ABSTRACT
Haploidentical-related donor transplantation using posttransplant cyclophosphamide (PTCy-haplo) and cord blood transplantation (CBT) are valid alternatives for patients with hematological malignancies when HLA-matched donor transplantation (MDT) is unavailable. However, the effects of graft-versus-host disease (GVHD) on outcomes after these transplants have not been fully elucidated. Therefore, we evaluated the effects of acute and chronic GVHD on transplant outcomes after PTCy-haplo transplants and compared them with CBT and MDT. We included a total of 914 adult patients with hematological malignancies in the Kyoto Stem Cell Transplantation Group registry who received PTCy-haplo (N = 120), CBT (N = 402), and MDT (N = 392), and achieved neutrophil engraftment. A multivariate analysis revealed that grade I-II acute GVHD improved of overall survival (OS) after PTCy-haplo [hazard ratio (HR) = 0.39, P = 0.018] and CBT (HR = 0.48, P < 0.001), but not after MDT (HR = 0.80, P = 0.267) compared with patients without acute GVHD. Grade I-II acute GVHD had a trend toward reducing the risk of nonrelapse mortality (NRM) after PTCy-haplo (HR = 0.13, P = 0.060) and this positive effect was significant after CBT (HR = 0.39, P = 0.003). A negative impact of grade III-IV acute GVHD on NRM was observed after CBT and MDT, but not after PTCy-haplo. Limited chronic GVHD had a positive impact on OS after CBT and MDT, but not after PTCy-haplo. In conclusion, mild acute GVHD improved outcomes after PTCy-haplo and CBT, and limited chronic GVHD improved outcomes after CBT and MDT. These data indicated that the effects of GVHD on transplant outcomes depended on transplant platforms.
Subject(s)
Bronchiolitis Obliterans Syndrome , Cord Blood Stem Cell Transplantation , Graft vs Host Disease , Hematologic Neoplasms , Hematopoietic Stem Cell Transplantation , Adult , Humans , Cyclophosphamide/therapeutic use , Cyclophosphamide/pharmacology , Graft vs Host Disease/drug therapy , Hematologic Neoplasms/therapy , Transplantation Conditioning , Retrospective StudiesABSTRACT
Although exposure-directed busulfan (BU) dosing can improve allogeneic hematopoietic stem cell transplantation outcomes, there is still large variability in BU exposure with test dose alone due to changes in BU clearance caused by drug interactions. We conducted a single-arm phase II trial using the combined test dose and therapeutic drug monitoring strategy (PK-guided group) and compared the outcomes with an external historical cohort receiving a fixed-dose (fixed-dose group). The first eight and second eight doses were adjusted based on the area under the blood concentration-time curve (AUC) of the test and first doses, respectively, targeting a total AUC of 82.1 mg·h/L. All patients received either BU and cyclophosphamide conditioning (BU/CY) or fludarabine (FLU)-containing conditioning. The BU clearance at the first dose decreased more in patients receiving FLU than in those receiving BU/CY; however, BU clearance also declined over time in patients who received BU/CY. The simulated total AUC (sAUC) with test dose only was significantly higher in patients who received FLU than in those who received BU/CY, but sAUC with the combined strategy was comparable. The 100-day progression-free survival was 85.5% (95% confidence interval [CI]: 71.9-92.8%), and was not inferior to that in the fixed-dose group. For the FLU-containing regimens, the PK-guided group showed decreased relapse (0.0% vs. 26.9%, p = 0.03), and favorable overall survival (75.1% vs. 57.0%, p = 0.07) at 1 year. The combined strategy effectively controlled the BU exposure close to the target levels, potentially improving efficacy, especially in patients receiving the FLU-containing regimen. Clinical evaluation of efficacy of dose-modified intravenous busulfan in allogeneic hematopoietic stem cell transplantation for hematological malignancy (#UMIN000014077, June 15th, 2014).
