ABSTRACT
The results of observational studies using real-world data, known as real-world evidence, have gradually started to be used in drug development and decision-making by policymakers. A good quality management system-a comprehensive system of process, data, and documentation to ensure quality-is important in obtaining real-world evidence. A risk-based approach is a common quality management system used in interventional studies. We used a quality management system and risk-based approach in an observational study on a designated intractable disease. Our multidisciplinary team assessed the risks of the real-world data study comprehensively and systematically. When using real-world data and evidence to support regulatory decisions, both the quality of the database and the validity of the outcome are important. We followed the seven steps of the risk-based approach for both database selection and research planning. We scored the risk of two candidate databases and chose the Japanese National Database of designated intractable diseases for this study. We also conducted a quantitative assessment of risks associated with research planning. After prioritizing the risks, we revised the research plan and outcomes to reflect the risk-based approach. We concluded that implementing a risk-based approach is feasible for an observational study using real-world data. Evaluating both database selection and research planning is important. A risk-based approach can be essential to obtain robust real-world evidence.
ABSTRACT
BACKGROUND: The molecular pathogenesis of acute myeloid leukemia (AML) was dramatically clarified over the latest two decades. Several important molecular markers were discovered in patients with AML that have helped to improve the risk stratification. However, developing new treatment strategies for relapsed/refractory acute myeloid leukemia (AML) is crucial due to its poor prognosis. PROCEDURE: To overcome this difficulty, we performed an assay for transposase-accessible chromatin with sequencing (ATAC-seq) in 10 AML patients with various gene alterations. ATAC-seq is based on direct in vitro sequencing adaptor transposition into native chromatin, and is a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq analysis revealed increased accessibility of the DOCK1 gene in patients with AML harboring poor prognostic factors. Following the ATAC-seq results, quantitative reverse transcription polymerase chain reaction was used to measure DOCK1 gene expression levels in 369 pediatric patients with de novo AML. RESULTS: High DOCK1 expression was detected in 132 (37%) patients. The overall survival (OS) and event-free survival (EFS) among patients with high DOCK1 expression were significantly worse than those patients with low DOCK1 expression (3-year EFS: 34% vs. 60%, p < .001 and 3-year OS: 60% vs. 80%, p < .001). To investigate the significance of high DOCK1 gene expression, we transduced DOCK1 into MOLM14 cells, and revealed that cytarabine in combination with DOCK1 inhibitor reduced the viability of these leukemic cells. CONCLUSIONS: Our results indicate that a DOCK1 inhibitor might reinforce the effects of cytarabine and other anti-cancer agents in patients with AML with high DOCK1 expression.
Subject(s)
Biomarkers, Tumor , Leukemia, Myeloid, Acute , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Child , Male , Female , Prognosis , Child, Preschool , Adolescent , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Infant , Survival Rate , Follow-Up Studies , East Asian People , rac GTP-Binding ProteinsABSTRACT
BACKGROUND AIMS: This study aimed to comprehensively assess the impact of stem cell selection between bone marrow (BM) and peripheral blood (PB) in unrelated hematopoietic stem cell transplantation (HSCT) for hematological malignancies. Our objective was to identify specific factors associated with better transplant outcomes. METHODS: A retrospective analysis was conducted using data from the Japanese HSCT registry. Inclusion criteria were patients aged 0-70 years who underwent their first unrelated HSCT with BM or PB, with an 8/8 or 7/8 allele HLA match for hematological malignancies between 2010 and 2020. RESULTS: Among 10 295 patients, no significant difference was observed in overall survival, relapse, graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) or non-relapse mortality between the groups. Patients who received PB showed no clear difference in acute GVHD but had a greater rate of chronic GVHD, resulting in poor chronic GVHD-free, relapse-free survival (CRFS). Subgroup analyses highlighted the importance of patient-specific factors in source selection. Patients with non-Hodgkin lymphoma and a greater hematopoietic cell transplantation-comorbidity index showed better CRFS and GRFS when BM was the preferred source. Similar trends were observed among patients with standard-risk disease for CRFS. However, no such trends were evident among patients aged 0-24 years, indicating that both sources are viable choices for young patients. CONCLUSIONS: This real-world retrospective analysis showed similar basic outcomes for BM and PB in an unrelated setting. The results support that BM may still be preferred over PB, especially when the long-term quality of life is a major concern. A consideration of individual factors can further optimize transplant success. Further research is warranted to explore the long-term implications of stem cell source selection.
