Biomedical subjects

Noriko Doki

Publications and source records attributed to Noriko Doki.

11 recordsLinked to original sources

PubMed2026

Case Report: Immune-driven clonal selection underlying lineage switch from B-Precursor acute lymphoblastic leukemia to acute myeloid leukemia following inotuzumab ozogamicin.

Lineage switch (LS), defined as a change in leukemic lineage during the disease course, is a rare but clinically significant event in acute leukemia and is typically associated with poor prognosis. Although LS has been increasingly reported following targeted immunotherapies, the clonal mechanisms underlying this phenomenon remain incompletely understood, particularly in cases without KMT2A rearrangement. We report a case of LS from B-precursor acute lymphoblastic leukemia (BCP-ALL) to acute myeloid leukemia (AML) following treatment with the CD22-targeted antibody-drug conjugate inotuzumab ozogamicin. To elucidate the clonal architecture underlying LS, targeted next-generation sequencing was performed on bone marrow samples obtained at multiple time points throughout the disease course. Genomic analysis demonstrated that the lymphoid and myeloid disease phases shared ancestral genetic alterations but displayed distinct mutational profiles. At the time of LS, TP53 and SMC1A mutations newly emerged, whereas only a subset of mutations detected at ALL relapse was retained. These findings suggest that the AML phase most likely resulted from the selective expansion of a genetically distinct subclone derived from a common progenitor, rather than the direct transdifferentiation of the dominant ALL clone, consistent with immunotherapy-driven clonal selection. Longitudinal genomic profiling revealed stepwise clonal evolution during disease progression, supporting a model of immunotherapy-driven clonal selection leading to LS. This case provides molecular evidence suggesting that immune-targeted therapy can promote expansion of minor pre-existing subclones with alternative lineage potential within a common progenitor even in non-KMT2A-rearranged leukemia. Our findings highlight the importance of comprehensive genomic monitoring during immunotherapy to identify therapy-resistant subclones and better understand mechanisms of lineage plasticity in acute leukemia.

Humans↗

PubMed2006

Molecular analysis of PDGFRalpha/beta genes in core binding factor leukemia with eosinophilia.

Eosinophilia sometimes occurs in acute myeloid leukemia (AML), especially in core binding factor (CBF) leukemia. However, the pathogenesis of the differentiation from leukemic progenitors to eosinophils is not well understood in this type of leukemia. Recent reports showed that a novel fusion tyrosine kinase, Fip1-like1 (FIP1L1) platelet-derived growth factor receptor alpha (PDGFRalpha), is found in idiopathic hypereosinophilic syndrome. The involvement of another chimeric gene, PDGFRbeta, was also reported in myeloproliferative disorder with eosinophilia. These chimeric genes cause constitutive activation of PDGFR tyrosine kinases. On the other hand, a two-hit model for the pathogenesis of AML, which seems to be caused by inactivating mutations in transcription factors and genetic lesions in tyrosine kinase resulting in constitutive activation, has been proposed. On the basis of these findings, we screened for the expression of the FIP1L1-PDGFRalpha fusion gene and for mutations in the juxtamembrane and tyrosine kinase domains of PDGFRalpha/beta genes in 22 cases of CBF leukemia with eosinophilia. Among these cases, no FIP1L1-PDGFRalpha fusion gene was found. Although cDNA sequencing also detected three types of single-nucleotide alterations at kinase domains in PDGFRalpha/beta genes, all of them were silent changes and polymorphisms. Therefore, PDGFRalpha/beta genes do not appear to play a significant pathogenetic role in eosinophilia or leukemogenesis of CBF leukemia.

Adult↗

PubMed2005

Pericardial graft vs. host disease in a patient with myelodysplastic syndrome following peripheral blood stem cell transplantation.