Subject(s)
Hematologic Neoplasms , Hematopoietic Stem Cell Transplantation , Humans , Busulfan , Cyclophosphamide , Drug Monitoring , Hematologic Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Transplantation Conditioning , VidarabineABSTRACT
Cord blood transplantation (CBT) is an attractive therapeutic option for patients with hematologic malignancies. CBT tolerates HLA mismatches between donors and recipients, but the HLA mismatches that generate graft-versus-tumor (GVT) effects remain unknown. Given that HLA molecules contain epitopes comprising polymorphic amino acids that determine their immunogenicity, we investigated associations between epitope-level HLA mismatches and relapse following single-unit CBT. A total of 492 patients with hematologic malignancies who underwent single-unit, T cell-replete CBT were included in this multicenter retrospective study. HLA epitope mismatches (EMs) were quantified using HLA matchmaker software from donor and recipient HLA-A, -B, -C, and -DRB1 allele data. Patients were dichotomized by median EM value and divided into 2 groups: patients who underwent transplantation in complete/partial remission (standard stage: 62.4%) and others (advanced stage: 37.6%). The median number of EMs in the graft-versus-host direction (GVH-EM) was 3 (range, 0 to 16) at HLA class I and 1 (range, 0 to 7) at HLA-DRB1. Higher HLA class I GVH-EM was associated with increased nonrelapse mortality (NRM) in the advanced stage group (adjusted hazard ratio [HR], 2.12; P = .021), with no significant advantage for relapse in either stage. In contrast, higher HLA-DRB1 GVH-EM was associated with better disease-free survival in the standard stage group (adjusted HR, .63; P = .020), which was attributed to lower relapse risk (adjusted HR, .46; P = .014). These associations also were observed even within HLA-DRB1 allele-mismatched transplantations in the standard stage group, indicating that EM might have an impact on relapse risk independent of allele mismatch. High HLA-DRB1 GVH-EM did not increase NRM in either stage. High HLA-DRB1 GVH-EM may lead to potent GVT effects and a favorable prognosis following CBT, especially in patients who underwent transplantation at the standard stage. This approach may facilitate appropriate unit selection and improve the overall prognosis of patients with hematologic malignancies who undergo CBT.
Subject(s)
Cord Blood Stem Cell Transplantation , Graft vs Host Disease , Hematologic Neoplasms , Humans , HLA-DRB1 Chains/genetics , Epitopes/genetics , Retrospective Studies , Histocompatibility Testing , Neoplasm Recurrence, Local/genetics , Hematologic Neoplasms/genetics , Hematologic Neoplasms/therapyABSTRACT
Graft-versus-host disease-free, relapse-free survival (GRFS) is a useful composite end point that measures survival without relapse or significant morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aimed to develop a novel analytical method that appropriately handles right-censored data and competing risks to understand the risk for GRFS and each component of GRFS. This study was a retrospective data-mining study on a cohort of 2207 adult patients who underwent their first allo-HSCT within the Kyoto Stem Cell Transplantation Group, a multi-institutional joint research group of 17 transplantation centers in Japan. The primary end point was GRFS. A stacked ensemble of Cox Proportional Hazard (Cox-PH) regression and 7 machine-learning algorithms was applied to develop a prediction model. The median age for the patients was 48 years. For GRFS, the stacked ensemble model achieved better predictive accuracy evaluated by C-index than other state-of-the-art competing risk models (ensemble model: 0.670; Cox-PH: 0.668; Random Survival Forest: 0.660; Dynamic DeepHit: 0.646). The probability of GRFS after 2 years was 30.54% for the high-risk group and 40.69% for the low-risk group (hazard ratio compared with the low-risk group: 2.127; 95% CI, 1.19-3.80). We developed a novel predictive model for survival analysis that showed superior risk stratification to existing methods using a stacked ensemble of multiple machine-learning algorithms.
