Circulating Tumor DNA Reflects Histologic and Clinical Characteristics of Various Lymphoma Subtypes / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#We designed and evaluated the clinical performance of a plasma circulating tumor DNA (ctDNA) panel of 112 genes in various subtypes of lymphoma. @*Materials and Methods@#Targeted deep sequencing with an error-corrected algorithm was performed in ctDNA from plasma samples that were collected before treatment in 42 lymphoma patients. Blood buffy coat was utilized as a germline control. We evaluated the targeted gene panel using mutation detection concordance on the plasma samples with matched tissue samples analyzed the mutation profiles of the ctDNA. @*Results@#Next-generation sequencing analysis using matched tissue samples was available for 18 of the 42 patients. At least one mutation was detected in the majority of matched tissue biopsy samples (88.9%) and plasma samples (83.3%). A considerable number of mutations (40.4%) that were detected in the tissue samples were also found in the matched plasma samples. Majority of patients (21/42) were diffuse large B cell lymphoma patients. The overall detection rate of ctDNA in patients was 85.7% (36/42). The frequently mutated genes included PIM1, TET2, BCL2, KMT2D, KLHL6, HIST1H1E, and IRF8. A cutoff concentration (4,506 pg/mL) of ctDNA provided 88.9% sensitivity and 82.1% specificity to predict ctDNA mutation detection. The ctDNA concentration correlated with elevated lactate dehydrogenase level and the disease stage. @*Conclusion@#Our design panel can detect many actionable gene mutations, including those at low frequency. Therefore, liquid biopsy can be applied clinically in the evaluation of lymphoma patients, especially in aggressive lymphoma patients.

Aurora A kinase expression is increased in leukemia stem cells, and a selective Aurora A kinase inhibitor enhances Ara-C-induced apoptosis in acute myeloid leukemia stem cells

BACKGROUND: The overexpression of Aurora A kinase (AurA) has been reported in various malignancies, including acute myeloid leukemia (AML). However, the expression of AurA and the effects of AurA inhibition in cancer stem cells are not yet fully understood. We investigated the expression and inhibition of AurA in AML stem cells (CD34+/CD38-). METHODS: Expression of AurA was investigated in cell lines (NB4 and KG1) that express high levels of CD34 and low levels of CD38. Primary AML cells were harvested from 8 patients. The expression of AurA and cell death induced by inhibition of AurA were analyzed in CD34+/CD38- cells. RESULTS: AurA was shown to be overexpressed in both primary AML cells and leukemia stem cells (LSCs) compared to normal hematopoietic stem cells. Inhibition of AurA plus cytarabine treatment in LSCs resulted in increased cytotoxicity compared to cytarabine treatment alone. Additional stimulation with granulocyte-colony stimulating factor (G-CSF) increased the cell death caused by AurA inhibition plus cytarabine treatment. CONCLUSION: To our knowledge, this is the first report describing increased expression of AurA in LSCs. Our results suggest that selective AurA inhibition may be used to reduce LSCs, and this reduction may be enhanced by stimulation with G-CSF. Further exploration of relationship between nuclear factor kappa-B and AurA inhibition and the potential of AurA inhibition for use in leukemia treatment is needed.

Clinical significance of B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) in acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

BACKGROUND: BAFF (B cell-activating factor) and APRIL (a proliferation-inducing ligand) are members of the tumor necrosis factor family and promote B cell survival and proliferation. We evaluated the correlation between serum concentration of BAFF or APRIL and severity of acute graft-versus-host disease (GVHD). METHODS: Fifteen patients who received allogeneic hematopoietic stem transplantation for leukemia and developed acute GVHD were enrolled. We determined serum concentrations of BAFF and APRIL at the onset of the first clinical manifestation of GVHD by enzyme-linked immunosorbent assay. RESULTS: Nine patients had grade 2 acute GVHD, and 6 had grade 3-4 acute GVHD. The BAFF serum concentration was higher in patients with grade 3-4 acute GVHD (1,093.42 in grade 2 vs. 2,171.99 pg/mL in grade 3-4), although the difference was not significant (P=0.077). However, the ratio of BAFF serum concentration to absolute lymphocyte count (ALC) (BAFF/ALC) was significantly higher in patients with grade 3-4 acute GVHD (P=0.045). The APRIL serum concentration and APRIL/ALC ratio showed similar results (P=0.077 and P=0.013, respectively). CONCLUSION: Patients with grade 3-4 acute GVHD had higher BAFF/ALC and APRIL/ALC ratios than patients with grade 2 acute GVHD. These findings suggest that B cells might play an important role in the development of acute GVHD, and that the BAFF and APRIL concentrations in serum might be significant predictive factors for estimating the severity of acute GVHD. Their clinical significance should be further evaluated in a larger patient population.

Polymyositis as a manifestation of chronic graft-versus-host disease after allogeneic bone marrow transplantation / 대한내과학회지

Chronic graft-versus-host disease (cGVHD) remains one of the major complications of allogeneic hematopoietic stem cell transplantation. Although cGVHD has various manifestations in almost all organs, cases of cGVHD involving skeletal muscle are rare. We experienced a 26-year-old man with polymyositis with no other concurrent cGVHD after HLA-matched myeloablative transplantation for acute myelogenous leukemia. He had a history of acute and chronic GVHD. The patient complained of fever and myalgia 3 years after transplantation. The serum creatine kinase (CK, 2,223 IU/L) and aldolase (87.6 sigmaU/mL) were elevated. The muscle biopsy and electromyographic findings were consistent with myositis with necrosis. His condition improved dramatically with immunosuppressive therapy. Although muscle involvement, alone, in cGVHD is very rare, early diagnosis and proper treatment are still important.

A Case Report of Posttransplant Lymphoproliferative Disorders Successfully Treated with R-CHOP in Korea

Posttransplant lymphoproliferative disorder (PTLD) is a group of heterogeneous lymphoid diseases that cause serious complications after organ or stem cell transplantation. The onset of PTLD is mostly due to EBV infection-induced B-cell proliferation and a defect in cytotoxic T cell function that occurs with immunosuppression. The usual treatment strategy for PTLD is reduction or withdrawal of immunosuppressive drugs with or without the administration of antiviral agents. Recently, various studies on the efficacy of rituximab or chemotherapy have been reported. We report two cases of rapidly progressing and complicated PTLDs after kidney transplantation that were successfully treated with a combination regimen consisting of rituximab, cyclophosphamide, adriamycin, vincristine and prednisolone (R-CHOP).