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Atypical lipomatous tumors (ALTs) are locally aggressive adipocytic malignancies that frequently occur in middle-aged adults. We report the rare case of an ALT of the thigh that occurred in a 4-year-old girl. Since the tumor was initially diagnosed as a lipoblastoma by incisional biopsy, marginal resection was performed. Histopathological findings of the surgical specimen revealed the proliferation of mature and variously sized adipocytes, as well as ectopic ossification; these features differ from the typical findings of lipoblastoma. Immunohistochemical findings showed nuclear positivity for a murine double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) and negativity for pleomorphic adenoma gene 1 (PLAG1). Fluorescence in situ hybridization showed abnormal amplification of the MDM2 gene. The patient was thus finally diagnosed as having an ALT. No signs of local recurrence or metastasis were noted 1 year postoperatively. This case is instructive in the differential diagnosis of primary adipocytic tumors. Lipoblastomas are the most common adipocytic tumors in children, but if a tumor is located in the deep tissue or imaging findings are not typical, the possibility of ALT should be considered and immunohistochemistry for MDM2 and CDK4 should be added.
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The prognosis of patients with osteosarcoma who experience recurrence or progression (R/P) is extremely poor, and more effective and less toxic therapies are needed. In the current study, the clinical data of osteosarcoma patients who experienced R/P were retrospectively analyzed to verify the reliability of O-6-methylguanine-DNA methyltransferase (MGMT) protein expression or MGMT promoter methylation for predicting the response to off-label temozolomide (TMZ)-containing chemotherapy. Of the 30 evaluable patients, 9 (30%) showed no/low MGMT protein expression, whereas all 16 evaluable patients had unmethylated MGMT promoter irrespective of MGMT protein expression levels. Twenty-three patients received TMZ-containing chemotherapy for measurable lesions (n = 14) or as adjuvant therapy following resection of recurrent lesions (n = 9). Among 14 patients with radiologically measurable lesions, the objective response rate was higher in the MGMT no/low-expression group (50.0%) than in the MGMT intermediate/high-expression group with borderline significance (0%, p = 0.066). The 6-month progression-free survival (PFS) rate in patients with radiologically measurable lesions was significantly higher in the MGMT no/low-expression group (50.0%) than in the MGMT intermediate/high-expression group (0%, p = 0.036). In the multivariate analysis of the 23 patients receiving TMZ-containing chemotherapy, MGMT expression and disease status before TMZ-containing chemotherapy were significantly associated with PFS. No severe adverse effects were observed during TMZ-containing chemotherapy. MGMT protein expression, but not MGMT promoter methylation, could predict a favorable outcome in patients receiving TMZ-containing chemotherapy.
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BACKGROUND: Asparaginase is essential for treating T-cell acute lymphoblastic leukemia (T-ALL). Despite the ongoing debate on whether T-ALL and T-cell lymphoblastic lymphoma (T-LBL) are the same disease entity or two distinct diseases, patients with T-LBL often receive the same or similar treatment protocols as those with T-ALL. METHODS: The outcomes of patients with or without L-asparaginase discontinuation were retrospectively analyzed among four national protocols: Japan Association of Childhood Leukemia Study (JACLS) ALL-02 and ALL-97 for T-ALL and Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 and JACLS NHL-98 for T-LBL. The hazard ratio (HR) was calculated with the Cox regression model by considering L-asparaginase discontinuation as a time-dependent variable. RESULTS: In total, 199 patients with T-ALL, and 133 patients with T-LBL were included. L-asparaginase discontinuation compromised event-free survival (EFS) of T-ALL patients (ALL-02: HR 3.32, 95% confidence interval [CI] 1.40-7.90; ALL-97: HR 3.39, 95%CI 1.19-9.67). Conversely, EFS compromise was not detected among T-LBL patients (ALB-NHL03: HR 1.39, 95%CI 0.41-4.68; NHL-98: HR 0.92, 95%CI 0.11-7.60). CONCLUSION: The effects of L-asparaginase discontinuation differed between T-ALL and T-LBL. We assume that the differential impact results from (1) the inherent differential response to L-asparaginase between them and/or (2) a less stringent assessment of early treatment response in T-LBL than in T-ALL. Given the poor salvage rate of refractory or relapsed T-ALL and T-LBL, optimization of the frontline therapy is critical, and the current study provides a new suggestion for further treatment modifications. However, larger studies in contemporary intensified treatment protocols are required.
