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Acquired pure red cell aplasia (PRCA), caused by thymic hyperplasia, is extremely rare. We herein report a previously healthy 41-year-old man who presented with severe anemia, lymphadenopathy, an upper mediastinal mass, and hypogammaglobulinemia. The patient was eventually diagnosed with PRCA and adult T-cell leukemia/lymphoma (ATLL). The mediastinal mass was pathologically diagnosed as thymic hyperplasia without clear ATLL invasion. Although his anemia improved rapidly after thymectomy, PRCA recurred approximately 500 days later and was accompanied by ATLL exacerbation. The findings in this patient suggest that the Good's syndrome-like symptoms (thymic hyperplasia and hypogammaglobulinemia) in this patient and PRCA may have been paraneoplastic syndromes caused by ATLL.

A 76-year-old man presented with skin plaque and splenic nodules, and diffuse large B-cell lymphoma (DLBCL) with infiltration of T-cells was suspected based on the skin lesions. The disease showed indolent clinical behavior for three months, when systemic lymphadenopathy rapidly evolved. An inguinal lymph node biopsy revealed DLBCL with abundant infiltration of T follicular helper (TFH) cells. A polymerase chain reaction-based analysis of immunoglobulin variable heavy chain showed that the skin, splenic nodules, and inguinal lymph node shared the same clone. This case indicates that the dysregulated infiltration of TFH cells in the tumor microenvironment accelerates the lymphomagenesis and progression of DLBCL.

To elucidate the long-term outcomes of non-anthracycline-containing therapies and central nervous system (CNS) events in patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL), the clinical data of 313 patients with ENKTL diagnosed between 2000 and 2013 in a nationwide retrospective study in Japan were updated and analyzed. At a median follow-up of 8.4 years, the 5-year overall survival (OS) and progression-free survival (PFS) were 71% and 64%, respectively, in 140 localized ENKTL patients who received radiotherapy-dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) in clinical practice. Nine (6.4%) patients experienced second malignancies. In 155 localized ENKTL patients treated with RT-DeVIC, 10 (6.5%) experienced CNS relapse (median, 12.8 months after diagnosis). In five of them, the events were confined to the CNS. Nine of the 10 patients who experienced CNS relapse died within 1 year after CNS relapse. Multivariate analysis identified gingival (hazard ratio [HR], 54.35; 95% confidence interval [CI], 8.60-343.35) and paranasal involvement (HR, 7.42; 95% CI, 1.78-30.89) as independent risk factors for CNS relapse. In 80 advanced ENKTL patients, 18 received steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy as first-line treatment. Patients who received SMILE as their first-line treatment tended to have better OS than those who did not (p = 0.071). Six (7.5%) advanced ENKTL patients experienced isolated CNS relapse (median, 2.6 months after diagnosis) and died within 4 months of relapse. No second malignancies were documented in advanced ENKTL patients. In the entire cohort, the median OS after first relapse or progression was 4.6 months. 12 patients who survived 5 years after PFS events were disease-free at the last follow-up. Of those, 11 (92%) underwent hematopoietic stem cell transplantation. Our 8-year follow-up revealed the long-term efficacy and safety of RT-DeVIC and SMILE. The risk of CNS relapse is an important consideration in advanced ENKTL., (© 2022 John Wiley & Sons Ltd.)

Recently, allogeneic peripheral blood stem cell transplantation from human leukocyte antigen (HLA)-haploidentical donors using post-transplantation cyclophosphamide (PTCY-haploPBSCT) has become available in clinical practice. However, the efficacy of PTCY in adult T-cell leukemia (ATL) is not fully established yet. In this study, we retrospectively examined data of seven patients who underwent PTCY-haploPBSCT. The overall survival rate at 100 days after transplantation was 85.7%, and the 1-year overall survival rate was 68.6%. The cumulative incidence of relapse at 1 year was 31.4%, whereas the 1-year nonrelapse mortality was 17.1%. The cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) on day 100 was 14.3%, and the incidence of chronic GVHD at 1 year was 33.3%. These results suggest that PTCY-haploPBSCT can be a viable option even in patients with ATL. Further accumulation of knowledge and improvement of transplantation outcomes are warranted in the future.

Discontinuation of tyrosine kinase inhibitors (TKIs) is now a feasible therapeutic goal for patients with chronic phase chronic myeloid leukemia (CML-CP). Whereas approximately half of patients experience molecular relapse, after resuming with any TKI; the majority re-achieve a deep molecular response (DMR). It is unclear whether such patients who re-achieve a durable DMR can discontinue TKI safely again. Here, we retrospectively assessed first, second, and third attempts to stop TKIs in patients with CML-CP. At the first attempt, 28 out of a total of 53 patients achieved sustained treatment-free remission (TFR; 53.4%; 95% confidence interval [CI], 39.0%-65.9%). Subsequently, 10 of 25 patients attempted a second TKI discontinuation, and in all cases, this was after receiving second-generation TKIs. Four of 10 patients successfully achieved TFR (37.5%; 95% CI, 9.9%-65.9%). All patients who relapsed at the second TKI discontinuation attempt were re-administered TKIs, and soon achieved at least a major molecular remission. All six second relapse patients had a loss of MR 4.5 at 3 months after TKI discontinuation. These findings suggest that second and third attempts to successfully stop TKI treatment are feasible in patients with CML-CP., (© 2021 John Wiley & Sons Ltd.)

