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We report a case of fulminant hepatitis in a hepatitis B surface antigen (HBsAg)‐positive patient with aggressive adult T‐cell leukemia‐lymphoma who received monotherapy with an anti‐CCR4 monoclonal antibody, mogamulizumab, with decreased hepatitis B virus (HBV)‐ DNA levels by entecavir prophylaxis. Although HBV reactivation‐related hepatitis was considered in the differential diagnosis, the patient did not meet the conventional criteria for HBV reactivation and was finally diagnosed with drug‐induced hepatitis. Considering that the immunoenhancing effects of mogamulizumab can lead to HBV reactivation‐related hepatitis in HBsAg‐positive patients, we should differentiate drug‐induced hepatitis from HBV reactivation, especially in patients receiving immunomodulatory drugs, if HBV‐DNA levels are reduced by antiviral prophylaxis. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an incurable B‐cell malignancy often accompanied by profound immunodeficiency. Lenalidomide (Len) is an immunomodulatory drug that exerts promising therapeutic effects on MM through the immune system. However, predictive markers related to the effects of Len treatment are not fully understood. This study aimed to identify candidate biomarkers for predicting the clinical efficacy of Len and dexamethasone (Ld) therapy through a comprehensive analysis of serum cytokines. The levels of 48 cytokines in the serum of patients with MM just before Ld therapy (n = 77), at the time of best response (n = 56), and at disease progression (n = 49) were measured and evaluated. Patients with high IL‐18 and M‐CSF levels showed significantly shorter progression‐free survival and overall survival (OS). In contrast, patients with high PDGF‐BB levels had longer survival. Moreover, low levels of G‐CSF, IL‐7, IL‐8, and SDF‐1α were associated with shorter OS after Ld therapy. During Ld therapy, pro‐inflammatory cytokines such as IL‐2Rα, IL‐18, and TNF‐α were decreased, while IFN‐γ was increased. IL‐4 and IL‐6 levels increased during disease progression. In conclusion, this study provides a better understanding of the association between cytokines and the efficacy of Ld therapy as well as the unique changes in cytokines related to inflammatory and immune responses during Ld therapy. [ABSTRACT FROM AUTHOR]

Cytokine release syndrome (CRS) can be a major side effect of chimeric antigen receptor T-cell (CAR-T) therapy, and may occasionally become life-threatening in patients with factors such as high tumor burden or poor performance status. Among the many CRS events observed in B-cell maturation antigen (BCMA)-targeting CAR-T therapy, local symptoms (also called local CRS) are poorly understood due to their low frequency. Here, we present the case of a 54-year-old woman with refractory multiple myeloma exhibiting laryngeal edema as a local CRS. Before CAR-T therapy, she was diagnosed with progressive disease indicated by a left thyroid mass. After local irradiation, she received the BCMA-targeting CAR-T agent idecabtagene vicleucel (ide-cel). On day 2, the patient developed CRS, which resolved on treatment with tocilizumab. However, on day 4, laryngeal edema worsened, and was judged to be a local CRS. Intravenous dexamethasone rapidly reduced this edema. In conclusion, laryngeal edema rarely occurs as a local CRS, and to the best of our knowledge, has never been reported after ide-cel infusion. Dexamethasone was effective for reducing the local reaction that persisted after treatment of systemic symptoms with tocilizumab. [ABSTRACT FROM AUTHOR]

Indoleamine 2,3‐dioxygenase 1 (IDO), an enzyme that metabolizes tryptophan (Trp) to kynurenine (Kyn), is an important microenvironmental factor suppressing antitumor immunity. Here, we investigated the clinical impact of aberrant Trp metabolism in patients with multiple myeloma (MM) treated with lenalidomide (Len) and evaluated its effects on T cell immunity ex vivo. Kyn and Trp concentrations were quantified in sera from 72 patients with relapsed or refractory MM prior to the initiation of therapy with Len plus dexamethasone (Ld). Associations of the Kyn/Trp ratio with progression‐free survival (PFS) and overall survival (OS) were analyzed. The expressions of IDO in tumor and stromal cells were evaluated during co‐culture, and the effects of culture medium containing low Trp and high Kyn concentrations on T cells in the presence of Len were investigated. Patients with high serum Kyn/Trp ratios (≥46.0, n = 22) had significantly shorter PFS and OS than those with low ratios (4.9 vs. 12.6 months, and 15.5 vs. 45.7 months, respectively). MM cells promoted IDO expression in stromal cells during co‐culture in both a direct contact and an indirect manner. Incubation in medium with a high Kyn/Trp ratio significantly inhibited T cell cytokine production and upregulated the expression of inhibitory immune receptors. These effects were sustained even in the presence of Len. In conclusion, a high serum Kyn/Trp ratio is associated with poor prognosis in patients with MM. We propose that aberrant Trp metabolism reduces anti‐tumor immunity and the efficacy of Len therapy. [ABSTRACT FROM AUTHOR]