Subject(s)
Hematopoietic Stem Cell Transplantation , Adult , Chronic Disease , Disease-Free Survival , Hematopoietic Stem Cell Transplantation/methods , Humans , Machine Learning , Middle Aged , Recurrence , Retrospective Studies , Risk FactorsABSTRACT
BACKGROUND: Unrelated cord blood (UCB) and haploidentical related donor transplantation using posttransplant cyclophosphamide (PTCy-haplo) have become alternative options to treat patients with hematological malignancies without a HLA-matched donor. METHODS: We conducted a retrospective study using registry data from the Kyoto Stem Cell Transplantation Group for patients with hematological malignancies who received their first allogeneic hematopoietic cell transplantation using a single UCB unit (nâ=â460) or PTCy-haplo (Nâ=â57) between 2013 and 2019. RESULTS: We found that overall survival in the UCB group was comparable to that in the PTCy-haplo group (hazard ratio, 1.00; 95% confidence interval, 0.66-1.52), although neutrophil and platelet engraftment were significantly delayed. Nonrelapse mortality risk and the incidence of graft-versus-host disease in the UCB group were also comparable to those in the PTCy-haplo group. Although the relapse risk was similar between the UCB group and the PTCy-haplo group regardless of the disease risk, acute myeloid leukemia patients benefit from UCB transplant with a significantly lower relapse rate (hazard ratio, 0.38; 95% confidence interval, 0.18-0.76). CONCLUSIONS: UCB transplant gives outcomes comparable to PTCy-haplo transplant, and both UCB and PTCy-haplo units are suitable as alternative donor sources for patients without an HLA-matched sibling or unrelated donor.
Subject(s)
Cord Blood Stem Cell Transplantation , Graft vs Host Disease , Hematologic Neoplasms , Hematopoietic Stem Cell Transplantation , Cord Blood Stem Cell Transplantation/adverse effects , Cyclophosphamide/therapeutic use , Graft vs Host Disease/epidemiology , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Hematologic Neoplasms/therapy , Humans , Recurrence , Retrospective Studies , Transplantation Conditioning , Unrelated DonorsABSTRACT
BACKGROUND: BCR-ABL1 tyrosine kinase inhibitors (TKIs) are commonly initiated in older patients with chronic myeloid leukaemia in the chronic phase at standard doses. However, because of their safety profile in this population, appropriate therapy has not been established. We aimed to investigate whether a lower than standard dose of dasatinib was an appropriate therapy for older patients with chronic myeloid leukaemia in the chronic phase. METHODS: DAsatinib, Very Low-dose, for Elderly CML-CP patients (DAVLEC) was a multicentre, single-arm, phase 2 trial done in 25 Japanese hospitals. We enrolled patients older than 70 years with newly diagnosed chronic myeloid leukaemia in the chronic phase, ECOG performance status 0-2, and no previous treatment for CML other than hydroxyurea within 4 weeks. Second-generation TKI dasatinib was given orally at a starting dose of 20% of the standard dose (20 mg/day). If the treatment was assessed as optimal response at 3 months, 6 months, and 9 months and adverse events were grade 2 or better (according to the NCI Common Toxicity Criteria v 4.0), the same dose was continued. If response was suboptimal and adverse events were grade 2 or better, the dose was increased by 20 mg/day. Once a dose reduction had been made because of a grade 3 or worse adverse event, there were no further dose increases. Treatment was discontinued if assessed as failure (disease progression to the accelerated phase or acute phase). The primary endpoint was the achievement of major molecular response at 12 months, assessed using a per-protocol analysis. This trial is registered at with the UMIN clinical trial registry, UMIN000024548, and has completed its planned observation period. FINDINGS: Between Nov 1, 2016, and Oct 30, 2019, 52 patients received first-line dasatinib therapy at 20 mg/day. The median age at diagnosis was 77·5 years (73·5-83·0). 35 (67%) patients were male and 17 (33%) were female. 31 (60%) of 52 patients reached major molecular response at 12 months (one-sided 95% CI 48-71), with a median follow-up of 366 days (IQR 353-372). Grade 3-4 adverse events were reported in 12 (23%) patients. Neutropenia was the most frequent grade 3-4 adverse event, occurring in three (6%) patients. No treatment-related deaths were observed. INTERPRETATION: Low-dose dasatinib at 20mg/day is worthy of consideration as a starting dose for older patients with newly diagnosed chronic myeloid leukaemia in the chronic phase. However, this dose needs to be further studied in a larger cohort and with a more ethnically diverse population. FUNDING: Bristol-Myers Squibb.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Aged , Dasatinib/adverse effects , Drug Administration Schedule , Female , Fusion Proteins, bcr-abl , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Male , Treatment OutcomeABSTRACT
Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the key strategy to cure patients with mature T and natural killer (NK) cell lymphomas/leukemia, especially those with relapsed/refractory diseases, there is no consensus strategy for donor selection. We retrospectively analyzed the outcomes of allo-HSCT in 111 patients in 15 Japanese institutions as a multi-institutional joint research project. Thirty-nine patients received bone marrow or peripheral blood stem cell transplantation from related donors (rBMT/rPBSCT), 37 received BMT/PBSCT from unrelated donors (uBMT/uPBSCT), and 35 received cord blood transplantation (CBT). Overall survival (OS) and progression-free survival (PFS) at 4 years were 42% and 34%, respectively. The cumulative incidences of relapse and nonrelapse mortality were 43% and 25%. In multivariate analysis, CBT showed comparable OS with rBMT/rPBSCT (rBMT/rPBSCT versus CBT: hazard ratio [HR], 1.63; P = .264) and better OS compared with uBMT/uPBSCT (HR, 2.99; P = .010), with a trend toward a lower relapse rate (rBMT/rPBSCT versus CBT: HR, 2.60; P = .010; uBMT/uPBSCT versus CBT: HR, 2.05; P = .082). This superiority of CBT was more definite in on-disease patients (OS: rBMT/rPBSCT versus CBT: HR, 5.52; P = .021; uBMT/uPBSCT versus CBT: HR, 6.80; P = .007). Better disease control was also strongly associated with better OS and PFS with lower relapse rate. In conclusion, allo-HSCT is beneficial for the survival of patients with mature T and NK cell lymphomas/leukemia if performed in a timely fashion. Since CBT showed favorable survival with a lower relapse risk, it could be a preferred alternative, especially in on-disease patients.
Subject(s)
Cord Blood Stem Cell Transplantation , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Neoplasms , Bone Marrow Transplantation , Humans , Killer Cells, Natural , Retrospective Studies , T-LymphocytesABSTRACT
A 44-year-old woman in the first remission phase of mixed-phenotype acute leukemia (T-lymphoid and myeloid lineages) suddenly exhibited thrombocytopenia (1.1×104/µl) with generalized petechiae approximately 150 days after bone marrow transplantation (BMT) from a one-locus (HLA-B) mismatched unrelated donor. Until then, the donor bone marrow had smoothly engrafted, and the platelet count had promptly normalized. Despite extensively searching for the triggering agent such as GVHD, graft failure, relapsed leukemia, or adverse drug effects, it could not be determined. Suspecting immune thrombocytopenia secondary to BMT, prednisolone (1 mg/kg/2 days) therapy was initiated, but its effects were unsatisfactory. Next, eltrombopag, a thrombopoietin receptor agonist (TPO-RA), was administered, which exhibited a marked effect on thrombocytopenia, resulting in the withdrawal of prednisolone. Even though the efficacy of eltrombopag against immune thrombocytopenia is well established, limited studies have reported the efficacy and safety of eltrombopag against immune thrombocytopenia after allogeneic stem cell transplantation. Herein we report a case in which thrombocytopenia occurred late after transplantation but was successfully treated with a TPO-RA. In addition, we discuss suspected causative mechanisms and review the literature.
Subject(s)
Benzoates/therapeutic use , Hematopoietic Stem Cell Transplantation , Hydrazines/therapeutic use , Purpura, Thrombocytopenic, Idiopathic/therapy , Pyrazoles/therapeutic use , Thrombocytopenia , Adult , Female , Humans , Treatment OutcomeABSTRACT
INTRODUCTION: We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective. PATIENTS AND METHODS: The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for ≥ 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment-free remission (TFR) were analyzed. RESULTS: The median follow-up period was 44.0 months (interquartile range, 40.5-48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%-56.2%). Only 2 patients developed a molecular relapse after the 1-year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low γδ+ T-cell and CD4+ regulatory T-cell (CD25+CD127low) counts before discontinuation correlated significantly with successful therapy discontinuation. CONCLUSION: These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.
