Acquisition of monosomy 7 and a RUNX1 mutation in Pearson syndrome.

Pearson syndrome (PS) is a very rare and often fatal multisystem disease caused by deletions in mitochondrial DNA that result in sideroblastic anemia, vacuolization of marrow precursors, and pancreatic dysfunction. Spontaneous recovery from anemia is often observed within several years of diagnosis. We present the case of a 4-month-old male diagnosed with PS who experienced prolonged severe pancytopenia preceding the emergence of monosomy 7. Whole-exome sequencing identified two somatic mutations, including RUNX1 p.S100F that was previously reported as associated with myeloid malignancies. The molecular defects associated with PS may have the potential to progress to advanced myelodysplastic syndrome .

Prognostic and therapeutic factors influencing the clinical outcome of metastatic Ewing sarcoma family of tumors: A retrospective report from the Japan Ewing Sarcoma Study Group.

BACKGROUND: The prognosis of patients with metastatic Ewing sarcoma family of tumors (ESFT) remains poor. PROCEDURE: We retrospectively analyzed 57 patients diagnosed with metastatic ESFT between 2000 and 2018 to identify prognostic and therapeutic factors affecting the clinical outcome. RESULTS: The 3-year overall survival (OS) rate of the entire cohort was 46.8% (95% confidence interval [CI], 33.0-59.4%). Treatment-related death was not observed. Multivariate analysis identified stem cell transplantation (SCT), response to first-line chemotherapy, and bone metastasis as independent risk factors for OS. Objective response rate to first-line chemotherapy was 65.1% in the 43 evaluable patients. There was no significant difference in the response to different types of first-line chemotherapy. Among patients with lung metastasis alone, the 3-year OS rate was higher in 13 patients who received local treatment than in four who did not, although the difference was not significant. CONCLUSIONS: One possible reason for the high OS rates was the absence of treatment-related mortality even in patients receiving SCT, which could be attributed to advances in the management of post-SCT complications. Novel first-line chemotherapy strategies need to be established to improve the disease status prior to SCT in a higher proportion of patients.

[Transplantation-associated thrombotic microangiopathy confirmed by renal biopsy].

An eight-year-old girl with myelodysplastic syndrome (refractory cytopenia) received a bone marrow transplant (BMT) from an unrelated donor because of immunosuppressive therapy failure. Following administration of foscarnet for cytomegalovirus reactivation at day40 post-BMT, serum creatinine increased, and proteinuria, hematuria, and hypertension gradually exacerbated and became prolonged. However, neither schistocytosis nor other organ damage was evident. At six months post-BMT, renal biopsy revealed diffuse glomerular damage with glomerular lobulation, a double contour of the glomerular basement membrane, erythrocyte congestion and thrombi in the glomerular endocapillaries, and mesangiolysis, confirming the diagnosis of transplantation-associated thrombotic microangiopathy (TA-TMA). We initiated strict controls regarding fluid balance, salt intake, and blood pressure. The patient's renal function improved 10 months post-BMT. TA-TMA often presents as non-specific symptoms, making diagnosis difficult. In cases of post-transplant renal damage, TA-TMA should be differentiated regardless of whether specific symptoms such as hemolytic anemia and other organ failure are evident, and a renal biopsy should, therefore, be considered.

Infantile fibrosarcoma treated with postoperative vincristine and dactinomycin.

Infantile fibrosarcoma is a non-rhabdomyosarcoma soft-tissue sarcoma that occurs in infancy and which has a relatively good prognosis. A vincristine and dactinomycin (VA) regimen has been shown to be effective, although the duration of chemotherapy has not been well defined. We describe the case of a 4-month-old boy with a mass at the left dorsum of the foot who was diagnosed with infantile fibrosarcoma after resection of the tumor, the margin of which was macroscopically positive. VA treatment was carried out with careful monitoring of response and adverse effects. Pancytopenia was seen during the second cycle, and therapy was reduced thereafter. The treatment was continued for 38 weeks (12 cycles). There was no functional impairment, and no evidence of recurrence at 18 months after therapy.

Chemotherapy for a child with relapsed acute myeloid leukemia complicated with persistent hepatitis C virus infection.

An 8-year-old Mongolian female was diagnosed with acute myeloid leukemia (AML) and treated at a hospital in Mongolia according to the BFM-AML2004 SR protocol. Although complete remission (CR) was achieved, chemotherapy was interrupted because of shortage of drugs. The patient moved to Japan 7 months after diagnosis. Screening for viral infection revealed the presence of hepatitis C virus (HCV) antibody and RNA. At 11 months after initial diagnosis, the patient experienced bone marrow relapse and a RUNX1-RUNX1T1 fusion transcript was detected. Considering the inadequate intensity of initial treatment and the persistent HCV infection, chemotherapy was preferred and initiated over hematopoietic cell transplantation. After the first course of induction therapy, a second CR was confirmed and the chimeric transcript disappeared. The viral load mildly increased during myelosuppression and transient elevation of liver enzymes was observed along with hematological recovery. HCV infection remained stable, without progression to reactivation of hepatitis C. Given the high risk of second relapse and liver fibrosis and sclerosis following chronic HCV infection, treatment against HCV may be indicated during second remission.