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Asparaginasa , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Asparaginasa/uso terapéutico , Asparaginasa/administración & dosificación , Niño , Masculino , Femenino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidad , Preescolar , Estudios Retrospectivos , Adolescente , Lactante , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Japón , Antineoplásicos/uso terapéuticoRESUMEN
BACKGROUND: Bifocal germ cell tumors, with primarily identical tissue composition, occur concurrently in the neurohypophyseal and pineal regions. OBSERVATIONS: A 16-year-old male patient exhibited increased intracranial pressure symptoms, with concurrent tumors in the pineal and neurohypophyseal regions, causing obstructive hydrocephalus. His serum human chorionic gonadotropin level was elevated, measuring 506.6 mIU/mL. Upon gross endoscopic examination, the pineal tumor appeared white, whereas the neurohypophyseal tumor appeared red and hemorrhagic. Because of the limited sample size of the latter, a frozen section biopsy was feasible only for the pineal lesion, which indicated the presence of a germinoma. Subsequently, carboplatin and etoposide were administered, resulting in the reduction of the pineal tumor, but no effect was observed in the neurohypophyseal tumor. Histopathological analysis confirmed the pineal lesion as a germinoma, whereas the neurohypophyseal lesion was an embryonal carcinoma. Thus, the treatment was altered to ifosfamide, carboplatin, and etoposide (ICE), leading to a response in both tumors. The patient underwent three additional cycles of ICE therapy and high-dose chemotherapy, followed by whole craniospinal irradiation, achieving complete remission. LESSONS: Although most bifocal germ cell tumors share the same histological tissue, occasional differences may arise, necessitating separate biopsies for accurate assessment.
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Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described on the basis of its unique immunophenotype and clinical phenotype. However, there is no consensus on the characteristics for identifying this disease type because of its rarity and lack of defined distinctive molecular characteristics. In this study, multiomics analysis revealed that MNKPL is distinct from acute myeloid leukemia, T cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia (MPAL), and NOTCH1 and RUNX3 activation and BCL11B down-regulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, the results of our single-cell analysis using MNKPL cells suggest that NK cells and myeloid cells share common progenitor cells. Treatment outcomes for MNKPL are unsatisfactory, even when hematopoietic cell transplantation is performed. Multiomics analysis and in vitro drug sensitivity assays revealed increased sensitivity to l-asparaginase and reduced levels of asparagine synthetase (ASNS), supporting the clinically observed effectiveness of l-asparaginase.
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Asparaginasa , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/terapia , Enfermedad Aguda , Células Asesinas Naturales , Resultado del Tratamiento , Proteínas Represoras , Proteínas Supresoras de TumorRESUMEN
TCF3-HLF-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has an extremely poor prognosis. A 2-year-old boy with TCF3-HLF-positive BCP-ALL had an isolated extramedullary relapse in multiple bones after allogeneic hematopoietic stem cells transplantation (HSCT) from a human leukocyte antigen-matched unrelated donor. In this study, he received a T-cell-replete haploidentical HSCT (TCR-haplo-HSCT) from his father when in nonremission state, which resulted in a sustained complete remission for over 3 years. Immune therapies for patients with an extramedullary relapse of TCF3-HLF-positive BCP-ALL have been attempted; however, long-term efficacies of these therapies remain unknown. Our TCR-haplo-HSCT may be an effective therapeutic option for such patients.