Background: The recently developed severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) mRNA vaccine has a short history of use and further information is needed regarding its efficacy, especially in immunocompromised conditions, such as plasma cell dyscrasia (PCD). Methods: We retrospectively measured serum SARS‐CoV‐2 antibodies against the spike protein (S‐IgG) after the second and third mRNA vaccine doses (doses 2 and 3, respectively) in 109 patients with PCD. We evaluated the proportion of patients with an adequate humoral response (defined as S‐IgG titers ≥300 antibody units/mL). Results: Although active anti‐myeloma treatments prior to vaccination had a significantly negative impact on adequate humoral response, specific drug subclasses including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies were not negatively associated, except for B‐cell maturation antigen‐targeted therapy. Dose 3 (booster vaccination) led to significantly higher S‐IgG titers and more patients acquired an adequate humoral response. Furthermore, evaluation of vaccine‐induced cellular immune response in patients using T‐spot Discovery SARS‐CoV‐2 kit, revealed an enhanced cellular immune response after Dose 3. Conclusions: This study highlighted the significance of booster SARS‐CoV‐2 mRNA vaccination in patients with PCD with respect to humoral and cellular immunity. Moreover, this study highlighted the potential impact of certain drug subclasses on vaccine‐induced humoral immune response. [ABSTRACT FROM AUTHOR]

More information is needed regarding the efficacy of SARS-CoV-2 mRNA vaccines in immunocompromised populations, including patients with malignant lymphoma. This study aimed to evaluate humoral responses to the second and third mRNA vaccine doses in 165 lymphoma patients by retrospective analysis of serum SARS-CoV-2 spike protein antibody (S-IgG) titers. Patients with S-IgG titers ≥ 300, 10–300, and ≤ 10 binding antibody units (BAU)/mL were defined as adequate responders, low responders, and non-responders, respectively. S-IgG titers > 10 BAU/mL were considered to indicate seroconversion. After the second dose, 56%, 16%, and 28% of patients were adequate responders, low responders and non-responders, respectively. Multivariate analysis revealed that being an adequate responder after the second dose was associated with receiving the vaccine > 12 months after last chemotherapy, total peripheral lymphocyte count of ≥ 1000/µL, estimated glomerular filtration rate of ≥ 50 mL/min/1.73 m2, and vaccine type (mRNA-1273). After the third dose, patients had significantly higher S-IgG titers and a greater proportion achieved seroconversion. With this third dose, 26% of second-dose non-responders achieved seroconversion and 68% of second-dose low responders became adequate responders. Subsequent SARS-CoV-2 mRNA vaccinations may elicit an immune response in immunocompromised patients who do not initially respond to vaccination. [ABSTRACT FROM AUTHOR]

Background: Treatment for ocular myasthenia gravis (OMG) has not yet been well established. Few reports have been published on the clinical practice and outcomes of OMG. Objectives: We investigated treatment of OMG and its outcomes in Japan.We investigated treatment of OMG and its outcomes in Japan. Design: We performed a retrospective cross-sectional survey of OMG patients from eight hospitals in Japan. Methods: Clinical information, including sex, age at onset, initial symptoms, autoantibodies, clinical course, treatment history, complications, and outcomes, was obtained. In addition, we recorded the total number of patients with MG and OMG separately. Results: In total, 135 patients with OMG (67 men, 68 women) were included. Treatment of OMG was not simple and involved various immunotherapeutic strategies. Eight patients went into remission spontaneously without immunotherapy. A total of 117 patients showed improvements after treatment, whereas 10 patients showed refractory responses to treatment. Overall outcomes were good; however, symptoms persisted in 60.7% of patients even after treatment. Among 90 patients who received immunotherapy, only two showed a refractory response. Meanwhile, for 45 patients who did not receive immunotherapy, 8 were refractory. Thus, the rate of refractory disease in the group with immunotherapy was significantly lower (p = 0.001, u-test) than in the group without immunotherapy. The proportion of generalized MG patients among all MG cases was low in medical centers where immunotherapy for OMG was frequently performed. Conclusion: Although the overall prognosis for patients with OMG was good, symptoms remained in more than half of the patients. Immunotherapy, including corticosteroids, may be beneficial for patients with OMG. Plain language summary: Is immunosuppressive therapy beneficial for myasthenia gravis patients with ocular symptoms only? Patients with ocular myasthenia gravis (OMG) have only eye symptoms for more than 2 years. Whether this condition is an initial stage of the disease before eventually progressing to generalized myasthenia gravis (gMG) is still uncertain. Different from gMG, OMG is not life-threatening. But eye symptoms often cause troublesome problems in life. Doctors have treated OMG patients similarly to patients with gMG. There is no standard clinical practice for OMG. In this study, we examined how patients with OMG were treated at eight different specialist centers in Japan. In 135 patients with OMG, 8 patients became symptom free without treatment, 117 patients showed improvements after treatment, whereas 10 patients did not get well. Overall outcomes were good, but symptoms remained in 60.7% of patients even after treatment. Among 90 patients who received one or more immunotherapies, only 2 did not get well. Meanwhile, for 45 patients who did not receive immunotherapy, 8 remained ill. We found that treatment of OMG was not simple and often needed multiple immunotherapies. Administering immunotherapy, including corticosteroids, may be beneficial for patients with OMG. [ABSTRACT FROM AUTHOR]

We report a case of recurrent pain attacks during romiplostim treatment in a woman with immune thrombocytopenia carrying a heterozygous MEFV mutation. Five months after starting treatment with romiplostim for immune thrombocytopenia, she was diagnosed with idiopathic pericarditis. She was switched to eltrombopag, but thrombocytopenia did not improve. Romiplostim was restarted 7 months later, although she then developed recurrent right hypochondrial pain. The pain typically occurred three days after the romiplostim injection and resolved two days later. She had never experienced such recurrent pain before starting romiplostim or after discontinuing it. Genetic analysis showed that she carried a heterozygous R202Q alteration in exon 2 of the MEFV gene. MEFV mutation is known to cause familial Mediterranean fever, which is characterized by symptoms such as recurrent fever, abdominal and chest pain, arthritis, and pericarditis. This case suggests that romiplostim has the potential to trigger recurrent pain/inflammation attacks in individuals with systemic inflammatory abnormalities. [ABSTRACT FROM AUTHOR]