Subject(s)
Graft vs Host Disease , Hematologic Neoplasms , Hematopoietic Stem Cell Transplantation , Peripheral Blood Stem Cell Transplantation , Peripheral Blood Stem Cells , Humans , Bone Marrow , Bone Marrow Transplantation/methods , Retrospective Studies , Japan , Quality of Life , Neoplasm Recurrence, Local/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Hematologic Neoplasms/therapy , Graft vs Host Disease/etiology , Graft vs Host Disease/therapy , Peripheral Blood Stem Cell Transplantation/methodsABSTRACT
BACKGROUND: Cisplatin is commonly used to treat solid tumors; however, its use can be complicated by drug-induced hearing loss (ie, ototoxicity). The presence of certain genetic variants has been associated with the development/occurrence of cisplatin-induced ototoxicity, suggesting that genetic factors may be able to predict patients who are more likely to develop ototoxicity. The authors aimed to review genetic associations with cisplatin-induced ototoxicity and discuss their clinical relevance. METHODS: An updated systematic review was conducted on behalf of the Canadian Pharmacogenomics Network for Drug Safety, based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 statement. Pharmacogenomic studies that reported associations between genetic variation and cisplatin-induced ototoxicity were included. The evidence on genetic associations was summarized and evaluated, and knowledge gaps that can be used to inform future pharmacogenomic studies identified. RESULTS: Overall, 40 evaluated reports, considering 47 independent patient populations, captured associations involving 24 genes. Considering GRADE criteria, genetic variants in 2 genes were strongly (ie, odds ratios ≥3) and consistently (ie, replication in ≥3 independent populations) predictive of cisplatin-induced ototoxicity. Specifically, an ACYP2 variant has been associated with ototoxicity in both children and adults, whereas TPMT variants are relevant in children. Encouraging evidence for associations involving several other genes also exists; however, further research is necessary to determine potential clinical relevance. CONCLUSIONS: Genetic variation in ACYP2 and TPMT may be helpful in predicting patients at the highest risk of developing cisplatin-induced ototoxicity. Further research (including replication studies considering diverse pediatric and adult patient populations) is required to determine whether genetic variation in additional genes may help further identify patients most at risk.
Subject(s)
Antineoplastic Agents , Ototoxicity , Adult , Humans , Child , Cisplatin/adverse effects , Antineoplastic Agents/adverse effects , Pharmacogenetics , Ototoxicity/genetics , Ototoxicity/drug therapy , Canada , AcylphosphataseABSTRACT
Autoimmune lymphoproliferative syndrome (ALPS) is a disease of lymphocyte homeostasis caused by FAS-mediated apoptotic pathway dysfunction and is characterized by non-malignant lymphoproliferation with an increased number of TCRαß+CD4-CD8- double-negative T cells (αßDNTs). Conversely, RAS-associated leukoproliferative disease (RALD), which is caused by gain-of-functional somatic variants in KRAS or NRAS, is considered a group of diseases with a similar course. Herein, we present a 7-year-old Japanese female of RALD harboring NRAS variant that aggressively progressed to juvenile myelomonocytic leukemia (JMML) with increased αßDNTs. She eventually underwent hematopoietic cell transplantation due to acute respiratory distress which was caused by pulmonary infiltration of JMML blasts. In general, αßDNTs have been remarkably increased in ALPS; however, FAS pathway gene abnormalities were not observed in this case. This case with RALD had repeated shock/pre-shock episodes as the condition progressed. This shock was thought to be caused by the presence of a high number of αßDNTs. The αßDNTs observed in this case revealed high CCR4, CCR6, and CD45RO expressions, which were similar to Th17. These increased Th17-like αßDNTs have triggered the inflammation, resulting in the pathogenesis of shock, because Th17 secretes pro-inflammatory cytokines such as interleukin (IL)-17A and granulocyte-macrophage colony-stimulating factor. The presence of IL-17A-secreting αßDNTs has been reported in systemic lupus erythematosus (SLE) and Sjögren's syndrome. The present case is complicated with SLE, suggesting the involvement of Th17-like αßDNTs in the disease pathogenesis. Examining the characteristics of αßDNTs in RALD, JMML, and ALPS may reveal the pathologies in these cases.
