AMP-activated protein kinase activation primes cytoplasmic translocation and autophagic degradation of the BCR-ABL protein in CML cells.

Chronic myeloid leukemia is driven by the BCR-ABL oncoprotein, a constitutively active protein tyrosine kinase. Although tyrosine kinase inhibitors (TKIs) have greatly improved the prognosis of CML patients, the emergence of TKI resistance is an important clinical problem, which deserves additional treatment options based on unique biological properties to CML cells. In this study, we show that metabolic homeostasis is critical for survival of CML cells, especially when the disease is in advanced stages. The BCR-ABL protein activates AMP-activated protein kinase (AMPK) for ATP production and the mTOR pathway to suppress autophagy. BCR-ABL is detected in the nuclei of advanced-stage CML cells, in which ATP is sufficiently supplied by enhanced glucose metabolism. AMP-activated protein kinase is further activated under energy-deprived conditions and triggers autophagy through ULK1 phosphorylation and mTOR inhibition. In addition, AMPK phosphorylates 14-3-3 and Beclin 1 to facilitate cytoplasmic translocation of nuclear BCR-ABL in a BCR-ABL/14-3-3τ/Beclin1/XPO1 complex. Cytoplasmic BCR-ABL protein undergoes autophagic degradation when intracellular ATP is exhausted by disruption of the energy balance or forced autophagy flux with AMP mimetics, mTOR inhibitors, or arsenic trioxide, leading to apoptotic cell death. This pathway represents a novel therapeutic vulnerability that could be useful for treating TKI-resistant CML.

[A Case of Platinum-Resistant Recurrent Ovarian Cancer with Idiopathic Thrombocytopenic Purpura].

In the present report, the patient was a 55-year-old woman who had undergone an oophorectomy in October 2016 as surgical intervention for ovarian cancer, followed by 6 courses of TC therapy as postoperative adjuvant therapy. She was diagnosed with recurrent ovarian cancer in August 2017, and we planned anticancer drug treatment considering that the tumor exhibited platinum resistance. However, the platelet count decreased significantly to 2.4×104/µL. Accordingly, she was referred to the hematology department and was diagnosed with idiopathic thrombocytopenic purpura. She was started on oral eltrombopag, and her platelet level recovered to 5.8×104/µL on day 68. Next, gemcitabine plus bevacizumab therapy was initiated. However, as the platelet level again decreased to 1.6×104/µL on day 8, the eltrombopag dose was increased only for 5 days before and after the anticancer drug administration on day 1. Accordingly, after increasing the eltrombopag dose, the anticancer drug treatment was performed without interruptions. Moreover, the gemcitabine dose could be increased. Herein, we report that in patients with platinum-resistant recurrent ovarian cancer complicated with idiopathic thrombocytopenic purpura, increasing the oral hematopoietic stimulant dose for 5 days before and after day 1 had beneficial results in continuing anticancer drug treatment.

Pretreatment evaluation of fluorescence resonance energy transfer-based drug sensitivity test for patients with chronic myelogenous leukemia treated with dasatinib.

Tyrosine kinase inhibitors (TKI) are used for primary therapy in patients with newly diagnosed CML. However, a reliable method for optimal selection of a TKI from the viewpoint of drug sensitivity of CML cells has not been established. We have developed a FRET-based drug sensitivity test in which a CrkL-derived fluorescent biosensor efficiently quantifies the kinase activity of BCR-ABL of living cells and sensitively evaluates the inhibitory activity of a TKI against BCR-ABL. Here, we validated the utility of the FRET-based drug sensitivity test carried out at diagnosis for predicting the molecular efficacy. Sixty-two patients with newly diagnosed chronic phase CML were enrolled in this study and treated with dasatinib. Bone marrow cells at diagnosis were subjected to FRET analysis. The ΔFRET value was calculated by subtraction of FRET efficiency in the presence of dasatinib from that in the absence of dasatinib. Treatment response was evaluated every 3 months by the BCR-ABL1 International Scale. Based on the ΔFRET value and molecular response, a threshold of the ΔFRET value in the top 10% of FRET efficiency was set to 0.31. Patients with ΔFRET value ≥0.31 had significantly superior molecular responses (MMR at 6 and 9 months and both MR4 and MR4.5 at 6, 9, and 12 months) compared with the responses in patients with ΔFRET value <0.31. These results suggest that the FRET-based drug sensitivity test at diagnosis can predict early and deep molecular responses. This study is registered with UMIN Clinical Trials Registry (UMIN000006358).