Introduction: Plasmapheresis is a well‐recognized treatment for autoimmune neurological diseases in Japan. However, the practice varies depending on the facility, and the actual treatment conditions are unclear. Methods: To clarify real‐world conditions, a prospective observational study was conducted on patients with neurological diseases who were scheduled to receive plasmapheresis. A dataset was analyzed that included 887 treatments from 210 patients with myasthenia gravis (MG), multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and other diseases for 82, 30, 24, and 74 patients, respectively. Results: The types of plasmapheresis performed included immunoadsorption plasmapheresis, plasma exchange, and double filtration plasmapheresis with 620, 213, and 54 treatments, respectively. Approximately, 60% of the treatments were performed using peripheral blood access alone. Non‐serious adverse events were observed in 10 patients. Conclusions: A statistically significant improvement was observed after plasmapheresis in patients with MG, MS, and NMOSD. These were evaluated using the modified Rankin Scale. [ABSTRACT FROM AUTHOR]

Aims: To prevent hepatitis B virus (HBV) reactivation‐related hepatitis, we examined the clinical usefulness of a highly sensitive HB core‐related antigen (iTACT‐HBcrAg) assay in patients with resolved HBV infection after nucleos(t)ide analog (NA) treatment for HBV reactivation. Methods: We retrospectively analyzed 27 patients with resolved HBV infection who experienced HBV reactivation (defined as HBV DNA levels of 1.3 log IU/ml or more), and who received systemic chemotherapies for hematological malignancies between 2008 and 2020. iTACT‐HBcrAg, HBsAg‐HQ, and antibodies against hepatitis B surface antigen (anti‐HBs) were measured using samples stored after HBV reactivation. The lower limit of quantification for iTACT‐HBcrAg was 2.0 log U/ml. Results: HBV reactivation was diagnosed at a median HBV DNA level of 1.8 log IU/ml, and then all patients received NA treatment. No patient had HBV‐related hepatitis with a median maximum HBV DNA level of 2.0 log IU/ml. The positivities of iTACT‐HBcrAg and HBsAg‐HQ were 96% and 52% after HBV reactivation, respectively. Of 25 patients with detectable iTACT‐HBcrAg at the initiation of NA treatment, 17 (68%) achieved iTACT‐HBcrAg loss. Median durations from NA treatment to HBV DNA loss and iTACT‐HBcrAg loss or the last follow‐up were 35 and 175 days, respectively. Recurrence of HBV reactivation after NA cessation was not observed in seven of eight patients who achieved iTACT‐HBcrAg loss or seropositive for anti‐HBs during follow‐up, except for one without anti‐HBs after allogeneic transplantation. Conclusions: iTACT‐HBcrAg could be a potential surrogate marker for diagnosing early‐stage HBV reactivation as well as safe cessation of NA treatment in patients with resolved HBV infection after HBV reactivation. [ABSTRACT FROM AUTHOR]

Background: Maintenance ± consolidation or continuous therapy is considered a standard of care for both transplant–eligible and –ineligible patients with multiple myeloma (MM). However, long-term benefits of such therapy have not yet been clarified in the context of clinical practice. Purpose: To clarify the efficacy of maintenance/continuous approach, we retrospectively analyzed the cohort data of newly diagnosed MM patients by propensity-score matching based on age, gender, revised International Staging System (R-ISS) stage, and implementation of transplantation to reduce the bias due to confounding variables. Findings: Among 720 patients, 161 were identified for each of the maintenance and no maintenance groups. Maintenance/continuous therapy employed immunomodulatory drugs (n = 83), proteasome inhibitors (n = 48), combination of both (n = 29), or dexamethasone alone (n = 1). Progression-free survival (PFS) was significantly prolonged in the maintenance group compared with the no maintenance group (median 37.7 and 21.9 months, p = 0.0002, respectively). Prolongation of PFS was observed in both transplanted and non-transplanted patients (p = 0.017 and p = 0.0008, respectively), with standard risk (p < 0.00001), R-ISS stage I (p = 0.037) and stage II (p = 0.00094), and those without obtaining complete response (p = 0.0018). There was no significant benefit in overall survival (OS), but it tended to be better in the maintenance group in non-transplanted patients. Regarding the treatment pattern, the substitution or addition of drugs different from the induction therapy and the combination with immunomodulatory drugs and proteasome inhibitors appeared to be more beneficial for PFS but not OS. Conclusion: These results support the benefit of current maintenance/continuous approach in routine clinical practice in the management of MM. [ABSTRACT FROM AUTHOR]

