Respiratory dysfunction in childhood cancer survivors: A single institution study.

BACKGROUND: Recently, while the overall survival rate of childhood cancer has improved, research has highlighted a high incidence of comorbidities in childhood cancer survivors (CCSs). However, it is likely that many asymptomatic comorbidities go unnoticed. The purpose of the current study was to identify comorbidities unique to Japanese CCSs through comparisons with a general population that underwent comparable comprehensive medical checkups. METHODS: The patient group included CCSs who had completed their cancer treatment, were aged 16 years or older, and underwent the comprehensive medical checkups at the University of Tsukuba Hospital between 2018 and 2020. The control group included members of the general population who underwent comprehensive medical checkups at the same hospital in 2018. RESULTS: Seventeen CCSs and 59 controls were included. Among the CCSs, the median ages at medical checkup and diagnosis were 22.1 years (range, 16-39) and 8.7 years (range, 1.3-14.8), respectively. Incidence of abnormalities in respiratory function, hearing function, and body mass index was higher in CCSs (52.9%, p = 0.013; 17.6%, p < 0.001; and 41.2%, p = 0.080, respectively) compared with controls. CONCLUSION: Asymptomatic pulmonary dysfunction was detected in the comprehensive medical checkup as a unique comorbidity in CCSs. Because the odds ratio of mortality due to respiratory failure is high in CCSs, as previously reported, we believe that detection of pulmonary dysfunction and the promotion of a healthy lifestyle are important. The evaluation of the pulmonary function may not typically be included in routine clinical visits, but it could be necessary for comprehensive medical evaluation in CCSs.

A Case of Anorexia Nervosa with Focal Cortical Dysplasia.

Anorexia nervosa (AN) is a fatal condition associated with extreme underweight and undernutrition. It is more common in young females, with a female-to-male ratio of 10 : 1. Focal cortical dysplasia (FCD) is characterized by dysplasia of the cerebral cortex and is a common cause of pharmacoresistant epilepsy. However, FCD associated with AN has never been reported. We report the first case of AN in a 12-year-old male diagnosed with FCD-type 2 on head magnetic resonance imaging (MRI). He became concerned about lower abdominal distention and began reducing his food intake. He was admitted to our hospital after weight loss of 10 kg in a 1 year. Head MRI showed a localized high-signal area from the cortex to the white matter of the fusiform gyrus near the left hippocampus, with no associated decreased blood flow or electroencephalography (EEG) abnormalities. These findings were characteristic of FCD type II. In males with AN, the search for underlying disease is particularly important. The pathophysiology of the association between AN and FCD is unclear. However, both conditions are reportedly associated with autism spectrum disorder. Further cases are needed to clarify whether FCD is associated with eating disorders.

Early hematopoietic cell transplantation for familial hemophagocytic lymphohistiocytosis in a regional treatment network in Japan.

Familial hemophagocytic lymphohistiocytosis (FHLH) is a fatal hyperinflammation syndrome arising from the genetic defect of perforin-mediated cytolysis. Curative hematopoietic cell transplantation (HCT) is needed before development of central nervous system (CNS) disease. We studied treatment outcomes of 13 patients (FHLH2 n = 11, FHLH3 n = 2) consecutively diagnosed from 2011 to 2022 by flow cytometric screening for non-myeloablative HCT in a regional treatment network in Kyushu, Japan. One patient with a novel PRF1 variant escaped screening, but all patients with FHLH2 reached diagnosis and 8 of them received HCT until 3 and 9 months of age, respectively. The earliest HCT was conducted 65 days after birth. Three pretransplant deaths occurred in newborns with liver failure at diagnosis. Ten posttransplant patients have remained disease-free, 7 of whom had no neurological involvement. Time from first etoposide infusion to HCT was shorter in patients without CNS disease or bleeding than in patients with those factors (median [range] days: 62 [50-81] vs. 122 [89-209], p = 0.016). Six of 9 unrelated patients had a PRF1 c.1090_1091delCT variant. These results suggest that the critical times to start etoposide and HCT are within 3 months after birth and during etoposide control, respectively. Newborn screening may increase the percentage of disease-free survivors without complications.

Identification of a novel splice-site WWOX variant with paternal uniparental isodisomy in a patient with infantile epileptic encephalopathy.