Ewing sarcoma/primitive neuroectodermal tumor of the kidney treated with chemotherapy including ifosfamide.

Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) of the kidney is extremely rare, and is usually diagnosed after nephrectomy without neoadjuvant chemotherapy. Although ifosfamide and etoposide improve survival to a great extent in ES/PNET, the use of nephrotoxic agent, particularly ifosfamide, is a concern after nephrectomy. We describe the case of a 14-year-old female patient with abdominal mass who was diagnosed with ES/PNET of the right kidney after nephrectomy. Adjuvant chemotherapy including ifosfamide and etoposide were given. The estimated glomerular filtration rate decreased to 75% after the end of therapy. There was no evidence of recurrence 70 months after initial diagnosis.

Severe 6-mercaptopurine-induced hematotoxicity in childhood an ALL patient with homozygous NUDT15 missence variants.

Thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants are considered to be genes responsible for severe myelotoxicity induced by 6-mercaptopurine (6MP). We report a 4-year-old girl with acute lymphoblastic leukemia, who developed the complication of severe 6MP-induced myelotoxicity due to homozygous NUDT15 variant alleles. In early consolidation therapy containing 6MP, her course was complicated by severe neutropenia (Grade 4) and chemotherapy had to be discontinued for 33 days. The 6MP dose was subsequently adjusted based on the white blood cell count. The ratios of the prescribed 6MP dose over the protocol dose in early consolidation, central nervous system (CNS) prophylaxis, re-induction, interim maintenance and maintenance therapy were 63%, 27%, 4%, 26% and 7%, respectively. Suspension of therapy was required during early consolidation, CNS prophylaxis and interim maintenance therapy. We investigated candidate genes for 6MP-associated myelotoxicity and found homozygous NUDT15 variant alleles and a heterozygous inosine triphosphate pyrophosphatase (ITPA) variant allele. In patients with homozygous NUDT15 variants, drastic reduction (less than 10%) of the 6MP dose from the protocol dose might be required not only during maintenance therapy, but also during other treatment courses containing 6MP. Screening of candidate genes at diagnosis is recommended in order to avoid serious adverse events.

Myelopathy mimicking subacute combined degeneration in a Down syndrome patient with methotrexate treatment for B lymphoblastic leukemia: report of an autopsy case.

We report clinicopathological features of a 23-year-old woman with Down syndrome (DS) presenting with subacute myelopathy treated with chemotherapy, including intravenous and intrathecal administration of methotrexate (MTX), and with allogenic bone-marrow transplantation for B lymphoblastic leukemia. Autopsy revealed severe demyelinating vacuolar myelopathy in the posterior and lateral columns of the spinal cord, associated with macrophage infiltration, marked axonal loss and some swollen axons. Pathological changes of posterior and lateral columns were observed from the medulla oblongata to lumbar cord. Proximal anterior and posterior roots were preserved. Cerebral white matter was relatively well preserved. There were no vascular lesions or meningeal dissemination of leukemia. Longitudinal extension of cord lesions was extensive, unlike typical cases of subacute combined degeneration (SACD), but distribution of lesions and histological findings were similar to that of SACD. DS patients show heightened sensitivity to MTX because of their genetic background. Risk factors for toxic myelopathy of DS are discussed, including delayed clearance of MTX despite normal renal function, alterations in MTX polyglutamation and enhanced folic acid depletion due to gene dosage effects of chromosome 21. Alteration of folate metabolism and/or vitamin B12 levels through intravenous or intrathecal administration of MTX might exist, although vitamin B12 and other essential nutrients were managed using intravenous hyperalimentation. To the best of our knowledge, this is the first report of an autopsy case that shows myelopathy mimicking SACD in a DS patient accompanied by B lymphoblastic leukemia. The case suggests a pathophysiological mechanism of MTX-related myelopathy in DS patients with B lymphoblastic leukemia mimicking SACD.

Dosimetric Comparison of 3D Conformal Radiotherapy (3D-CRT), Intensity-Modulated Radiotherapy (IMRT), and Volumetric-Modulated Arc Therapy (VMAT) in Cardiac-Sparing Whole Lung Irradiation.

Introduction Whole lung irradiation (WLI) is used for the treatment of lung metastasis in Wilms tumor and Ewing sarcoma; however, cardiac complications are one of the concerns. We report the dosimetric advantages of WLI using volumetric-modulated arc therapy (VMAT) and present a dosimetric comparison of VMAT with anteroposterior-posteroanterior (AP-PA) and static-field intensity-modulated radiation therapy (IMRT). Additionally, we evaluated the dosimetric impact of respiratory motion and intra-fractional motion during VMAT treatment. Methods Seven patients were recruited in this study. AP-PA, IMRT, one-isocenter (1-IC) VMAT, and 2-IC VMAT were planned on the maximum inspiration and expiration CT, respectively. The prescribed dose was 15 Gy in 10 fractions. To determine the effects of respiratory motion, the CT series was replaced and the dose was evaluated while maintaining the beam information. To determine the effect of patient motion, perturbed dose calculations were performed using a two-IC VMAT. The perturbation doses were calculated by shifting only the IC of the one side beam by 3 mm or 5 mm in the right-to-left (RL) direction. Results The mean heart dose was 1467.0 cGy, 790.0 cGy, 764.2 cGy, and 738.4 cGy for AP-PA, IMRT, 1-IC VMAT, and 2-IC VMAT, respectively. When the expiration CT plan was recalculated with inspiration CT, Dmax increased approximately by 8%. In the 2-IC VMAT plan, the D50%, D98%, and D2% dose differences were within ±2%, even with a 5 mm IC shift. Conclusion We confirmed a significant dosimetric advantage of VMAT over other techniques. 2-IC VMAT should be considered an effective treatment option during irradiation for large target volumes.