Background and purpose: Neuromyelitis optica spectrum disorder (NMOSD) often presents in the elderly with an insidious onset of symptoms and aggressive progression. There have been anecdotal cases of very late onset (VLO)‐NMOSD, but case series reports are rare. The aim of this retrospective study was to clarify the clinical features of VLO‐NMOSD. Methods: According to the age at onset, we classified patients with NMOSD into three subgroups: ≤49 years, early onset NMOSD (EO‐NMOSD); 50–69 years, late onset NMOSD (LO‐NMOSD); and ≥70 years, VLO‐NMOSD. We evaluated the clinical characteristics, magnetic resonance imaging (MRI) findings, laboratory data, and immunotherapies of the groups. Results: Overall, 12 men and 64 women with a median (interquartile range) age at onset and duration of disease of 42.0 (29.0–55.8) years and 70.0 (16.3–143.0) months, respectively, were included. Eight (11%) patients had VLO‐NMOSD, 22 (29%) had LO‐NMOSD, and 46 (61%) had EO‐NMOSD. Patients with EO‐NMOSD had a significantly longer interval between episodes as well as time between the first symptom and diagnosis of NMOSD than did those with VLO‐NMOSD and LO‐NMOSD (p = 0.046). Optic neuritis and nerve lesions on MRI were significantly less frequent in patients with VLO‐NMOSD than in those with LO‐NMOSD and EO‐NMOSD (p = 0.002 and p = 0.028, respectively). In contrast, patients with VLO‐NMOSD had higher nadir Expanded Disability Status Scale and Nurick scale scores and a significantly longer spinal lesion length than did those with LO‐NMOSD and EO‐NMOSD (p = 0.029, p = 0.049, and p = 0.032, respectively). Conclusions: Patients with VLO‐NMOSD tend to develop severe myelitis with long cord lesions but not optic neuritis. [ABSTRACT FROM AUTHOR]

Introduction: The majority of patients with myasthenia gravis (MG) initially present with ocular symptoms, but it is difficult to predict which cases will remain as ocular MG (OMG) or will progress to generalized MG. Herein we evaluated the serologic profile of Japanese OMG and its relationship with clinical features.Methods: Seventy-three patients with OMG from five Japanese myasthenia gravis (MG) centers were enrolled. Live cell-based assays (CBAs) were used to determine the presence of autoantibodies (Abs) to clustered adult (2α, β, δ, ε) and fetal (2α, β, δ, γ) acetylcholine receptor (AChR) isoforms, muscle-specific receptor tyrosine kinase (MuSK), and lipoprotein receptor-related protein-4 (LRP4).Results: Thirty-four of 73 (46.5%) serum samples were positive for Abs against both the adult-type and fetal-type AChR, as expected, but 7 (9.6%) and 2 (2.7%) were positive only for fetal or adult AChR-Abs, respectively. Four (5.4%) samples were positive for MuSK-Abs, but two of these also contained antibodies to fetal AChR or LRP4. Twenty-six (35.6%) samples were seronegative.Discussion: Abs against fetal-specific AChR, MuSK, and LRP4 are found in some patients with OMG. Future studies attempting to predict conversion from ocular symptoms to generalized MG may benefit from measurement of these antibodies. [ABSTRACT FROM AUTHOR]

The enzyme, indoleamine 2,3‐dioxygenase 1 (IDO), catabolizes tryptophan (Trp) in the kynurenine (Kyn) pathway, and is important in suppressing antitumor immune responses in the tumor microenvironment. With regard to previously untreated patients with follicular lymphoma (FL), we sought to establish the prognostic significance of Trp catabolism in this disease. Serum Trp and Kyn levels in 110 patients with FL were quantified, and their relationship to different clinical parameters studied. IDO expression in the lymph nodes of affected patients was studied. Study participants included 54 males and 56 females (age range 39–86, median 62 years), showing a 5‐year overall survival (OS) rate of 78.5%. Patients with a high Kyn level (5‐year OS, 65.0% vs. 81.7%; p = 0.026), high Kyn/Trp ratio (71.1% vs. 81.7%; p = 0.002), and low hemoglobin (Hb) level (<12.0 g/dL; p = 0.001; a component of FL international prognostic indexes) demonstrated a significantly shorter OS. Multivariate analysis included the following 10 variables: age, sex, serum β2‐microglobulin, Hb, longest diameter of the largest involved node, Ann Arbor stage, serum lactate dehydrogenase, histologic grading, B symptoms, and serum Kyn/Trp ratio; a lower Hb level and a high Kyn/Trp ratio (HR, 3.239; 95% CI, 1.296–8.096) led to a significantly inferior OS. In the microenvironment, some CD11c‐positive myeloid dendritic cells but not FL tumor cells were found to produce IDO. Overall, measuring levels of serum Kyn and Trp in individual patients with FL contributed to predicting their prognosis. [ABSTRACT FROM AUTHOR]

Summary: Previous genomic studies have revealed the genomic landscape of myeloma cells. Although some of the genomic abnormalities shown are believed to be correlated to the molecular pathogenesis of multiple myeloma and/or clinical outcome, these correlations are not fully understood. The aim of this study is to elucidate the correlation between genomic abnormalities and clinical characteristics by targeted capture sequencing in the Japanese multiple myeloma cohort. We analysed 154 patients with newly diagnosed multiple myeloma. The analysis revealed that the study cohort consisted of a less frequent hyperdiploid subtype (37·0%) with relatively high frequencies of KRAS mutation (36·4%) and IGH‐CCND1 translocation (26·6%) compared with previous reports. Moreover, our targeted capture sequencing strategy was able to detect rare IGH‐associated chromosomal translocations, such as IGH‐CCND2 and IGH‐MAFA. Interestingly, all 10 patients harboured MAX mutations accompanied by 14q23 deletion. The patients with del(17p) exhibited an unfavourable clinical outcome, and the presence of KRAS mutation was associated with shorter survival in patients with multiple myeloma, harbouring IGH‐CCND1. Thus, our study provides a detailed landscape of genomic abnormalities, which may have potential clinical application for patients with multiple myeloma. [ABSTRACT FROM AUTHOR]

