Incidence of lymphoid neoplasms among atomic bomb survivors by histological subtype, 1950 to 1994.

Epidemiological data have provided limited and inconsistent evidence on the relationship between radiation exposure and lymphoid neoplasms. We classified 553 lymphoid neoplasm cases diagnosed between 1950 and 1994 in the Life Span Study cohort of atomic bomb survivors into World Health Organization subtypes. Mature B-cell neoplasms represented 58%, mature T-cell and natural killer (NK)-cell neoplasms 20%, precursor cell neoplasms 5%, and Hodgkin lymphoma (HL) 3%, with the remaining 15% classified as non-Hodgkin lymphoid (NHL) neoplasms or lymphoid neoplasms not otherwise specified. We used Poisson regression methods to assess the relationship between radiation exposure and the more common subtypes. As in earlier reports, a significant dose response for NHL neoplasms as a group was seen for males but not females. However, subtype analyses showed that radiation dose was strongly associated with increased precursor cell neoplasms rates, with an estimated excess relative risk per Gy of 16 (95% Confidence interval: 7.0, >533) at age 50. The current data based primarily of tissue-based diagnoses suggest that the association between radiation dose and lymphoid neoplasms as a group is largely driven by the radiation effect on precursor cell neoplasms while presenting no evidence of a radiation dose response for major categories of mature cell neoplasms, either B- or T-/NK-cell, or more specific disease entities (diffuse large B-cell lymphoma, plasma cell myeloma, adult T-cell leukemia/lymphoma) or HL.

Comparison of Skeletal Stability after Le Fort I Osteotomy With Bone Fixation Using Biodegradable and Titanium Systems: A Retrospective Study.

The titanium osteosynthesis system used for fixing bone segments after maxillary osteotomy provides reliable outcomes owing to its biocompatibility and adequate strength. In addition, several studies have evaluated the skeletal stability after maxillary osteotomy with fixation using a biodegradable system. However, the indications for applying a biodegradable system after maxillary osteotomy remain controversial. Therefore, this study aimed to compare the long-term skeletal stability of bone segments after maxillary osteotomy with bone fixation using biodegradable and titanium osteosynthesis systems and to assess the usefulness of a biodegradable osteosynthesis system. Patients who underwent Le Fort I osteotomy of the maxilla to correct jaw deformities between April 2008 and March 2021 were included in this study. A total of 45 patients were included, with 28 in the biodegradable osteosynthesis system group and 17 in the titanium group. Cephalometric and computed tomography analyses were performed to evaluate the skeletal stability of the bone segments after maxillary osteotomy with bone fixation using biodegradable or titanium osteosynthesis systems. The maxillary segment was repositioned anteriorly with a clockwise rotation. Skeletal stability was similar between the biodegradable and titanium osteosynthesis systems. Segmental changes occurred mainly in the first 6 months after surgery, and the segment was completely stable between 6 and 12 months after surgery. This study revealed no significant differences in skeletal stability after maxillary osteotomy between the biodegradable and titanium osteosynthesis systems. However, the findings in this study should be interpreted with caution owing to the small sample size and small amount of maxillary-segment movement.

Comparison of the skeletal stability after mandibular counter-clockwise rotation in three surgical procedures.