Subject(s)
Antineoplastic Agents/therapeutic use , Dasatinib/therapeutic use , Deprescriptions , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/therapeutic use , Female , Follow-Up Studies , Fusion Proteins, bcr-abl/genetics , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Male , Middle Aged , Recurrence , Remission Induction , Risk Factors , Treatment OutcomeABSTRACT
IgG4-related disease (IgG4RD) is a multi-organ disorder characterized by an elevated serum IgG4 level and IgG4-positive plasma cell infiltration of the affected organs, accompanied by tissue fibrosis and sclerosis. Although it can affect any organ, to our knowledge, no cases involving concurrent autoimmune neutropenia and thrombocytopenia have been reported. A 62-year-old man visited our hospital and was diagnosed with IgG4RD accompanied by interstitial pneumonitis, lymphadenopathy, and interstitial nephritis. During his clinical course, he developed autoimmune neutropenia and idiopathic thrombocytopenic purpura. Our case, invoving multiple hematological abnormalities, might help deepen our understanding of the pathophysiology of IgG4RD.
Subject(s)
Autoimmune Diseases/complications , Immunoglobulin G/blood , Neutropenia/complications , Purpura, Thrombocytopenic, Idiopathic/complications , Autoimmune Diseases/immunology , Humans , Inflammation/complications , Lung Diseases, Interstitial/complications , Male , Middle Aged , Nephritis, Interstitial/complicationsABSTRACT
Myeloid blast crisis of chronic myeloid leukemia (CML-MBC) is rarely seen at presentation and has a poor prognosis. There is no standard therapy for CML-MBC. It is often difficult to distinguish CML-MBC from acute myeloid leukemia expressing the Philadelphia chromosome (Ph+ AML). We present a case in which CML-MBC was seen at the initial presentation in a 75-year-old male. He was treated with conventional AML-directed chemotherapy followed by imatinib mesylate monotherapy, which failed to induce response. However, he achieved long-term complete molecular response after combination therapy involving dasatinib, a second-generation tyrosine kinase inhibitor, and conventional chemotherapy.
ABSTRACT
BACKGROUND: First-line imatinib treatment can be successfully discontinued in patients with chronic myeloid leukaemia after deep molecular response has been sustained for at least 2 years. We investigated the safety and efficacy of discontinuing second-line or subsequent dasatinib after at least 1 year of deep molecular response. METHODS: The Dasatinib Discontinuation trial was a prospective multicentre trial done in Japan. Eligible patients taking dasatinib and with confirmed stable deep molecular response were enrolled between April 1, 2011, and March 31, 2012. All patients received dasatinib consolidation therapy for at least 1 year. In those with sustained deep molecular response, dasatinib was discontinued. Patients were followed up every month in year 1 (clinical cutoff), every 3 months in year 2, and every 6 months in year 3 for deep molecular response and immunological profiles. The primary endpoint was the proportion of patients with treatment-free remission at 6 months after discontinuation. Molecular relapse was defined as loss of deep molecular response at any assessment. This study is registered, number UMIN000005130. FINDINGS: 88 patients were enrolled in the consolidation phase, 24 were excluded from the discontinuation phase due to fluctuations in BCR-ABL1 transcript levels. One patient was excluded because of positive expression of major and minor BCR-ABL1 transcripts in chronic myeloid leukaemia cells and the detection of minor BCR-ABL1 transcripts during consolidation. Thus, 63 patients discontinued dasatinib treatment. The 25 patients who were excluded from discontinuation continued to receive dasatinib and none showed disease progression. Median follow-up was 20.0 months (IQR 16.5-24.0). Of the 63 patients who discontinued and were not excluded, 30 patients maintained deep molecular response while 33 patients had molecular relapses, all within the first 7 months after discontinuation. The estimated overall treatment-free remission was 49% (95% CI 36-61) at 6 months. No severe treatment-related toxic effects were seen. Treatment was restarted in the 33 patients with relapse; rapid molecular responses were seen in all 33 patients, of whom 29 (88%) regained deep molecular response within 3 months, as did the remaining four by 6 months. INTERPRETATION: Dasatinib discontinuation after sustained deep molecular response for more than 1 year is feasible. FUNDING: Epidemiological and Clinical Research Information Network (ECRIN).