Objective: To determine the usefulness of MRI measurements in patients with pure akinesia with gait freezing (PAGF), Richardson's syndrome, and Parkinson's disease for diagnosis. Methods: We obtained MRI measurements for patients with PAGF, Richardson's syndrome, or Parkinson's disease: 9 patients with PAGF, 26 with Richardson's syndrome, and 93 with Parkinson's disease. We measured the area of the pons and midbrain on midsagittal MRIs and the midbrain width on axial MRIs. We also calculated the mean values of the superior cerebellar peduncle, middle cerebellar peduncle, and cerebral crus width; the pons area-to-midbrain area ratio; the middle cerebellar peduncle width-to-superior cerebellar peduncle width ratio; and the magnetic resonance (MR) Parkinsonism index. Results: The Richardson's syndrome group had the highest pons area-to-midbrain area ratio and MR Parkinsonism index; the Parkinson's disease group had the lowest values. The Parkinson's disease group also had the highest midbrain width and cerebral crus width, with the lowest values being seen in the Richardson's syndrome group. The PAGF group had the intermediate values of the pons area-to-midbrain area ratio and MR Parkinsonism index between the Richardson's syndrome group and the Parkinson's disease group, whereas significant differences were found only in the pons area-to-midbrain area ratio. Results from receiver operating characteristic curve analyses showed that the pons area-to-midbrain area ratio has a higher sensitivity, specificity, and accuracy than the MR Parkinsonism index. Conclusions: The pons area-to-midbrain area ratio is more useful to distinguish PAGF from Richardson's syndrome and Parkinson's disease than the MR Parkinsonism index. [ABSTRACT FROM AUTHOR]

Lenalidomide is an effective therapeutic agent for multiple myeloma (MM). However, its efficacy in the context of chromosomal abnormalities (CA) is poorly understood. We retrospectively analyzed 83 patients with relapsed/refractory (RR) MM, who received lenalidomide plus low-dose dexamethasone (Ld), in the context of CA. The median age and number of prior therapies were 69 and 2, respectively. Three, 11, 45, and 19 patients achieved complete response, very good partial response, partial response, and stable disease, respectively. Median progression-free survival (PFS) and overall survival (OS) were 11.1 and 38.8 months, respectively. Seventy-two patients were evaluated for frequently observed translocations; median PFS was 24.4 months in 20 patients with t(11;14), 13.0 months in 16 patients with t(4;14), and 3.7 months in seven patients with t(14;16). G-banded karyotype analysis detected 11 hypodiploid patients, who had shorter PFS and OS (2.5 and 6.2 months, respectively) compared to others (13.0 and 43.7 months, respectively). Hypodiploid patients showed poor clinical outcome, whereas patients with t(11;14) showed favorable outcome. In summary, the present study presents the clinical impact of chromosomal abnormalities on the outcome of Ld therapy, and contributes to understanding the appropriate choice of lenalidomide-based therapy to achieve effective treatment of RR MM. [ABSTRACT FROM AUTHOR]

The t(11;14)/CCND1‐IGH, t(4;14)/NSD2(MMSET)‐IGH, and t(14;16)/IGH‐MAF gene rearrangements detected by fluorescence in situ hybridization (FISH) are used for risk stratification in patients with multiple myeloma (MM). Compared with conventional FISH techniques using fresh cells, immunohistochemistry (IHC) is much more cost‐ and time‐efficient, and can be readily applied to routinely prepared formalin‐fixed, paraffin‐embedded (FFPE) materials. In this study, we performed tissue FISH and IHC employing FFPE specimens, and examined the usefulness of IHC as a tool for detecting CCND1,NSD2, and MAF gene rearrangements. CD138 signals were used to identify plasma cells in tissue FISH and IHC analyses. With cohort 1 (n = 70), we performed tissue FISH and subsequently IHC, and determined IHC cut‐off points. In this cohort, the sensitivity and specificity for the 3 molecules were ≥.90 and ≥.96, respectively. With cohort 2, using MM cases with an unknown gene status (n = 120), we performed IHC, and the gene status was estimated using the cut‐off points determined with cohort 1. The subsequent FISH analysis showed that the sensitivity and specificity for the 3 molecules were ≥.92 and ≥.98, respectively. CCND1, NSD2, and MAF gene rearrangements were estimated accurately by IHC, suggesting that conventional FISH assays can be replaced by IHC. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies against surface antigens on MM cells, such as anti-SLAMF7 and anti-CD38 antibodies, represent an attractive therapeutic modality for the eradication of multiple myeloma (MM) cells. However, further exploration of target molecules is urgently needed for the development of more effective therapies. In the present study, we studied the expression of CD48 in a total of 74 primary MM samples derived from patients to evaluate SLAMF2 (CD48) as a candidate in mAb therapy for MM. Of 74 samples, 39 were subjected to SLAMF7 analysis. Most of the MM cells, defined as CD38 and CD138 double-positive cells, showed strong expression of CD48 or SLAMF7 independent of disease stage or treatment history. In these 39 samples, most MM cells showed expression of both SLAMF7 and CD48; however, several samples showed expression of either only CD48 or only SLAMF7, including seven cases that were only highly positive for SLAMF7, and five that were only highly positive for CD48. Our study demonstrates that the immune receptor CD48 is overexpressed on MM cells together with SLAMF7, and that CD48 may be considered as an alternative target for treatment of MM in cases showing weak expression of SLAMF7. [ABSTRACT FROM AUTHOR]

