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Chimeric antigen receptor (CAR) T‐cell therapy has become a commercially available treatment option for relapsed or refractory (r/r) diffuse large B‐cell lymphoma (DLBCL) with two or more lines of prior therapies, and recently for high‐risk r/r DLBCL with one prior line of therapy. The successful development of CAR T‐cell therapy for multiple relapsed DLBCL has led to a boom in subsequent trials that investigated its utility in patients with other r/r B‐cell lymphoma subtypes. However, CAR T‐cell therapy is a multistep process that includes leukapheresis and manipulation which take several weeks. Therefore, patients with rapidly progressing or bulky disease may not be able to complete the therapeutic regimen involving CAR T‐cell products. This raises the question of the generalizability of the results of pivotal studies to the entire population. In this review, we summarize the development of CAR‐T cell therapy for B‐cell lymphoma and discuss strategies to further improve the clinical outcomes of this treatment. [ABSTRACT FROM AUTHOR]

Identification of genetic alterations through next‐generation sequencing (NGS) can guide treatment decision‐making by providing information on diagnosis, therapy selection, and prognostic stratification in patients with hematological malignancies. Although the utility of NGS‐based genomic profiling assays was investigated in hematological malignancies, no assays sufficiently cover driver mutations, including recently discovered ones, as well as fusions and/or pathogenic germline variants. To address these issues, here we have devised an integrated DNA/RNA profiling assay to detect various types of somatic alterations and germline variants at once. Particularly, our assay can successfully identify copy number alterations and structural variations, including immunoglobulin heavy chain translocations, IKZF1 intragenic deletions, and rare fusions. Using this assay, we conducted a prospective study to investigate the feasibility and clinical usefulness of comprehensive genomic profiling for 452 recurrently altered genes in hematological malignancies. In total, 176 patients (with 188 specimens) were analyzed, in which at least one alteration was detected in 171 (97%) patients, with a median number of total alterations of 7 (0–55). Among them, 145 (82%), 86 (49%), and 102 (58%) patients harbored at least one clinically relevant alteration for diagnosis, treatment, and prognosis, respectively. The proportion of patients with clinically relevant alterations was the highest in acute myeloid leukemia, whereas this assay was less informative in T/natural killer‐cell lymphoma. These results suggest the clinical utility of NGS‐based genomic profiling, particularly for their diagnosis and prognostic prediction, thereby highlighting the promise of precision medicine in hematological malignancies. [ABSTRACT FROM AUTHOR]