WOREE syndrome is an early infantile epileptic encephalopathy characterized by drug-resistant seizures and severe psychomotor developmental delays. We report a case of a WWOX splice-site mutation with uniparental isodisomy. A 1-year and 7-month-old girl presented with nystagmus and epileptic seizures from early infancy, with no fixation or pursuit of vision. Physical examination revealed small deformities, such as swelling of both cheeks, folded fingers, rocking feet, and scoliosis. Brain imaging revealed slight hypoplasia of the cerebrum. Electroencephalogram showed focal paroxysmal discharges during the interictal phase of seizures. Vitamin B6 and zonisamide were administered for early infantile epileptic encephalopathy; however, the seizures were not relieved. Despite altering the type and dosage of antiepileptic drugs and ACTH therapy, the seizures were intractable. Whole-exome analysis revealed the homozygosity of WWOX(NM_016373.4):c.516+1G>A. The WWOX mRNA sequencing using peripheral blood RNA confirmed that exon 5 was homozygously deleted. Based on these results, the patient was diagnosed with WOREE syndrome at 5 months. The WWOX variant found in this study is novel and has never been reported before. WOREE syndrome being extremely rare, further case series and analyses of its pathophysiology are warranted.

Possible correlation between serum interleukin-8 levels and the activity of myositis in anti-NXP2 antibody-positive dermatomyositis.

Anti-nuclear matrix protein 2 (NXP2) antibody-positive dermatomyositis (DM) is characterized by extensive and severe myositis. In this study, we evaluated which cytokines/chemokines involved with the activity of the myositis. We performed quantitative immunoassays using the MILLIPLEX® Multiplex Assays Using Luminex to evaluate serum levels of interferon-γ, interleukin (IL)-1ß, IL-6, IL-8, IL-12p40, and tumor necrosis factor-α in samples collected over time from a 9-year-old female with anti-NXP2 antibody-positive DM. In our case, the serum level of IL-8 was elevated when the myositis worsened, and decreased in accordance with the improvement of myositis, suggesting that the serum IL-8 levels were correlated with the myositis activity. Serum levels of IL-8 in samples from five patients with anti-NXP2 antibody-positive DM and five patients with anti-transcriptional intermediary factor 1γ (TIF1γ) antibody-positive DM without both interstitial lung disease (ILD) and malignancy before starting treatments, along with five healthy controls, were also evaluate by an enzyme-linked immunosorbent assay. Serum IL-8 levels were significantly elevated in anti-NXP2 or anti-TIF1γ antibody-positive DM patients with myositis but not ILD, than healthy controls. It was suggested that serum levels of IL-8 correlate with the activity of myositis in DM including anti-NXP2 antibody-positive DM.

Non-conditioned cord blood transplantation for infection control in athymic CHARGE syndrome.

OBJECTIVE: CHARGE syndrome is a congenital malformation syndrome caused by heterozygous mutations in the CHD7 gene. Severe combined immunodeficiency (SCID) arises from congenital athymia called CHARGE/complete DiGeorge syndrome. While cultured thymus tissue implantation (CTTI) provides an immunological cure, hematopoietic cell transplantation (HCT) is an alternative option for immuno-reconstitution of affected infants. We aimed to clarify the clinical outcomes of patients with athymic CHARGE syndrome after HCT. METHODS: We studied the immunological reconstitution and outcomes of four patients who received non-conditioned unrelated donor cord blood transplantation (CBT) at Kyushu University Hospital from 2007 to 2022. The posttransplant outcomes were compared with the outcomes of eight reported patients. RESULTS: Four index cases received CBT 70-144 days after birth and had no higher than grade II acute graft-versus-host disease. One infant was the first newborn-screened athymic case in Japan. They achieved more than 500/µL naïve T cells with balanced repertoire 1 month post transplant, and survived more than 12 months with home care. Twelve patients including the index cases received HCT at a median 106 days after birth (range: 70-195 days). One-year overall survival rate was significantly higher in patients who underwent non-conditioned HCT than in those who received conditioned HCT (100% vs. 37.5%, p = .02). Nine patients died, and the major cause of death was cardiopulmonary failure. CONCLUSIONS: Athymic infants achieved a prompt reconstitution of non-skewing naïve T cells after non-conditioned CBT that led to home care in infancy without significant infections. Non-conditioned CBT is a useful bridging therapy for newborn-screened cases toward an immunological cure by CTTI.