The treatment of mandibular deformities with an anterior open bite is challenging. In this study, skeletal stability after mandibular osteotomies was evaluated to determine the best treatment for mandibular prognathism with an anterior open bite in three procedures: intraoral vertical ramus osteotomy (IVRO), conventional sagittal split ramus osteotomy (conv-SSRO), and SSRO without bone fixation (nonfix-SSRO). Patients who underwent mandibular osteotomy to correct skeletal mandibular protrusion were included. Changes in skeletal and soft tissues were assessed using lateral cephalograms taken before (T1), 3 ± 2 days (T2), and 12 ± 3 months (T3) after surgery. Thirty-nine patients were included: nine in the IVRO group and 11 and 19 in the conv- and nonfix-SSRO groups, respectively. The mandibular plane angles (MPAs) of the T2-T1 were - 2.7 ± 2.0 (p = 0.0040), - 3.7 ± 1.7 (p < 0.0001), and - 2.3 ± 0.7 (p < 0.0001) in the IVRO, conv-SSRO, and nonfix-SSRO groups, respectively. The skeletal relapse of the MPAs was not related to the MPA at T2-T1, and it was approximately 1.3° in the conv-SSRO group. The skeletal relapse of the MAPs was significantly correlated with the MPA of T2-T1 in the IVRO (p = 0.0402) and non-fix-SSRO (p = 0.0173) groups. When the relapse of the MPAs was less than 1.3°, the MPA of T2-T1 was calculated as 2.5° in the nonfix-SSRO group. When the MPA of T2-T1 is less than 2.5°, non-fix SSRO may produce a reliable outcome, and when it is more than 2.5°, conv-SSRO may produce better outcomes.

Biomechanical effect of dual-dimensional archwire on controlled movement of anterior teeth compared with rectangular archwire: A finite element study.

INTRODUCTION: This study aimed to determine and compare the effectiveness of the use of the dual-dimensional archwire and conventional rectangular archwire on tooth movement patterns when combined with various lengths of power arms. METHODS: Displacements of the maxillary central incisor and the deformation of the wire section were calculated when applying retraction forces from different lengths of power arms using the finite element method. RESULTS: Torque control of the incisor could be carried out more effectively when using the dual-dimensional archwire combined with long power arms than with the rectangular archwire. The use of the dual-dimensional archwire produced bodily movement of the central incisor at height levels of the power arm between 8 and 10 mm and lingual root tipping at the level of 10 mm. CONCLUSIONS: The use of the dual-dimensional archwire provided better-controlled movement of the incisor, including bodily movement or root movement, than the rectangular archwire.

Rab44 negatively regulates myoblast differentiation by controlling fusogenic protein transport and mTORC1 signaling.

Skeletal muscle is composed of multinucleated myotubes formed by the fusion of mononucleated myoblasts. Skeletal muscle differentiation, termed as myogenesis, have been investigated using the mouse skeletal myoblast cell line C2C12. It has been reported that several "small" Rab proteins, major membrane-trafficking regulators, possibly regulate membrane protein transport in C2C12 cells; however, the role of Rab proteins in myogenesis remains unexplored. Rab44, a member of "large" Rab GTPases, has recently been identified as a negative regulator of osteoclast differentiation. In this study, using C2C12 cells, we found that Rab44 expression was upregulated during myoblast differentiation into myotubes. Knockdown of Rab44 enhanced myoblast differentiation and myotube formation. Consistent with these results, Rab44 knockdown in myoblasts increased expression levels of several myogenic marker genes. Rab44 knockdown increased the surface accumulation of myomaker and myomixer, two fusogenic proteins required for multinucleation, implying enhanced cell fusion. Conversely, Rab44 overexpression inhibited myoblast differentiation and tube formation, accompanied by decreased expression of some myogenic markers. Furthermore, Rab44 was found to be predominantly localized in lysosomes, and Rab44 overexpression altered the number and size of lysosomes. Considering the underlying molecular mechanism, Rab44 overexpression impaired the signaling pathway of the mechanistic target of rapamycin complex1 (mTORC1) in C2C12 cells. Namely, phosphorylation levels of mTORC1 and downstream mTORC1 substrates, such as S6 and P70-S6K, were notably lower in Rab44 overexpressing cells than those in control cells. These results indicate that Rab44 negatively regulates myoblast differentiation into myotubes by controlling fusogenic protein transport and mTORC1 signaling.

Occlusal Plane Angle as a Key Factor for Chin Protrusion After Mandibular Osteotomy in Skeletal Class III.