A 42-year-old female complaining of fever and night sweats was diagnosed with acute megakaryoblastic blast phase chronic myeloid leukemia (CML-BP). She had massive splenomegaly, left pleural effusion with leukemia infiltration, and moderate myelofibrosis. She received dasatinib monotherapy (140 mg/day) as for induction, after which her pleural effusion rapidly resolved and hematological remission was achieved. However, CML relapsed 4 months after starting dasatinib due to increased BCR-ABL fusion signals in the peripheral blood. The T315I mutation was also detected at the recurrence of CML. As a salvage treatment, ponatinib monotherapy (45 mg/day) was started immediately. After 5 months, BCR-ABL fusion signals decreased to 5%, and myelofibrosis improved from MF Grade 2 to 1; she then underwent allogeneic bone marrow transplantation from an unrelated donor. However, the graft failed, and cord blood transplantation (CBT) was performed. Ponatinib (15 mg/day) was continued after CBT as a maintenance treatment, with molecular complete response continuing for more than 1 year with no severe adverse events, including cardiovascular events. There is limited evidence regarding the optimal dose and schedule of ponatinib before and after allogeneic hematopoietic stem cell transplantation, especially in patients with CML-BP having T315I mutation; thus, well-designed clinical trials are warranted. [ABSTRACT FROM AUTHOR]

Aim: Recently, the measurement of hepatitis B surface antigen and anti‐hepatitis B core antigen (HBcAb) and/or anti‐hepatitis B surface antigen has been recommended before various therapies to identify patients at risk of hepatitis B virus (HBV) reactivation. However, a recent study reported that HBV reactivation occurred in HBcAb‐negative patients, indicating that it is challenging to identify patients with a history of HBV infection using conventional HBcAb reagent. We developed a highly sensitive HBcAb (HBcAb‐HS) assay for reducing the risk of HBV reactivation. Methods: The HBcAb‐HS assay is an automated chemiluminescent enzyme immunoassay system, which is suitable for clinical use. The cut‐off was set at 0.020 IU/mL from the distribution patterns of HBcAb‐negative specimens, and we evaluated the performance of this assay compared with conventional reagents. Results: This new assay showed a 27–81‐fold greater sensitivity than conventional HBcAb reagents; the quantified measurement range was from 0.005 IU/mL to 1.500 IU/mL, and it showed excellent quantitative performance and correlated well with two conventional assays, using the HBcAb‐positive specimens. Moreover, it showed 100% specificity for the 469 purchased HBcAb‐negative specimens. Notably, this newly developed HBcAb‐HS assay showed positivity in the preserved specimens before HBV reactivation, for which conventional HBcAb reagents gave negative results, and the HBcAb‐HS assay could detect the lower HBcAb levels even after intensive immunosuppressive therapies, including autologous hematopoietic stem cell transplantation. Conclusions: The clinical efficacy of the newly developed, highly sensitive HBcAb assay would enable the identification of patients at risk of HBV reactivation more accurately. [ABSTRACT FROM AUTHOR]

Adult T‐cell leukemia/lymphoma (ATL) is caused by Human T‐cell lymphotropic/leukemia virus type 1 (HTLV‐1), and a higher HTLV‐1 provirus load in PBMC is a risk factor for ATL development. Here, we document a significant inverse correlation between the function of HTLV‐1 Tax‐specific CTL (Tax‐CTL), as assessed by ex vivo cytokine production in response to cognate peptide, and the HTLV‐1 provirus load in PBMC in both HTLV‐1 asymptomatic carriers (AC) (Spearman rank correlation coefficient [Rs] = −0.494, P = .037, n = 18) and ATL patients (Rs = −0.774, P = .001, n = 15). There was also a significant correlation between the HTLV‐1 provirus load and the percentage of PD‐1‐positive Tax‐CTL in both HTLV‐1 AC (Rs = 0.574, P = .013) and ATL patients (Rs = 0.676, P = .006). Furthermore, the percentage of PD‐1‐positive Tax‐CTL was inversely correlated with their function in HTLV‐1 AC (Rs = −0.542, P = .020), and ATL patients (Rs = −0.639, P = .010). These findings indicate that the function of Tax‐CTL decreased as their programmed cell death protein 1 (PD‐1) levels increased, parallel to the increased HTLV‐1 provirus load in PBMC. We propose that functional Tax‐CTL are crucial for determining the HTLV‐1 provirus load in PBMC, not only in HTLV‐1 AC, but also in ATL, and that PD‐1 expression levels are reliable markers of Tax‐CTL function. Thus, modulating the immunological equilibrium between Tax‐CTL and HTLV‐1‐infected cells to achieve dominance of functional effectors could represent an ideal strategy for controlling HTLV‐1‐associated disease. [ABSTRACT FROM AUTHOR]

