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Extranodal NK/T-cell lymphoma, nasal type (ENKTL) is an Epstein-Barr virus-positive, aggressive lymphoma with a heterogeneous cell of origin and variable clinical course. Several clinical prognostic indices have been proposed for ENKTL; however, there are few pathological biomarkers. This multi-institutional study sought to identify histologically assessable prognostic factors. We investigated mutation profiles by targeted next-generation sequencing (NGS) and immunohistochemical assessments of expression of MYC, Tyr705-phosphorylated (p-)STAT3, and CD30 in 71 ENKTL samples. The median age of the patients was 66 years (range, 6-100). The most frequent mutations were in STAT3 (27%), JAK3 (4%), KMT2D (19%), TP53 (13%), BCOR (10%), and DDX3X (7%). Immunohistochemistry (IHC) revealed that ENKTLs with STAT3 mutations exhibited higher expression of pSTAT3 and CD30. BCOR mutations were associated with increased MYC expression. Univariate analysis in the entire cohort showed that stage (II, III, or IV), BCOR mutations, TP53 mutations, and high MYC expression (defined as ≥40% positive neoplastic cells) were associated with reduced overall survival (OS). Multivariate modeling identified stage (II, III, or IV) and high MYC expression as independent adverse prognostic factors. In a subgroup analysis of patients treated with anthracycline (AC)-free chemotherapy and/or radiotherapy (RT) with curative intent, BCOR but not high MYC expression was an independent adverse prognostic factor. In conclusion, activating STAT3 mutations are common in ENKTLs and are associated with increased CD30 expression. MYC overexpression is, at least in part, associated with deleterious BCOR mutations, and this BCOR–MYC linkage may have prognostic significance, underscoring the potential utility of IHC for MYC in risk stratification of patients with ENKTL.

This paper reviews recent advances in the research and development of graphene-based plasmonic metamaterials for terahertz (THz) laser transistors. The authors’ theoretical discovery on THz laser transistors in 2007 was realized as a distributed-feedback dual-gate graphene-channel field-effect transistor (DFB-DG-GFET) in 2018, demonstrating ∼0.1 µW single-mode emission at 5.2 THz and ∼80 µW amplified spontaneous 1–7.6 THz emission at 100 K. To realize room-temperature, dry-cell-battery operating intense THz lasing with fast direct modulation, various approaches based on graphene plasmonic metamaterials are investigated and introduced as real device implementations, including (i) replacement of the laser photonic cavity with plasmonic cavity enormously improving the THz photon field confinement with larger gain overlapping, (ii) introduction of THz amplification of stimulated emission via current-driven graphene Dirac plasmons (GDPs), and (iii) controlling the parity and time-reversal symmetry of GDPs enabling ultrafast direct gain-switch modulation. Possible real device structures and design constraints are discussed and addressed toward coherent light sources applicable to future 6G- and 7G-class THz wireless communication systems.

Patients with plasma cell type idiopathic multicentric Castleman disease (PC-iMCD) often show elevated serum IgG4 levels and IgG4-positive cell infiltration in tissues due to overproduction of interleukin-6, and may meet the diagnostic criteria for IgG4-related disease (IgG4-RD). Although PC-iMCD has been listed as a major exclusion disease for IgG4-RD, distinguishing between these diseases is challenging due to a lack of highly specific diagnostic biomarkers. In 2020, we proposed exclusion criteria of IgG4-RD mimickers. In this paper, we validated the accuracy of the criteria in excluding one of the mimickers, PC-iMCD, from IgG4-RD. Validation was performed on 57 PC-iMCD patients (39 presenting lymph node lesions and 19 with lung lesions) and 29 IgG4-RD patients (22 presenting lymph node lesions and seven with lung lesions). According to our results, 20.5% of the PC-iMCD patients with lymph node lesions and 42.1% of those with lung lesions met the diagnostic criteria for IgG4-RD. All these patients with PC-iMCD were excluded from a diagnosis of IgG4-RD by the proposed criteria. Additionally, 6.9% of IgG4-RD patients met the exclusion criteria. Thus, if the exclusion criteria are met, diagnosis should be made based on a combination of findings including organ distribution of disease, response to steroid therapy, and other pathological findings.

Primary adrenal diffuse large B-cell lymphoma (PA-DLBCL) is rare. We investigate 23 Japanese patients with PA-DLBCL to understand the clinicopathologic features and biological behavior of this disease. The 17 males and 6 females had a median age of 74 years (range: 40 to 86 y). Tumor cells harbored Epstein-Barr virus-encoded small RNA (EBER) in 9 (39%) samples, including samples from the 2 patients with methotrexate-associated B-cell lymphoproliferative disorder. Programmed cell death ligand 1 (PD-L1) expression was detected in tumor cells of 6 (26%) samples, including 1 EBER+ and 5 EBER- samples. Four (17%) patients exhibited an intravascular proliferating pattern, and all 4 patient samples showed positive staining for PD-L1 in tumor cells. Among those patients, 3 showed intravascular proliferating pattern accompanied by a diffuse extravascular proliferation of tumor cells, and 1 patient was diagnosed with intravascular large B-cell lymphoma. We divided the 23 patients into 3 groups: EBER+ (n=9, 39%), EBER-PD-L1+ (n=5, 22%), and EBER-PD-L1- (n=9, 39%). A comparison of the outcomes among the 3 groups showed significant differences in overall survival (P=0.034). The EBER+ group had the worst prognosis, and the EBER-PD-L1- group had the best prognosis. We also compared the outcomes among the 3 groups that received rituximab-containing chemotherapies. Both the overall survival and progression-free survival were significantly different among these groups (P