We conducted a nationwide retrospective analysis of 116 hepatitis B virus (HBV) surface antigen (HBsAg)‐positive patients with diffuse large B‐cell lymphoma (DLBCL) and 278 HBsAg‐negative patients with DLBCL, as a control cohort, who received rituximab‐containing regimens as an induction chemotherapy at 30 Japanese medical centers between January 2004 and December 2014. Hepatitis was defined as an absolute serum alanine aminotransferase (ALT) level of ≥100 U/L. HBV reactivation‐related hepatitis was defined as hepatitis with an absolute serum HBV DNA level of ≥3.3 log IU/mL or an absolute increase of ≥2 log compared with the baseline value. HBsAg‐positive patients were divided into three groups based on anti–HBV prophylactic therapy: no nucleos(t)ide analogue (non–NA, n = 9), lamivudine (LAM, n = 20), and entecavir (ETV, n = 87). The 4‐year cumulative incidence (CI) of hepatitis in HBsAg‐positive and HBsAg‐negative patients was 21.1% and 14.6% (P =.081), respectively. The 4‐year CI of HBV reactivation‐related hepatitis was higher in HBsAg‐positive patients than in HBsAg‐negative patients (8.0% vs 0.4%; P <.001). Among HBsAg‐positive patients, the 4‐year CI of HBV reactivation‐related hepatitis was the highest in the non–NA group (33.3%), followed by the LAM (15.0%) and ETV (3.8%) groups (P <.001). Of note, 3 non–NA patients (33%) and 1 LAM patient (5%) (but no ETV patients) died due to HBV hepatitis. Based on Cox multivariate analysis, HBsAg positivity was not associated with poor overall survival. Prophylactic use of ETV would reduce the occurrence of HBV reactivation‐related hepatitis and mortality in HBsAg‐positive DLBCL patients receiving rituximab‐containing chemotherapy. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to evaluate the outcomes of local radiotherapy (LRT) in patients with histologic transformation (HT) following rituximab‐containing chemotherapy. Methods: We retrospectively analysed 92 patients with biopsy‐confirmed HT undergoing rituximab‐containing chemotherapy at our institution between 2003 and 2015. Results: Of the 36 patients with limited‐stage disease at diagnosis of HT, 29 (78%) received LRT. The estimated 5‐year progression‐free survival (PFS) rate was significantly better in patients who underwent LRT than in those who did not (93% and 42%, respectively; P < 0.05). Multivariate analyses employing age, sex, performance status, LRT and treatment response demonstrated that LRT was an independent prognostic factor for PFS (hazard ratio [HR]: 11.8; 95% confidence interval [CI]: 1.28‐108.1; P < 0.05). Of the 32 patients who underwent LRT for HT lesion treatment, 31 (97%) did not show disease progression within radiation fields; among them, 27 patients (84%) survived without disease progression during the follow‐up period. One patient developed hypothyroidism due to LRT; the others had no acute or late‐onset complications of LRT. Conclusions: Our data support the recommendation of LRT for HT lesion treatment following rituximab‐containing chemotherapy in select patients with localised HT, as a rational treatment approach with potentially limited toxicity. [ABSTRACT FROM AUTHOR]

Although histologic analysis is the gold standard for diagnosing follicular lymphoma (FL) transformation, many patients are diagnosed with transformation by clinical factors as biopsy specimens often cannot be obtained. Despite the frequency of clinical diagnosis, no clinical assessment tool has yet been established for FL transformation in the rituximab era. We derived and validated a transformation scoring system (TSS) based on retrospective analyses of 126 patients with biopsy‐proven FL and histologic transformation (HT) at two hospitals of the National Cancer Center of Japan. In the derivation set (76 patients), the detailed analyses of the clinical characteristics at disease progression showed that lactate dehydrogenase (LDH) elevation, focal lymph nodal (LN) enlargement, hemoglobin <12 g/dl, and poor performance status (PS) (2‐4) were associated with HT. The weights of these variables were decided based on the regression coefficients. Next, we constructed a TSS encompassing the above four factors: LDH, (> upper limit of normal [ULN], ≤ULN ×2) (1 point), (≥ULN ×2) (2 points); focal LN enlargement, (≥3 cm, <7 cm) (1 point), (≥7 cm) (2 points); hemoglobin <12 g/dl (1 point); poor PS (2 points). We identified a high positive predictive value (PPV) (96.4%) and negative predictive value (NPV) (85.4%) for diagnosing HT when a cutoff score of 2 was selected for our TSS. In an external validation set (50 patients), the probability of HT was high with scores ≥2 (PPV, 93.3%; NPV, 82.9%). We developed a TSS that offers a simple, yet, valuable tool, for diagnosing HT, especially in patients who cannot undergo biopsy. [ABSTRACT FROM AUTHOR]