Afuresertib (AFU), a novel inhibitor of the serine/threonine kinase AKT, has clinical efficacy as a monotherapy against hematological malignancies and is expected to be used in combination with standard therapies for multiple myeloma (MM). To develop a more effective and less toxic combination of immunomodulatory drugs (IMiDs) for therapy, the antitumor effect of sub‑optimal doses of AFU, pomalidomide plus dexamethasone (PD), and the AFU‑PD combination on MM cells were examined in the present study. Two MM cell lines, XG‑7 and U266, with low sensitivity to both PD and AFU monotherapies, were subjected to these combinations and analyzed. Although the cell lines showed a slight reduction in viability with the sub‑optimal doses of each monotherapy, the combination of the treatments resulted in a reduction in cell viability and the progression of apoptosis. Co‑treatment with sub‑optimal doses of PD and AFU enhanced caspase activation and highly suppressed the expression of IKZF1 and IKZF3. In addition, this combination promoted the dephosphorylation and stabilization of 4EBP1, an inhibitor of eIF4E activation, which led to the impairment of eIF4E‑mediated translational activity. Furthermore, AFU showed a sufficient inhibitory effect on the phosphorylation of FOXO1, a tumor suppressor, in monotherapy or in combination with PD, which may be attributable to the activation of FOXO1, the subsequent inhibition of tumor growth, and the induction of cell death. In conclusion, the combination therapy with sub‑optimal doses of PD and AFU exhibited potent antitumor activity in MM cells and may provide a novel strategy for the treatment of patients who experienced intolerable toxicity or insufficient response during IMiD therapy. [ABSTRACT FROM AUTHOR]

Bortezomib (Btz) is an active agent used to treat multiple myeloma (MM). Not all patients who receive Btz-containing therapy show a favorable response. Interaction of cellular adhesion molecules with MM and bone marrow stromal cells is crucial for the survival of MM cells. However, little is known about the role of these molecules in the sensitivity of MM to Btz-containing therapy. Thus, we evaluated the correlation between the level of cellular adhesion molecules in MM cells and the efficacy of Btz plus dexamethasone (Bd) therapy. The expression of the neural cell adhesion molecule gene (NCAM, also known as CD56), ITGA4, CXCR4, and other genes were analyzed in 74 samples of primary MM cells collected from patients before they received Bd therapy. Of the eight genes tested, expression of NCAM was lower among patients who responded poorly to Bd therapy. In vitro expression of NCAM induced by transfection of MM cells enhanced their sensitivity to Btz treatment by causing accumulation of polyubiquitinated proteins. Our results indicate that expression of NCAM is associated with better response to Btz treatment and is a promising candidate biomarker for predicting response to therapies involving Btz. [ABSTRACT FROM AUTHOR]

Indoleamine 2,3‐dioxygenase 1 (IDO) is an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway. The purpose of the present study was to determine the clinical significance of Trp catabolism in newly diagnosed Hodgkin lymphoma (HL) patients. We quantified serum Trp and Kyn in 52 HL patients, and analyzed their associations with different clinical parameters including serum soluble CD30 concentration. The IDO expression was evaluated in the patients’ affected lymph nodes. The cohort comprised 22 male and 30 female patients (age range, 15‐81 years; median, 45 years), with a 5‐year overall survival (OS) of 88.6%. The OS was significantly shorter for patients with a high Kyn/Trp ratio (OS at 5 years, 60.0% vs 92.2%), for those with stage IV disease, and for those with lymphocytopenia (<600/mm3 and/or <8% white blood cell count). The latter two parameters are components of the international prognostic score for advanced HL. In contrast, there were no significant differences in OS according to age, serum albumin, hemoglobin, sex, white blood cell count, or serum soluble CD30 (≥ or <285.6 ng/mL). Multivariate analysis using the three variables stage, lymphocytopenia, and serum Kyn/Trp ratio showed that only the latter significantly affected OS. Indoleamine 2,3‐dioxygenase 1 was produced by macrophages/dendritic cells, but not by HL tumor cells, and IDO levels determined by immunohistochemistry had a significant positive correlation with the serum Kyn/Trp ratio. In conclusion, quantification of serum Kyn and Trp is useful for predicting prognosis of individual HL patients. [ABSTRACT FROM AUTHOR]

Cytogenetic/molecular heterogeneity is the hallmark of multiple myeloma ( MM). However, we recently showed that the serine/threonine kinase PDPK1 and its substrate RPS6 KA3 (also termed RSK2) are universally active in MM, and play pivotal roles in myeloma pathophysiology. In this study, we assessed involvement of aberrant miR-375 repression in PDPK1 overexpression in MM. An analysis of plasma cells from 30 pre-malignant monoclonal gammopathies of undetermined significance and 73 MM patients showed a significant decrease in miR-375 expression in patient-derived plasma cells regardless of the clinical stage, compared to normal plasma cells. Introduction of miR-375 reduced PDPK1 expression in human myeloma cell lines ( HMCLs), indicating that miR-375 is the dominant regulator of PDPK1 expression. In addition, miR-375 introduction also downregulated IGF1R and JAK2 in HMCLs. CpG islands in the MIR375 promoter were pathologically hypermethylated in all 8 HMCLs examined and in most of 58 patient-derived myeloma cells. Treatment with SGI-110, a hypomethylating agent, and/or trichostatin A, a histone deacetylase inhibitor, increased miR-375 expression, but repressed PDPK1, IGF1R and JAK2 in HMCLs. Collectively, these results show the universal involvement of overlapping epigenetic dysregulation for abnormal miR-375 repression in MM, which is likely to contribute to myelomagenesis and to subsequent myeloma progression by activating oncogenic signalling pathways. [ABSTRACT FROM AUTHOR]

