Successful treatment with nilotinib after bosutinib-induced pulmonary arterial hypertension recurrence following dasatinib in chronic myeloid leukemia in chronic phase.

A 52-year-old man was diagnosed with chronic myeloid leukemia in the chronic phase (CML-CP). He experienced bosutinib-induced pulmonary arterial hypertension (PAH) recurrence following dasatinib use. Symptoms and examination findings associated with PAH improved after bosutinib cessation. Although nilotinib was started because of the loss of response after bosutinib cessation, a deep molecular response without PAH recurrence was achieved 3 months after the initiation of nilotinib therapy. PAH recurrence after switching to bosutinib due to dasatinib-induced PAH should be closely monitored. In addition, nilotinib therapy might be an effective approach in PAH cases related to dasatinib and/or bosutinib in patients with CML-CP.

[Extranodal NK/T cell lymphoma, nasal type with local recurrence in the contralateral nasal cavity 15 years after initial sequential chemoradiotherapy].

A 72-year-old woman was diagnosed with extranodal NK/T cell lymphoma of the right nasal cavity and received sequential radiochemotherapy comprising focal radiotherapy and THP-COP chemotherapy. Showed a complete tumor response to the treatment; however, the tumor recurred in the contralateral right nasal cavity 15 years after the initial treatment. This was judged to be a marginal recurrence in the radiation field. After four cycles of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy, a second complete response was achieved. It is possible that another recurrence occurs in the future, and if the lesion is localized at the time of recurrence, it may be possible to control the disease again. Careful follow-up is considered necessary.

[Successful treatment with imatinib for a patient with myeloid neoplasms with eosinophilia and abnormalities of PDGFRB due to t (5;14)(q33;q22)].

A 50-year old man with a 1-year history of eosinophilia presented with an eosinophil count exceeding 13,800/mm3 in the peripheral blood at the first visit. Bone marrow examination revealed that eosinophils accounted for 30% of the nucleated cell count, and G-band karyotyping analysis detected t (5;14)(q33;q22). Using peripheral blood FISH test, he was found to have platelet-derived growth factor receptor ß (PDGFRB) locus rearrangement at 5q32-33. The level of eosinophils in the peripheral blood reduced markedly 3 days after the initiation of Imatinib mesylate, 400 mg daily. This treatment was administered for 2 years, after which the peripheral blood FISH test was negative for PDGFRB. In this disease, although most cases are with t (5;12), those with t (5;14) are relatively rare, and the long-term course of this translocation is unknown.

Prognostic impact of the dosage of methotrexate combined with tacrolimus for graft-versus-host disease prophylaxis after cord blood transplantation.

The optimal dosage of methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis after cord blood transplantation (CBT) has not been well elucidated. Therefore, we conducted a retrospective study comparing a mini-MTX group (5 mg/m2 on day 1, 3 and 6) to a short-MTX group (10 mg/m2 on day 1 and 7 mg/m2 on day 3 and 6) after CBT. Sixty-three patients were classified as the mini-MTX group and 20 as the short-MTX group. The median time and cumulative incidence of neutrophil engraftment did not vary between the two groups. The cumulative incidence of grade 2-4 and grade 3-4 acute GVHD was similar in both groups. Overall survival in the mini-MTX group was significantly lower than in the short-MTX group (46.9% vs. 88.7% at 1 year, p < 0.01), contributing to higher non-relapse mortality (NRM) in the mini-MTX group (32.0% vs. 5.0% at 1 year, p = 0.02). In multivariate analysis, the mini-MTX regimen was the most powerful prognostic factor for OS (hazard ratio 4.11; p = 0.03). Although the reduced dosage of MTX had no effect on neutrophil engraftment, increased NRM due to higher incidence of infection, graft failure, and severe acute GVHD resulted in a lower survival rate in the mini-MTX group after CBT.

[A Case of Philadelphia Chromosome-Positive Acute Myeloid Leukemia Extramedullary Recurrence in a Patient Undergoing Thoracoscopy for Massive Pleural Effusion].