Subject(s)
Autoimmune Lymphoproliferative Syndrome , Lupus Erythematosus, Systemic , Lymphoproliferative Disorders , Female , Humans , Child , Autoimmune Lymphoproliferative Syndrome/diagnosis , Autoimmune Lymphoproliferative Syndrome/genetics , CD4-Positive T-Lymphocytes , Receptors, Antigen, T-Cell, alpha-beta/geneticsABSTRACT
Fatal cardiac complications can occur from the early to late phases after hematopoietic cell transplantation (HCT). Herein, the Japanese transplant registry database was used to retrospectively analyze health records of 33,791 allogeneic HCT recipients to elucidate the pathogenesis and risk factors involved. Overall, 527 patients died of cardiac complications at a median of 130 (range 0-3924) days after HCT. The cumulative incidence of fatal cardiac complications was 1.2% (95% confidence interval [CI]: 1.0-1.3) and 1.6% (95% CI: 1.5-1.8) at 1 and 5 years after HCT, respectively. Fatal cardiovascular events were significantly associated with an HCT-specific comorbidity index (HCT-CI) score of ≥1 specific to the three cardiovascular items, lower performance status, conditioning regimen cyclophosphamide dose of >120 mg/kg, and female sex. Cardiovascular death risk within 60 days after HCT was associated with the type of conditioning regimen, presence of bacterial or fungal infections at HCT, and number of blood transfusions. Contrastingly, late cardiovascular death beyond 1 year after HCT was associated with female sex and older age. Lower performance status and positive cardiovascular disease-related HCT-CI were risk factors for cardiac complications in all phases after HCT. Systematic follow-up may be necessary according to the patients' risk factors and conditions.
Subject(s)
East Asian People , Hematopoietic Stem Cell Transplantation , Female , Humans , Cyclophosphamide/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Retrospective Studies , Risk Factors , Transplantation Conditioning/adverse effects , MaleABSTRACT
Hypertrophic pachymeningitis (HP) is a rare inflammatory disorder characterised by local or diffuse thickening of the cranial and spinal dura mater. HP occurs owing to idiopathic or secondary causes, including autoimmune disease, infection, and trauma. HP has mainly been reported in adults, with few reported cases in children. We encountered an 11-year-old boy with idiopathic HP who presented with chronic inflammation and daily occipital headache. Gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) helped us to diagnose him with HP. He was successfully treated with corticosteroids and azathioprine with no recurrence. We also conducted a literature review of childhood-onset HP and found only 16 cases, including our patient. Seven patients had idiopathic HP, and the remaining nine had secondary HP, including two with rheumatic disease. The most common clinical symptoms were headache (68.8%) and cranial nerve-related symptoms (68.8%). Inflammatory laboratory markers were elevated in 60% of patients with available data. Fifteen cases were diagnosed using Gd-enhanced MRI. The main initial treatment was steroids and/or immunosuppressants, to which 87.5% of patients responded. However, two patients with HP associated with trauma and neuroblastoma (12.5%) died, and seven patients (43.8%) had left cranial nerve-related sequelae. As the prognosis for childhood HP is poor, early diagnosis and treatment are essential. Children with headache, cranial nerve symptoms, and elevated inflammatory marker levels should be suspected of having HP and Gd-enhanced MRI should be considered.
