Analyzing the risk factors for disease progression within 2 years and histological transformation in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone as first-line treatment: A 15-year follow-up of patients with advanced follicular lymphoma in JCOG0203.

Follicular lymphoma (FL) is an indolent lymphoma that becomes aggressive due to histological transformation (HT), leading to reduced survival. Patients with FL have different clinical courses and various treatment options. Some patients exhibit shorter survival and experience disease progression within 24 months of diagnosis/treatment (POD24); the optimal treatment remains an unmet needs. Thus, identifying factors that predict shorter survival is essential to stratify treatment and prolong the survival of patients with FL. To analyze risk factors for POD24 and HT in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line treatment, we performed this post-hoc analysis of patients with advanced indolent B-cell lymphoma in a randomized clinical trial wherein six cycles of R-CHOP were administered every 2-3 weeks. The primary analysis showed no differences in outcomes, which enabled the analysis of 248 patients with FL, assigned to two arms. All histopathological specimens from the 300 enrolled patients were reviewed by three expert hematopathologists. Multivariable analysis implicated Follicular Lymphoma International Prognostic Index (FLIPI) intermediate (odds ratio [OR] 2.531, 95% confidence interval [CI] 0.676-9.466) and high- (OR 2.236, 95% CI 0.160-31.226) risks, B symptoms (OR 2.091, 95% CI 0.747-5.851), and grade 3A (G3A) (OR 1.833, 95% CI 0.634-5.299) as risk factors for POD24. Furthermore, multivariable analysis through a median follow-up of 15.9 years implicated G3A (OR 2.628, 95% CI 0.806-8.575) and high-risk FLIPI (OR 4.401, 95% CI 0.186-104.377) as risk factors for HT. However, an analysis limited to the first 10 years revealed that the prognostic factors elucidated from the longer-term analysis had a greater impact on HT. G3A and high-risk FLIPI may independently predict POD24 and HT, thereby informing treatment stratification of patients with untreated advanced-stage FL in future trials, particularly to address the unmet needs of patients with POD24.

Efficacy of elotuzumab for multiple myeloma deteriorates after daratumumab: a multicenter retrospective study.

Elotuzumab-based regimens are sometimes selected for multiple myeloma treatment after daratumumab-based regimens. However, there has been insufficient discussion on the efficacy of elotuzumab after daratumumab. We used Kansai Myeloma Forum registration data in a multicenter retrospective evaluation of the efficacy of elotuzumab after daratumumab. Overall survival (OS) rate and time to next treatment (TTNT) were significantly worse in the cohort given elotuzumab after daratumumab (Dara cohort, n = 47) than in the cohort with no history of daratumumab administration before elotuzumab (No-Dara cohort, n = 80, OS: P = 0.03; TTNT: P = 0.02; best response: P < 0.01). In the Dara cohort, OS and TTNT rates were worse with sequential elotuzumab use after daratumumab than with non-sequential (OS: P = 0.02; TTNT: P = 0.03). In patients given elotuzumab < 180 days after daratumumab, OS (P = 0.08) and best response (P = 0.21) tended to be worse, and TTNT was significantly worse (P = 0.01), than in those given elotuzumab after ≥ 180 days. These findings were confirmed by subgroup analyses and multivariate analyses. Monoclonal-antibody-free treatment might be preferable after daratumumab-based regimens. If possible, elotuzumab-based regimens should be considered only ≥ 180 days after daratumumab use.

Prognostic model for relapsed/refractory transplant-ineligible diffuse large B-cell lymphoma utilizing the lymphocyte-to-monocyte ratio.