A patient with myelodysplastic syndrome developed pericardial effusion 20 month after allogenic peripheral blood stem cell transplantation. Sclerotic and erythematous skin lesions were observed over the face and extremities, and a diagnosis of chronic graft vs. host disease (GVHD) was made based on skin biopsy findings. Pericardial fluid contained numerous CD8+/HLA-DR+ lymphocytes, but no leukaemic cells. Tumour necrosis factor alpha (TNFalpha) and soluble Fas (sFas) levels were highly elevated in both the effusion and serum. The patient was treated with methylprednisolone and tacrolimus. Skin GVHD improved rapidly associated with resolution of pericardial effusion and reductions in cytokine levels. We concluded that pericardial effusion was due to pericarditis and was a manifestation of chronic GVHD in this patient, and that cytotoxic lymphocytes and specific cytokines played significant roles.

Adult↗

PubMed2005

X-linked lymphoproliferative disease in an adult.

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by an extreme susceptibility to Epstein-Barr virus (EBV) infection. Patients with XLP mainly present with the 3 clinical manifestations of fulminant infectious mononucleosis, lymphoproliferative disorder, and dysgammaglobulinemia and in rare cases have aplastic anemia and lymphocytic vasculitis. The causative gene for XLP was identified as SH2D1A/DSHP/SLAM-associated protein (SAP) in 1998, and genetic analysis has been used for the definite diagnosis of XLP. Diagnosis for most patients occurs at ages younger than 10 years, and there are few adult patients. Here we describe a 23-year-old man with hypogammaglobulinemia and EBV-associated hemophagocytic lymphohistiocytosis and a diagnosis of XLP. In addition, the patient showed type 1 helper T-cell (Th1) skewing, as has been described in Sap knock-out mice. Th1/Th2 imbalance in humans, as well as in mice, may play an important role in the pathogenesis of XLP.

Adult↗

PubMed2005

[Acute myeloid leukemia complicated with pulmonary alveolar proteinosis at presentation].

A 47-year-old male had symptoms of coughing and with fever and was admitted to our hospital where tests revealed he had anemia and thrombocytopenia. Following the results obtained from a bone marrow aspiration, he was diagnosed as having acute myeloid leukemia (AML). A chest radiograph and a CT scan demonstrated nodular shadows and pleural exudate in both lungs. We suspected atypical pneumonia, or fungal pneumonia, and he was subsequently given antibiotics and antifungal agents, which were, however, ineffective. On the third day after admission, he was put on mechanical ventilation, and a bronchoalveolar lavage examination revealed no germs. His respiration, however, progressively worsened and he died on the twelfth day after admission. Although the autopsy findings revealed no infectious lesions in his lungs, a PAS-positive intra-alveolar eosinophilic material, which was positive for surfactant apoprotein A staining, was present. As a result of the autopsy findings, a diagnosis of secondary pulmonary alveolar proteinosis (PAP) associated with AML was made. Among the reported cases of PAP in hematological malignancy, there has not been one case detected at the time AML was diagnosed. If there is evidence of an unknown cause of lung infiltration when AML is diagnosed, attention should be paid to the possibility of the presence of PAP.

Fatal Outcome↗

PubMed2005

[Acute myelogenous leukemia with mediastinal and subcutaneous emphysema following chronic GVHD after allogeneic bone marrow transplantation].

A 38-year-old man was diagnosed as having acute myelogenous leukemia in December 2001. He achieved a complete remission after undergoing three courses of induction chemotherapy. As the patient's prognosis was considered to be poor, he was then treated with a bone marrow transplant from his HLA 1 antigen mismatched sister in May 2002. Grade 2 skin graft-versus-host-disease (GVHD) developed on day 14 but reduced with methylprednisolone (mPSL). Prednisolone (PSL) was discontinued on day 104, and the patient was discharged on day 112. There was no evidence of clinical chronic GVHD, the serum creatinine level remained high, and cyclosporine (CsA) was gradually tapered off and discontinued on day 165. However chronic GVHD of the skin appeared on day 179, and CsA (100 mg/day) was restarted. On day 186 he was admitted to our hospital complaining of fever. A CT scan of the chest demonstrated bilateral interstitial infiltrates, which were considered as lung GVHD lesions and PSL was started, following which chronic GVHD of the skin and liver improved. The lung GVHD worsened, however, subcutaneous and mediastinal emphysema developed and the patient died on day 206. Interstitial pneumonia had progressively worsened as the manifestation of the chronic lung GVHD. We concluded that this clinical course was rare.