Subject(s)
Meningitis , Male , Adult , Humans , Child , Meningitis/diagnosis , Meningitis/etiology , Meningitis/drug therapy , Headache/etiology , Adrenal Cortex Hormones/therapeutic use , Immunosuppressive Agents/therapeutic use , Diagnosis, Differential , Hypertrophy/diagnosisABSTRACT
Mutations in the MECOM encoding EVI1 are observed in infants who have radioulnar synostosis with amegakaryocytic thrombocytopenia. MECOM-associated syndrome was proposed based on clinical heterogeneity. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for progressive bone marrow failure. However, data regarding allogeneic HSCT for this rare disease are limited. We retrospectively assessed overall survival, conditioning regimen, regimen-related toxicities and long-term sequelae in six patients treated with allogeneic HSCT. All patients received a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, cyclophosphamide or melphalan, and rabbit anti-thymocyte globulin and/or low-dose total body/thoracic-abdominal/total lymphoid irradiation, followed by allogeneic bone marrow or cord blood transplantation from unrelated donors between 4 and 18 months of age. All patients survived and achieved stable engraftment and complete chimerization with the donor type. Moreover, no patient experienced severe regimen-related toxicities, and only lower grades of acute graft-versus-host disease were observed. Three patients treated with low-dose irradiation had relatively short stature compared to three patients not treated with irradiation. Therefore, allogeneic HSCT with RIC is an effective and feasible treatment for infants with MECOM-associated syndrome. Future studies are needed to evaluate the use of low-dose irradiation to avoid risks of other long-term sequelae.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Humans , Retrospective Studies , Transplantation, Homologous , Hematopoietic Stem Cell Transplantation/adverse effects , Bone Marrow , Transcription Factors , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Graft vs Host Disease/drug therapy , Unrelated Donors , Transplantation Conditioning , Vidarabine/therapeutic use , MDS1 and EVI1 Complex Locus ProteinABSTRACT
PURPOSE: Hematopoietic cell transplantation (HCT) is a curative therapy for most patients with inborn errors of immunity (IEI). We conducted a nationwide study on HCT for patients with IEI other than severe combined immunodeficiency (non-SCID) in Japan. METHODS: Data from the Japanese national database (Transplant Registry Unified Management Program, TRUMP) for 566 patients with non-SCID IEI, who underwent their first HCT between 1985 and 2016, were retrospectively analyzed. RESULTS: The 10-year overall survival (OS) and event-free survival (EFS) were 74% and 64%, respectively. The 10-year OS for HCT from unrelated bone marrow (URBM), accounting for 39% of HCTs, was comparable to that for HCT from matched sibling donor (MSD), 79% and 81%, respectively. HCT from unrelated cord blood (URCB), accounting for 28% of HCTs, was also common, with a 10-year OS of 69% but less robust engraftment. The intensity of conditioning was not associated with OS or neutrophil recovery; however, myeloablative conditioning was more frequently associated with infection-related death. Patients who received myeloablative irradiation showed poor OS. Multivariate analyses revealed that HCT in 1985-1995 (hazard ratio [HR], 2.0; P = 0.03), URCB (HR, 2.0; P = 0.01), and related donor other than MSD (ORD) (HR, 2.9; P < 0.001) were associated with poor OS, and URCB (HR, 3.6; P < 0.001) and ORD (HR, 2.7; P = 0.02) showed a higher incidence of retransplantation. CONCLUSIONS: We present the 1985-2016 status of HCT for non-SCID IEI in Japan with sufficient statistical power, highlighting the potential of URBM as an alternative donor and the feasibility of reduced intensity conditioning.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Severe Combined Immunodeficiency , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Japan/epidemiology , Retrospective Studies , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/epidemiology , Severe Combined Immunodeficiency/therapy , Transplantation Conditioning/adverse effectsABSTRACT
Anthracyclines are widely used as part of chemotherapeutic regimens in paediatric oncology patients. The most serious adverse drug reaction caused by anthracycline use is cardiotoxicity, a serious condition that can lead to cardiac dysfunction and subsequent heart failure. Both clinical and genetic factors contribute to a patient's risk of experiencing anthracycline-induced cardiotoxicity. In particular, genetic variants in RARG, UGT1A6 and SLC28A3 have been consistently shown to influence an individual's risk of experiencing this reaction. By combining clinical and genetic risks, decision-making can be improved to optimize treatment and prevent potentially serious adverse drug reactions. As part of a precision medicine initiative, we used pharmacogenetic testing, focused on RARG, UGT1A6 and SLC28A3 variants, to help predict an individual's risk of experiencing anthracycline-induced cardiotoxicity. Pharmacogenetic results are currently being used in clinical decision-making to inform treatment regimen choice, anthracycline dosing and decisions to initiate cardioprotective agents. In this case series, we demonstrate examples of the impact of genetic testing and discuss its potential to allow patients to be increasingly involved in their own treatment decisions.