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is an aggressive leukemia that occurs in 20-40% of adult patients. Ph + ALL is caused by the Philadelphia chromosome (Ph), which consists of a t(9;22)(q34;q11) reciprocal translocation leading to the formation of a BCR-ABL1 fusion gene. The disease is treated with targeted therapy comprising ABL1 tyrosine kinase inhibitors (TKIs). Ponatinib is a third generation TKI that demonstrates higher binding affinity for ABL1 than first/second generation TKIs. Although intensive combined immunotherapy with ponatinib greatly improves the prognosis of Ph + ALL, the safety and efficacy profiles of ponatinib in Japanese patients are unclear. This retrospective study investigated five cases of Ph + ALL at a single institute to evaluate safety and efficacy profiles. Three patients achieved a deep molecular response (DMR) following combined intensive treatment with ponatinib as induction chemotherapy. Four patients received consolidative allogenic stem cell transplantation (allo-SCT) during their first complete response. Three of the four experienced early relapse within 100 days; they subsequently received ponatinib, and one of the three achieved a DMR. No patient experienced severe cardiovascular events. This case series suggests that ponatinib at a concentration of least 30 mg exhibits anti-leukemia effects in Japanese patients with Ph + ALL., (© 2021. Japanese Society of Hematology.)

Objective: A primary cause of cognitive decline after carotid endarterectomy (CEA) is cerebral injury due to cerebral hyperperfusion. However, the mechanisms of how cerebral hyperperfusion induces cerebral cortex and white matter injury are not known. The presence of cerebral microbleeds (CMBs) on susceptibility-weighted imaging (SWI) is independently associated with a decline in global cognitive function. The purpose of this prospective observational study was to determine whether cerebral hyperperfusion following CEA leads to the development of CMBs and if postoperative cognitive decline is related to these developed CMBs., Methods: During the 27-month study period, patients who underwent CEA for ipsilateral internal carotid artery stenosis (≥ 70%) also underwent SWI and neuropsychological testing before and 2 months after surgery, as well as quantitative brain perfusion SPECT prior to and immediately after surgery., Results: According to quantitative brain perfusion SPECT and SWI before and after surgery, 12 (16%) and 7 (9%) of 75 patients exhibited postoperative cerebral hyperperfusion and increased CMBs in the cerebral hemisphere ipsilateral to surgery, respectively. Cerebral hyperperfusion was associated with an increase in CMBs after surgery (logistic regression analysis, 95% CI 5.08-31.25, p < 0.0001). According to neuropsychological assessments before and after surgery, 10 patients (13%) showed postoperative cognitive decline. Increased CMBs were associated with cognitive decline after surgery (logistic regression analysis, 95% CI 6.80-66.67, p < 0.0001). Among the patients with cerebral hyperperfusion after surgery, the incidence of postoperative cognitive decline was higher in those with increased CMBs (100%) than in those without (20%; p = 0.0101)., Conclusions: Cerebral hyperperfusion following CEA leads to the development of CMBs, and postoperative cognitive decline is related to these developed CMBs.

Cronkhite-Canada syndrome (CCS) is a rare polyposis disorder accompanied by alopecia and onychodystrophy. A 63-year-old man with a history of CCS and repeated embolism developed progressive thrombocytopenia and mild anemia. Laboratory testing, a bone marrow examination, and magnetic resonance imaging of the spine resulted in a diagnosis of concurrent aplastic anemia (AA). Paroxysmal nocturnal hemoglobinuria (PNH)-type cells were detected in a peripheral blood specimen. In addition, human leukocyte antigen (HLA) included DRB1*15:01 and DRB1*15:02. Mesalazine was discontinued in consideration of possible drug-induced pancytopenia. Immunosuppressive therapy ameliorated both the gastrointestinal symptoms of CCS and pancytopenia. A common autoimmune abnormality might underlie both CCS and AA.

Membranous nephropathy (MN) is a common glomerular disease that is characterized by diffuse thickening of the glomerular basement membrane, and a common cause of nephrotic syndrome (NS). MN is often accompanied with malignant disease; The solid tumors are commonly associated with MN, whereas hematological malignancies are rarely found in patients with MN. A 68-year-old man with a history of diabetes mellitus visited a hospital with a chief complaint of general fatigue. He was previously not diagnosed with any complications of diabetes. Computed tomography revealed a pancreatic tumor, and the pathological findings of the biopsied tumor revealed the tumor was diffuse large B-cell lymphoma (DLBCL). Concurrently, he developed severe proteinuria, hypoalbuminemia, systemic edema and hyperlipidemia, consistent with the diagnosis of NS. The biopsied renal specimen revealed minute spike lesions of glomerular basement membrane, and abnormal lymphocytes infiltrated in the kidney interstitially. Anti-glomerular basement membrane antibody, proteinase-3-/myeloperoxidase antineutrophil cytoplasmic antibody and hepatitis B antigenemia, are absent in the patient. Serum anti-phospholipase A2 receptor (PLA2R) antibody (marker for primary MN) was not detected. A diagnosis of secondary MN induced by DLBCL was made. He received rituximab containing chemotherapy for DLBCL, resulting in amelioration of both DLBCL and MN. We report the rare case of a patient co-existing NS and DLBCL. DLBCL might be pathogenesis of NS; the findings are supported by the presence of MN, an underlying malignancy (DLBCL), and the lack of anti-PLA2R antibodies. Although further investigation is warranted, our case suggests that DLBCL is a possible cause of secondary MN.