Subject(s)
Antineoplastic Agents/therapeutic use , Dasatinib/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Adult , Aged , Aged, 80 and over , Female , Humans , Japan , Male , Middle Aged , Neoplasm Recurrence, Local , Prospective Studies , Remission Induction , Treatment Outcome , Young AdultABSTRACT
We describe a 65-year-old woman with follicular lymphoma (FL), grade 1, stage IV, which occurred concurrently with B lymphoblastic leukemia/lymphoma. Through the evaluation of FL, the cells that were morphologically suspected of having undergone transformation were found in the bone marrow, and flow cytometric and cytogenetic analyses detected the transformed population that suggested concomitant t(8;22) with typical t(14;18) FL cells. Repeated analyses of the lymph nodes demonstrated the typical morphological, phenotypic, and cytogenetic features of FL. The patient received several multiagent chemotherapy regimens, but the disease gradually became resistant, and the patient died of leukemic progression. In B-cell malignancies, cases involving both BCL2 and MYC translocations simultaneously, so-called "double-hit leukemia/lymphoma (DHL)", have occasionally been reported. Patients with this type of translocation have a very poor clinical outcome, and no standard therapy has been established. In our case, FL was supposed to have transformed into B lymphoblastic leukemia via Burkitt's lymphoma-like phase. Our case is unique in that the transformed DHL cells, derived from clonally related FL cells, showed ongoing transformation from Burkitt-like feature to B lymphoblastic leukemia exclusively in the bone marrow, which suggests that the bone marrow may provide a preferable milieu for malignant transformation. Similar cases should be accumulated and analyzed carefully.
Subject(s)
Lymphoma, Follicular/pathology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B-Lymphocytes/pathology , Bone Marrow/pathology , Clone Cells , Drug Resistance, Neoplasm , Fatal Outcome , Female , Humans , Karyotyping , Lymph Nodes/pathology , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Translocation, GeneticABSTRACT
The complexity and heterogeneity of tumours have hindered efforts to identify commonalities among different cancers. Furthermore, because we have limited information on the prevalence and nature of ubiquitous molecular events that occur in neoplasms, it is unfeasible to implement molecular-targeted cancer screening and prevention. Here, we found that the FEAT protein is overexpressed in most human cancers, but weakly expressed in normal tissues including the testis, brain, and liver. Transgenic mice that ectopically expressed FEAT in the thymus, spleen, liver, and lung spontaneously developed invasive malignant lymphoma (48%, 19/40) and lung-metastasizing liver cancer (hepatocellular carcinoma) (35%, 14/40) that models human hepatocarcinogenesis, indicating the FEAT protein potently drives tumorigenesis in vivo. Gene expression profiling suggested that FEAT drives receptor tyrosine kinase and hedgehog signalling pathways. These findings demonstrate that integrated efforts to identify FEAT-like ubiquitous oncoproteins are useful and may provide promising approaches for cost-effective cancer screening and prevention.
Subject(s)
Cell Transformation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic/genetics , Genetic Predisposition to Disease/genetics , Methyltransferases/genetics , Neoplasm Proteins/genetics , Neoplasms/genetics , Promoter Regions, Genetic/genetics , Animals , Cell Line, Tumor , Humans , Mice , Mice, Transgenic , Neoplasm Proteins/metabolism , Up-RegulationABSTRACT
Progressive multifocal leukoencephalopathy (PML) is a rare and fatal demyelinating disease of the central nervous system caused by JC polyomavirus (JCV) reactivation in an immunocompromised host. We describe a case of PML in a 76-year-old woman with myelodysplastic syndrome, who had been treated with azathioprine for a pure red cell aplasia-like condition. PML was diagnosed based on the neurologic symptoms, the magnetic resonance imaging patterns and the detection of JCV DNA in the cerebrospinal fluid. She died ten months after the diagnosis. An autopsy confirmed the diagnosis, and JCV DNA was detected in the cerebrum. Azathioprine might have triggered PML.