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Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Masculino , Humanos , Preescolar , Trasplante de Médula Ósea , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Linfocitos T , Trasplante de Células Madre Hematopoyéticas/métodos , Recurrencia , Enfermedad Aguda , Receptores de Antígenos de Linfocitos T , Estudios Retrospectivos , Donante no Emparentado , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Proteínas de Fusión OncogénicaRESUMEN
OBJECTIVES: Delirium is a neuropsychiatric disorder that commonly occurs in elderly patients with cognitive impairment. The economic burden of delirium in Japan has not been well characterised. In this study, we assessed incremental medical costs of delirium in hospitalised elderly Japanese patients with cognitive impairment. DESIGN: Retrospective, cross-sectional, observational study. SETTING: Administrative data collected from acute care hospitals in Japan between April 2012 and September 2020. PARTICIPANTS: Hospitalised patients ≥65 years old with cognitive impairment were categorised into groups-with and without delirium. Delirium was identified using a delirium identification algorithm based on the International Classification of Diseases 10th Revision codes or antipsychotic prescriptions. OUTCOME MEASURES: Total medical costs during hospitalisation were compared between the groups using a generalised linear model. RESULTS: The study identified 297 600 hospitalised patients ≥65 years of age with cognitive impairment: 39 836 had delirium and 257 764 did not. Patient characteristics such as age, sex, inpatient department and comorbidities were similar between groups. Mean (SD) unadjusted total medical cost during hospitalisation was 979 907.7 (871 366.4) yen for patients with delirium and 816 137.0 (794 745.9) yen for patients without delirium. Adjusted total medical cost was significantly greater for patients with delirium compared with those without delirium (cost ratio=1.09, 95% CI: 1.09 to 1.10; p<0.001). Subgroup analyses revealed significantly higher total medical costs for patients with delirium compared with those without delirium in most subgroups except patients with hemiplegia or paraplegia. CONCLUSIONS: Medical costs during hospitalisation were significantly higher for patients with delirium compared with those without delirium in elderly Japanese patients with cognitive impairment, regardless of patient subgroups such as age, sex, intensive care unit admission and most comorbidities. These findings suggest that delirium prevention strategies are critical to reducing the economic burden as well as psychological/physiological burden in cognitively impaired elderly patients in Japan.
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Disfunción Cognitiva , Delirio , Humanos , Anciano , Delirio/prevención & control , Estudios Retrospectivos , Estudios Transversales , Japón/epidemiología , Disfunción Cognitiva/complicacionesRESUMEN
Chimerism analysis is a surrogate indicator of graft rejection or relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Although short tandem repeat PCR (STR-PCR) is the usual method, limited sensitivity and technical variability are matters of concern. Quantitative PCR-based methods to detect single nucleotide polymorphisms (SNP-qPCR) are more sensitive, but their informativity and quantitative accuracy are highly variable. For accurate and sensitive chimerism analysis, a set of KMR kits (GenDx, Utrecht, Netherlands), based on detection of insertions/deletions (indels) by qPCR, have been developed. Here, we investigated informativity and validated the accuracy of KMR kits in Japanese donor/recipient pairs and virtual samples of DNA mixtures representative of Japanese genetic diversity. We found that at least one recipient-specific marker among 39 KMR-kit markers was informative in all of 65 Japanese donor/recipient pairs. Moreover, the percentage of recipient chimerism estimated by KMRtrack correlated well with ratios of mixed DNA in virtual samples and with the percentage of chimerism in HSCT recipients estimated by STR-PCR/in-house SNP-qPCR. Moreover, KMRtrack showed better sensitivity with high specificity when compared to STR-PCR to detect recipient chimerism. Chimerism analysis with KMR kits can be a standardized, sensitive, and highly informative method to evaluate the graft status of HSCT recipients.
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Trasplante de Células Madre Hematopoyéticas , Quimera por Trasplante , Humanos , Quimera por Trasplante/genética , Pueblos del Este de Asia , Quimerismo , ADNRESUMEN
OBJECTIVES: Delirium commonly occurs during hospitalisation and is associated with increased mortality, especially in elderly patients. This study aimed to determine the demographic and clinical characteristics of patients with delirium in the Japanese real-world clinical setting using a nationwide database comprising claims and discharge abstract data. DESIGN: This was an observational, cross-sectional, retrospective study in hospitalised patients with an incident delirium identified by a diagnosis based on International Classification of Diseases, 10th Revision codes or initiating antipsychotics recommended for delirium treatment in Japan during their hospitalisation. SETTING: Patients from the Medical Data Vision database including more than 400 acute care hospitals in Japan were evaluated from admission to discharge. PARTICIPANTS: Of the 32 910 227 patients who were included in the database between April 2012 and September 2020, a total of 145 219 patients met the criteria for delirium. PRIMARY AND SECONDARY OUTCOME MEASURES: Demographic and baseline characteristics, comorbidities, clinical profiles and pharmacological treatments were evaluated in patients with delirium. RESULTS: The mean (SD) patient age was 76.5 (13.8) years. More than half of the patients (n=82 159; 56.6%) were male. The most frequent comorbidities were circulatory system diseases, observed in 81 954 (56.4%) patients. Potentially inappropriate medications (PIMs) with risk of delirium including benzodiazepines and opioids were prescribed to 76 798 (52.9%) patients. Approximately three-fourths of these patients (56 949; 74.2%) were prescribed ≥4 PIMs. The most prescribed treatment for delirium was injectable haloperidol (n=82 490; 56.8%). Mean (SD) length of hospitalisation was 16.0 (12.1) days. CONCLUSIONS: The study results provide comprehensive details of the clinical characteristics of patients with delirium and treatment patterns with antipsychotics in the Japanese acute care setting. In this patient population, the prescription rate of injectable haloperidol and PIMs was high, suggesting the need for improved understanding among healthcare providers about the appropriate management of delirium, which may benefit patients.