Subject(s)
Anthracyclines/administration & dosage , Antibiotics, Antineoplastic/administration & dosage , Cardiotoxicity/etiology , Neoplasms/drug therapy , Adolescent , Anthracyclines/adverse effects , Antibiotics, Antineoplastic/adverse effects , Cardiotoxicity/genetics , Child , Female , Glucuronosyltransferase/genetics , Humans , Infant , Male , Membrane Transport Proteins/genetics , Pharmacogenetics , Pharmacogenomic Testing , Receptors, Retinoic Acid/genetics , Risk Factors , Retinoic Acid Receptor gammaABSTRACT
Pineal parenchymal tumor of intermediate differentiation (PPTID) is a WHO grade II and III tumor arising from pineal parenchymal cells. PPTID is a rare tumor accounting for less than 1% of all primary central nervous system neoplasms. Therefore, reports describing the clinical characteristics and biological features of PPTID are lacking. Moreover, the therapeutic strategy remains controversial. The current study aimed to evaluate treatment results and problems of contemporary therapeutic modalities of PPTID based on its features compared with other pineal parenchymal tumors. A comprehensive systematic literature review of 69 articles was performed, including articles on PPTID (389 patients) and similar tumors. Patient demographics, disease presentation, imaging characteristics, biological features, and current therapeutic options and their results were reviewed. We found that histopathological findings based on current WHO classification are well associated with survival; however, identifying and treating aggressive PPTID cases with uncommon features could be problematic. A molecular and genetic approach may help improve diagnostic accuracy. Therapeutic strategy, especially for grade III and aforementioned uncommon and aggressive tumors, remains controversial. A combination therapy involving maximum tumor resection, chemotherapy, and radiotherapy could be the first line of treatment. However, although challenging, a large prospective study would be required to identify ways to improve the clinical results of PPTID treatment.
Subject(s)
Brain Neoplasms , Pineal Gland , Pinealoma , Brain Neoplasms/diagnosis , Brain Neoplasms/pathology , Brain Neoplasms/therapy , Combined Modality Therapy , Humans , Pineal Gland/surgery , Pinealoma/diagnosis , Pinealoma/surgery , Prospective StudiesABSTRACT
This article summarizes the background, content and outcomes of a special meeting that was convened among oncologists and scientists to discuss the role of pharmacogenetic (PGx) testing in pediatric clinical oncology practice. This meeting provided an opportunity for what the lead author (AM Issa) refers to as the 'voice of the clinician' dynamic to be amplified in order to better understand how personalized or precision medicine applications such as PGx testing are adopted and incorporated into clinical settings and what we can learn from the experiences of current and ongoing implementation PGx approaches to further the implementation of precision medicine applications in real-world environments. Group dynamics and clinical experience with PGx testing and return of results shaped the discussion.
Subject(s)
Neoplasms , Pharmacogenetics , Child , Humans , Medical Oncology , Neoplasms/drug therapy , Neoplasms/genetics , Pharmacogenomic Testing , Precision MedicineABSTRACT
The clinical implementation of pharmacogenetic biomarkers continues to grow as new genetic variants associated with drug outcomes are discovered and validated. The number of drug labels that contain pharmacogenetic information also continues to expand. Published, peer-reviewed clinical practice guidelines have also been developed to support the implementation of pharmacogenetic tests. Incorporating pharmacogenetic information into health care benefits patients as well as clinicians by improving drug safety and reducing empiricism in drug selection. Barriers to the implementation of pharmacogenetic testing remain. This review explores current pharmacogenetic implementation initiatives with a focus on the challenges of pharmacogenetic implementation and potential opportunities to overcome these challenges.