A man in his early 70s visited a previous hospital because of pancytopenia and was diagnosed with acute myeloid leukemia based on a bone marrowexamination. The karyotype was 46,XY, t(9;22)(q34;q11.2)[2/20], and real-time polymerase chain reaction(PCR)revealed minor bcr-abl chimeric mRNA. Finally, the patient was judged as having Philadelphia chromosome- positive acute myeloid leukemia, and remission induction chemotherapy with the JALSG AML 201 protocol was initiated in combination with dasatinib to achieve complete remission. After 3 courses of consolidation chemotherapy, the anticancer drugs were discontinued because of deterioration of his general condition and renal insufficiency. Six months after the initial treatment, he was referred to our department, and no evidence of recurrence was confirmed on bone marrow examination. However, 2 months later, right massive pleural effusion was detected, and he was admitted to the department of pneumology at our hospital. Thoracoscopic pleural biopsy was performed at the time of chest tube insertion, and he was diagnosed with acute myeloid leukemia extramedullary recurrence. Peripheral myeloblasts appeared and increased rapidly, accompanied by further exacerbation of renal function; thus, he received palliative care at the department of hematology and oncology.

[A Case of POEMS Syndrome Treated by Ld Prior to HDCTx Followed by aPBSCT].

A man in his late 40s was presented to a hospital with complaints of peripheral numbness and fatigue. Systemic edema, pleural effusion and ascites, pigmentation, splenomegaly, and CT findings of osteoplastic changes suggested POEMS syndrome. He was referred to our division, and a bone marrow examination indicated MGUS. However, his serum level of vascular endothelial growth factor(VEGF)was elevated to 1,520 pg/mL, and IgA-l type M protein was detected. He was diagnosed with POEMS syndrome and received four cycles of induction chemotherapy containing lenalidomide and dexamethasone( Ld). All symptoms improved gradually, and after auto peripheral blood stem cell harvest(aPBSCH), high-dose melphalan was administered, followed by auto peripheral blood stem cell transplantation(aPBSCT)being performed. Pleural effusion and ascites disappeared, while numbness remained slightly. His serum level of VEGF decreased to 68 pg/mL when the planned primary treatment was completed. Many cases of POEMS syndrome involve peripheral neuropathy; therefore, a lenalidomide-containing regimen may be a more adequate strategy than ones containing thalidomide and bortezomib.

[Sarcoidosis-lymphoma syndrome showing abnormal FDG uptake in lymph nodes and muscles upon post-chemotherapy PET/CT imaging].

A 65-year-old woman was diagnosed with rheumatoid arthritis in 2010 and was treated with methotrexate (MTX). In 2012, she was diagnosed with sarcoidosis and underwent a follow-up therapy for mild peripheral neuropathy due to neurosarcoidosis. In 2018, she experienced primary splenic diffuse large B-cell lymphoma (DLBCL) and was diagnosed with sarcoidosis-lymphoma syndrome (SLS). MTX was discontinued, and six cycles of rituximab were administered combined with chemotherapy. Positron emission tomography combined with computed tomography performed 18 weeks after the last cycle of chemotherapy showed new abnormal fluoro-2-deoxy-D-glucose (FDG) uptake in the mediastinal and hilar lymph nodes and skeletal muscles. Sarcoidosis was suspected because of increased serum angiotensin-converting enzyme levels and magnetic resonance imaging findings in the lower limb muscles. However, pathological findings of DLBCL and sarcoidosis were not confirmed in the hilar lymph node biopsy. Therefore, malignant lymphoma can be distinguished from sarcoidosis using abnormal FDG uptake after chemotherapy for SLS.

[Azacitidine for Therapy-Related Myelodysplastic Syndrome Following Oxaliplatin (L-OHP)Therapy for Metastatic Rectal Cancer].