Acute monocytic leukemia with KMT2A::LASP1 developed 9 months after diagnosis of acute megakaryoblastic leukemia in a 2-year-old boy.

Acute myeloid leukemia (AML) is known as one of the subsequent malignant neoplasms that can develop after cancer treatment, but it is difficult to distinguish from relapse when the preceding cancer is leukemia. We report a 2-year-old boy who developed acute megakaryoblastic leukemia (AMKL, French-American-British classification [FAB]: M7) at 18 months of age and achieved complete remission with multi-agent chemotherapy without hematopoietic stem cell transplantation. Nine months after diagnosis and 4 months after completing treatment for AMKL, he developed acute monocytic leukemia (AMoL) with the KMT2A::LASP1 chimeric gene (FAB: M5b). The second complete remission was achieved using multi-agent chemotherapy and he underwent cord blood transplantation 4 months after AMoL was diagnosed. He is currently alive and disease free at 39 and 48 months since his AMoL and AMKL diagnoses, respectively. Retrospective analysis revealed that the KMT2A::LASP1 chimeric gene was detected 4 months after diagnosis of AMKL. Common somatic mutations were not detected in AMKL or AMoL and no germline pathogenic variants were detected. Since the patient's AMoL was different from his primary leukemia of AMKL in terms of morphological, genomic, and molecular analysis, we concluded that he developed a subsequent leukemia rather than a relapse of his primary leukemia.

A novel de-novo RB1 mutation identified in a patient with bilateral retinoblastoma.

Retinoblastoma manifests as ocular malignancy due to mutations in the RB1 gene. A 17-month-old girl with bilateral retinoblastoma having no family history was admitted to our hospital. The right eye was enucleated but the other was preserved with systemic chemotherapy and topical treatment. The patient has been tumor-free for over 7 years since diagnosis. All exons of RB1 were sequenced and a novel 1-base pair deletion (NM_000321.2:c.2409del, p.Asn803Lysfs*7) was detected.

Successful treatment of DOCK8 deficiency by allogeneic hematopoietic cell transplantation from alternative donors.

Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare autosomal recessive inborn error of immunity (IEI) characterized by eczematous dermatitis, elevated serum IgE, and recurrent infections, comprising a seemingly hyper-IgE syndrome (HIES). DOCK8 deficiency is only curable with allogeneic hematopoietic cell transplantation (HCT), but the outcome of HCT from alternative donors is not fully understood. Here, we describe the cases of two Japanese patients with DOCK8 deficiency who were successfully treated by allogeneic HCT from alternative donors. Patient 1 underwent cord blood transplantation at the age of 16 years, and Patient 2 underwent haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide at the age of 22 years. Each patient received a fludarabine-based conditioning regimen. Their clinical manifestations, including refractory molluscum contagiosum, promptly improved post-HCT. They achieved successful engraftment and immune reconstitution without serious complications. Alternative donor sources such as cord blood and haploidentical donors can be options for allogeneic HCT for DOCK8 deficiency.

Longitudinal health-related quality of life analysis in childhood cancer survivors after proton beam therapy.

PURPOSE: Whilst proton beam therapy (PBT) for children with cancer is expected to reduce their comorbidities, to date only a limited number of studies have been published. To analyze the long-term comorbidity and health-related quality of life (HRQoL) of childhood cancer survivors (CCSs) after PBT, we conducted a questionnaire-based study. METHODS: Questionnaires were sent to CCSs who underwent PBT at the University of Tsukuba Hospital during the period from 1984 to 2020. Scores from 41 CCSs who did not undergo PBT (noPBT-CCSs) and from the general population were used for comparison. RESULTS: In total, 110 individuals who underwent PBT participated in the study. Among them, 40 individuals were longitudinally analyzed. The range of change in the scores was significantly greater in the CCSs whose initial scores were low. Although the comorbidity levels were more severe, HRQoL tended to be better in the PBT-CCSs than in the noPBT-CCSs with central nervous system (CNS) or solid tumors, respectively. When compared with the general population, the psychosocial health summary scores and its components were not different in the noPBT-CNS-CCSs. On the other hand, the psychosocial health summary scores and/or at least one of the scores of emotional, social, and school functioning were significantly higher in the other CCSs groups. CONCLUSIONS: The HRQoL scores of CCSs with low initial scores can be greatly changed over time. Appropriate psychosocial support for this population is warranted. PBT may avoid reduction in HRQoL in terms of the psychosocial functioning of CCSs with CNS tumors.