We conducted a multi-institutional retrospective study in 100 transplant-ineligible (TI) patients with diffuse large B-cell lymphoma (DLBCL) that relapsed or progressed after first-line R-CHOP (or -like) therapy to develop a robust predictive model for TI relapsed/refractory (r/r) DLBCL, which has a heterogeneous but poor prognosis by currently available treatment modalities other than chimeric antigen receptor T-cell (CAR-T) therapy or bispecific antibodies. The median age at relapse or progression was 76 years. The median progression-free survival (PFS) and overall survival (OS) from the first progression were 11.5 months and 21.9 months, respectively. Multivariate analysis identified low lymphocyte-to-monocyte ratio (LMR), elevated high lactate dehydrogenase, and elevated C-reactive protein at progression as independent predictors of OS. A predictive model based on these three factors, here designated as the Kyoto Prognostic Index for r/r DLBCL (KPI-R), successfully stratified their OS and PFS with statistical significance. In addition, event-free survival less than 24 months for R-CHOP and low LMR were identified as significant predictive factors for non-response in any sequence of salvage therapy. We concluded that LMR is a bonafide predictor of treatment response and prognosis in patients with TI r/r DLBCL, and may be helpful in treatment decision-making.

Primary analysis of a prospective cohort study of Japanese patients with plasma cell neoplasms in the novel drug era (2016-2021).

The emergence of novel drugs has significantly improved outcomes of patients with plasma cell neoplasms (PCN). The Japanese Society of Hematology conducted a prospective observational study in newly diagnosed PCN patients between 2016 and 2021. The analysis focused on 1385 patients diagnosed with symptomatic PCN between 2016 and 2018. The primary endpoint was the 3-year overall survival (OS) rate among patients requiring treatment (n = 1284), which was 70.0% (95%CI 67.4-72.6%). Approximately 94% of these patients received novel drugs as frontline therapy. The 3-year OS rate was 90.3% (95%CI 86.6-93.1%) in the 25% of patients who received upfront autologous stem cell transplantation (ASCT), versus just 61.4% (95%CI 58.0-64.6%) in those who did not receive upfront ASCT. The only unfavorable prognostic factor that affected OS in ASCT recipients was an age of 65 or higher. For patients who did not receive ASCT, independent unfavorable prognostic factors included frontline treatment with conventional chemotherapies, international staging system score of 2/3, extramedullary tumors, and Freiberg comorbidity index of 2/3. This study unequivocally demonstrates that use of novel drugs improved OS in Japanese myeloma patients, and underscores the continued importance of upfront ASCT as the standard of care in the era of novel drugs.

ctDNA improves prognostic prediction in relapsed/refractory MM receiving ixazomib, lenalidomide, and dexamethasone.

It remains elusive how driver mutations, including those detected in circulating tumor DNA (ctDNA), affect prognosis in relapsed/refractory multiple myeloma (RRMM). Here we performed targeted-capture sequencing using bone marrow plasma cells (BMPC) and ctDNA of 261 RRMM cases uniformly treated with ixazomib, lenalidomide, and dexamethasone in a multicenter, prospective, observational study. We detected 24 and 47 recurrently mutated genes in BMPC and ctDNA, respectively. In addition to clonal hematopoiesis-associated mutations, varying proportion of driver mutations, particularly TP53 mutations (59.2% of mutated cases), were present in only ctDNA, suggesting their subclonal origin. In univariable analyses, ctDNA mutations of KRAS, TP53, DIS3, BRAF, NRAS, and ATM were associated with worse progression-free survival (PFS). BMPC mutations of TP53 and KRAS were associated with inferior PFS, while KRAS mutations were prognostically relevant only when detected in both BMPC and ctDNA. A total number of ctDNA mutations in the six relevant genes was a strong prognostic predictor (2-year PFS rates: 57.3%, 22.7%, and 0% for 0, 1, and ≥ 2 mutations, respectively) and independent of clinical factors and plasma DNA concentration. Using the number of ctDNA mutations, plasma DNA concentration, and clinical factors, we developed a prognostic index (ctRRMM-PI), classifying patients into three categories with 2-year PFS rates of 57.9%, 28.6%, and 0%. Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM.

Autologous HSCT with novel agent-based induction and consolidation followed by lenalidomide maintenance for untreated multiple myeloma.