A nationwide survey of hypoplastic myelodysplastic syndrome (a multicenter retrospective study).

Hypoplastic myelodysplastic syndrome (hMDS) is a distinct entity with bone marrow (BM) hypocellularity and the risk of death from BM failure (BMF). To elucidate the characteristics of hMDS, the data of 129 patients diagnosed between April 2003 and March 2012 were collected from 20 institutions and the central review team of the National Research Group on Idiopathic Bone Marrow Failure Syndromes, and compared with 115 non-hMDS patients. More RA and fewer CMMoL and RAEB-t in French-American-British (FAB) and more RCUD and MDS-U and fewer RCMD in World Health Organization (WHO) classifications were found in hMDS than non-hMDS with significant differences. The overall survival (OS) and AML progression-free survival (AML-PFS) of hMDS were higher than those of non-hMDS, especially in patients at age ≥50 and of lower risk in Revised International Prognostic Scoring System (IPSS-R). In competing risks analysis, hMDS exhibited decreased risk of AML-progression in lower IPSS or IPSS-R risk patients, and higher risk of death from BMF in patients at age ≥50. Poor performance status (PS ≥2) and high karyotype risks in IPSS-R (high and very high) were significant risk factors of death and AML-progression in Cox proportional hazards analysis.

Bleeding Risk of Acupuncture for Patients with Hematological Malignancies Accompanying Thrombocytopenia: A Retrospective Chart Review.

Introduction: In recent years, it has been reported that acupuncture is useful for alleviating the symptoms of patients with hematological malignancies, but the safety of acupuncture for such patients has not been established. This study evaluated the risk of bleeding from acupuncture in patients with hematological malignancies accompanying thrombocytopenia. Methods: The authors performed a retrospective investigation of the medical records of patients with hematological malignancies who received acupuncture during hospitalization at the hematology department of a single medical center in Japan. The bleeding risk at the acupuncture site was evaluated in the following four groups according to the platelet count measured on the day of acupuncture treatment: (1) <20 × 103/µL, (2) 20-49 × 103/µL, (3) 50-99 × 103/µL, and (4) 100 × 103/µL or more. Occurrence of grade 2 or higher bleeding according to the Common Terminology Criteria for Adverse Events, version 5.0, within 24 h from the acupuncture session or before the next session was defined as an event, and the risk of occurrence of bleeding was examined in each group. Results: Of 2423 acupuncture sessions conducted on 51 patients with hematological malignancies, 815 were included in the analysis. Ninety sessions were performed in the <20 × 103/µL platelet count group, 161 in the 20-49 × 103/µL group, 133 in the 50-99 × 103/µL group, and 431 in the 100 × 103/µL or more group. No bleeding event according to the authors' definition occurred in any of these groups. Conclusions: This study is the largest to date to assess the bleeding risk of acupuncture in patients with hematological malignancies accompanying thrombocytopenia. The authors considered that acupuncture could be safely performed without causing serious bleeding for patients with hematological malignancies accompanying thrombocytopenia.

MTX-HOPE is a low-dose salvage chemotherapy for aged patients with relapsed or refractory non-Hodgkin lymphoma.