Patients with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML) respond to conventional induction chemotherapy, with remission rates similar to those seen in other subtypes; however, they are much more likely to relapse and relapse is rapid. For this reason, eligible patients receive consolidation therapy with early allogenic transplantation, but the recurrence rate remains high, even after transplantation. Moreover, the optimal therapy for patients with FLT3-ITD AML who relapse after allogeneic hematopoietic stem cell transplantation remains unclear. Here, we report a case in which graft-versus-leukemia (GVL) effects were induced by gilteritinib administration after a second transplant from the same donor, resulting in sustained remission of early FLT3-ITD AML relapse after allogeneic transplantation. Several studies suggest that the benefits of FLT3 tyrosine kinase inhibitors (FLT3-TKI) after allogeneic transplantation are attributable to GVL induction, as well as direct effects on FLT3 mutation-positive leukemia cells. With this in mind, we induced lymphodepletion using L-PAM to further enhance GVL induction by donor lymphocytes and FLT3-TKI. We believe that enhancement of GVL induction by lymphodepletion should be considered before FLT3-TKI use, if the prognosis is very poor, such as in patients with recurrence following allogeneic transplantation.

Patients with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) are often asymptomatic and thus can remain undiagnosed until they become symptomatic due to progression to the accelerated phase (AP) or transformation to acute leukemia (leukemic transformation; LT). We herein report the case of a previously healthy 38-year-old man who had hyperleukocytosis with dysplastic myeloid precursor cells and severe disseminated intravascular coagulation. Hematopoietic recovery with features of atypical chronic myeloid leukemia (aCML) after induction chemotherapy was a diagnostic clue. Although rare, this case highlights the limitation of the diagnostic approach for aCML with AP or LT at the initial presentation.

Regulatory T-cells (Tregs) are major mediators of mammalian self-tolerance via cytotoxic T-lymphocyte antigen 4 (CTLA4) signaling pathways. An immune dysregulation syndrome associated with heterozygous germline mutations in CTLA4 was recently reported. Clinical features include recurrent infections, systemic lymphadenopathy, various autoimmune conditions, hypogammaglobulinemia, and autosomal dominant inheritance, characteristic of primary immunodeficient disease (PID). PID symptoms are variable and few patients with sporadic de novo CTLA4 germline mutations have been described. Here, we report the case of a 26-year-old man with an immune dysregulation syndrome and a de novo CTLA4 germline mutation. The patient exhibited several clinical features associated with PID. Next-generation sequencing revealed a CTLA4 germline mutation, c.436G>A; p.G146R, in exon 2 of CTLA4. Sanger sequencing confirmed the patient was the only member of his family with this germline mutation. The patient was diagnosed with an immune dysregulation syndrome associated with de novo germline CTLA4 mutation, complicated by steroid-refractory rheumatoid arthritis. Treatment with abatacept, a CTLA4-immunoglobulin fusion molecule, was initiated, resulting in dramatic resolution of the patient's clinical symptoms. As PID with CTLA4 germline mutation is rare and patients may be under-diagnosed, physicians should be aware of the features of PID.

Graft-versus-host disease (GVHD) is a potentially life-threatening complication of allogeneic stem cell transplantation (Allo-SCT). Chronic GVHD, which typically presents more than 100 days after Allo-SCT, can resemble manifestations of autoimmune disease; however, there are only a few reports on the development of Crohn's disease (CD) after Allo-SCT. Here, we report a case of steroid-refractory CD after umbilical cord blood transplantation (CBT), which was dramatically improved with administration of anti-tumor necrosis factor-alpha (anti-TNF-alpha) antibodies. A 21-year-old woman with refractory Hodgkin lymphoma underwent CBT and achieved complete remission. About 1 year after CBT, she complained of intermittent abdominal pain and bloody diarrhea, and colonoscopy revealed multiple longitudinal colonic ulcers with a cobblestone appearance; thus, based on the colonoscopy findings, she was diagnosed with CD. We considered a CD-like manifestation of gastrointestinal GVHD and initially administered steroids, but the therapeutic effect was poor. Then, we administered anti-TNF-alpha antibodies, infliximab, and then adalimumab, which resulted in rapid improvement of abdominal symptoms, with no recurrence despite discontinuation of this therapy. Anti-TNF-alpha antibodies are effective for CD after Allo-SCT, which can be considered as a subsequent complication of GVHD.