The efficiency of upfront consolidation with high‐dose chemotherapy/autologous stem‐cell transplantation (HDCT/ASCT) for newly diagnosed high‐risk diffuse large B‐cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in high‐risk DLBCL patients having an age‐adjusted International Prognostic Index (aaIPI) score of 2 or 3. As induction chemotherapy, 6 cycles of R‐CHOP‐14 (arm A) or 3 cycles of R‐CHOP‐14 followed by 3 cycles of CHASER (arm B) were planned, and patients who responded proceeded to HDCT with LEED and ASCT. The primary endpoint was 2‐y progression‐free survival (PFS), and the main secondary endpoints included overall survival, overall response rate, and adverse events (AEs). In total, 71 patients were enrolled. With a median follow‐up of 40.3 mo, 2‐y PFS in arms A and B were 68.6% (95% confidence interval [CI], 50.5%‐81.2%) and 66.7% (95% CI: 48.8%‐79.5%), respectively. Overall survival at 2 y in arms A and B was 74.3% (95% CI: 56.4%‐85.7%) and 83.3% (95% CI: 66.6%‐92.1%). Overall response rates were 82.9% in arm A and 69.4% in arm B. During induction chemotherapy, 45.7% and 75.0% of patients in arms A and B, respectively, had grade ≥ 3 non‐hematologic toxicities. One patient in arm A and 6 in arm B discontinued induction chemotherapy due to AEs. In conclusion, R‐CHOP‐14 showed higher 2‐y PFS and less toxicity compared with R‐CHOP‐14/CHASER in patients with high‐risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations (UMIN‐CTR, UMIN000003823). [ABSTRACT FROM AUTHOR]

Aims: The Lugano classification is a novel staging system for lymphomas established in 2014. In this staging system, 18F‐fluorodeoxyglucose‐positron emission tomography/computed tomography (FDG‐PET/CT) was formally incorporated into standard staging for FDG‐avid lymphomas, including Hodgkin lymphoma (HL). We retrospectively analyzed patients with HL who were newly diagnosed and treated at our institution to evaluate the utility of the Lugano classification compared to the Ann Arbor classification in Japanese patients with this type of lymphoma. Methods: Patients newly diagnosed with HL between 2005 and 2011 were identified through our departmental database. Data from neck‐chest‐abdomen‐pelvis CT scans, BM examinations, and FDG‐PET/CT that were routinely performed for staging at our clinical practice were retrieved and analyzed. Results: Fifty‐four patients with a median age of 35.5 years (range: 15‐78 years) were investigated in this retrospective study. The Lugano stage matched the Ann Arbor stage in 46 patients (85%). Six patients (11%) were upstaged while two (4%) were downstaged per the Lugano classification. Four patients (7%) were converted from early stage to advanced stage, but none was converted in the reverse. Among 11 patients (20%) with PET‐positive bone/bone marrow lesions, only one (2%) exhibited biopsy‐proven bone marrow involvement of HL cells. Conclusion: Our data revealed a high concordance rate between the Lugano and Ann Arbor staging system in Japanese patients with HL. Because of its low diagnostic value, routine bone marrow examination might be unnecessary for staging when FDG‐PET/CT is used as a substitute. [ABSTRACT FROM AUTHOR]

Endometrial gene expression is primarily regulated by the ovarian steroids and pregnancy recognition factors. This study was aimed to characterize differential expression genes (DEGs) in bovine endometrium together with the analysis of their promoter region. Bovine uteri at follicular stage (FS), luteal stage (LS), and implantation stage (IS) at Day 18 of pregnancy were collected. Total RNA extracted and prepared cDNA were then subjected to high‐throughput sequencing. For promoter analysis, 1 kb upstream promoter region of each DEG was analyzed. The numbers of highly expressed DEGs were 496 and 597 at FS and LS, respectively. When compared the gene expression of IS with LS, 383 and 346 DEGs showed higher and lower expression at IS, respectively. It was also observed that 20–30 transcription factors (TFs) were included in each DEGs. In addition, promoter analyses estimated 150–160 TFs for each stage. DLX4 and interferon regulatory factor 4 (IRF4) at FS, and IRF5, IRF9, STAT1, and STAT2 at IS were in common to DEGs and estimated TFs, respectively. This study highlighted potential molecular mechanisms controlling endometrial function during estrus cycle and IS, which will further guide to better understand the endometrial functions in future studies. [ABSTRACT FROM AUTHOR]