As the aging society advances, the number of non-Hodgkin lymphoma (NHL) patients is increasing. Aged relapsed or refractory (r/r) NHL patients have limited treatment options. Therefore, a safe and effective regimen is urgently needed for these patients. Thus, we originally developed the MTX-HOPE (methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide) regimen for r/r NHL and validated the safety and efficacy of this regimen in a clinical setting. We analyzed the data of 42 r/r NHL patients who received MTX-HOPE in this single-center retrospective cohort study. The median age of the patients was 81 years. The overall response rate was 45.3%. The median overall survival (OS) was 7 months, the one-year OS was 43.7%, and the two-year OS was 40.8%. Grade ≥3 neutropenia and renal dysfunction were observed in 47.6% and 11.9% of patients, respectively, and treatment-related death were not observed. Appropriate supportive care enabled these patients to continue the MTX-HOPE regimen. The proportion of patients who needed hospitalization during MTX-HOPE therapy was only 21.4%. Multivariable analyses with the Cox proportional hazards model revealed that both OS and progression-free survival (PFS) were significantly influenced by high Ki-67 expression in pathology, with response to the MTX-HOPE regimen after three to five cycles as a time-dependent covariate. Our results suggest that MTX-HOPE therapy can be an option for non-aggressive r/r NHL patients. To validate MTX-HOPE therapy, further prospective investigation is needed.

Femoral marrow MRI is a non-invasive, non-irradiated and useful tool for detecting bone marrow involvement in non-Hodgkin lymphoma.

Femoral marrow magnetic resonance imaging (MRI) is a non-invasive, non-irradiated and useful modality for evaluating bone marrow (BM) conditions. Human adult femoral BM is almost uniformly fatty marrow and has the largest volume of a single bone. MRI has an extremely high resolution for fat and water, which allows high-contrast imaging of cellular infiltration into fat tissue. In hematological diseases, femoral BM MRI can clearly detect cell infiltration, which is symmetrically imaged from the proximal to the distal direction of abnormal signal areas. Thus, we investigated the significance of femoral MRI for non-Hodgkin lymphoma (NHL). We analyzed the data of 69 NHL patients who received femoral MRI at diagnosis in this single-center retrospective cohort study. The median patient age was 73 years. MRI patterns were mainly classified as uniform patterns or nonuniform patterns. We also classified the range of cellular marrow as high-grade or low-grade based on whether it had spread to over half of the femur. Both overall survival (OS) and progression-free survival (PFS) were significantly influenced by abnormal femoral marrow MRI. In particular, the patients with cellular femoral marrow lesions had a worse OS and PFS based on log-rank tests. Multivariable analyses with the Cox proportional hazards model revealed that OS and PFS were significantly influenced by cellular marrow diagnosed by femoral MRI. We concluded that femoral marrow MRI is a useful tool for detecting BM involvement and an independent prognostic factor in NHL patients.

Angiogenic mediators of the angiopoietin system are highly expressed by CD10-positive lymphoma cells in angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AILT) is a malignant disease of peripheral T-cell origin that is characterized by a prominent proliferation of high endothelial venules in the lymph node. To investigate angiogenic mechanisms in AILT we measured the angiogenic mediator gene expression levels in the lymph nodes of 54 non-Hodgkin lymphoma patients, by immunostaining and quantitative reverse transcription polymerase chain reaction. Angiogenic mediators angiopoietin (Ang) 1 (ANGPT1), Ang2 (ANGPT2) and their receptor, Tie2 (TEK), vascular endothelial growth factor (VEGF; VEGFA) and its receptor, VEGFR2 (KDR), and hepatocyte growth factor (HGF) and its receptor, c-Met (MET) were all more highly expressed in AILT lymph nodes (16 cases) than in B-cell lymphomas (24 cases). Moreover, significantly higher Ang1 and Tie2 expression was detected in AILT cases with CD10-positive neoplastic T-cells by comparison with unspecified peripheral T-cell lymphoma (14 cases). Immunostaining confirmed the expression of Ang1 and VEGF by both neoplastic T-cells and follicular dendritic cells. These results suggest that the angiopoietin system may play an important role in the development of high vascularity in AILT lymph nodes. Consequently, as neoplastic T-cells and follicular dendritic cells are both increased in AILT and may represent an important source of angiogenic mediators, targeting these cells with anti-angiogenic strategies might represent a novel therapy for AILT.

[Analysis of multiple cancers in autopsy cases of elderly hematological malignancies].