There is no treatment algorithm to decide whether maxillomandibular or mandibular osteotomy alone should be performed in borderline cases. This study assessed the factors that affect the changes in soft tissue after mandibular setback. Patients who underwent mandibular osteotomy alone to correct mandibular protrusion were included in this study. Hard and soft tissue analyses were performed on lateral cephalograms before and 12±3 months after surgery. The popular points were set for referencing hard and soft tissues on the lateral cephalogram. Nasolabial, labiomental, and soft tissue facial plane angles were measured for the soft tissue assessment. To assess the mandibular setback amount, SNB was calculated. Twenty-one patients were included in this study. The nasolabial angle was increased after surgery and its change significantly correlated with the change in SNB ( P =0.00815). The change in soft tissue facial plane angle after surgery per change in SNB significantly correlated with the occlusal plane angle ( P =0.0009). An occlusal plane angle of at least 15.45 degrees was required for the SNB and soft tissue facial plane angle to change to the same degree. The occlusal plane angle (whether or not it was ≥15.45 degrees) may help in determining the surgical approach in borderline cases, specifically on whether maxillomandibular or mandibular osteotomy alone should be performed if the mandibular setback is simple.

Mesial or distal to canine: Which is better for the position of closing loops? Analysis of tooth movements based on numerical simulation.

INTRODUCTION: Although many studies investigating the mechanical behavior of loop mechanics have focused on loop designs to produce a higher moment-to-force ratio, few studies have clarified the effect of loop position on the force system and resultant tooth movements. This study aimed to simulate orthodontic tooth movements during space closure and to compare the effects of loop position in association with different degrees of gable bend on tooth movements using the finite element method. METHODS: Two finite element models of the maxillary dentition were constructed, with the loop placed mesial or distal to the canine. Tooth movements during loop activation were simulated while varying the degree of gable bend. RESULTS: When the loop was placed distal to the canine, the incisor showed uncontrolled tipping even with the gable bend. Placement of the loop mesial to the canine produced controlled tipping or root movement of the incisor, depending on the degree of gable bend. CONCLUSIONS: Placement of the closing loop mesial to the canine in combination with the incorporation of a gable bend into the archwire distal to the canine could provide better control of incisor movements, such as controlled tipping or root movement, as compared with placement of a gable bend into the loop located distal to the canine.

Genomic landscape of young ATLL patients identifies frequent targetable CD28 fusions.

Adult T-cell leukemia/lymphoma (ATLL) in Japan presents at a median age of 70 years and only 5% of patients are <50 years of age. We conducted RNA and targeted DNA sequencing of 8 ATLLs from Japanese patients <50 years of age and identified 3 (37.5%) with both CTLA4-CD28 and inducible costimulator (ICOS)-CD28 fusions. Mutations of PLCG1, PRKCB, and STAT3, which were frequent in other ATLL-sequencing studies, were not identified. Differential expression analysis identified the negative checkpoint molecule LAG3 as the most downregulated gene among cases with the fusions. Immunohistochemistry demonstrated expression of CD80 and CD86, the ligands for CTLA4 and CD28, on ATLL cells and tumor-associated macrophages, respectively. Expression of CTLA4-CD28 in Ba/F3 cells conferred cytokine-independent growth when cocultured with Raji cells that express CD80 and CD86. Growth was associated with recruitment of the p85 subunit of phosphatidylinositol 3-kinase to CTLA4-CD28 and phosphorylation of AKT and extracellular signal-regulated kinase. A CTLA4-blocking antibody reduced cytokine-independent growth in a dose-dependent manner. Together, these results suggest that young Japanese ATLL cases have a unique biology dependent on cell-nonautonomous interactions that drive CD28 signaling. Assessment for CD28 fusions and treatment with CTLA4 blockade should be considered in younger patients with relapsed/refractory ATLL.

Effect of masseter muscle mass on the rate of experimental tooth movement in rats.