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Antipsicóticos , Delirio , Anciano , Antipsicóticos/uso terapéutico , Estudios Transversales , Delirio/inducido químicamente , Delirio/tratamiento farmacológico , Delirio/epidemiología , Demografía , Femenino , Haloperidol/uso terapéutico , Humanos , Japón/epidemiología , Masculino , Estudios RetrospectivosRESUMEN
The effects of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on systemic chronic active Epstein-Barr virus infection (sCAEBV) are yet to be analyzed in a large number of patients. Using the Japanese registry database, Transplant Registry Unification Management Program, we investigated the outcomes of 102 sCAEBV patients who underwent allo-HSCT. The median age at HSCT was 21 years, and the three-year overall survival (3-year OS) rate was 72.5%. Of the 90 patients whose viral load after allo-HSCT was evaluated, 56 (62.2%) achieved a virological complete response, defined by the complete resolution of disease activity with a significant decrease in EBV-DNA in peripheral blood. The multivariate Cox proportional hazard model indicated that advanced age, in adolescents and young adults (AYA) (age, 15-39) and adults (age, ≥40 years) was a risk factor of poor OS. The hazard ratios (HRs) of the AYA and adult groups were 10.87 (95% confidence interval [CI]: 1.98-59.56, p = .006) and 15.93 (95% CI: 2.45-103.8, p = .004), respectively. Disease activity (HR 5.74), elevated soluble IL-2 receptor (sIL-2R) (≥ median, 691 U/mL) at HSCT (HR 6.93), and conditioning without radiotherapy (HR 3.53) were also independently associated with poor survival. Notably, 79% of radiotherapy doses were less than 6 Gy. Regardless of the presence of hemophagocytic lymphohistiocytosis, the group with a high sIL-2R level (≥2000 U/mL) showed a poorer prognosis. Although allo-HSCT is the only curative therapy for sCAEBV, treatment strategies need to be improved for high-risk patients, especially those with high levels of sIL-2R.
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Infecciones por Virus de Epstein-Barr , Trasplante de Células Madre Hematopoyéticas , Adolescente , Adulto , Análisis de Datos , Infecciones por Virus de Epstein-Barr/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Herpesvirus Humano 4 , Humanos , Japón/epidemiología , Sistema de Registros , Estudios Retrospectivos , Adulto JovenRESUMEN
NTRK gene fusion is rare in gynecological cancer. Entrectinib is a novel targeted drug, which is a potent inhibitor of TRK A, B and C. The present case report described a case of recurrent ovarian cancer with TPM3-NTRK1 rearrangement, which was detected by next-generation sequencing (NGS) and treated with entrectinib. A 56-year-old woman was diagnosed as having stage IV ovarian cancer with positive pleural fluid cytology. Neoadjuvant chemotherapy and interval debulking surgery, followed by chemotherapy, were performed. A total of 10 months after completion of chemotherapy, the disease recurred and the patient was treated with multimodal therapy for recurrence. DNA-based NGS detected TPM3-NTRK1 rearrangement and entrectinib therapy was initiated; however, the disease progressed despite 6 weeks of entrectinib administration, and 1 month after discontinuation of entrectinib, the patient died. After their death, immunohistochemistry with a pan-Trk monoclonal antibody was performed to determine the expression levels of TRK; however, immunohistochemistry was negative for TRK. In conclusion, the present case report described a rare case of recurrent ovarian cancer with TPM3-NTRK1 gene fusion, in which entrectinib was not effective. While NTRK gene fusion was detected by DNA-based NGS, immunohistochemistry was negative for TRK. These findings indicated that immunohistochemistry may be required for confirmation of TRK protein expression prior to entrectinib administration.