Significance of active screening for detection of health problems in childhood cancer survivors.

Background: Childhood cancer survivors (CCSs) have a lifelong increased risk of chronic health problems, most of which are associated with the curative therapies. Recent studies have suggested that prospective active screening using comprehensive assessments for CCSs is superior in identifying undiagnosed chronic health problems. Methods: To assess the significance of active screening using comprehensive medical examinations for detecting chronic health problems in multiple organ systems in CCSs, we retrospectively compared the frequency and severity of health problems between two different cohorts of CCSs in a single institution: 110 CCSs who visited the outpatient clinic for regular follow-ups between December 2010 and December 2015 (regular follow-up group) vs. 58 CCSs who underwent comprehensive medical examinations between February 2016 and September 2019 (active screening group). CCSs were defined as patients aged ≥ 18 years who had been diagnosed as having childhood cancer ≥ 10 years before and had survived without cancer for ≥ 5 years. Results: Patient characteristics were similar between the two groups except for primary diagnosis (more brain tumors and embryonal tumors in the active screening group) and treatment history (more alkylating agents used and surgical interventions performed in the active screening group). The prevalence and the median number of health problems were significantly higher in the active screening group than in the regular follow-up group: 93% vs. 67% and 1.0 [0.0-8.0] vs. 2.0 [0.0-7.0] respectively. In term of organ-specific health problems, pulmonary dysfunction, neurocognitive impairment, ocular abnormalities, and dental abnormalities were identified more in the active screening group, partly because these problems had not been assessed in the regular follow-up group. Nevertheless, the prevalence of grade 3-5 health problems was similar between the two groups, except for pulmonary dysfunction. Conclusion: Active screening using comprehensive medical examinations was effective for identifying health problems in CCSs. Although the prevalence of severe problems identified by both approaches was similar, comprehensive medical examinations could detect overlooked problems such as severe pulmonary dysfunction, dental maldevelopment, and borderline intellectual functioning, which might have an impact on quality of life in CCSs.

Factors related to employment in childhood cancer survivors in Japan: A preliminary study.

Purpose: Previous research has revealed vocational and academic difficulties in childhood cancer survivors, and explored impact of survivors' medical history and physical function on vocational and academic status. However, we often encounter survivors with similar diagnoses and late effects but different academic or employment statuses. This raises the question of what affects academic attainment and employment other than treatment or late effects. This study aimed to explore factors associated with childhood cancer survivors' employment status and academic achievement. Methods: Comprehensive health check-up and questionnaire survey were conducted for 69 survivors who were over the age of 18 and participated in St. Luke's Lifetime cohort study. We obtained survivors' biological function using comprehensive health check-up, neurocognitive states, quality of life, transition readiness, and family function. We conducted univariate analysis (Mann-Whitney U tests or chi-square tests) to compare the differences between the regular workers/students and non-regular workers/unemployed groups. The variables with p-values <0.1 were used as independent variables multivariate logistic regression to explore predictors of employment status and academic attainment. Results: Result of the univariate analysis, intelligence quotient, SF-8 PCS, transition readiness, family function were used for multivariate logistic regression as independent variables. The stepwise likelihood method was conducted; intelligence quotient (odds ratio [OR] = 1.100; 95% confidence interval [CI] 1.015-1.193; p = 0.021), transition readiness (OR = 0.612; 95% CI 0.396-0.974; p = 0.038), and family function (OR = 2.337; 95% CI 1.175-4.645; p = 0.015) were found to be associated with survivors' regular workers/students in the final regression model. Conclusion: Long-term follow-up of pediatric cancer survivors requires the provision of total care, which supports physical, psychological, and social functions to improve health, readiness for transition to self-management, and family functioning.

Ruxolitinib for hematopoietic cell transplantation-associated hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a severe complication after allogeneic hematopoietic cell transplantation (HCT) and can cause graft failure or multi-organ failure. Here, we report two children with refractory HCT-associated HLH treated with ruxolitinib. In the first patient, ruxolitinib resolved fever, cytopenia and hyperferritinemia. In another patient, although severe hepatic failure, which developed and worsened before the administration of ruxolitinib, was irreversible, rapid improvement in fever, leukopenia and hyperferritinemia was observed. Of note, multiplex cytokine profiling showed amelioration of cytokine storm in both patients. Ruxolitinib may be an encouraging option for HCT-associated HLH.