Therapy-related myelodysplasticsyndrome(t-MDS)has been reported to occur after treatment with cytotoxic agents and radiation. Here, we report a case of t-MDS following oxaliplatin(L-OHP)exposure, which was successfully treated with azacitidine(AZA). A 71-year-old man was referred to our department because of pancytopenia. He had been diagnosed with rectal cancer(cT4aNXM0, stage II B-III C, RAS gene status wild-type)3 years ago and had received 8 courses of capecitabine(CAP)and L-OHP(XELOX regimen), followed by 48 courses of CAP and bevacizumab. Before referral, recurrence of rectal cancer was detected using CT after the last course of chemotherapy. A bone marrow examination revealed multilineage dysplasia and 9.0%myeloblasts. Cytogenetic analysis disclosed a chromosome 7 abnormality. The diagnosis of t- MDS was made and treatment with AZA was initiated. Subsequently, temporary but significant hematological improvements were observed, which enabled the patient to receive additional palliative radiation therapy against the locally relapsed rectal cancer. AZA might be useful in t-MDS because of its efficacy and low toxicity.

Farnesoid X receptor regulates the growth of renal adenocarcinoma cells without affecting that of a normal renal cell-derived cell line.

The farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor which is abundant in the liver, intestine, and kidney. FXR is a pivotal factor in cholesterol/bile acid homeostasis but is involved in the growth of hepatocellular carcinoma cells. In the present study, we investigated whether FXR is also involved in the growth of renal adenocarcinoma cells. The cell growth of renal adenocarcinoma cell line ACHN was inhibited by FXR knockdown and stimulated by FXR ligand, while that of a normal renal cell-derived cell line, HK-2, was not affected. The carcinoma-specific stimulation of cell growth by FXR was found to arise from down-regulation of p53 and p21/Cip1 mRNA expression. Our study showed that FXR stimulates proliferation of renal adenocarcinoma cells and that FXR knockdown is useful for growth suppression of renal adenocarcinoma without cytotoxicity to normal renal cells.

Cardenolide glycosides from the seeds of Digitalis purpurea exhibit carcinoma-specific cytotoxicity toward renal adenocarcinoma and hepatocellular carcinoma cells.

Four cardenolide glycosides, glucodigifucoside (2), 3'-O-acetylglucoevatromonoside (9), digitoxigenin 3-O-ß-D-glucopyranosyl-(1 → 4)-ß-D-glucopyranosyl-(1 → 4)-3-O-acetyl-ß-D-digitoxopyranoside (11), and purpureaglycoside A (12), isolated from the seeds of Digitalis purpurea, exhibited potent cytotoxicity against human renal adenocarcinoma cell line ACHN. These compounds exhibited significantly lower IC50 values against ACHN than that against normal human renal proximal tubule-derived cell line HK-2. In particular, 2 exhibited the most potent and carcinoma-specific cytotoxicity, with a sixfold lower IC50 value against ACHN than that against HK-2. Measurement of cyclin-dependent kinase inhibitor levels revealed that upregulation of p21/Cip1 expression was involved in the carcinoma-specific cytotoxicity of 2. Further, compound 2 also exhibited the carcinoma-specific cytotoxicity toward hepatocellular carcinoma cell line.

Crystallization and preliminary X-ray analysis of TBP-interacting protein from the hyperthermophilic archaeon Thermococcus kodakaraensis strain KOD1.

The 26 kDa TBP (TATA-binding protein) interacting protein from the hyperthermophilic archaeon Thermococcus kodakaraensis KOD1 (Tk-TIP26) is a possible transcriptional regulatory protein in Thermococcales. Here, the crystallization of both the native and selenomethionine-substituted proteins and data collection are described. The native crystals belong to the tetragonal space group P4(1)2(1)2 or P4(3)2(1)2, with unit-cell parameters a = 73.83, c = 86.41 A, and diffract to 2.2 A using synchrotron radiation. MAD data was collected and a Bijvoet difference Patterson map showed strong peaks sufficient to determine the positions of the Se atoms.