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Multiple myeloma (MM) is an intractable hematological malignancy caused by abnormalities in plasma cells. Combination therapy using antibodies and natural killer (NK) effectors, which are innate immune cells with safe and potent antitumor activity, is a promising approach for cancer immunotherapy and can enhance antitumor effects. Elotuzumab (Elo) is an immune-stimulatory antibody that targets the signaling lymphocytic activation molecule family 7 (SLAMF7) expressed on the surface of MM and NK cells. We confirmed that Elo strongly promoted NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against SLAMF7-positive MM cells in a CD16-dependent NK cell line, and also activated expanded NK cells derived from peripheral blood mononuclear cells of healthy donors and patients with MM in the present study. However, the antitumor effects and genes involved in the direct promotion of NK cell-mediated activation using Elo in CD16-independent NK cells are not clearly known. In this study, we demonstrated that Elo pretreatment significantly enhanced CD16-independent NK cell-mediated cytotoxicity in both SLAMF7-positive MM.1S and SLAMF7-negative K562, U266, and RPMI 8226 tumor cells. Upon direct simulation of CD16-independent NK cells with Elo, increased levels of CD107a degranulation and IFN-γ secretion were observed along with the upregulation of granzyme B, TNF-α, and IL-1α gene expression. The enhanced NK cell function could also be attributed to the increased expression of the transcription factors T-BET and EOMES. Furthermore, the augmentation of the antitumor effects of CD16-independent NK cells upon pretreatment with Elo enhanced the expression of CRTAM, TNFRSF9, EAT-2, and FOXP3 genes and reduced the expression of HSPA6. Our results suggest that Elo directly promotes the cytotoxic function of CD16-independent NK cells against target cells, which is associated with the upregulation of the expression of several NK cell-enhancing genes.

Primary bone marrow diffuse large B-cell lymphoma (DLBCL) is a rare type of extranodal lymphoma with poor prognosis. Here, we report a case of primary bone marrow DLBCL successfully treated with high-dose chemotherapy and rescued by in vivo rituximab-purged autologous stem cells. A 39-year-old woman visited our hospital because of anemia. Bone marrow examination revealed a large B-cell lymphoma invasion. An 18F-fluorodeoxyglucose positron emission tomography scan revealed disseminated bone marrow uptake without evidence of dissemination at other sites. These findings led to a diagnosis of primary bone marrow DLBCL. Our patient underwent R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy and achieved complete remission. Subsequently, she received high-dose chemotherapy with an in vivo rituximab-purged autologous stem cell transplant. Seven years have passed since the transplantation, and she remains in remission. This suggests that transplantation of an in vivo rituximab-purged autograft is a promising strategy for primary bone marrow DLBCL.

Adult T‐cell leukemia/lymphoma (ATL) is a mature T‐cell neoplasm and is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, established in 1991 through several nationwide surveys based on the clinical diversity of patients diagnosed in 1983‐1987 in Japan. Thereafter, no such studies have been conducted. Recently, we conducted a nationwide hospital survey using the method of the 1980s studies, collected baseline data on 996 ATL patients diagnosed in 2010‐2011 from 126 hospitals, and reported their unique epidemiological characteristics. Here, we report the follow‐up results of registered ATL patients with the goal of evaluating current prognoses and treatment modalities as of 2016‐2017. Of 770 evaluable patients, 391 (50.8%) had acute‐type, 192 (24.9%) had lymphoma‐type, 106 (13.8%) had chronic‐type, and 81 (10.5%) had smoldering‐type ATL. The initial therapy regimens used for acute/lymphoma‐type ATL were vincristine, cyclophosphamide, doxorubicin and prednisone, followed by doxorubicin, ranimustine, and prednisone and then by vindesine, etoposide, carboplatin, and prednisone (VCAP‐AMP‐VECP)‐like in 38.5/41.7% and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)‐like in 14.6/13.7% of patients. Allogeneic hematopoietic stem cell transplantation was used to treat 15.9/10.4% of acute/lymphoma‐type ATL patients. The 4‐year survival rates (the median survival time, days) for acute‐, lymphoma‐, unfavorable chronic‐, favorable chronic‐, and smoldering‐type ATL were 16.8% (252), 19.6% (305), 26.6% (572), 62.1% (1937), and 59.8% (1851), respectively. The 4‐year survival rates for acute‐ and lymphoma‐type ATL improved compared with those reported in 1991, but those for chronic‐ and smoldering‐type ATL were not. Further efforts are warranted to develop more efficient therapeutic strategies to improve the prognosis of ATL in Japan. The survival curve shows that the prognoses of patients with acute and lymphoma‐type ATL in Japan have improved modestly, but those of patients with chronic and smoldering‐type ATL have not improved.