Triplet regimen comprising proteasome inhibitors, immunomodulatory drugs, and dexamethasone (DEX) is a recommended induction/consolidation therapy for multiple myeloma (MM) patients eligible for transplant. In this Japanese phase II study conducted from 2017 to 2019, newly diagnosed MM patients aged 20-65 received four induction cycles with bortezomib (Bor), lenalidomide (Len), and DEX (VRD), followed by Bor and high-dose melphalan with autologous stem cell rescue. Subsequently, they underwent four consolidation cycles with carfilzomib, Len, and DEX (KRD), followed by Len maintenance until disease progression. A total of 141 patients were analyzed. In an intent-to-treat population, the complete or better response post induction was 19.9%, rising to 39.7%, 58.9%, and 62.4% after transplant, consolidation, and 1-year maintenance, respectively. With a median follow-up of 38 months, the 3-year progression-free survival (PFS) rate was 83.5% and the 3-year overall survival rate was 92.5%. Severe adverse events (≥grade 3) occurred in ~30% of patients; however, there was no treatment-related mortality. These findings clearly showed the tolerability and effectiveness of this protocol. Nevertheless, patients with high-risk cytogenetics showed a trend toward lower 3-year PFS than those without (77.8% vs. 89.4%, p = 0.051), and ultra-high-risk cytogenetics (≥2 high-risk cytogenetics) had an even worse prognosis, with 61.2% 3-year PFS. To overcome this situation, a more potent treatment strategy incorporating novel agents such as the CD38-antibody should be assessed in future studies.

Clinical impacts of severe thrombocytopenia in the first cycle of azacitidine monotherapy and cytogenetics in patients with myelodysplastic syndrome: The Kyoto Conditional Survival Scoring System.

Azacitidine (AZA) has been one of the standard treatments for transplantation-ineligible patients with myelodysplastic syndrome (MDS); however, hematological toxicities frequently cause treatment interruption in the early phase of the therapy. The present study conducted a multicenter retrospective study to investigate the prognostic impacts of various factors, including factors included in the Revised International Prognostic Scoring System (IPSS-R) and severe cytopenia in the early phase of AZA monotherapy in 212 patients with MDS. Severe cytopenia was evaluated after the initiation of therapy by absolute neutrophil counts on the 29th day after AZA (ANC29) initiation, and red cell concentrates (RCC) and platelet concentrate (PC) transfusion units required within 28 days from the start of AZA, designated in the present study as RCC28 and PC28, respectively. The survival period was determined from the 29th day of AZA treatment to death from any cause as the conditional survival period after the first cycle of AZA (CS-AZA1). Multivariate analysis demonstrated that severe thrombocytopenia defined by >30 units of PC28 and very poor risk cytogenetics according to IPSS-R were independent prognostic factors for CS-AZA1. The Kyoto Conditional Survival Scoring System was subsequently developed by incorporating severe thrombocytopenia defined by PC28 and very poor risk cytogenetics, which successfully stratified the risks of the patients in CS-AZA1. In conclusion, extreme PC transfusion dependency during the first cycle of AZA and very poor risk cytogenetics are important prognostic factors in AZA monotherapy for MDS.

Skeletal muscle index impacts the treatment outcome of elderly patients with diffuse large B cell lymphoma.

Sarcopenia is a crucial factor in the physical fitness of elderly individuals. This study investigated the prognostic values of multiple parameters of sarcopenia in association with established prognostic factors in elderly Japanese patients with diffuse large B cell lymphoma (DLBCL). As candidate indicators for sarcopenia, the skeletal muscle index (SMI) (cm2 /m2 ), the psoas muscle index, the erector spinae muscle index, the visceral fat index, the subcutaneous fat index, and the visceral to subcutaneous fat area ratio at the third lumbar level were assessed by computed tomography at their initial diagnosis in 102 patients with DLBCL over 75 years old those were diagnosed and treated in our institute from 2007 to 2020. The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). The median age of patients analyzed was 80 years at diagnosis. The sex-specific cut-offs for the indices adopted two approaches: (i) the historical cut-off values established in the previous study for healthy Japanese individuals (Hamaguchi Y. J Cachexia Sarcopenia Muscle. 2018), and (ii) each sex-specific lowest quartile in our cohort. As the results, SMI evaluated by the historical cut-off and sex-specific lowest quartile was identified as the most influential independent prognostic factor for both OS and PFS among various parameters for sarcopenia. Furthermore, we developed an elderly sarcopenia prognostic index (ESPI). ESPI, which combines SMI evaluated by the historical cut-off and LDH > ULN, demonstrated statistically significant prognostic impacts on OS and PFS. Moreover, compared to the R-IPI, ESPI showed the ability to identify intermediate-risk groups and indicated a trend toward improved predictive accuracy. Our study revealed that SMI is the most appropriate assessment method for evaluating sarcopenia and the critical prognostic factor in OS and PFS of elderly patients with DLBCL.

