or the presence of mass lesions.
Results
According to the 3D‐CT criteria, nine of 25 patients (36%) had renal involvement. All of them had bilateral mass lesions except for one who had diffuse nephromegaly alone. This method detected renal involvement more accurately than ultrasonography. When using conventional criteria based on the length of the renal axis, 19 of 25 (76%) had renal involvement, including many cases of false‐positive nephromegaly. Patients with renal involvement had significantly more extramedullary involvement according to the 3D‐CT‐based criteria.
Conclusions
The use of 3D‐CT reconstruction was accurate in detecting renal involvement in childhood ALL, most of which consisted of piled up mass lesions. Patients with renal involvement should be worked up for the detection of other extramedullary lesions.
Objective
Children with relapsed neuroblastoma have a poor prognosis despite modern multimodality therapy. Novel and more effective therapeutic strategies are required for relapsed neuroblastoma. We ...retrospectively examined the utility of consolidation therapy with high-dose
131
I-meta-iodo-benzyl-guanidine (
131
I-mIBG) in relapsed neuroblastoma or ganglioneuroblastoma patients with complete response (CR) to induction therapy as demonstrated by diagnostic
123
I-mIBG scintigraphy.
Methods
Between December 2009 and 2014, five patients with relapsed neuroblastoma and one with relapsed ganglioneuroblastoma received high-dose
131
I-mIBG therapy. Overall and progression-free survival rates at five years after
131
I-mIBG therapy were analyzed by the Kaplan–Meier method.
Results
During follow-up, three children showed no signs of disease relapse, whereas three died. One child without a relapse died from post-transplant side effects, and two children with a relapse died owing to tumor progression. The 5-year progression-free and overall survival rates after
131
I-mIBG therapy were 44% and 67%, respectively.
Conclusions
Consolidation therapy with high-dose
131
I-mIBG for patients with 2
nd
CR showed good overall and progression-free survival. While the risks of radiation exposure must be considered, high-dose
131
I-mIBG therapy as consolidation therapy needs to be further investigated.