The red blood cell distribution width–albumin ratio (RAR) is a prognostic factor for adverse outcomes in various populations. However, whether RAR is associated with renal outcomes remains unclear. Therefore, we aimed to investigate the impact of RAR on the prognosis in patients with chronic kidney disease (CKD). We conducted a retrospective cohort study using 997 CKD patients who were enrolled in the Fukushima Cohort Study. Patients were categorized into tertiles (T1-3) according to the baseline RAR. The associations of RAR with end-stage kidney disease (ESKD) were assessed using Kaplan–Meier curves and multivariable cox regression analyses. Receiver operating characteristic (ROC) curves were performed to test whether significant differences were present between red cell distribution width (RDW) and RAR. The median age was 66, 57% were men, the median eGFR was 47.8 ml/min/1.73 m 2 , and the median value of RAR was 3.5. The higher RAR group showed an increased risk for ESKD in the Kaplan–Meier curve analysis. Compared to the lowest RAR group, higher RAR groups had a higher risk of ESKD (hazard ratio [HR] 1.37, 95% CI 0.68–2.78 and 2.92, 95% CI 1.44–5.94) for T2 and T3 groups, respectively. ROC curve analysis proved that the discriminating ability of RAR for ESKD was superior to RDW. A higher RAR value was associated with worse renal outcomes in patients with CKD. RAR could be a convenient and useful prognostic marker for renal prognosis.

BackgroundMean corpuscular volume (MCV) and red cell distribution width (RDW), as well hemoglobin, are reported to be associated with mortality in various populations. However, associations between such hematological parameters and adverse outcomes in patients with CKD have not been sufficiently elucidated.MethodsA total of 1,320 participants enrolled in the Fukushima CKD Cohort Study were examined to investigate associations between hematological parameters of anemia (MCV and RDW) and adverse outcomes, such as ESKD, all-cause death, and cardiovascular events, in patients with non-dialysis-dependent CKD. Baseline hematological parameters were grouped as follows: hemoglobin into 3 categories (< 11.0 g/dL, 11.0 ≤  −  < 13.0 g/dL [reference], and ≥ 13.0 g/dL); MCV into 5 categories (< 90 fL, ≥ 90 – < 94 fL [reference], ≥ 94 −  < 98 fL, ≥ 98 −  < 102 fL, and ≥ 102 fL); and RDW into 2 categories (< 13.6% [reference] vs ≥ 13.6%).ResultsDuring the median observational period of 4.7 years, 120 patients developed ESKD, 160 developed cardiovascular events, and 122 died. Hemoglobin < 11 g/dL (hazard ratio [HR] 1.56, 95% confidence interval [CI], 1.00–2.42), MCV < 90 fL (HR 2.01, 95% CI 1.14–3.54), and RDW ≥ 13.6% (HR 1.57, 95% CI 1.01–2.42) were significantly associated with higher risks of ESKD. Hemoglobin < 11 g/dL, MCV ≥ 98 fL, and RDW ≥ 13.6% were significantly associated with higher risks of all-cause death. No significant associations between hematological parameters and risk of cardiovascular events were confirmed.ConclusionIn patients with non-dialysis-dependent CKD, MCV, RDW, and hemoglobin were associated with increased risks of ESKD and all-cause mortality.