Although the prognosis of chronic myeloid leukemia (CML) in blastic crisis remains poor, some patients achieve long-term remission after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This may be attributable to graft-versus-leukemia (GVL) effects by donor lymphocytes, but their regulating mechanisms are unclear. Antitumor natural killer (NK) cell immunity is assumed to be important in CML, and we have previously shown that allelic polymorphisms of killer immunoglobulin-like receptors (KIRs) and histocompatibility leukocyte antigens (HLAs) are associated with the response of CML to tyrosine kinase inhibitors. Here, we report a case of CML in blastic phase who received HLA-matched but KIR3DL1 allelic-mismatched allo-HSCT. After transplant, decreased BCR-ABL transcript levels and enhanced NK cell activity were transiently observed. However, reconstitution of KIR3DL1-expressing NK cells occurred, which was associated with diminished NK cell activity and increased BCR-ABL. This case indicates the potential significance of KIR3DL1 in NK cell-mediated GVL activity following allo-HSCT. To the best of our knowledge, this is the first report to analyze the association between sequential KIR3DL1 expression and activity of NK cells after allo-HSCT. Selecting donors with KIR3DL1-null alleles may maintain competent GVL effects and provide improved outcomes in allo-HSCT for CML.

Hematopoietic stem cell transplantation (HSCT) from a related donor with an human leukocyte antigen (HLA) 1-antigen mismatch without in vivo T cell depletion is associated with an elevated risk of severe, acute, and chronic graft-versus-host (GVH) disease (GVHD) and poor survival. Therefore, we conducted a multicenter phase II trial of HSCT using low-dose anti-thymocyte globulin (ATG, thymoglobulin). We recruited patients aged 16-65 years with leukemia, myelodysplastic syndrome, or lymphoma who planned to receive HSCT from a related donor with HLA 1-antigen mismatch in the GVH direction at the HLA-A, -B, or -DR locus. Pretransplantation ATG was administered with standard GVHD prophylaxis consisting of tacrolimus and methotrexate. Thirty-eight patients were eligible for the analysis. The 1-year GVHD-free relapse-free survival (GRFS) was 47%. The 3-year overall survival (OS) was 57%. Age of less than 50 years was associated with better OS. OS in patients with high/very high refined disease risk indexes (rDRIs) was comparable to that in those with low/intermediate rDRIs. The 100-day cumulative incidences of grades II-IV and III-IV acute GVHD were 45% and 18%, respectively. HSCT from a related donor with two allele mismatches showed higher incidences of grades II-IV and III-IV acute GVHD. Three-year cumulative incidences of moderate to severe or severe chronic GVHD were 13% and 3%, respectively. HSCT from a related donor with one locus mismatch at the antigen level using low-dose ATG showed lower incidences of acute and chronic GVHD, which led to acceptable GRFS, OS, relapse, and nonrelapse mortality.

Novel anti-myeloma drugs have significantly improved the overall survival (OS) of patients with multiple myeloma (MM). However, not all MM patients treated with these drugs show survival benefits, and biologic and genetic prognostic factors are insufficient to predict the response to treatment. Decreasing treatment-related complications is important to improve the efficacy of treatment in patients with MM. The Controlling Nutritional Status (CONUT) score is a screening method for poor nutritional status, which is associated with poor prognosis in several cancers because it increases the rate of treatment-related complications. We retrospectively analyzed the OS of 64 patients with symptomatic MM and evaluated the correlation between the CONUT score and patient prognosis in MM. The median age at diagnosis was 66 years, and multivariate analysis showed that a high CONUT score (≥ 5; hazard ratio, 3.937; 95% confidence interval, 1.214-12.658; P = 0.022) was an independent prognostic risk factor. Subgroup analysis was performed according to patient age because the choice of treatment strategy, particularly autologous peripheral blood stem cell transplantation (auto-PBSCT), can vary depending on age in MM patients. Younger patients (< 65 years old) who received auto-PBSCT and had a lower CONUT score (0-3) showed a significantly better survival outcome than those with a higher CONUT score (≥ 4) (median OS, not reached vs. 64.1 months; P = 0.011). The CONUT score is simple to calculate and provides a useful prognostic indicator in patients with MM, especially transplant-eligible patients.

AminoIndex Cancer Screening (AICS) is a novel cancer screening test based on plasma free amino acid (PFAA) levels. This system categorises subjects as rank A, B, or C in order of increasing probability of each cancer incidence. The current study aimed to validate the potential of AICS for cancer detection. AICS values were determined from the PFAA levels in subjects examined at Chiba Cancer Center Cohort, Mitsui Memorial Hospital, and Saihaku Hospital, and the cancer incidence was investigated. The sensitivities of rank C for cancer diagnosis within 1 year after AICS examination were 83.3% (10/12) for gastric, 50.0% (2/4) for lung, 46.2% (6/13) for colorectal, 50.0% (8/16) for prostate, 43.8% (7/16) for breast, and 50.0% (1/2) for uterine/ovarian cancer. The total cancer detection rate via AICS was 0.33% (34/10,245). The sensitivities during the maximum follow-up period of 6.2 years were 51.7% (15/29) for gastric, 18.2% (2/11) for lung, 28.6% (8/28) for colorectal, 36.4% (8/22) for prostate, 29.0% (9/31) for breast, and 33.3% (2/6) for uterine/ovarian cancers. In conclusion, AICS is a more useful method for evaluating the probability of cancer incidence than for predicting onset, suggesting that annual AICS should be recommended to detect any malignancy.