Gastrointestinal bleeding/ulcer among paediatric cancer patients after proton beam therapy.

BACKGROUND: The details of gastrointestinal bleeding/ulcer in paediatric cancer patients treated with proton beam therapy have not been reported previously. METHODS: Patients aged 15 years or younger at the time of proton beam therapy and whose gastrointestinal tract was included in the irradiated field participated. RESULTS: A total of 124 patients participated in the study; their median age at irradiation was 5.4 years. Concurrent chemotherapies were vincristine-cyclophosphamide (16 patients), irinotecan-based treatment (16 patients), vincristine-cyclophosphamide-ifosfamide-etoposide (14 patients), other chemotherapy (27 patients) and no chemotherapy (51 patients). Gastrointestinal bleeding/ulcer occurred in four patients (3.2%), with no death due to the bleeding/ulcer. The sites of the gastrointestinal bleeding/ulcer were the stomach (two patients) and the duodenum (two patients). The ages of the four patients at PBT were 5.3, 13.8, 14.2 and 14.8 years, which were significantly older than those of patients without GI bleeding/ulcer (p = 0.017). The maximum irradiated doses to the GI tract in the four patients were 43.2, 45, 50.4 and 50.4 gray equivalent, respectively. The concomitant chemotherapy was vincristine-cyclophosphamide-ifosfamide-etoposide 3 and vincristine-cyclophosphamide 1. Weeks from proton beam therapy to bleeding/ulcer were 15, 20, 22 and 264. DISCUSSION AND CONCLUSIONS: Patients who developed gastrointestinal bleeding/ulcer were treated concurrently with vincristine-cyclophosphamide-ifosfamide-etoposide or vincristine-cyclophosphamide, and their ages were older than those of patients without gastrointestinal bleeding/ulcer. Bleeding occurred in the upper gastrointestinal tract in all the cases, and most cases occurred early and during chemotherapy. Upper gastrointestinal irradiation in older children undergoing intensive chemotherapy may increase the risk of developing gastrointestinal complications.

Recovery of lymphocyte subpopulations is incomplete in the long-term setting in pediatric solid tumor survivors.

BACKGROUND: Childhood cancer survivors (CCSs) may have comorbidities including a long-term abnormality in the immune system. Immune reconstitution in CCSs after treatment for acute leukemia has been reported previously, while analyses of immune reconstitution in CCSs with solid tumors have been limited. METHODS: Childhood cancer survivors who received chemotherapy for solid tumors and who visited University of Tsukuba Hospital between November 2019 and March 2021 were included the study. Peripheral blood was collected for flow cytometry analysis. RESULTS: Forty-nine samples from 35 CCSs (18 male, 17 female) were included in the study. High-dose chemotherapy and cerebral spinal irradiation were conducted in 14 CCSs (40%) and in five CCSs (14%), respectively. The median time between the completion of chemotherapy and the collection of the present samples was 15.0 months (range, 0-286 months). The total lymphocyte count, B cells, and CD8-positive T cells recovered to the normal range of controls (NR-CTLs) in 0 (0%), four (66.7%), and four (66.7%) of six samples at 0-3 months after the completion of chemotherapy, and in three (60%), four (80%), and three (60%) of five samples at 3-12 months after the completion of chemotherapy, respectively. Meanwhile, CD4-positive T cells remained lower than NR-CTLs in 0 (0%) of six samples, one (20%) of five samples, and seven (63.7%) of 11 samples at 0-3, 3-12 and 12-60 months after the completion of chemotherapy, respectively. CONCLUSIONS: Recovery to the NR-CTLs was rapidly achieved in B cells and CD8-positive T cells, while the recovery was slower and incomplete in CD4-positive T cells. Careful observation of infection in long-term follow-up clinics is needed.