Proteasome inhibitors (PIs) in combination with immunomodulatory drugs (IMiDs) have been shown to be effective against relapsed/refractory multiple myeloma (RRMM). To determine the optimal dosing schedule of once weekly bortezomib (BTZ) combined with lenalidomide (LEN) and dexamethasone (DEX), especially in the outpatient setting, we conducted a phase I dose escalation study. A 21-day cycle of BTZ 1.3 mg/m(2) on days 1 and 8, LEN 10 mg/day (cohort 1) or 15 mg/day (cohort 2) on days 1-14, and DEX 20 mg/day on days 1, 2, 8, and 9 was administered. Three patients were enrolled in each cohort. No dose-limiting toxicity was observed in either cohort. Although hematological toxicities estimated as >grade 3 were common, non-hematological toxicities of grade 3 or higher were rare. Two cases of newly diagnosed peripheral neuropathy (PN) were observed, while no grade 3/4 PN was observed. Two patients achieved partial response and two achieved stable disease. The recommended doses of BTZ and LEN were determined to be 1.3 mg/m(2) and 15 mg, respectively. Combination therapy of once weekly BTZ with LEN and DEX was well tolerated and shows promise as a regimen for patients with RRMM previously treated with both PIs and IMiDs. [ABSTRACT FROM AUTHOR]

Amylase-producing myeloma exhibits refractoriness to chemotherapy and a dismal prognosis. In this study, we established a human myeloma cell line, 8226/AMY1, in which a lentivirally transfected AMY1 gene was stably expressed and explored its biological characteristics. 8226/AMY1 showed a survival advantage over mock control when treated with dexamethasone, bortezomib, and lenalidomide in vitro partly through inhibition of apoptosis induced by these reagents. In a xenograft murine model, 8226/AMY1 showed rapid tumor growth and reduced sensitivity to bortezomib compared with mock. A microarray gene expression analysis identified TCL1A, which functions as a coactivator of the cell survival kinase Akt, differentially up-regulated in 8226/AMY1. The expression of phosphorylated Akt was increased in the 8226/AMY1 cells following bortezomib treatment, but not in the mock cells. In addition, treatment with perifosine, an inhibitor of Akt phosphorylation, enhanced the anti-myeloma effect of bortezomib in the 8226/AMY1 cells. Our data suggest that amylase-producing myeloma reduced the sensitivity to bortezomib in vitro and in vivo, and the up-regulation of TCL1A may influence the drug susceptibility of 8226/AMY1 via the phosphorylation of Akt. These findings provide clues for developing treatment approaches for not only amylase-producing myeloma, but also relapsed and refractory myelomas. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to evaluate the therapeutic potential of bevacizumab with or without systemic chemotherapy for adult T-cell leukemia/lymphoma ( ATL) and clarify the significance of angiogenesis for ATL pathogenesis. Methods NOD/ Shi- scid, IL-2 Rγnull ( NOG) mice were used as recipients of tumor cells from a patient with ATL, which engraft and proliferate in a microenvironment-dependent manner. The ATL cells could be serially transplanted in NOG mice, but could not be maintained in in vitro cultures. Results Injection of bevacizumab alone significantly increased necrosis and decreased vascularization in the tumor tissue. Levels of human soluble interleukin two receptor in the serum (reflecting the ATL tumor burden) of bevacizumab-treated mice were significantly lower than in untreated mice. Although bevacizumab monotherapy showed these clear anti-angiogenesis effects, it did not prolong survival. In contrast, injection of bevacizumab together with cyclophosphamide, doxorubicin, vincristine, prednisolone ( CHOP) led to a significant prolongation of survival of the ATL mice relative to CHOP alone. Conclusions This is the first report to evaluate the efficacy of bevacizumab for ATL in a tumor microenvironment-dependent model. Bevacizumab therapy combined with chemotherapy could be a valuable treatment strategy for that subgroup of ATL probably depending to a large extent on angiogenesis via vascular endothelial growth factor. [ABSTRACT FROM AUTHOR]

We expanded CTL specific for Tax (a human T-lymphotropic virus type-1-encoded gene product) in vitro from PBMC of several adult T-cell leukemia/lymphoma ( ATL) patients, and document its potential significance as a target for ATL immunotherapy. Tax-specific CTL responses against tumor cells were restricted by Tax-expression and the appropriate human leukocyte antigen ( HLA) type. Tax-specific CTL recognized HLA/Tax-peptide complexes on autologous ATL cells, even when their Tax expression was so low that it could only be detected by RT-PCR but not by flow cytometry. Recognition resulted in interferon gamma ( IFN-γ) production and target cell lysis. This would be the first report that Tax-specific CTL from ATL patients specifically recognized and killed autologous tumor cells that expressed Tax. The Tax-specific CTL responded to as little as 0.01 p M of the corresponding peptide, indicating that their T-cell receptor avidity was much higher than that of any other CTL recognizing viral or other tumor antigens. This is presumably the reason why the Tax-specific CTL recognized and killed autologous ATL cells despite their very low Tax expression. In addition, cell cycle analyses and experiments with primary ATL cell-bearing mice demonstrated that ATL cells present at the site of active cell proliferation, such as in the tumor masses, expressed substantial amounts of Tax, but it was minimally expressed by the tumor cells in a quiescent state, such as in the blood. The present study not only provides a strong rationale for exploiting Tax as a possible target for ATL immunotherapy but also contributes to our understanding of the immunopathogenesis of ATL. [ABSTRACT FROM AUTHOR]