miR-17-92 cluster-BTG2 axis regulates B-cell receptor signaling in mantle cell lymphoma.

B-cell receptor (BCR) signaling is critically activated and stable for mantle cell lymphoma (MCL), but the underlying mechanism of the activated BCR signaling pathway is not clear. The pathogenic basis of miR-17-92 cluster remains unclear although the oncogenic microRNA (miRNA) miR-17-92 cluster is highly expressed in patients with MCL. We revealed that miR-17-92 cluster overexpression is partly dependent on SOX11 expression and chromatin acetylation of MIR17HG enhancer regions. Moreover, miR-17-92 cluster regulates not only cell proliferation but BCR signaling activation in MCL cell lines. To comprehensively identify miR-17-92 cluster target genes, we performed pulldown-seq, where target RNA of miRNA was captured using the biotinylated miRNA mimics and magnetic bead-coated streptavidin, and quantified using next-generation sequencing. The pulldown-seq identified novel miRNA target genes, including tumor suppressors such as BTG2 (miR-19b), CDKN2A (miR-17), SYNE1 (miR-20a), TET2 (miR-18, miR-19b, and miR-92a), TNFRSF10A (miR-92a), and TRAF3 (miR-17). Notably, the gene expression profile data of patients with MCL revealed that BTG2 expression was negatively associated with that of BCR signature genes, and low BTG2 expression was associated with poor overall survival. Moreover, BTG2 silencing in MCL cell lines significantly induced BCR signaling overactivation and cell proliferation. Our results suggest an oncogenic role of miR-17-92 cluster-activating BCR signaling throughout BTG2 deregulation in MCL. Furthermore, this may contribute to the prediction of the therapeutic efficacy and improved outcomes of MCL.

A prospective, multicenter, observational study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in Japan.

Real-world studies permit inclusion of a more diverse patient population and provide more information on the effectiveness of treatments used in routine clinical practice. This prospective, multicenter, observational study investigated the effectiveness and safety of ixazomib plus lenalidomide and dexamethasone (IRd) in 295 patients with relapsed/refractory multiple myeloma (RRMM) in routine clinical practice in Japan. Patients had a median age of 74 years, 80.0% were aged ≥ 65 years, 42.0% had received ≥ 3 lines of prior treatment, and 28.5% were "frail" according to the International Myeloma Working Group frailty score. After a median follow-up of 25.0 months, median progression-free survival (PFS) was 15.3 (95% CI 12.4-19.5) months, while median overall survival was not reached. The overall response rate was 53.9%, and 31.5% of patients had a very good partial response or better. In the subgroup analysis, median PFS was better in patients with 1 versus 2 or ≥ 3 lines of prior treatment (29.0 vs 19.2 or 6.9 months) and paraprotein versus clinical relapse (16.0 vs 7.9 months), but median PFS was not notably affected by frailty score or age group. Dose adjustment was more frequent among patients aged > 75 years, especially early after IRd treatment initiation. Treatment-emergent adverse events (TEAEs) of any grade occurred in 84.4% of patients and 24.7% of patients discontinued treatment due to TEAEs; no new safety concerns were found. These findings suggest that oral IRd triplet regimen is an effective and tolerable treatment option for RRMM patients in real-world settings outside of clinical trials.ClinicalTrials.gov identifier: NCT03433001; Date of registration: 14 February 2018.