This study analysed incidence, patient outcome, immunophenotype and prognostic factors of histological transformation ( HT) from extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue ( MALT lymphoma) to diffuse large B-cell lymphoma ( DLBCL) in 467 patients (median age, 61 years). The primary sites of MALT lymphoma were the stomach (43%), ocular adnexa (25%), lung (8%), systemic (8%) and other tissues (16%). HT occurred in 8% of MALT lymphomas. Risk of HT by 15 years was 5%: 4% in limited-stage diseases ( n = 385) and 16% in advanced-stage diseases ( n = 56) ( P = 0·02). The median time to HT was 48 months (range, 4-139). Five-year progression-free survival ( PFS) and overall survival ( OS) rates after HT were 80% and 94%, respectively. Immunohistochemical results of DLBCL were as follows: germinal centre B-cell ( GCB)/non- GCB, 37%/63%; CD10, 9%; BCL6, 59%; MUM1, 38%; MYC, 42%; BCL2, 35%; Ki67 ≥ 90%, 23%; and CD5, 3%. The majority (75%, 9/12) of GCB-type DLBCLs exhibited CD10−, BCL6+ and MUM1− immunophenotypes; the remainder had CD10+ immunophenotypes. Multivariate analysis revealed that only advanced stage at HT was a significant adverse factor for PFS ( P = 0·037). Thus, overall risk of HT was low and prognosis after HT was favourable; however, in advanced-stage cases, risk of HT was relatively high and prognosis was unfavourable. [ABSTRACT FROM AUTHOR]

This study investigated the knockdown (KD) of Kid on maturation developmental competence and multinucleation of mouse germinal vesicle (GV) oocytes after parthenogenetic activation. Data revealed that Kid messenger RNA (mRNA) was expressed in GV and MII stage oocyte and 1- and 2-cell embryos. Additionally, Kid mRNA expression in the Kid KD group decreased by nearly 46% compared to the control small interfering RNA (siRNA) groups. The rate of multinucleated embryos in the Kid KD group (52.4%) was significantly higher ( P < 0.05) than the control siRNA group (4.7%). Finally, the developmental rates were significantly lower in the Kid siRNA group at > 4-cell stage (28.6% vs. 53.5%) and the blastocyst stage (2.4% vs. 23.3%) compared to the control siRNA groups. Suppression of Kid using siRNA caused multinucleation in early embryos with high frequency and it may increase 2- to 4-cell arrested embryos and reduce the developmental competence to blastocyst. [ABSTRACT FROM AUTHOR]

Cellular oscillators in the uterus play critical roles in the gestation processes of mammals through entraining of the clock proteins to numerous downstream genes, including growth/differentiation factor ( Gdf) 10 and Gdf15. The expression of Gdf10 and Gdf15 is significantly increased in the uterus during decidualization, but the mechanism underlying the regulation of Gdf gene expression in the uterus is poorly understood. Here, we focused on the function of the cellular oscillators in the expression of Gdf family by using uterine endometrial stromal cells ( UESCs) isolated from pregnant Per2- dLuc transgenic rats. A significant decline of Per2- dLuc bioluminescence activity was induced in in vitro decidualized UESCs, and concomitantly the expression of canonical clock genes was downregulated. Conversely, the expression of Gdf10 and Gdf15 of the Gdf was upregulated. In UESCs transfected with Bmal1-specific si RNA, in which Rev-erbα expression was downregulated, Gdf10 and Gdf15 were upregulated. However, Gdf5, Gdf7, and Gdf11 were not significantly affected by Bmal1 silencing. The expression of Gdf10 and Gdf15 was enhanced after treatment with a REV- ERB α antagonist in the presence or absence of progesterone. Chromatin immunoprecipitation- PCR analysis revealed the inhibitory effect of REV- ERB α on the expression of Gdf10 and Gdf15 in UESCs by recognizing their gene promoters. Collectively, our findings indicate that the attenuation of REV- ERB α leads to an upregulation of Gdf10 and Gdf15 in decidual cells, in which cellular oscillators are impaired. Our results provide novel evidence regarding the functions of cellular oscillators regulating the expression of downstream genes during the differentiation of UESCs. [ABSTRACT FROM AUTHOR]