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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the preferred treatment for children with high-risk hematologic malignancies, but post-allo-HSCT relapse has a poor prognosis and limited treatment options. We evaluated the feasibility, outcome, and risk factors influencing survival after T-cell-replete haploidentical HSCT with low-dose anti-thymocyte globulin (ATG) in 30 patients with post-allo-HSCT relapse of acute lymphoblastic leukemia and acute myeloid leukemia. Overall, 50% of the patients had complete remission (CR) before the second transplant and the overall survival (OS) rate was 52%. In surviving patients (median follow-up 614 days), Kaplan-Meier analysis revealed estimated 2-year leukemia-free survival and OS rates of 48.1% and 61.1%, respectively. Cumulative incidences of 2-year non-relapse mortality and relapse were 24.7% and 36.3%, respectively. Achieving CR before the second allo-HSCT was a predominant independent prognostic factor identified in the multivariate analysis, with a significantly improved 2-year OS rate of 86.7%. T-cell-replete haplo-HSCT with low-dose ATG for second allo-HSCT may benefit a selected patient population.
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Suero Antilinfocítico/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/cirugía , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirugía , Reoperación/métodos , Linfocitos T/trasplante , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Estudios de Factibilidad , Femenino , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Lactante , Leucemia Mieloide Aguda/mortalidad , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Recurrencia , Tasa de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Juvenile myelomonocytic leukemia (JMML) is a pediatric hematological malignancy with a poor prognosis. Although several case series have been published describing hematological and molecular responses to azacitidine (AZA) treatment in patients with JMML, the efficacy and safety profile of AZA is not well investigated, especially in Asian children and children undergoing hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed 5 patients who received a total of 12 cycles (median 2 cycles) of AZA treatment in Japan. All five patients were boys and their ages at the time of treatment were 21, 23, 24, 26, and 46 months, respectively. All five patients tolerated AZA treatment, including four patients who received AZA after HSCT. Therapeutic toxicity with AZA was mostly limited to hematological toxicity. The only serious non-hematological adverse event was hyperbilirubinemia (grades III-IV) observed in a patient who received AZA after a second HSCT. Two out of five patients treated with AZA achieved a partial response (PR), while three patients treated for post-transplant relapse did not have an objective response. Future prospective studies should be conducted to develop combination therapies with AZA and other molecular targeted drugs for high-risk patients.
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Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Leucemia Mielomonocítica Juvenil/tratamiento farmacológico , Antimetabolitos Antineoplásicos/efectos adversos , Azacitidina/efectos adversos , Preescolar , Humanos , Lactante , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Despite intensive multimodal therapies, the prognosis of relapsed/ refractory Ewing sarcoma family tumors (RR-ESFTs) is dismal. Some case reports using allogeneic stem cell transplantation (allo SCT) for RR-ESFTs have been reported, however, the efficacy of allo SCT is yet to be established. AIM: The purpose of this study was to evaluate the response and toxicity of T-cell replete haploidentical SCT (TCR-haplo-SCT) in RR-ESFTs. METHODS AND RESULTS: In this study, we retrospectively analyzed six patients with RR-ESFTs who received TCR-haplo-SCT. Four patients had relapsed and two patients had refractory Ewing sarcoma. Before the TCR-haplo-SCT, all patients received a reduced intensity-conditioning regimen containing fludarabine, melphalan, and low-dose rabbit anti-thymocyte globulin (2.5 mg/kg), as well as graft-versus-host disease (GVHD) prophylaxis, which consisted of tacrolimus, methotrexate, and prednisolone. Primary neutrophil engraftment was achieved in all the patients. Four patients developed acute GVHD (aGVHD) (grade I, 1; grade II, 1; grade III, 2), and two patients developed chronic GVHD (cGVHD). Among the four that developed aGVHD, three survived for 14, 116, and 129 months without relapse, while one died due to a transplant-related complication. In contrast, the two patients who did not develop aGVHD experienced relapse early after TCR-haplo-SCT. CONCLUSIONS: In this study, three of the six patients with RR-ESFTs survived for more than one year without relapse, and the treatment toxicity was considered acceptable even for patients who underwent high-intensity pretreatment. TCR-haplo-SCT could be a potential therapeutic option for patients with RR-ESFTs.