Extranodal NK/T cell lymphoma (NKTCL), nasal type (ENKL) that shows no apparent nasal involvement, is termed extranasal NKTCL or non-nasal NKTCL. In this study, we aimed to explore therapeutic approaches and outcomes in patients with extranasal NKTCL in current clinical practice. A data set of patients with newly diagnosed NKTCL who were diagnosed at 31 institutes in Japan between 2000 and 2013 was used for analysis. The patients' fitness for steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy was assessed using the major inclusion criteria of the SMILE phase 2 study. Of 358 patients, 47 (13%) had extranasal NKTCL. The most frequent extranodal sites of involvement in extranasal NKTCL were skin/subcutaneous tissue (n = 18). Six (13%) of the patients with extranasal NKTCL had localized disease and were diagnosed before 2010. With a median follow-up of 5.8 years, the 2-year overall survival (OS) in patients with nasal and extranasal NKTCL was 70% (95% confidence interval [CI], 65-75%) and 34% (95% CI, 21-47%), respectively. OS in patients with nasal NKTCL had a trend toward better according to treatment era (P = 0.063). In contrast, no obvious improvement of OS was observed in extranasal NKTCL (P = 0.43). The major inclusion criteria of the SMILE-P2 were met in 21% (10/47) of patients with extranasal NKTCL and 60% (188/311) of those with nasal NKTCL (P < 0.001). Despite the advent of new treatments for ENKL, OS remains unfavorable in extranasal NKTCL. A more effective therapy is needed for extranasal NKTCL.

Accurate risk assessment to determine the eligibility for allogeneic hematopoietic stem cell transplantation (allo-HCT) in patients with adult T cell leukemia (ATL) is necessary to improve survival outcomes. The controlling nutritional status (CONUT) score predicts prognosis in several tumors; however, the prognostic significance of the CONUT score in ATL remains unclear. The present study investigated the correlation between the CONUT score and the survival outcomes of transplant-eligible ATL patients. Mogamulizumab, a humanized monoclonal antibody against C-C chemokine receptor 4, was recently identified as a promising salvage chemotherapy agent for transplant-ineligible ATL patients. We therefore evaluated the efficacy of mogamulizumab in transplant-ineligible ATL patients. Patients diagnosed with aggressive ATL (acute lymphoma of unfavorable chronic type) between January 2008 and March 2017 at Saga University Hospital, Japan, were retrospectively enrolled. Of 54 patients, 25 were < 70 years of age and 14 received allo-HCT. The median overall survival (OS) and non-relapse mortality (NRM) rate at 1 year among patients receiving allo-HCT were 1685.5 days and 30% in those with a CONUT score 0-3 (n = 10) and 184.5 days and 100% in those with a score ≥ 4 (n = 4) (p = 0.017, OS; p = 0.064, NRM). Older patients who received mogamulizumab had a significantly longer OS (n = 12, median 432 days) than those who did not receive mogamulizumab (n = 17, median 199 days) (p = 0.018). The CONUT score was identified as a prognostic tool for transplant-eligible ATL patients, and mogamulizumab improved OS in transplant-ineligible ATL patients.

Composite lymphoma (CL) is a rare disorder defined as the coexistence of two or more distinct lymphoma subtypes at a single anatomic site. Discordant lymphoma (DL), which is the simultaneous occurrence of two or more distinct lymphoma subtypes at different sites, is also rare. CL complicated with DL involving three distinct subtypes of lymphoma in the same patient is an extremely rare disease. Clonal relationships in CL and DL are commonly investigated by molecular analysis using mutational status with t(14;18)BCL2/IgH translocation and immunoglobulin heavy chain variable-region (IgV H ) gene rearrangement. A 73-year-old woman was admitted to our hospital with systemic lymphadenopathy and was initially diagnosed with diffuse large B-cell lymphoma based on pathological features of the biopsied esophageal tumor. However, the results of inguinal lymph node biopsy led to a revised pathological diagnosis CL consisting of Hodgkin lymphoma and follicular lymphoma. Three distinct coexisting lymphomas were identified in this individual patient. Molecular analysis revealed CL derived from common germinal center B-cell precursors, while clonal relationship between CL and DL was not clarified. This case suggests a mechanism underlying B-cell lymphoma pathogenesis involving two pivotal somatic mutations, t(14;18)BCL2/IgH translocation and IgV H rearrangement.