This study aimed to develop an in vitro model for the analysis of the bovine endometrium. Immunofluorescent staining revealed that the hetero-spheroids and the cultured explants showed almost similar structure in the localization of bovine endometrial epithelial cells and endometrial stromal cells, except the glandular-like structure of the epithelial cells inside the explants. Gelatin zymography revealed that the hetero-spheroids did not express matrix metalloproteinases ( MMPs) after 4 days of culture, but strong MMP expressions were observed in the cultured explants until 7 days of culture. Additionally, expression of progesterone receptor ( PR), estrogen receptor alpha ( ERα), type I interferon receptor 1 (IFNAR1) and 2 (IFNAR2) messenger RNA was observed both in the homo- and hetero-spheroids. The expression of oxytocin receptor ( OTR) mRNA in E2 and E2+ P4 (1,3,5(10)-Estratrien-3, 17β-diol + 4-Pregnen-3, 20-dinone) treated groups were significantly ( P < 0.05) higher than that of the control group of spheroids. In case of cultured explants, the expression of PR and OTR mRNA were significantly ( P < 0.05) higher in E2 treated groups compared to the control groups. Hepatocyte growth factor ( HGF) mRNA expression was also higher in P4 treated groups at 10 days in culture ( P < 0.05). In a nutshell, the in vitro model developed in this study for the analysis of the endometrium may provide a new platform for extensive research on bovine endometrial function. [ABSTRACT FROM AUTHOR]

BACKGROUND The present study was conducted to evaluate the developmental toxicity in the endometrium and placenta due to GW501516 administration by gavage to pregnant rats. METHODS GW501516 was orally administered repeatedly to pregnant rats from gestation day ( GD) 6 to 17 at a dose of 0, 30, and 100 mg/kg/day. In next study, GW501516 was also orally administered to pregnant rats on GD 7, 8, 9, 10, or 11 at a single dose of 275 or 350 mg/kg. In these studies, caesarean section was performed to examine the pregnancy outcome on GD21. Additionally, GW501516 was orally administered to pregnant rats on GD 10 at a single dose of 275 mg/kg. Placentae were subjected for temporal histological examinations on GD 11, 13, 15, or 17. RESULTS Placental malformation was induced by repeated administration of GW501516 at a dose of 100 mg/kg/day. Single oral administration of GW501516 at a dose of 275 and/or 350 mg/kg on GD 8, 9, 10, or 11 induced placental malformation, whereas GW501516 administered on GD 10 was the most effective for increasing placental malformation. Histopathologically, single oral administration of GW501516 on GD 10 induced cystic degeneration associated with cellular lysis of glycogen cells started from GD 15 in the basal zone. CONCLUSIONS High frequency of placental malformation was observed by the administration of GW501516. From GD 8 to 11, especially GD 10, is more sensitive period to induce the placental malformation. [ABSTRACT FROM AUTHOR]

The present study aimed to evaluate the effect of organic and inorganic selenium (Se) supplementation on semen quality and blood serum profiles of buffalo bulls. Nine mature buffalo bulls were divided into three groups: control (non-supplemented); organic Se (10 mg Sel-Plex®/head twice weekly) and inorganic Se (10 mg sodium selenite/head twice weekly). Semen was collected twice a week for 3 months during Se supplementation. Semen properties were evaluated from fresh ejaculate. Moreover, fructose concentration, aspartate and alanine transaminase (AST and ALT) activities, total protein and total cholesterol were assayed in seminal plasma. Additionally AST, ALT, testosterone and Se levels were determined in the blood serum. Results showed that Se supplementation significantly ( P < 0.05) influences the semen parameters during 3 months of treatment. Organic Se significantly ( P < 0.05) increased the percentage of viable sperms compared to inorganic Se and the control group. Fructose concentration was significantly higher ( P < 0.05) in the seminal plasma of organic Se-treated bulls. Serum testosterone and Se concentrations were significantly ( P < 0.05) increased in the Se supplemented groups than the control group. In conclusion, Se supplementation improved the parameters of buffalo bull semen and more precisely, organic Se was more effective for the improvement of semen quality and some blood components than inorganic Se. [ABSTRACT FROM AUTHOR]