Negative impact of immunoparesis in response to anti-SARS-CoV-2 mRNA vaccination of patients with multiple myeloma.

Multiple myeloma reduces cellular and humoral immunity. Optimal prediction of antibody response to anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in patients with MM and related disorders is essential to prevent coronavirus disease 2019 (COVID-19) during the SARS-CoV-2 pandemic. This study analyzed the humoral response to the anti-SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine and its associated factor in 83 patients from June to November 2021 at seven member institutions of the Kyoto Clinical Hematology Study Group. SARS-CoV-2 neutralizing antibody (nAb) was measured from 12 to 210 days. The result revealed that 40 (48.2%) patients with MM and 59 (100%) healthy controls became seropositive after vaccination. Receiver operating characteristic curve analysis identified serum immunoglobulin (Ig) M of > 18 mg/dL at vaccination as the optimal threshold level associated with seropositivity in the whole cohort. Moreover, the multivariate analysis identified serum IgM of > 18 mg/dL as the independent predictor for a favorable response. Serum IgA level was positively associated with vaccine response in a sub-cohort. Our findings indicate a significant association between immunoparesis and impaired humoral response against mRNA vaccination, including that against SARS-CoV-2, and that serum non-M-protein Ig levels can serve as surrogate biomarkers of nAb production ability.

Impact of cytogenetic abnormalities in symptomatic multiple myeloma; a Japanese real-world analysis from Kansai Myeloma Forum.

To evaluate the specific prognostic value of CAs, we conducted an analysis of 923 symptomatic multiple myeloma patients. Among this cohort, 480 patients had complete data set of high-risk CAs by interphase fluorescent in situ hybridization at diagnosis. In the high-risk group analysis, the median OS of patients without CAs (n = 338, 72 %) was 6.5 years, patients with del(17p) (n = 42, 9 %) was 4.4 years, patients with t(4;14) or t(14;16) (n = 72, 15 %) was 4.4 years, and patients with double-positive CAs(del(17p) and t(4;14) or t(14;16)) (n = 18, 4 %) was 2.1 years (p = 0.032). Patients with double-positive CAs had a significantly worse prognosis.

R-CHOP treatment for patients with advanced follicular lymphoma: Over 15-year follow-up of JCOG0203.

Anti-CD20 antibody in combination with chemotherapy extends overall survival (OS) in untreated advanced-stage follicular lymphoma (FL), yet the optimal associated therapy is unclear. Data on the cumulative incidence of secondary malignancies postrelapse after conventional immunochemotherapy are scarce. A long-term analysis of rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) as first-line treatment was conducted in a randomised clinical trial. A six-cycle R-CHOP regimen was administered every 2 or 3 weeks without rituximab maintenance. A prespecified evaluation was conducted 15 years after the completion of enrolment, following initial analysis results that showed no significant differences in outcomes at the 3-year mark. In-depth analyses were performed on the cohort of 248 patients with FL who were allocated to the two treatment arms. With a median follow-up period of 15.9 years, the 15-year OS was 76.2%. There were no protocol treatment-related deaths, nor were there any fatal infections attributable to subsequent lymphoma treatment. At 15 years, the cumulative incidence of non-haematological and haematological malignancies was 12.8% and 3.7% respectively. Histological transformation appeared after a median of 8 years. R-CHOP maintains safety and efficacy in patients with advanced FL over extended follow-up, making it a viable first-line option for patients with advanced-stage FL.

Triple targeting of RSK, AKT, and S6K as pivotal downstream effectors of PDPK1 by TAS0612 in B-cell lymphomas.