Background: The clinical outcomes of patients with chronic myeloid leukemia (CML) treated with BCR-ABL tyrosine kinase inhibitors has improved markedly; however, the occurrence of adverse events (AEs) means that elderly patients often cannot be administered the standard dose. Nevertheless, some patients treated with low doses of tyrosine kinase inhibitor have achieved good molecular responses., Patients and Methods: We retrospectively analyzed the efficacy and safety of low-dose dasatinib treatment of elderly CML patients. The study enrolled 21 patients with newly diagnosed, imatinib-resistant, or imatinib-intolerant chronic phase CML. All the patients were aged ≥ 65 years and received dasatinib at a dose of < 100 mg/day. Of these 21 patients, 77% had newly diagnosed CML., Results: Overall, 91% and 72% of patients received a mean dasatinib dose of ≤ 50 mg and ≤ 20 mg, respectively. A molecular response of MR 3 (major molecular response, indicating > 3 log reduction in the number of leukemic cells), MR 4 , and MR 4.5 were achieved in 96%, 77%, and 62% of the patients, respectively. Of the 15 patients who received a mean dose of ≤ 20 mg, 94% achieved a major molecular response, and 74% achieved MR 4 . The most common nonhematologic AE was plural effusion (29%), which was controlled by diuretics and regulating the drug dose., Conclusion: Low-dose (eg, ≤ 20 mg) dasatinib therapy generates an adequate molecular response in most elderly patients with chronic phase CML without causing severe AEs., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Derivative (5;19)(p10;q10) [der(5;19)(p10;q10)] is a rare chromosomal abnormality in myelodysplastic syndrome (MDS), and is genetically similar to deletion 5q [del(5q)]. However, MDS with der(5;19)(p10;q10) and 5q- syndrome are generally characterized as distinct subtypes. Here, we report a case of a patient with 5q- syndrome-like features as the first manifestation of MDS with der(5; 19)(p10;q10). A 59-year-old woman was admitted to our hospital for anemia without leukopenia and thrombocytopenia. She had received chemotherapy comprising carboplatin and docetaxel for endometrial cancer eight years before. Bone marrow aspirate (BM) revealed low blast counts with trilineage dysplastic cells, and fluorescent in situ hybridization revealed the loss of colony-stimulating factor 1 receptor (CSF1R) signals at 5q33-34. Although the initial manifestation was 5q- syndrome, G-banded metaphase analysis and spectral karyotyping analysis revealed der(5;19)(p10;q10). Consequently, a diagnosis of therapy-related MDS (t-MDS) was made. She failed to respond to azacitidine and lenalidomide therapy. Consequently, transfusion-dependent anemia and thrombocytopenia developed with increasing myeloblasts. Cytarabine, aclarubicin, and granulocyte colony-stimulating factor therapy also failed, and unfortunately the patient died. Thus, MDS with der(5;19)(p10;q10) may represent a platinum agent-related t-MDS that is highly resistant to chemotherapy.

Amino acids are present in the blood. In healthy people, the concentrations of these amino acids in the blood are maintained at stable levels. However, different diseases disturb the balance of amino acids in the blood in different ways. AminoIndex® is a service that uses the latest medical technology to measure the concentration of amino acids in the blood to check a person's health and detect various diseases. It is now possible to conduct an AminoIndex® Cancer Screening (AICS®) test that can detect cancer from early stages. The AICS® measures the concentrations of amino acids in the blood and statistically analyzes the differ- ences in the balance of amino acid concentrations between healthy people and those with cancer. As a result, we can simultaneously screen for certain types of cancer. Currently, the test can screen for gastric cancer, lung cancer, colorectal cancer, prostate cancer (in males), breast cancer (in females), and uterine/ovarian cancer* (in females). The application of AminoIndex® technology will spread through the fields of medicine, such as in the treat- ment of metabolic syndrome. (*The uterine/ovarian cancer test determines the overall risk of having any of the three cancers: cervical cancer, endometrial cancer, and ovarian cancer, and can not determine the individual risk of having each cancer.) [Review].

Reactivation of hepatitis B virus (HBV) following immunosuppressive therapy or hematopoietic stem cell transplantation is a potentially fatal complication that may occur even in patients with prior resolution of HBV infection. Dasatinib is a small-molecule inhibitor of the tyrosine kinases SRC and ABL that has been approved for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia. Here, we report the first case of reactivation of resolved infection with the HBV immune escape mutant G145R in a CML patient receiving dasatinib. Although dasatinib is not recognized as an immunosuppressant, our observations suggest that dasatinib may enhance HBV replication and induce its reactivation in immunocompetent patients, that HBV escape mutants may contribute to the pathogenesis of HBV reactivation, and that close monitoring of HBV status is advisable in patients with current or resolved HBV infection.

Recent advances in the treatment of lymphoid leukemias have incorporated molecular targeted drugs (CD20-targeting rituximab and BCR-ABL tyrosine kinase inhibitors) into the traditional chemotherapeutic agents. This article reviews novel molecular targeted therapies for patients with lymphoid leukemias including acute lymphoblastic leukemia, chronic lymphocytic leukemia, hairly cell leukemia and HTLV-I-related adult T-cell leukemia. Investigational agents that will be discussed in this review include inotuzumab, blinatumomab, alemtuzumab, ofatumumab, ibrutinib, idelalisib, bafetinib, lenalidomide, ABT-199 and mogamulizumab. Novel approaches warrant continued research to improve outcomes for patients with lymphoid leukemias.

The autogenic lens tumors induced by the Simian vacuolating virus 40 (SV40) T antigen in α-crystallin/SV40 T antigen transgenic (TG) mice, provide a tool to screen anti-tumor reagents in vivo and to clarify the underlying mechanisms. Juzen-taiho-to, a Chinese medicine composed of 10 herbs, was frequently used as an alternative medicine for cancer patients by clinicians and occasionally it was demonstrated to have beneficial effects on the prognosis and general condition of cancer patients. However, it was not scientifically verified. In the present study, the anti-tumor effects and underlying mechanisms of Juzen-taiho-to in the TG mice model was examined using cDNA microarray analysis and the results were confirmed by real-time PCR. The TG mice demonstrated a higher cumulative survival rate after treatment with the drug compared with the control group (P<0.05). Gene chip profiles demonstrated that cell functions involving the membrane, glycoprotein, cell membrane, signal and ionic channel for the lens tumor, the cell cycle, DNA replication, homeobox, mitosis and cell division for the spleen and the acetylation, mitochondrion, ribosomal protein, ribonucleoprotein for the liver, were altered by the administration of Juzen‑taiho-to. The important canonical pathways were those of the mitogen-activated protein kinase (MAPK), the cell cycle and the ribosome for the altered genes of the lens tumor, spleen and liver after drug administration, respectively. From real-time PCR, in the eyeball, epidermal growth factor receptor (Egfr), Rasgrf1 and heat shock protein 1B (Hspa1b) mRNAs were found to be significantly lower in treated lenses than in those not exposed to the drug, while Rps25 mRNA demonstrated the opposite association in the liver. It was suggested that Juzen-taiho-to may prolong the survival time of SV40 T antigen TG mice by improving their nutritional condition, inhibiting the MAPK pathway and strengthening the immune system without causing hepatic toxicity.