Adult↗

PubMed2004

[Analysis of acute liver "graft-versus-host disease" following allogeneic myeloablative stem cell transplant].

The purpose of this study was to evaluate liver graft-versus-host disease (GVHD) after allogeneic myeloablative stem cell transplant (within day 100). We retrospectively reviewed the data on 61 patients with incidence of hepatic GVHD, the clinical course, laboratory data and histologic features of the liver biopsy. Between February 1998 and March 2002, 61 patients received an allogeneic myeloablative stem cell transplant. The diagnosis of liver dysfunction was based on marked (more than 3 times the upper normal limit) elevation of serum aminotransferases or on a level above 2 mg/dl of total bilirubin. We used criteria for grading (GVHD) on consensus conference. The diagnosis of hepatic "GVHD" was based on classical liver GVHD, on histological GVHD without jaundice or on elevation of serum aminotransferases with other GVHD. Liver function abnormality occurred in 50 out of 61 (82%). The main causes of hepatic dysfunction were hepatic "GVHD" (19 out of 50, 38%). Of the 19 hepatic "GVHD" patients, elevation of serum aminotransferases alone was seen in 13 patients (68%), jaundice alone was seen in 1 patient (5%) and both were seen in 5 patients (27%). The treatment with glucocorticoids was successful in those patients with elevation of serum aminotransferases alone.

Acute Disease↗

PubMed2004

[Acute myeloid leukemia with Aspergillus tracheobronchitis after allogeneic peripheral blood stem cell transplant].

A 51-year-old female with acute myeloid leukemia was admitted to our hospital in December 2001. Though she had undergone two courses of induction chemotherapy (idarubicin hydrochloride + cytarabine), she failed to achieve a complete remission. In April 2002, while in non-complete remission, she subsequently underwent total body irradiation (TBI) and treatment with cyclophosphamide (CY) and etoposide (VP-16) before receiving an allogeneic peripheral blood stem cell transplant from her HLA-identical brother. For graft-versus-host disease (GVHD) prophylaxis, she was given tacrolimus and methotrexate. The infused CD34 positive cells provided 8.1 x 10(6) cells per kg. Engraftment was obtained on post-transplant day 14, and there was no evidence of clinical acute GVHD. The use of tacrolimus was discontinued on post-transplant day 60. As there was no occurrence of clinical acute GVHD, the patient received a donor lymphocyte infusion (CD3 cells 0.57 X 10(7) cells per kg) on post-transplant day 105. On day 132, however, she complained of coughing and fever, and on day 135, she was admitted to our hospital again for dyspnea. A CT scan demonstrated ground-glass opacity in the right pulmonary lobe. After considering her clinical course, symptoms, blood gas, CT scans, etc., we suspected interstitial pneumonia. The dyspnea progressively worsened, however, and despite the use of mechanical ventilation from day 143, the patient died on day 149. From the day she was admitted till the day she was intubated, she was unable to produce sputum. Autopsy findings revealed yellow-white tracheal pseudomembranes, as well as Aspergillus hyphae in the trachea, bronchus, and bilateral lungs. These findings are characteristic of Aspergillus tracheobronchitis. The clinical course of Aspergillus tracheobronchitis in allogeneic stem cell transplant recipients is, however, different from that of the usual invasive Aspergillus infection, and although Aspergillus tracheobronchitis is a very rare disease, attention should be paid to the possibility of its occurrence.