BACKGROUND: Previous clinical observational studies have suggested that orthodontic tooth movement (OTM) is related, at least partly, to the mass and/or capabilities of the masticatory muscles. OBJECTIVES: Our study aimed to examine the influence of masticatory muscle mass on the OTM in an animal experimental model in which the masseter muscle was modulated by botulinum neurotoxin type A (BTX) injection. METHODS: Eighteen Wistar rats were equally divided into two groups: BTX injection and control. BTX was injected bilaterally into the masseter muscles. Three days after the injection, the maxillary left first molars were orthodontically moved for 14 days. At the end of the experiment, micro-computed tomography was performed to evaluate the rate of OTM and bone morphometry. The masseter muscles were weighed and prepared for histological analyses. RESULTS: The masseter muscle mass in the BTX group was less than that in the control group, and histological findings showed atrophy of muscle fibres. The rate of OTM was significantly higher in the BTX group than in the control group. Furthermore, a negative correlation was detected between masseter muscle mass and OTM in the BTX group. Bone morphometry showed no difference between the control and BTX groups. CONCLUSION: Decreased masseter muscle mass was found to be closely related to an increase in the rate of OTM in rats using BTX injection to modify the masseter muscle mass. Masseter muscle mass could be a predictive factor for OTM in rats injected with BTX.

Sp7 Transgenic Mice with a Markedly Impaired Lacunocanalicular Network Induced Sost and Reduced Bone Mass by Unloading.

The relationship of lacunocanalicular network structure and mechanoresponse has not been well studied. The lacunocanalicular structures differed in the compression and tension sides, in the regions, and in genders in wild-type femoral cortical bone. The overexpression of Sp7 in osteoblasts resulted in thin and porous cortical bone with increased osteoclasts and apoptotic osteocytes, and the number of canaliculi was half of that in the wild-type mice, leading to a markedly impaired lacunocanalicular network. To investigate the response to unloading, we performed tail suspension. Unloading reduced trabecular and cortical bone in the Sp7 transgenic mice due to reduced bone formation. Sost-positive osteocytes increased by unloading on the compression side, but not on the tension side of cortical bone in the wild-type femurs. However, these differential responses were lost in the Sp7 transgenic femurs. Serum Sost increased in the Sp7 transgenic mice, but not in the wild-type mice. Unloading reduced the Col1a1 and Bglap/Bglap2 expression in the Sp7 transgenic mice but not the wild-type mice. Thus, Sp7 transgenic mice with the impaired lacunocanalicular network induced Sost expression by unloading but lost the differential regulation in the compression and tension sides, and the mice failed to restore bone formation during unloading, implicating the relationship of lacunocanalicular network structure and the regulation of bone formation in mechanoresponse.

Biomechanical features of tooth movement from a lingual appliance in comparison with a labial appliance during space closure in sliding mechanics.

INTRODUCTION: The objectives of this study were to simulate long-term orthodontic tooth movement in en-masse retraction using the finite element method and investigate the effects of power arms on tooth movements when using a lingual appliance in comparison with a labial appliance. METHODS: A 3-dimensional finite element model of the maxillary dentition was constructed with 0.018-in brackets and 0.016 × 0.022-in stainless steel archwire. An en-masse retraction was performed by applying retraction force at various lengths of the power arm (4, 6, 8, and 10 mm) to the second molar tube, and long-term tooth movements with the lingual and labial appliances were analyzed using the finite element method. RESULTS: Although lingual crown tipping of the incisor was more marked with the lingual appliance than with the labial appliance in the early phase of space closure, only a slight difference was evident after space closure. Although the power arm was effective for achieving better-controlled tooth movement and reducing vertical and transverse bowing effects, bodily movement of the incisor could not be achieved, and bowing effects could not be eliminated. CONCLUSIONS: To provide better torque control of the incisor or prevent a vertical bowing effect, the incorporation of extra torque into brackets of incisors was recommended, and the use of power arms for the lingual appliance. To prevent a transverse bowing effect, incorporation of the antibowing bend or application of retraction force from both buccal and lingual sides or temporary skeletal anchorage devices was recommended.