Treatment of chronic myeloid leukemia (CML) has been drastically changed by the emergence of the ABL tyrosine kinase inhibitor (TKI), imatinib mesylate. However, resistance and intolerance have frequently been reported, particularly in patients with advanced-stage disease. Point mutations within the ABL kinase domain that interfere with imatinib binding are the most critical cause of imatinib resistance. To overcome this resistance, four second-generation ATP competitive ABL TKIs, dasatinib, nilotinib, bosutinib and bafetinib, have been developed. Dasatinib and nilotinib also demonstrated higher efficacy than imatinib in previously untreated CML patients in chronic phase. Despite promising clinical results, the frequently observed mutant T315I is not effectively targeted by any of the second-generation ABL TKIs. Thus, a third-generation ABL TKI, ponatinib, was developed to inhibit all mutated BCR-ABL and showed clinical efficacy in CML cells harbouring T315I. CML treatment is rapidly progressing and further evolution is surely expected. Moreover, it was recently reported that some CML patients who achieved sustained complete molecular response could stop TKI. CML may become the first human cancer to be conquered solely with oral medicines.

Amino acids are a group of metabolites that are important substrates for protein synthesis, are important as signaling molecules and play central roles as highly connected metabolic hubs, and therefore, there are many reports that describe disease-specific abnormalities in plasma amino acids profile. However, the causes of progression from a healthy control to a manifestation of the plasma amino acid changes remain obscure. Here, we extended the plasma amino acids profile to relationships that have interactive properties, and found remarkable differences in the longitudinal transition of hyperglycemia as a diabetes emergency. What is especially important is to understand pathogenesis for better treatment and early diagnosis of diabetes. In this study, we performed interactive analysis using time course data of the plasma samples of AKITA mice, which develop hyperglycemia. Primarily, we decided to analyze the interactive property of amino acids which had highly significant association with hyperglycemia, namely alanine, glycine, leucine, isoleucine and valine. Next, we inferred the interactive network structure, which reproduces the actual time course within an error allowance of 10% using an S-system model (a conceptual mathematical model for analyzing and simulating networks). The emphasis of this study was altered interactions of plasma amino acids that show stabilizing and destabilizing features in a variety of clinical settings. By performing sensitivity analysis, the most dominant relations in this network were selected; the control paths from glycine to isoleucine in healthy control and from alanine to glycine in hyperglycemia. This result is in good agreement with the biological knowledge regarding branched-chain amino acids, and suggests the biological importance of the effect from alanine to glycine.

Acute myeloid leukemia may manifest as myeloid sarcoma in a variety of extramedullary (EM) tissues at diagnosis or at relapse. Although EM relapse after allogeneic hematopoietic stem cell transplantation (alloSCT) has been considered to be rare, recent studies have suggested that it occurs in 5% to 12% of patients who receive alloSCT, accounting for 7% to 46% of total relapses. The incidence of EM relapse after immunomodulation (eg, donor lymphocyte infusion) or a second SCT is even higher. Moreover, patients with EM relapse are more likely to have had preceding acute graft-versus-host disease or chronic graft-versus-host disease relative to those with bone marrow relapse. Collectively, these observations suggest that the preferential occurrence of the graft-versus-leukemia effect underlies the pathogenesis of EM relapse. Establishing an early diagnosis of EM relapse has been challenging because of the immense diversity in the relapse sites; however, recent studies have suggested the usefulness of (18)F-fluorodeoxyglucose positron emission tomography scans in the detection of EM relapse. As a treatment for EM relapse, a combination of local and systemic therapy should be considered, because local therapy alone often results in subsequent systemic relapse. The prognosis for patients who develop EM relapse after SCT remains poor but is slightly better than that after bone marrow relapse. In addition to an early diagnosis with new modalities, clinical studies using new agents that may offer systemic activity while preserving the graft-versus-leukemia effect are warranted as part of an effort to improve the clinical outcome., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Hematopoietic stem cell transplantation (HSCT) has become a standard method for treating patients with hematological malignancies. Preconditioning chemotherapeutic drugs, total body irradiation (TBI), or chronic graft-versus-host disease (GVHD) can cause several chest complications after HSCT. Because immunosuppression is marked after HSCT, it takes at least 1 year for the immune system to recover completely. Therefore, several infectious and noninfectious complications may occur within the year after HSCT. HSCT-specific complications occur in a characteristic temporal sequence associated with the period following HSCT. During the neutropenic phase, bacterial pneumonia, fungal infection, pulmonary edema, and diffuse alveolar hemorrhage may occur. During the early phase, pneumocystis pneumonia, cytomegalovirus pneumonia, engraftment syndrome, and idiopathic pneumonia syndrome are the common complications. During the late phase, constrictive bronchiolitis and organizing pneumonia may occur probably associated with chronic GVHD. Although high-resolution CT findings lack specificity, the frequency and likelihood of occurrence of certain complications in certain phases and sometimes characteristic features (such as a CT halo sign for fungal infection) facilitate early detection of a life-threatening complication.