B-cell lymphomas (BCLs) are the most common disease entity among hematological malignancies and have various genetically and molecularly distinct subtypes. In this study, we revealed that the blockade of phosphoinositide-dependent kinase-1 (PDPK1), the master kinase of AGC kinases, induces a growth inhibition via cell cycle arrest and the induction of apoptosis in all eight BCL-derived cell lines examined, including those from activated B-cell-like diffuse large B-cell lymphoma (DLBCL), double expressor DLBCL, Burkitt lymphoma, and follicular lymphoma. We also demonstrated that, in these cell lines, RSK2, AKT, and S6K, but not PLK1, SGK, or PKC, are the major downstream therapeutic target molecules of PDPK1 and that RSK2 plays a central role and AKT and S6K play subsidiary functional roles as the downstream effectors of PDPK1 in cell survival and proliferation. Following these results, we confirmed the antilymphoma efficacy of TAS0612, a triple inhibitor for total RSK, including RSK2, AKT, and S6K, not only in these cell lines, regardless of disease subtypes, but also in all 25 patient-derived B lymphoma cells of various disease subtypes. At the molecular level, TAS0612 caused significant downregulation of MYC and mTOR target genes while inducing the tumor suppressor TP53INP1 protein in these cell lines. These results prove that the simultaneous blockade of RSK2, AKT, and S6K, which are the pivotal downstream substrates of PDPK1, is a novel therapeutic target for the various disease subtypes of BCLs and line up TAS0612 as an attractive candidate agent for BCLs for future clinical development.

Analysis of False-negative Findings of the Incomparable Accuracy and Swiftness of Flow Cytometric Diagnosis of Primary Central Nervous System Lymphoma.

Primary central nervous system lymphoma (PCNSL), a relatively rare brain tumor, bears a dire prognosis. On occasion, the rapid progression of the tumor makes immediate diagnosis and initiation of therapy imperative. To achieve swift diagnosis, we adopt flow cytometry (FCM) in addition to conventional histopathology. This study aimed to reveal the utility of FCM diagnosis for PCNSL and the cause of false-negative results of FCM diagnosis. We investigated 33 patients with suspected PCNSL on neuroradiological findings and received both FCM and histological diagnosis. The patients' electronic medical records were investigated, and histological findings, results of FCM, and other clinical data were evaluated. Overall, 27 patients (14 males and 13 females) were diagnosed with PCNSL by histological confirmation. The median age at diagnosis was 68 years. FCM analysis showed lymphoma pattern in 24 cases; however, FCM results did not show lymphoma pattern (sensitivity: 88.9%, specificity: 100%) in the other three lymphoma cases (FCM discordant: FCM-D) and six nonlymphomatous tumor cases. Analysis of FCM-D cases showed the infiltration of T lymphocytes or astrocytes into the tumor tissue, indicating tumor microenvironmental reaction; it is assumed that these reactions deceived FCM diagnosis. The survival of FCM-D patients was superior to FCM concordant counterpart, although the difference was not significant (p = 0.459). The diagnosis of PCNSL by FCM is rapid and highly reliable. Some FCM-D cases are PCNSLs with strong tumor microenvironmental reactions.

Real-world data on induction therapy in patients with transplant-ineligible newly diagnosed multiple myeloma: retrospective analysis of 598 cases from Kansai Myeloma Forum.

To investigate the real-world clinical outcomes and management of novel drug-containing therapies for newly diagnosed multiple myeloma (MM) patients, we retrospectively analyzed data on the first-line treatment for newly diagnosed transplant-ineligible MM patients from Kansai Myeloma Forum, a registry network in Japan. A total of 598 patients treated with novel drugs between March 2007 and February 2018 were analyzed. Regimens used were VD (n = 305), Rd (n = 103), VMP (n = 97), VCD (n = 71), and VRd (n = 22). Younger patients tended to receive VRd or VCD, whereas the regimen with the highest median patient age was Rd. More than three-quarters of patients in the Rd group received a reduced dose of lenalidomide. The Rd and VRd groups had a relatively high incidence of infection and skin complications, and the VMP group had the highest incidence of peripheral neuropathy. Overall response rate did not differ significantly between regimens. Multivariate analysis in all patients revealed several poor prognostic factors, such as poor performance status. Novel drug-containing regimens for newly diagnosed MM showed a durable response with manageable AEs in the real-world setting.

Progressive Multifocal Leukoencephalopathy Initially Suspected As Brain Relapse From Classical Hodgkin's Lymphoma.