Subject(s)
Leukoencephalopathy, Progressive Multifocal/diagnosis , Myelodysplastic Syndromes/diagnosis , Red-Cell Aplasia, Pure/diagnosis , Aged , Azathioprine/adverse effects , Female , Humans , Immunosuppressive Agents/adverse effects , Leukoencephalopathy, Progressive Multifocal/complications , Myelodysplastic Syndromes/complications , Red-Cell Aplasia, Pure/complicationsABSTRACT
Patients receiving splenectomy are at risk of a fatal fulminant infection called overwhelming post-splenectomy infection (OPSI). Here we report a rare case of toxic shock syndrome (TSS) evoked by group B streptococcus (GBS) in an asplenic young woman, which we considered a case of OPSI. A 34-year old woman consulted our hospital complaining of vomiting, diarrhea and fever that developed early in the morning. As the physical examination and routine laboratory tests did not disclose any serious abnormalities, she returned home after symptomatic treatment under a provisional diagnosis of acute enterocolitis. However, the next morning, she was transferred to the hospital complicated by acute renal failure, severe liver damage, respiratory insufficiency, disseminated intravascular coagulation and hypotension. She was admitted to ICU and treated with intravenous antibiotics, frequent transfusions of platelet concentrates, hemodialysis, and non-invasive positive pressure ventilation. Blood cultures grew gram-positive cocci, which later proved to be Streptococcus agalactiae (GBS). We diagnosed the patient with TSS due to GBS. Organ damage and symptoms improved gradually with intensive treatment, she was discharged from the hospital 26 days after admission. Although cases of TSS due to GBS are very rare, we must be aware of the potential risk of OPSI in a splenectomized patient.
Subject(s)
Postoperative Complications , Shock, Septic/diagnosis , Shock, Septic/microbiology , Splenectomy , Streptococcal Infections , Streptococcus agalactiae/isolation & purification , Adult , Disseminated Intravascular Coagulation/etiology , Female , Humans , Shock, Septic/complications , Shock, Septic/therapyABSTRACT
The development of autoimmune disease after autologous stem cell transplantation (ASCT) is very rare in multiple myeloma (MM). We describe the first case of Evans syndrome after ASCT for MM. A 60-year-old man with MM received ASCT and subsequently developed Evans syndrome following two febrile episodes. The syndrome was refractory to conventional therapies but it was managed with a second ASCT. This unique complication was thought to have been triggered by an infection during the recovery of the immune system. We assumed that reconstructing the immune system via ASCT might eliminate infection-induced autoantibodies to platelets and erythrocytes.
Subject(s)
Autoimmune Diseases/etiology , Autoimmune Diseases/surgery , Hematopoietic Stem Cell Transplantation/adverse effects , Multiple Myeloma/surgery , Autoimmune Diseases/diagnosis , Disease Management , Fatal Outcome , Hematopoietic Stem Cell Transplantation/methods , Humans , Male , Middle Aged , Multiple Myeloma/pathology , Syndrome , Transplantation Conditioning , Transplantation, AutologousABSTRACT
A 24-year-old man, who had suffered previous two episodes of non- Epstein-Barr virus (EBV)-associated hemophagocytic syndrome (HPS) at the ages of 16 and 18, developed EBV-induced infectious mononucleosis. His antibody pattern to EBV highlighted the initial infection. The disease took a self-limited course without developing into HPS. No reactivation of EBV infection was noted over the following 6 years. The patient may have attained immune competency in adulthood, which was somehow impaired during his adolescence.
Subject(s)
Infectious Mononucleosis/complications , Lymphohistiocytosis, Hemophagocytic/complications , Antibodies, Viral/blood , Herpesvirus 4, Human/immunology , Humans , Infectious Mononucleosis/etiology , Infectious Mononucleosis/immunology , Lymphohistiocytosis, Hemophagocytic/etiology , Lymphohistiocytosis, Hemophagocytic/immunology , Male , Time Factors , Young AdultABSTRACT
Thymic mucosa-associated lymphoid tissue (MALT) lymphoma shows distinct immunological characteristics, such as the expression of the IgA isotype, the frequent presence of immunoglobulin abnormalities, and a strong association with autoimmune disease, especially Sjögren's syndrome (SjS). We report a case of thymic MALT lymphoma, who exhibited biphasic changes in her clinical characteristics during the 4-year observation period after thymectomy. A 71-year-old woman was admitted because of suspected SjS. A diagnosis of primary thymic MALT lymphoma was made, and SjS was confirmed. Serological abnormalities such as polyclonal hypergammaglobulinemia, IgA M protein, and elevated levels of rheumatoid factor were noted. These abnormalities improved rapidly after the thymectomy, but did not completely disappear. Interestingly, the remaining abnormalities, which can be ascribed to the proliferation of B cells throughout the body under the influence of SjS, have been improving slowly but steadily during the 4-year observation period. It is suspected that the removal of the tumor by thymectomy has more or less normalized the immunological environment and alleviated the SjS disease activity.