Comprehensive genomic analysis identifying heterogeneity in peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous entity generally with a poor prognosis. Recent genomic analyses have characterized genomic alterations and described gene expression profiling and epigenetic mechanisms in PTCL, leading to reveal molecular pathophysiology in detail. One of several important findings is that heterogeneities exist in both the disease and in individuals. Among PTCL subtypes, adult T-cell leukemia/lymphoma (ATLL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are common in Japan. ATLL is an incurable T-cell malignancy induced by human T-cell lymphotropic virus type 1 (HTLV-1). The global genomics of ATLL can be summarized as alterations involving T-cell receptor (TCR) signaling and immune escape mechanisms. This highlights the fact that ATLL is a viral-mediated T-cell malignancy. Interestingly, several previous studies have found that the genomics of ATLL differ according to geographical region and age at diagnosis, suggesting disease heterogeneity, though they share HTLV-1 infection as initial disease hit. Clonal expansion of the cells acquired by somatic mutations in ATLL-related genes is identified in a part of HTLV-1 carriers who developed ATLL later. The risk for ATLL may be updated based on findings in detail. PTCL-NOS is a heterogeneous disease type of T-cell lymphoma that does not correspond to any other type of PTCL. Several studies have stratified PTCL-NOS according to transcriptional, genomic, microenvironmental, and clinical aspects. These kinds of analysis from multiple aspects are useful to understand the heterogeneous group. These efforts will help guide suitable translational research to target PTCL.

Human T-cell lymphotropic virus HBZ and tax mRNA expression are associated with specific clinicopathological features in adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is caused by human T-cell leukemia virus type 1 (HTLV-1). HTLV-1-associated mRNA, including HBZ and tax, is deeply involved in the pathogenesis of ATLL. Using 88 ATLL tissue samples, we performed in situ mRNA analysis of HBZ and tax, and investigated its association with clinicopathological characteristics of ATLL. The median value of HBZ signals (/1000 ATLL cells) was 795.2 (range: 0.4-4013.1) and of tax signals (/1000 ATLL cells) was 5.1 (range: 0.1-891.2). The low-expression HBZ group displayed significant increase in the number of skin lesion (P = 0.0283). The high-expression tax group displayed significant increase in the number of PD-1-positive tumor-infiltrating lymphocytes (P < 0.0001). In addition, we identified patients with very high-expression of tax signals (400 or more signals/1000 ATLL cells). These patients displayed significant reductions in the expression of HLA class I (P = 0.0385) and ß2M (P = 0.0124). Moreover, these patients displayed significantly poor overall survival (median survival time [MST] 7.7 months, 95% confidence interval [CI] [4.7-NA]), compared with the survival in patients with less than 400 tax signals (MST 22.6 months, 95% CI [13.7-41.7]) (P = 0.0499). These results suggest that Tax-mediated treatment of ATLL should be performed carefully in the high-expression tax group. More detailed studies could elucidate the clinicopathological significance of HBZ and tax mRNA expressions in ATLL.

Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A /B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2 R172 mutation. CN losses were enriched in genes regulating PI3K-AKT-mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.

Simulation of orthodontic tooth movement during activation of an innovative design of closing loop using the finite element method.

INTRODUCTION: Although many attempts have been made to study the mechanical behavior of closing loops, most have been limited to analyses of the magnitude of forces and moments acting on the end of the closing loop. The objectives of this study were to simulate orthodontic tooth movement during the activation of a newly designed closing loop combined with a gable bend and to investigate the optimal loop activation condition to achieve the desired tooth movement. METHODS: We constructed a 3-dimensional model of maxillary dentition reproducing the state wherein a looped archwire combined with a gable bend was engaged in brackets and tubes. Orthodontic tooth movements were simulated for both anterior and posterior teeth while varying the degree of gable bend using the finite element method. RESULTS: The incorporation of a 5° gable bend into the newly designed closing loop produced lingual crown tipping for the central incisor and bodily movement for the first molar. The incorporation of 10° and 15° gable bends produced bodily movement and root movement, respectively, for the central incisor and distal tipping for the first molar. CONCLUSIONS: Torque control of the anterior teeth and anchorage control of the posterior teeth can be carried out effectively and simply by reducing by half the thickness of a teardrop loop with a height of 10 mm and a 0.019 × 0.025-in cross-section, to a distance of 3 mm from its apex, and by incorporating various degrees of gable bend into the loop corresponding to the treatment plan.