HIV-negative progressive multifocal leukoencephalopathy (PML) has a poor prognosis due to a lack of standard treatment. Herein, we report a patient with HIV-negative PML which occurred after the treatment for classical Hodgkin's lymphoma (CHL). A 71-year-old male patient was admitted to our hospital due to various neurological symptoms, including memory disturbance, dysgraphia, ataxia, and ideomotor apraxia, at 16 months after high-dose salvage chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) for primary treatment-refractory CHL. The patient's blood and serological examination results were mainly normal, including CD4-positive T lymphocyte count and serum immunoglobulin levels. T2-weighted fluid-attenuated inversion recovery MRI showed high-intensity lesions from the left occipital lobe to the corpus callosum. Moreover, the rapid intraoperative pathological assessment of biopsy specimens obtained from abnormal brain lesions suggested brain relapse of CHL. The patient's symptoms progressed rapidly; therefore, treatment with high-dose methotrexate was started, which significantly improved the patient's symptoms and MRI findings within a week. However, further examinations of the biopsy specimens with in situ hybridization and immunohistochemical examinations showed reactivation of the John Cunningham virus (JCV) in the astrocytes. Further, cells initially believed to be Hodgkin cells based on the rapid intraoperative pathological assessment were found to be destructive astrocytes, thereby confirming the diagnosis of PML. The patient was then successfully treated with combined mefloquine and mirtazapine and did not have any fatal outcomes. Based on this case, a differential diagnosis of PML from CNS involvement of CHL is important even in cases without evident biomarkers for immunodeficiency. Moreover, methotrexate was likely to be effective in improving neurological symptoms by decreasing brain parenchyma inflammation in the acute phase in this particular patient.

Management of Acquired Factor X Deficiency Caused by In Vitro Non-neutralizing Anti-factor X Autoantibodies with Pre-emptive Corticosteroid Therapy.

Coagulation factor X (FX) deficiency causes severe hemorrhagic symptoms. We herein report a 90-year-old man with hemorrhagic symptoms and prolongation of prothrombin time (PT) and activated partial thromboplastin time (APTT). Cross-mixing tests showed a factor deficiency pattern, but administration of plasma products was not effective. Acquired coagulation factor deficiency was suspected, and immunosuppressive therapy was started. After the intervention, his hemorrhagic symptoms improved. A decrease in FX activity was later confirmed, and anti-FX autoantibody was retrospectively detected by an enzyme-linked immunosorbent assay. Immediate intervention is important for patients suspected of having acquired coagulation factor deficiency.

Tumour-derived exosomes promote the induction of monocytic myeloid-derived suppressor cells from peripheral blood mononuclear cells by delivering miR-106a-5p and miR-146a-5p in multiple myeloma.

The shift of the tumour immune microenvironment to a suppressive state promotes not only the development and progression of the disease in multiple myeloma (MM) but also the development of resistance to immunotherapy. We previously demonstrated that myeloma cells can induce monocytic myeloid-derived suppressor cells (M-MDSCs) from healthy peripheral blood mononuclear cells (PBMCs) via the concomitant secretion of CC motif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF), but an unknown mediator also promotes M-MDSC induction. This study demonstrates that miR-106a-5p and miR-146a-5p delivered by tumour-derived exosomes (TEXs) from myeloma cells play essential roles in M-MDSC induction in MM. MiR-106a-5p and miR-146a-5p upregulate various immunosuppressive/inflammatory molecules in PBMCs, such as IDO1, CD38, programmed death-ligand 1, CCL5 or MYD88, which are involved in interferon (IFN)-α response, IFN-γ response, inflammatory response, tumour necrosis factor-α signalling and Interleukin-6-JAK-STAT3 signalling. These molecular features mirror the increases in myeloid cellular compartments of PBMCs when co-cultured with myeloma cells. MiR-106a-5p and miR-146a-5p have a compensatory relationship, and these two miRNAs collaborate with CCL5 and MIF to promote M-MDSC induction. Collectively, novel therapeutic candidates may be involved in TEX-mediated sequential cellular and molecular events underlying M-MDSC induction, potentially improving the efficacy of immunotherapy.