To investigate the actual situation of multiple cancers including hematological malignancies, 266 autopsy cases with one or more hematological malignancies were compiled from autopsy case files between January 1995 and October 2006 in our hospital. The median age at death was 75 years (range 48 to 102 yr). Of 266 cases, 72 (27.1%) had multiple cancers. Of these 72 cases, 62 cases were complicated with non-hematological malignancy, and 10 cases showed duplication of other hematological malignancies. Prostate and colon cancers were frequent as complicating cancers. Seventeen of 256 cases without duplication of other hematological malignancies demonstrated 3 or 4 cancers (6.6%). Of 10 cases showing duplication of other hematological malignancies, 9 cases had NHL. The rate of multiple cancers in elderly patients with hematological malignancy was higher than that of non-hematological cancers.

[Anemia in the elderly].

In the elderly, non-specific symptoms tend to come to the fore in addition to the symptoms resulted directly from anemia. Moreover, mild anemia could give the excessive effects to the heart and the lungs because of less function of organs. There is no great difference in the epidemiology of anemia in the elderly and the youth. However, the anemia associated with chronic illness, especially due to malignancy, is frequent in the elderly. The research for the original disease and its treatment should take priority in the anemia of chronic disorder.

Abnormal N-glycosylation of the immunoglobulin G kappa chain in a multiple myeloma patient with crystalglobulinemia: case report.

Spontaneous crystallization of monoclonal immunoglobulins (crystalglobulin) is a rare complication of multiple myeloma. We describe a 64-year-old Japanese man with skin ulcers and renal failure associated with immunoglobulin G kappa multiple myeloma. Crystallized immunoglobulin was detected in his serum at room temperature. Analysis of the patient's crystalglobulin by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and mass spectrometry suggested that the crystallization was due to abnormal glycosylation of the immunoglobulin light chain. Treatment with thalidomide and dexamethasone improved the severe skin ulcers on the patient's extremities and partially reversed his renal failure. This report is the first of abnormal glycosylation of immunoglobulin possibly caused by modification of N-glycans in the light chain. We concluded that abnormal glycosylation of the immunoglobulin light chain might be the cause of the patient's skin ulcers and renal dysfunction.

The BCR/ABL tyrosine kinase inhibitor, nilotinib, stimulates expression of IL-1ß in vascular endothelium in association with downregulation of miR-3p.

BCR/ABL tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis for in dividuals with chronic myeloid leukemia (CML). However, many patients treated with TKIs suffer from TKI-related complications. In particular, vascular events such as peripheral artery occlusive disease have become aserious clinical problem for patients who receive the TKI, nilotinib. At present, the molecular mechanisms by which TKIs cause vascular endothelial cell insults remain unknown.This study explored the effects of the TKIs, imatinib, nilotinib and dasatinib, on vascular endothelial cells in vitro, and found that only nilotinib induced expression of interleukin-1ß (IL-1ß) by vascular endothelial cells. Nilotinib-induced IL-1ß expression stimulated the adhesion of monocytes to vascular endothelial cells in association with an increase in levels of adhesion molecules. MicroRNA database searching identified miR-3121-3p binding sites in the 3'-UTR of the IL-1ß gene. Exposure of endothelial cells to nilotinib caused downregulation of miR-3121-3p in these cells. Importantly, forced-expression of miR-3121-3p counteracted nilotinib-induced expression of IL-1ß. Importantly, serum levels if IL-1ß were significantly elevated in CML patients receiving nilotinib (n=14) compared to those receiving other TKIs (n=16) (3.76±1.22pg/ml vs 0.27±0.77pg/ml, p<0.05). Taken together, our data suggest that nilotinib decreases levels of miR-3121-3p resulting in an increase in expression of IL-1ß and adhesion molecules in vascular endothelial cells. The miR-3121-3p/IL-1ß axis could be a potential target to prevent vascular events in CML patients with high risk of vascular events.

Treatment of acute myeloid leukemia patients aged more than 75 years: results of the E-AML-01 trial of the Japanese Elderly Leukemia and Lymphoma Study Group (JELLSG).