Dual-section versus conventional archwire for en-masse retraction of anterior teeth with direct skeletal anchorage: a finite element analysis.

BACKGROUND: The aim of this study is to compare the biomechanical effects of the conventional 0.019 × 0.025-in stainless steel archwire with the dual-section archwire when en-masse retraction is performed with sliding mechanics and skeletal anchorage. METHODS: Models of maxillary dentition equipped with the 0.019 × 0.025-in archwire and the dual-section archwire, whose anterior portion is 0.021 × 0.025-in and posterior portion is 0.018 × 0.025-in were constructed. Then, long-term tooth movement during en-masse retraction was simulated using the finite element method. Power arms of 8, 10, 12 and 14 mm length were employed to control anterior torque, and retraction forces of 2 N were applied with a direct skeletal anchorage. RESULTS: For achieving bodily movement of the incisors, power arms longer than 14 mm were required for the 0.019 × 0.025-in archwire, while between 8 and 10 mm for the dual-section archwire. The longer the power arms, the greater the counter-clockwise rotation of the occlusal plane was produced. Frictional resistance generated between the archwire and brackets and tubes on the posterior teeth was smaller than 5% of the retraction force of 2 N. CONCLUSIONS: The use of dual-section archwire might bring some biomechanical advantages as it allows to apply retraction force at a considerable lower height, and with a reduced occlusal plane rotation, compared to the conventional archwire. Clinical studies are needed to confirm the present results.

Visualization of mandibular movement relative to the maxilla during mastication in mice: integration of kinematic analysis and reconstruction of a three-dimensional model of the maxillofacial structure.

BACKGROUND: Mastication is one of the most fundamental functions for the conservation of human life. To clarify the pathogenetic mechanism of various oral dysfunctions, the demand for devices for evaluating stomatognathic function has been increasing. The aim of the present study was to develop a system to reconstruct and visualize 3-dimensional (3D) mandibular movements relative to the maxilla, including dynamic transition of occlusal contacts between the upper and lower dentitions during mastication in mice. METHODS: First, mandibular movements with six degrees of freedom were measured using a motion capture system comprising two high-speed cameras and four reflective markers. Second, 3D models of maxillofacial structure were reconstructed from micro-computed tomography images. Movement trajectories of anatomical landmark points on the mandible were then reproduced by integrating the kinematic data of mandibular movements with the anatomical data of maxillofacial structures. Lastly, 3D surface images of the upper dentition with the surrounding maxillofacial structures were transferred to each of the motion capture images to reproduce mandibular movements relative to the maxilla. We also performed electromyography (EMG) of masticatory muscles associated with mandibular movements. RESULTS: The developed system could reproduce the 3D movement trajectories of arbitrary points on the mandible, such as incisor, molars and condylar points with high accuracy and could visualize dynamic transitions of occlusal contacts between upper and lower teeth associated with mandibular movements. CONCLUSIONS: The proposed system has potential to elucidate the mechanisms underlying motor coordination of masticatory muscles and to clarify their roles during mastication by taking advantage of the capability to record EMG data synchronously with mandibular movements. Such insights will enhance our understanding of the pathogenesis and diagnosis of oral motor disorders by allowing comparisons between normal mice and genetically modified mice with oral behavioral dysfunctions.

Combination of CD47 and signal-regulatory protein-α constituting the "don't eat me signal" is a prognostic factor in diffuse large B-cell lymphoma.