Case report: HLA-haploidentical hematopoietic cell transplant with posttransplant cyclophosphamide in a patient with leukocyte adhesion deficiency type I.

Leukocyte adhesion deficiency type I (LAD-I) is a rare autosomal recessive inborn error of immunity (IEI) caused by the defects in CD18, encoded by the ITGB2 gene. LAD-I is characterized by defective leukocyte adhesion to the vascular endothelium and impaired migration of leukocytes. Allogeneic hematopoietic cell transplant (HCT) is the only curative treatment for LAD-I. In an absence of ideal donor for HCT, human leukocyte antigen (HLA)-haploidentical HCT is performed. Posttransplant cyclophosphamide (PT-CY) is a relatively new graft-versus-host disease (GVHD) prophylactic measure and has been increasingly used in HLA-haploidentical HCT for malignant and nonmalignant diseases. However, experience in using PT-CY for rare IEIs, such as LAD-I, is very limited. We report a case of LAD-I successfully treated with HLA-haploidentical HCT with PT-CY. Complete chimerism was achieved, and the patient was cured. Her transplant course was complicated by mild GVHD, cytomegalovirus reactivation and veno-occlusive disease/sinusoidal obstruction syndrome, which were successfully treated. HLA-haploidentical HCT with PT-CY is a safe and effective option for patients with LAD-I when HLA-matched donors are unavailable.

Effect of Germline MEFV Polymorphisms on the Prognosis of Japanese Children with Cancer: A Regional Analysis.

INTRODUCTION: MEFV is the gene responsible for familial Mediterranean fever. It encodes pyrin, which controls inflammation. Besides, previous studies have reported that some germline MEFV variants were associated with tumour susceptibility. MATERIALS AND METHODS: The loci of 12 germline MEFV variants were genotyped in 153 Japanese children with cancer, and the frequencies of these variants among the patient groups were compared with those in the general Japanese population. Additionally, the relationship between these variants and clinical data, including relapse and death, was investigated. RESULTS: Minor allele frequencies did not differ between patients and the general population, or between sex, age at diagnosis, and diagnosis among patients. P369S/R408Q associated with significantly lower relapse-free survival in all patient analyses and in patients with solid tumours. Additionally, although the results were not significant, E148Q/L110P was likely to associate with worse relapse-free survival in patients with solid tumours. DISCUSSION/CONCLUSION: Despite several limitations, this study provided the novel insight that the germline MEFV variants are associated with the clinical outcome of paediatric cancer.

Managing bleeding risk after cold snare polypectomy in patients receiving direct-acting oral anticoagulants.

BACKGROUND AND AIMS: The best strategy to manage direct-acting oral anticoagulants (DOACs) for patients undergoing cold snare polypectomy remains unclear. This study compared the effect of continuing versus stopping DOACs only on the day of the procedure on bleeding after cold snare polypectomy. METHODS: This prospective, observational, single-center cohort study enrolled consecutive patients receiving antithrombotic agents and undergoing cold snare polypectomy of colorectal polyps ≤10 mm in diameter. During period 1 (2017 and 2018) antithrombotic agents including DOACs were not discontinued (DOAC continued group). In period 2 (2019 and 2020) DOACs were withheld only on the day of the procedure (DOAC withheld group) and restarted the next day after the procedure. The primary outcome was delayed bleeding requiring endoscopic treatment occurring within 2 weeks after cold snare polypectomy. Secondary outcomes were immediate bleeding and the number of hemostatic clips used. RESULTS: For the 2 groups, 204 (DOAC continued group; 34% women; mean age, 75 years) and 264 (DOAC withheld group; 36% women; mean age, 74 years) patients were enrolled. Clinical features were similar between the 2 groups. Delayed bleeding after cold snare polypectomy occurred in 4 of 47 patients (8.5%) in the DOAC continued group versus 0 of 66 (0%) in the DOAC withheld group (P < .001). Immediate postpolypectomy bleeding occurred in 12 of 47 patients (25.5%) in the DOAC continued group versus 4 of 66 (6.1%) in the DOAC withheld group (P < .008). CONCLUSIONS: Cold snare polypectomy may be safely preformed if DOACs are withheld only on the day of the procedure. (Clinical trial registration number: NCT02594813.).

Cancer-Predisposition Genetic Analysis in Children with Brain Tumors Treated at a Single Institution in Japan.