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Suero Antilinfocítico , Trasplante de Células Madre Hematopoyéticas , Sarcoma de Ewing , Suero Antilinfocítico/uso terapéutico , Neoplasias Óseas , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Receptores de Antígenos de Linfocitos T , Recurrencia , Estudios Retrospectivos , Sarcoma de Ewing/complicaciones , Sarcoma de Ewing/terapia , Linfocitos TRESUMEN
Background: The prognosis of refractory/relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains dismal owing to acquired resistance to chemotherapeutic agents. This study aimed to evaluate the efficacy of T-cell replete HLA haploidentical hematopoietic stem cell transplantation (TCR-haplo-HSCT) for pediatric refractory/relapsed BCP-ALL (RR-BCP-ALL). Methods: Nineteen pediatric patients with RR-BCP-ALL underwent TCR-haplo-HSCT between 2010 and 2019 at the Fukushima Medical University Hospital. The disease status at TCR-haplo-HSCT included complete remission (CR) in eight patients and non-CR with active disease in 11 patients. Total body irradiation-based, busulfan-based, and reduced-intensity conditioning regimens were employed in 11, 6, and 2 patients, respectively. Low-dose anti-thymocyte globulin (thymoglobulin, 2.5 mg/kg) was used in all patients. Graft-vs.-host disease (GVHD) prophylaxis was administered with tacrolimus, methotrexate, and prednisolone. Results: All patients received peripheral blood stem cells as the stem cell source. The HLA disparities in graft vs. host directions were 2/8 in one, 3/8 in five, and 4/8 in 13 patients. Among 18 patients who achieved primary engraftment, acute GVHD occurred in all 18 evaluable patients (grade II, 9; grade III, 8; grade IV, 1), and chronic GVHD was observed in 10 out of 15 evaluable patients. Three patients died because of transplant-related mortality. The 3-year overall survival (OS) and leukemia-free survival rates were 57.4 and 42.1%, respectively. Compared to patients older than 10 years in age (N = 10), those younger than 10 years in age (N = 9) showed an excellent OS rate (3-year OS rate: patients < 10 years old, 100%; patients > 10 years old, 20% [95% confidence interval, 3.1-47.5]; p = 0.002). Conclusions: We suggest that TCR haplo-HSCT with low-dose ATG conditioning has the potential to improve the transplantation outcomes in patients with RR-BCP.
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BACKGROUND: Cancer vaccines that induce endogenous antitumor immunity represent an ideal strategy to overcome intractable cancers. However, doing this against a pre-established cancer using autologous immune cells has proven to be challenging. "Allogeneic effects" refers to the induction of an endogenous immune response upon adoptive transfer of allogeneic lymphocytes without utilizing hematopoietic stem cell transplantation. While allogeneic lymphocytes have a potent ability to activate host immunity as a cell adjuvant, novel strategies that can activate endogenous antitumor activity in cancer patients remain an unmet need. In this study, we established a new method to destroy pre-developed tumors and confer potent antitumor immunity in mice using alloantigen-activated CD4+ (named AAA-CD4+) T cells. METHODS: AAA-CD4+ T cells were generated from CD4+ T cells isolated from BALB/c mice in cultures with dendritic cells (DCs) induced from C57BL/6 (B6) mice. In this culture, allogeneic CD4+ T cells that recognize and react to B6 mouse-derived alloantigens are preferentially activated. These AAA-CD4+ T cells were directly injected into the pre-established melanoma in B6 mice to assess their ability to elicit antitumor immunity in vivo. RESULTS: Upon intratumoral injection, these AAA-CD4+ T cells underwent a dramatic expansion in the tumor and secreted high levels of IFN-γ and IL-2. This was accompanied by markedly increased infiltration of host-derived CD8+ T cells, CD4+ T cells, natural killer (NK) cells, DCs, and type-1 like macrophages. Selective depletion of host CD8+ T cells, rather than NK cells, abrogated this therapeutic effect. Thus, intratumoral administration of AAA-CD4+ T cells results in a robust endogenous CD8+ T cell response that destroys pre-established melanoma. This locally induced antitumor immunity elicited systemic protection to eliminate tumors at distal sites, persisted over 6 months in vivo, and protected the animals from tumor re-challenge. Notably, the injected AAA-CD4+ T cells disappeared within 7 days and caused no adverse reactions. CONCLUSIONS: Our findings indicate that AAA-CD4+ T cells reinvigorate endogenous cytotoxic T cells to eradicate pre-established melanoma and induce long-term protective antitumor immunity. This approach can be immediately applied to patients with advanced melanoma and may have broad implications in the treatment of other types of solid tumors.