Predicting the transition of kidney function in chronic kidney disease is difficult as specific symptoms are lacking and often overlooked, and progress occurs due to complicating factors. In this study, we applied time-series cluster analysis and a light gradient boosting machine to predict the trajectories of kidney function in non-dialysis dependent chronic kidney disease patients with baseline estimated glomerular filtration rate (GFR) ≥ 45 mL/min/1.73 m 2 . Based on 5-year changes in estimated GFR, participants were stratified into groups with similar trajectories by cluster analysis. Next, we applied the light gradient boosting machine algorithm and Shapley addictive explanation to develop a prediction model for clusters and identify important parameters for prediction. Data from 780 participants were available for analysis. Participants were classified into five classes (Class 1: n = 78, mean [± standard deviation] estimated GFR 100 ± 19.3 mL/min/1.73 m 2 ; Class 2: n = 176, 76.0 ± 9.3 mL/min/1.73 m 2 ; Class 3: n = 191, 59.8 ± 5.9 mL/min/1.73 m 2 ; Class 4: n = 261, 52.7 ± 4.6 mL/min/1.73 m 2 ; and Class 5: n = 74, 53.5 ± 12.0 mL/min/1.73 m 2 ). Declines in estimated GFR were 8.9% in Class 1, 12.2% in Class 2, 4.9% in Class 3, 12.0% in Class 4, and 45.1% in Class 5 during the 5-year period. The accuracy of prediction was 0.675, and the top three most important Shapley addictive explanation values were 1.61 for baseline estimated GFR, 0.12 for hemoglobin, and 0.11 for body mass index. The estimated GFR transition of patients with preserved chronic kidney disease mostly depended on baseline estimated GFR, and the borderline for estimated GFR trajectory was nearly 50 mL/min/1.73 m 2 .

Introduction The red blood cell distribution width/albumin ratio (RAR) has been reported to be a prognostic marker for adverse clinical outcomes. However, there is limited data on the relationship between RAR and renal function in patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the effect of RAR on renal prognosis in patients with T2DM. Research Design and Methods This retrospective cohort study included 907 patients with T2DM enrolled in the Fukushima Cohort Study, divided into two groups (high and low RAR) according to their baseline RAR. The association between RAR and renal events was assessed using Kaplan–Meier curves and multivariate Cox regression analyses. Receiver operating characteristic (ROC) curve analyses, as well as the net reclassification index (NRI) and integrated discrimination improvement (IDI), examined the differences between RAR and red blood cell distribution width (RDW) alone. Results The high RAR group showed an increased risk of renal events in the Kaplan–Meier curve analysis. Compared with the low RAR group, the high RAR group showed an increased risk of renal events (adjusted hazard ratio [HR]: 3.40, 95% confidence interval: 1.76–6.57). RAR exhibited a significantly higher area under the curve (AUC), NRI, and IDI for renal events than RDW. Conclusion We observed an association between high RAR and worse renal outcomes in patients with T2DM. RAR assessment may have potential utility as a predictive tool for renal prognosis. Red cell distribution width (RDW)/serum albumin ratio (RAR) is a novel and simple inflammatory marker and has emerged as a reliable prognostic marker in various diseases. Our study reveals that a high RAR is a practical and easily obtainable predictive tool for assessing renal risk in patients with T2DM, thereby offering a tangible benefit to healthcare professionals and patients. Given the increasing global prevalence of T2DM and its association with chronic kidney disease, identifying simple and accessible biomarkers for predicting renal outcomes is crucial for improving patient management. Our study significantly contributes to diabetes care in clinical practice for early risk stratification of patients with T2DM.

Animals combine multiple cues to navigate the environment. By performing calcium imaging in fruit flies navigating in a virtual space, the authors show that information about recent visual experience and self-motion is separately encoded in parallel neural pathways in the central brain of Drosophila . Animal navigation requires multiple types of information for decisions on directional heading. We identified neural processing channels that encode multiple cues during navigational decision-making in Drosophila melanogaster . In a flight simulator, we found that flies made directional choices on the basis of the location of a recently presented landmark. This experience-guided navigation was impaired by silencing neurons in the bulb (BU), a region in the central brain. Two-photon calcium imaging during flight revealed that the dorsal part of the BU encodes the location of a recent landmark, whereas the ventral part of the BU tracks self-motion reflecting turns. Photolabeling-based circuit tracing indicated that these functional compartments of the BU constitute adjacent, yet distinct, anatomical pathways that both enter the navigation center. Thus, the fly's navigation system organizes multiple types of information in parallel channels, which may compactly transmit signals without interference for decision-making during flight.