Subject(s)
Pharmacogenetics , Pharmacogenomic Testing , Delivery of Health Care , HumansABSTRACT
Peripheral blood stem cell transplantation (PBSCT) is being increasingly performed as an alternative to bone marrow transplantation (BMT); however, PBSCT has not been proven to have equivalent outcome to BMT. We conducted a meta-analysis to compare survival rates and treatment-related complications between PBSCT and BMT for pediatric hematologic malignancies. We searched Medline, Embase plus Embase classics, and the Cochrane Central Register of Controlled Trials for the terms "hematopoietic stem cell transplantation" AND "allogeneic transplantation" AND "children", including randomized controlled studies and cohort studies without language limitations. We identified 7 of 5368 studies for inclusion in our meta-analysis. The cohorts of these studies included a total of 4328 patients, 3185 who underwent BMT and 1143 who underwent PBSCT. Five-year overall survival was similar in the 2 groups (PBSCT, 56.2%; BMT, 63.5%; relative risk [RR], 1.17; 95% confidence interval [CI], .91 to 1.52), as was the 5-year event-free survival (PBSCT, 49.9%; BMT, 57.2%; RR, 1.14; 95% CI, .93 to 1.39). The incidences of nonrelapse mortality and chronic graft-versus-host disease were higher in the PBSCT group compared with the BMT group (RR, 1.73; 95% CI, 1.50 to 1.99 versus RR, 1.55; 95% CI, 1.18 to 2.03). This meta-analysis found insufficient evidence to conclude that peripheral blood stem cells are equivalent to bone marrow. The results indicate that bone marrow can still be a preferred donor source for pediatric hematologic malignancies.
Subject(s)
Bone Marrow Transplantation , Graft vs Host Disease , Hematologic Neoplasms , Peripheral Blood Stem Cell Transplantation , Adolescent , Allografts , Child , Child, Preschool , Chronic Disease , Disease-Free Survival , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Graft vs Host Disease/prevention & control , Hematologic Neoplasms/mortality , Hematologic Neoplasms/therapy , Humans , Male , Survival RateABSTRACT
Kawasaki disease is an acute systemic vasculitis in children. Antiplatelet medicines are commonly used for Kawasaki disease to attenuate vasculitis and prevent thromboembolism; however, the mechanisms have not been elucidated. The objective of this study is to assess the effectiveness of antiplatelet medications for Kawasaki disease. We used Medline, Embase, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi (Ichushi) from January 1947 to August 2018. Studies describing the platelet functions of antiplatelet drugs for Kawasaki disease were included. Twenty studies met the inclusion criteria. There were no randomized controlled trials. Seven studies compared platelet aggregation ability before and after treatment. Eight studies compared platelet aggregation with that in Kawasaki disease patients without treatment. Four studies compared aggregation among different types of antiplatelet drugs or at different doses. Antiplatelet medications administered in the studies included aspirin, flurbiprofen, dipyridamole, and choline salicylate. Methods for the measurement of platelet aggregation ability varied among studies. The groups with antiplatelet treatment tended to have a decreased platelet aggregation function. The statistical analyses were impossible due to insufficient quantitative data and heterogeneity among the studies.Conclusion: The present systematic review revealed that there was insufficient evidence for the effectiveness of antiplatelet therapy for Kawasaki disease. What is Known: ⢠Antiplatelet therapy is widely used for Kawasaki disease to mitigate cardiac complications. ⢠The mechanisms of antiplatelet therapy for Kawasaki disease are not clarified. What is New: ⢠This systematic review showed that the groups with antiplatelet treatment tended to have a decreased platelet aggregation function. ⢠There is insufficient evidence for the effectiveness of antiplatelet therapy for Kawasaki disease.