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Linfocitos T CD4-Positivos/metabolismo , Inmunoterapia/métodos , Isoantígenos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Humanos , RatonesRESUMEN
Although approximately 70% of pediatric hematological malignancies are curable, approximately 30% remain fatal. No standard treatment is available in patients showing relapse and those with refractory disease. Although different methods are adopted in different hospitals, its efficacy is extremely limited. In recent years, haploidentical stem cell transplantation, involving high-dose cyclophosphamide administration post-transplanta tion, has been used, mainly in adults; however, its application is limited to removal of alloreactive T cells. Multicenter single-arm clinical trials of T-cell replete haploidentical stem cell transplantation (TCR-haplo-SCT) will be conducted in children with relapsed and refractory acute leukemia. After myeloablative conditioning using total body irradiation or busulfan, intensive graft versus host disease prophylaxis is administered, consisting of low-dose rabbit anti-human thymocyte globulin, tacrolimus, methotrexate, and prednisolone. An external control group is set up for the study. The treatment period is around 3 months, and the follow-up period is 2 years from transplantation completion.The aim of this study is to verify the efficacy and safety of TCR-haplo-SCT and present it as a new immune cell therapy for improving survival rate in children with relapsed and refractory acute leukemia.
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Suero Antilinfocítico/administración & dosificación , Leucemia/terapia , Trasplante de Células Madre , Linfocitos T/trasplante , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , Adolescente , Suero Antilinfocítico/uso terapéutico , Niño , Femenino , Haplotipos , Humanos , Factores Inmunológicos , Inmunosupresores/uso terapéutico , Leucemia/mortalidad , Masculino , Receptores de Antígenos de Linfocitos T , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
In a secret communication system using chaotic synchronization, the communication information is embedded in a signal that behaves as chaos and is sent to the receiver to retrieve the information. In a previous study, a chaotic synchronous system was developed by integrating the wave equation with the van der Pol boundary condition, of which the number of the parameters are only three, which is not enough for security. In this study, we replace the nonlinear boundary condition with an artificial neural network, thereby making the transmitted information difficult to leak. The neural network is divided into two parts; the first half is used as the left boundary condition of the wave equation and the second half is used as that on the right boundary, thus replacing the original nonlinear boundary condition. We also show the results for both monochrome and color images and evaluate the security performance. In particular, it is shown that the encrypted images are almost identical regardless of the input images. The learning performance of the neural network is also investigated. The calculated Lyapunov exponent shows that the learned neural network causes some chaotic vibration effect. The information in the original image is completely invisible when viewed through the image obtained after being concealed by the proposed system. Some security tests are also performed. The proposed method is designed in such a way that the transmitted images are encrypted into almost identical images of waves, thereby preventing the retrieval of information from the original image. The numerical results show that the encrypted images are certainly almost identical, which supports the security of the proposed method. Some security tests are also performed. The proposed method is designed in such a way that the transmitted images are encrypted into almost identical images of waves, thereby preventing the retrieval of information from the original image. The numerical results show that the encrypted images are certainly almost identical, which supports the security of the proposed method.
RESUMEN
Chronic myeloid leukemia (CML) is an uncommon entity in pediatric patients. CML in chronic phase (CML-CP) has a relatively favorable outcome. Leukostasis occurs in 9.7% of patients with CML. One of the most serious leukostasis-related complications is intracranial hemorrhage (ICH). However, this is very rare in patients with CML-CP, and few early mortalities have been reported in CML patients with leukostasis. We report the case of a 14-year-old female patient with CML-CP who developed ICH 8 days after admission. A 14-year-old girl developed symptoms of fatigue and slight fever and was diagnosed with CML-CP. She was treated with imatinib and received low-molecular-weight heparin owing to coagulation abnormalities. However, 6 days later, she developed sensorineural hearing loss, which is a symptom of leukostasis. She received hydroxyurea to reduce her white blood cell (WBC) count, and her treatment was changed from imatinib to nilotinib. The WBC and platelet counts remained unchanged, blast counts did not increase, and mild coagulation abnormality persisted. Eight days after admission, she suddenly lost consciousness and experienced respiratory arrest. Cranial computed tomography revealed multiple ICH lesions and brain hernia. She received intensive care but was diagnosed with brain death by electroencephalography and died 14 days after hospitalization. ICH is very rare in patients with CML-CP; however, patients with leukostasis and coagulation abnormalities can develop severe hemorrhage, even in the chronic phase. Thus, it is necessary to accurately estimate the cause and provide appropriate treatment for these patients.