Brain tumors affect one-third of all children with cancer. Approximately 10% of children with cancer carry variants in cancer-predisposition genes. However, germline analyses in large cohorts of Asian children have not been reported. Thirty-eight Japanese patients with pediatric brain tumors were included in this study (19 boys, 19 girls). DNA was extracted from the patients' peripheral blood, and cancer-associated genes were analyzed using targeted resequencing. Rare variants with allele frequencies <0.1% in the general population and variants suspected to be pathogenic were extracted and analyzed. Pathogenic variants were found in 7 patients (18%): 2 nonsense variants of CHEK2 and FANCI; 2 frameshift deletions in SMARCB1 and PTCH1; and 3 missense variants of TSC1, WRN, and MLH1. The median age at diagnosis was 9.1 years, and three of the 7 patients had a family history of cancer. One patient diagnosed with basal cell nevus syndrome, also called Gorlin syndrome, developed a second neoplasm, and another with an SMARCB1 variant and an atypical teratoid/rhabdoid tumor developed a thyroid adenomatous nodule. This is the first cancer-related germline analysis with detailed clinical information reported in Japanese children with brain tumors. The prevalence was almost equivalent to that in white children.

Successful hematopoietic stem cell transplantation with reduced dose of busulfan for Omenn syndrome.

Omenn syndrome (OS) is typically observed in the autosomal recessive form of severe combined immunodeficiency (SCID) with autoreactive manifestations, and it requires allogeneic hematopoietic stem cell transplantation. Unlike non-OS SCID, a conditioning regimen is usually required to eradicate T-cells; however, optimal conditioning regimens are not established mainly because of the rarity of OS. Here, we report a case of hematopoietic stem cell transplantation with a reduced dose of busulfan, as a conditioning regimen and successful engraftment with complete chimerism. OS was diagnosed in a one-month-old boy based on a diffuse erythematous rash, absent B-cells, and activated T-cells. Genetic analysis failed to identify causative mutations for OS/SCID, such as RAG1/2. Bone marrow transplantation was performed from his HLA-matched sister with a conditioning regimen consisting of targeted busulfan, fludarabine, and anti-thymocyte globulin. Cyclosporine had been administered before transplantation to control abnormal T-cell activation and continued for graft-versus-host disease (GVHD) prophylaxis. Engraftment was achieved on day 12, and no GVHD symptoms were observed. For stem cell transplantation for OS, prior control of autoreactive symptoms with immunosuppressants is important for safe transplantation and reduced intensity conditioning (RIC) can be an option to achieve sustained engraftment.

A novel BMPR1A mutation affects mRNA splicing in juvenile polyposis syndrome.

BACKGROUND: Juvenile polyposis syndrome (JPS) is one of the hereditary polyposis syndromes caused by abnormal regulation of transforming growth factor ß signaling because of mutations in BMPR1A and SMAD4. Juvenile polyposis syndrome patients with SMAD4 mutations develop cardiovascular events, whereas those with BMPR1A usually do not. Analysis of genetic mutations in JPS patients can be helpful in devising suitable strategies for medical management. In this study, we demonstrate the pathogenicity of a novel intronic mutation in BMPR1A using mRNA extracted from colonic mucosa of a boy with JPS. METHODS: Genomic DNA extracted from peripheral blood and total RNA isolated from the colonic mucosa were used for DNA sequencing and reverse transcription polymerase chain reaction (RT-PCR) analyses, respectively. RESULTS: A 13-year-old boy, with no previous medical history, presented to the hospital complaining of bloody stools. Colonoscopy revealed multiple polyps in the colon, and the resected polyps were compatible with juvenile polyps. Sequencing analysis revealed a novel intronic mutation (c.778+5G>C) in BMPR1A. Reverse transcription polymerase chain reaction analysis of RNA extracted from the colonic mucosa showed an aberrant splicing form of BMPR1A. Trio analysis showed that his mother also had the same BMPR1A mutation. She was diagnosed with cancer of the cecum and polyposis of the colon at the age of 41. CONCLUSION: We demonstrate the presence of a novel BMPR1A intronic mutation that exhibits splicing abnormality in a family with JPS. Further research and development will help elucidate the genotype-phenotype relationship in JPS.