Subject(s)
Mucocutaneous Lymph Node Syndrome/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Platelet Aggregation/drug effects , Child , Dose-Response Relationship, Drug , Female , Humans , Male , Platelet Aggregation Inhibitors/pharmacology , Treatment OutcomeABSTRACT
BACKGROUND: Varicella zoster virus (VZV) disease is a common complication after hematopoietic cell transplantation (HCT). The mortality rate for disseminated VZV infection is 34%. Acyclovir has been used for the prophylaxis of VZV disease after HCT, but the effectiveness of prophylaxis is controversial. We conducted a meta-analysis of the incidence of VZV disease within the first 1 year after acyclovir prophylaxis had been discontinued and assessed the risk of VZV disease during acyclovir prophylaxis. METHODS: Medline, EMBASE plus EMBASE classics, and the Cochrane Central Register of Controlled Trials were used for a systematic search. The inclusion criteria were both randomized controlled trials and cohort studies that described the effectiveness of acyclovir as prophylaxis against VZV disease after allogeneic HCT. RESULTS: We included seven studies involving a total of 2265 patients. No mortality by VZV was identified. Acyclovir prophylaxis significantly reduced the rate of VZV infection within the first 1 year after discontinuation (risk ratio: 0.38, 95% confidence interval (CI): 0.29-0.51). The risk of VZV disease during acyclovir prophylaxis was also reduced (risk ratio: 0.17, 95% CI: 0.12-0.24). Both short-term and long-term prophylaxis reduced the incidence of VZV infection (RR: 0.51, 95% CI: 0.30-0.86 vs RR: 0.34, 95% CI: 0.22-0.54). Low-dose acyclovir (<400 mg/d) is sufficient to reduce the risk of VZV disease. CONCLUSION: This study showed that acyclovir prophylaxis reduced VZV infection after HCT with no fatal cases and acyclovir prophylaxis is beneficial. No significant adverse effects occurred and no delayed VZV disease was identified.
Subject(s)
Acyclovir/administration & dosage , Antiviral Agents/administration & dosage , Hematopoietic Stem Cell Transplantation/adverse effects , Herpes Zoster/prevention & control , Allografts , Herpesvirus 3, Human/drug effects , Humans , Incidence , Randomized Controlled Trials as Topic , Risk Factors , Virus Activation/drug effectsABSTRACT
In the revised World Health Organization classification 2016, anaplastic pleomorphic xanthoastrocytoma (PXA) has been newly defined as a variant of the PXA entity. Furthermore, some anaplastic PXA were reported to have extremely poor prognosis which showed a type of pediatric glioblastoma (GBM) molecular profile. Recent integrated molecular classification for primary central nervous system tumors proposed some differences between histological and molecular features. Herein, in a genome-wide molecular analysis, we show an extreme aggressive anaplastic PXA that resulted in a pediatric GBM molecular profile. A full implementation of the molecular approach is the key to predict prognosis and decide the treatment strategy for anaplastic PXA.
Subject(s)
Astrocytoma/genetics , Brain Neoplasms/genetics , DNA Methylation/genetics , Glioblastoma/genetics , Adolescent , Astrocytoma/pathology , Brain Neoplasms/pathology , Female , Genome-Wide Association Study/methods , Glioblastoma/pathology , Humans , PrognosisABSTRACT
Primary central nervous system lymphoma (PCNSL) is a rare and aggressive type of extranodal non-Hodgkin lymphoma that carries an unsatisfactory prognosis. Treating refractory PCNSL is challenging because of resistance to conventional cytotoxic and intrathecal chemotherapies. Therefore, novel therapeutic approaches are needed. Here, we report a 12-year-old boy with CD20-positive PCNSL, which was refractory to combination chemotherapy and intravenous rituximab. However, the patient achieved complete remission after repeated intraventricular rituximab administration. The results of this case indicate that intraventricular rituximab is an effective option to treat refractory PCNSL in children.