Isolated extramedullary (EM) relapse of acute myelogenous leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is rare. Predisposing factors include CD56 expression and the chromosomal abnormality t(8;21). We describe an AML patient showing the chromosomal abnormality t(8;21) and CD56 expression who experienced a unique EM relapse after allo-HSCT. Approximately 10 months after allo-HSCT, he experienced relapse involving the femur and lumbar vertebrae and, subsequently, an EM relapse of the stomach. Although we administered only local radiotherapy and not systemic chemotherapy, he showed no bone marrow relapse on long-term follow-up after achieving complete hematological remission. These findings suggest that the graft-versus-leukemia effect may preferentially maintain marrow remission rather than prevent EM relapse. In addition, our findings show that extended survival is possible after EM relapse following allo-HSCT in patients with marrow hematopoiesis of donor origin, and that augmentation of the graft-versus-leukemia effect may be useful.

Matrix metalloproteinases (MMPs) have been implicated in a variety of normal and pathological conditions that involve matrix degradation and remodelling. We investigated the role of MMPs in acute graft-versus-host disease (aGVHD) in 29 patients who had undergone allogeneic haematopoietic stem cell transplantation. The present study showed that the serum levels of MMP-9, but not those of MMP-2, significantly correlated with the occurrence and severity of aGVHD. Moreover, immunohistochemical analysis of the cutaneous lesions of patients with aGVHD revealed an increased number of inflammatory cells positive for MMP-9. These results suggest that MMP-9 might play an important role in the pathogenesis of aGVHD.

High mobility group box 1 (HMGB1) is a non-histone protein involved in maintaining the architecture of chromatin. HMGB1 also acts extracellularly as a cytokine, in processes such as inflammation, cell migration and stem cell recruitment. The involvement of HMGB1 in granulocyte colony-stimulating factor (G-CSF)-induced mobilisation of haematopoietic stem cells was investigated in 21 healthy donors. G-CSF treatment significantly elevated serum HMGB1 levels, which increased from 1.16 +/- 0.86 ng/ml, before treatment, to 31.1 +/- 5.99 ng/ml, after treatment. These findings suggest HMGB1 may play a role during the mobilisation of stem cells from the bone marrow into the systemic circulation.

Although the mobilization of peripheral blood stem cells from normal donors using granulocyte colony-stimulating factor is widely used, the ideal method for the administration of filgrastim has not been determined. Therefore, we compared the efficacy of peripheral blood stem cell mobilization on day 4 of filgrastim between once-daily (group O) and twice-daily (group T) administration of filgrastim at 400 microg/m(2)/d. In all, 38 and 34 donors were randomly assigned to groups O and T, respectively. The number of CD34(+) cells collected on day 4 was not significantly different (1.74 x 10(6) cells/kg in group O and 2.08 x 10(6) cells/kg in group T, P = .37). The incidence and severity of adverse events were similar in the two groups. The baseline white blood cell count was the strongest predictor of poor mobilization. Donor age, sex, and serum concentrations of several cytokines did not significantly affect the CD34(+) cell yield. In conclusion, once-daily administration of filgrastim at 400 microg/m(2)/d appeared to be appropriate for the mobilization of CD34(+) cells in normal donors when apheresis is planned on day 4 of filgrastim. Selection of a donor with a steady-state white blood cell count of 5.0 x 10(9)/L or more may lead to a lower incidence of poor mobilization.

A 24-year-old woman with acute promyelocytic leukemia was treated with all-trans retinoic acid (ATRA) as a remission induction therapy. After pneumonia in the neutropenic period was successfully treated with antibiotic treatment, there was recurrence of high fever alone, followed by the appearance of erythema nodosum with pain in her upper limbs on day 25 of ATRA therapy. Skin biopsy neither revealed infiltration of leukemic cells nor suggested Sweet's syndrome. We considered the eruptions to be associated with ATRA, and prednisolone (30 mg/day for 5 days) was administered. Although the administration of ATRA was continued until complete remission of the leukemia, the erythema nodosum rapidly disappeared following short-term steroid therapy and no recurrence was observed. ATRA-induced erythema nodosum is rare, however it should be recognized as a possible adverse effect in ATRA therapy.

We report on a 59-yr-old man with recurrent multiple myeloma. To reduce treatment-related mortality, while retaining the cytoreductive effects of high-dose chemotherapy, as well as graft vs. myeloma effect, we used a reduced-intensity conditioning umbilical cord blood (CB) transplantation following high-dose chemotherapy with autologous stem cell transplantation support. This patient was engrafted rapidly and extramedullary toxicities were acceptable. Although he had local recurrence in the right calf on day +130 after the CB transplantation, the tumor was successfully treated with radiation therapy, and he is alive and well at present (day +480)., ((c) Blackwell Munksgaard 2005)