Aspergillosis↗

PubMed2004

[Analysis of varicella zoster virus infection following allogeneic stem cell transplants].

The purpose of this study was to evaluate patients who contracted the varicella zoster virus infection (VZV) following their allogeneic stem cell transplants. We retrospectively reviewed the incidence and the timing of varicella zoster virus (VZV) infections, including the clinical course, complications, and associated clinical risk factors. Between January 1998 and April 2003, a total of 71 patients received allogeneic stem cell transplants in our hospital. For prophylaxis of the herpes virus infection, all patients were given a daily oral 1000 mg dose of acyclovir from day -7 to day +35. Among the 71 patients, 28 of them (39.4%) developed VZV infection between day 77 and day 980 (median 182 days) following their allogeneic stem cell transplants. In 21 of these infected patients (75%) the occurrence was within the first 300 days after the transplant. Twenty-two patients (78.5%) were under treatment with immunosuppressive agents. Twenty-six patients developed only one episode of the VZV infection after their transplants, but two other patients developed two episodes. Twenty one patients (75%) stricken with the VZV infections had cutaneous reactivation infections of a single dermatome, and in one patient two dermatomes were affected. Five patients (17.8%) developed disseminated cutaneous zoster, and one patient (3.6%) developed a visceral infection. Treatment with acyclovir (oral or drip infusion) was successful in 25 patients. Two patients improved with vidarabine treatment, however the patient with the visceral infection died despite the use of acyclovir. The incidence of visceral infection was low, but the one case was fatal.

Acyclovir↗

PubMed2003

[Successful recovery of an acute myelogenous leukemia patient from a coma possibly due to leukoencephalopathy].

A-36-year-old male diagnosed with acute myelogenous leukemia (AML, M2) failed to achieve a complete remission after having undergone two courses of induction chemotherapy (idarubicin hydrochloride + cytarabine, high-dose cytarabine), and moreover, his cerebrospinal fluid (CSF) then revealed abnormal blasts. Dosages of 30 mg of methotrexate, 80 mg of cytarabine, and 40 mg of prednisolone acetate were given via lumbar puncture, and following this treatment, the leukemic cells were no longer detectable in his CSF. As a prophylaxis for meningeal leukemia relapse, he continued to receive intrathecal chemotherapy (methotrexate, prednisolone acetate) twice a week, and later he underwent reinduction therapy (second high-dose cytarabine). He displayed mental disorientation on the thirty-seventh day after he had been given a high-dose of cytarabine (araC). Up to the thirty-seventh day, he had also been given a total of 135 mg of intrathecal methotrexate. On the thirty-ninth day he fell into a coma, and his brain computed tomography (CT) demonstrated low density areas in the white matter, in addition to edema. These findings were compatible with leukoencephalopathy. With the administration of glycerin and methylprednisolone, his condition, however, began to reverse, and by the fifty-third day his brain edema had subsided and his mental condition had improved. On the ninetieth day he began to walk without assistance, and after the third course of re-induction chemotherapy, he achieved complete remission. He is currently doing well.

Adult↗

PubMed2002

[Acute myeloid leukemia with infective endocarditis].

We present here a patient with acute myeloid leukemia (M2) who developed fatal infective endocarditis. On admission, the patient (67-year-old male) had mitral stenosis and atrial fibrillation. Complete remission was achieved after induction chemotherapy. During the course of consolidation therapy, he developed sepsis caused by coagulase-negative staphylococcus, which was successfully treated with antibiotics. Thereafter, blood culture yielded multidrug-resistant staphylococcus epidermidis. An echocardiogram revealed mitral valve regurgitation with vegetation. He was diagnosed as having infectious endocarditis. In spite of prolonged antibiotic therapy, destruction of the mitral valve progressed, and the patient underwent valve replacement therapy. He died of cardiac tamponade 5 days after the surgery.

Acinetobacter Infections↗