The interaction between CD47 and signal-regulatory protein-α (SIRPα) inhibits phagocytosis, thus affecting the clinical outcomes of neoplastic diseases. Although CD47 upregulation is associated with poor prognosis in several malignancies, the effect of SIRPα expression and its coexpression with CD47 remains unclear. This study aimed to investigate the clinicopathologic effect of CD47 and SIRPα expression in diffuse large B-cell lymphoma (DLBCL). Immunostaining of 120 biopsy samples showed that CD47 is primarily expressed in tumor cells, whereas SIRPα is expressed in nonneoplastic stromal cells, mostly macrophages. CD47high cases showed higher MYC protein expression and lower MYC translocation. The SIRPαhigh cases presented significantly shorter overall survival (OS) and progression-free survival (PFS) than SIRPαlow cases in the activated B-cell (ABC) subtype of DLBCL (P = .04 and P = .02, respectively). Both CD47high and SIRPαhigh presented significantly shorter OS and PFS than other cases among all DLBCL patients (P = .01 and P = .004, respectively), and the ABC type (P = .04 and P = .008, respectively) but not the germinal center B-cell type. Both CD47high and SIRPαhigh yielded a constant independent prognostic value for OS and PFS in multivariate analysis (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.20-7.43; P = .02; and HR, 2.87; 95% CI, 1.42-5.85; P = .003, respectively). To the best of our knowledge, this is the first study to report that combinatorial CD47 and SIRPα expression is a potential independent prognostic factor for DLBCL. Evaluation of CD47 and SIRPα expression could be useful before CD47 blockade therapy.

Cytokine-related genes play critical roles in extrafollicular growth of follicular lymphoma cells.

Follicular lymphoma (FL) is a germinal center-derived B-cell lymphoma that is known to proliferate in the intrafollicular region. However, lymphoma cells can be identified in the extrafollicular regions, which are related to disease dissemination. We purified the intrafollicular and extrafollicular regions of FL cells by laser microdissection and conducted microarray analysis in order to characterize the gene expression profiles of FL cells from both regions. BCL2 and genes of germinal B-cell markers clearly separated intrafollicular and extrafollicular regions of reactive follicular hyperplasia, suggesting the adequacy of the current analysis. In FL cases, cytokine-related genes were significantly enriched in extrafollicular regions compared with those in the intrafollicular regions. In intrafollicular regions of FL, cell-cycle-related genes were enriched. We found that the FL cells in the extrafollicular region more strongly expressed IL3RA and CXCL12 than those of intrafollicular regions. The cytokines might be also derived from stroma cells in the extrafollicular regions, which may initiate activation and migration of the tumor cells to this region. Our results suggest that FL cell interaction with surrounding stroma cells plays an important role in the pathophysiology of FL and that such interactions should be a good target for therapy.

Clinicopathological analysis of immunohistochemical expression of CD47 and SIRPα in adult T-cell leukemia/lymphoma.

The interaction of CD47 and signal-regulatory protein alpha (SIRPα) induces "don't eat me signal", leading suppression of phagocytosis. This signal can affect the clinical course of malignant disease. Although CD47 and SIRPα expression are associated with clinicopathological features in several neoplasms, the investigation for adult T-cell leukemia/lymphoma (ATLL) has not been well-documented. This study aimed to declare the association between CD47 and SIRPα expression and clinicopathological features in ATLL. We performed immunostaining on 73 biopsy samples and found that CD47 is primarily expressed in tumor cells, while SIRPα is expressed in non-neoplastic stromal cells. CD47 positive cases showed significantly higher FoxP3 (P = .0232) and lower CCR4 (P = .0214). SIRPα positive cases presented significantly better overall survival than SIRPα negative cases (P = .0132). SIRPα positive cases showed significantly HLA class I (P = .0062), HLA class II (P = .0133), microenvironment PD-L1 (miPD-L1) (P = .0032), and FoxP3 (P = .0229) positivity. In univariate analysis, SIRPα expression was significantly related to prognosis (Hazard ratio [HR] 0.470; 95% confidence interval [CI] 0.253-0.870; P = .0167], although multivariate analysis did not show SIPRα as an independent prognostic factor. The expression of SIRPα on stromal cells reflects activated immune surveillance mechanism in tumor microenvironment and induce good prognosis in ATLL. More detailed studies for gene expression or genomic abnormalities will disclose clinical and biological significance of the CD47 and SIRPα in ATLL.