The feasibility and effects of combination chemotherapy for very elderly patients with acute myeloid leukemia was examined in 65 patients (including previous myelodysplastic syndrome) aged 76 years or morewith a performance status of 0 - 3. Induction chemotherapy was performed with 30 mg/m2 daunorubicin on days 1 - 3, 150 mg/m2 behenoyl cytosine arabinoside on days 1 - 7, and 70 mg/m2 6-mercaptopurine with 300 mg allopurinol taken orally on days 1 - 7 (BHAC-DM). The complete remission (CR) rate was 38.5%, whereas overall survival at 2 and 5 years was 22.0% and 4.7%, respectively. Two- and 5-year survival of CR patients was 41.8% and 11.2%, respectively. The relapse rate of the 25 CR patients was 64.0% and disease-free survival at 2 and 5 years was 21.0% and 11.2%, respectively. The therapy-related mortality rate at induction was 13.8%. BHAC-DM is feasible and effective for selected very elderly acute myeloid leukemia patients.

Prognosis of elderly patients with acute myelogenous leukemia: analysis of 126 AML cases.

We retrospectively analyzed 126 acute myelogenous leukemia (AML) patients aged > or =60 years who had all been referred to the same hematological department between 1989 and 1999. In 76 de novo AML cases, 53 patients (median age, 72 years) were treated with combination chemotherapy (CT) for remission induction. Complete remission (CR) rate was 57.1%. The median overall survival (OS) was 16 months, and the rate of 3-year OS was 28%. The favorable prognostic factors were performance status < or =2, cholinesterase > or =100 IU, and intermediate or favorable karyotype (P < .01). Seventeen patients (median age, 78 years) with hypocellular bone marrow or poor general condition were treated with low-dose cytosine arabinoside (LDAraC). In these patients, the CR rate was 50% and the median OS was 11 months, with an OS estimate at 3 years of 14%. All patients with hypocellular bone marrow who received LDAraC for 21 days achieved CR. In 50 patients who developed AML following a myelodysplastic syndrome (MDS/AML), 22 patients (median age, 74 years) were treated with CT, and 14 (median age, 74 years) patients were treated with LDAraC. The CR rates were 22.7% and 21.4%, respectively, and the median OS durations were 8 months and 11 months, respectively. There were no significant factors that would indicate a good prognosis in MDS/AML patients.

Angiotropic B-cell lymphoma with telangiectasia, accompanied by panniculitic formation.

A 67-year-old female presented with diffuse edema, generalized telangiectasia, and indurated skin plaques. Histopathological findings of the skin lesion included CD45+/CD79+/CD20+ large lymphoma cells that filled the vascular lumina and infiltrated the subcutaneous tissues with panniculitic formations. Three cycles of a CHOP (cyclophosphamide, adriamycin, vincristine, and prednisolone) chemotherapy regimen resolved the skin manifestations. After five cycles of CHOP, however, she developed dementia-like symptoms. Three cycles of additional intrathecal chemotherapy (methotrexate, cytarabine and prednisolone) did not improve the neurological symptoms.

[Mantle cell lymphoma markedly infiltrated into adrenal glands with adrenal insufficiency].

A 66-year-old male was admitted to our hospital complaining of bilateral hypochondrial pain, back pain and loss of weight in May, 2002. Superficial lymph nodes were not palpable on admission. The leukocyte count was 3430/microl, hemoglobin concentration, 13.0g/dl, and platelet count, 174000/microl. LDH, soluble IL-2 receptor, ACTH and cortisol values were out of the normal range (LDH 1368IU/l, sIL-2R 2630U/ml, ACTH 132pg/ml, cortisol 7.4microg/dl). Abdominal CT scan showed bilateral adrenal masses, and abnormal uptake of Ga-scintigraphy was seen correspondent with the bilateral adrenal masses. The histological diagnosis of bilateral adrenal masses cannot be performed because of the bleeding tendency, but atypical cells were observed in the patient's bone marrow aspirate. Surface marker analysis of atypical cells showed CD5+, cyclin D1+, CD19+, CD20+ and HLA-DR+. From these results we diagnosed this case as a mantle cell lymphoma (stage IV B) markedly infiltrated into the adrenal glands with adrenal insufficiency. The bilateral adrenal masses dramatically reduced in size after CHOP chemotherapy with hydrocortisone supplementation. We report on the present case and summarize the reports of adrenal grand-infiltrating lymphomas.