Neoplastic programmed cell death ligand 1 (PD-L1) expression, activated by PD-L1 gene alterations, is strongly associated with classic Hodgkin lymphoma (CHL). This association enabled a diagnostic consensus for lymphocyte-depleted CHL (LD-CHL), a previously enigmatic disease. We describe two patients with LD-CHL and primary extranodal disease. One patient was a 92-year-old female (Case #1) with a large mass that involved the uterus combined with swollen lymph nodes in the pelvic cavity. The second patient was a 76-year-old female (Case #2) with human T-cell leukemia virus type 1 (HTLV-1) who initially exhibited massive bone marrow involvement without peripheral lymphadenopathies. Biopsies of these tumors from the cervix uteri and bone marrow, respectively, revealed lesions rich in Hodgkin and Reed-Sternberg (H-RS) cells and diminished populations of other cell populations. Immunohistochemistry demonstrated that these H-RS cells expressed CD30, BOB1, and fascin, but not CD15, CD20, PAX5, or OCT2. They also expressed PD-L1, which led to our preferred diagnosis of LD-CHL in both patients. Epstein-Barr virus was associated with LD-CHL in Case #1, but not in Case #2. Both patients were deemed too frail for treatment. They died of disease at 1 (Case #1) and 15 months (Case #2) after the diagnosis. These findings highlight the abnormal biological behavior of this immune-escape-related lymphoid neoplasm in patients with immunodeficiency due to immune senescence and HTLV1 infection.

Immunotherapy with immune‐checkpoint therapy has recently been used to treat oral squamous cell carcinomas (OSCCs). However, improvements in current immunotherapy are expected because response rates are limited. Transforming growth factor‐β (TGF‐β) creates an immunosuppressive tumor microenvironment (TME) by inducing the production of regulatory T‐cells (Tregs) and cancer‐associated fibroblasts and inhibiting the function of cytotoxic T‐lymphocytes (CTLs) and natural killer cells. TGF‐β may be an important target in the development of novel cancer immunotherapies. In this study, we investigated the suppressive effect of TGF‐β on CTL function in vitro using OSCC cell lines and their specific CTLs. Moreover, TGFB1 mRNA expression and T‐cell infiltration in 25 OSCC tissues were examined by in situ hybridization and multifluorescence immunohistochemistry. We found that TGF‐β suppressed the function of antigen‐specific CTLs in the priming and effector phases in vitro. Additionally, TGF‐β inhibitor effectively restored the CTL function, and TGFB1 mRNA was primarily expressed in the tumor invasive front. Interestingly, we found a significant negative correlation between TGFB1 mRNA expression and the CD8+ T‐cell/Treg ratio and between TGFB1 mRNA expression and the Ki‐67 expression in CD8+ T‐cells, indicating that TGF‐β also suppressed the function of CTLs in situ. Our findings suggest that the regulation of TGF‐β function restores the immunosuppressive TME to active status and is important for developing new immunotherapeutic strategies, such as a combination of immune‐checkpoint inhibitors and TGF‐β inhibitors, for OSCCs., We found that, TGF‐β suppressed the function of antigen‐specific CTLs in the priming and effector phases in vitro. And, we found a significant negative correlation between TGFB1 mRNA expression and the CD8+ T‐cell/Treg ratio. Inhibition of TGF‐β restores the immunosuppressive TME to active status by a mechanism different from that of immune‐checkpoint inhibitors, suggesting that the combination of both may lead to a new therapeutic strategy for OSCCs.

Primary central nervous system lymphomas (PCNSLs) rarely exhibit intratumoral hemorrhage. The differential diagnosis of hemorrhagic neoplasms of the central nervous system (CNS) currently includes metastatic carcinomas, melanomas, choriocarcinomas, oligodendrogliomas, and glioblastomas. Here we present the clinical, radiological, pathological, and molecular genetic features of six cases of PCNSL associated with intratumoral hemorrhage. The median age of patients was 75 years, with male predominance. While conventional PCNSLs were associated with low cerebral blood volume (CBV), perfusion magnetic resonance imaging (MRI) revealed elevated CBV in three cases, consistent with vascular proliferation. All six cases were diagnosed pathologically as having diffuse large B-cell lymphoma (DLBCL) with a non-germinal center B-cell-like (non-GCB) phenotype; marked histiocytic infiltrates and abundant non-neoplastic T-cells were observed in most cases. Expression of vascular endothelial growth factor and CD105 in the lymphoma cells and the small vessels, respectively, suggested angiogenesis within the neoplasms. Neoplastic cells were immunohistochemically negative for programmed cell death ligand 1 (PD-L1), while immune cells in the microenvironment were positive for PD-L1. Mutations in the MYD88 gene (MYD88) (L265P) and the CD79B gene (CD79B) were detected in five and one case, respectively. As therapeutic modalities used for PCNSLs differ from those that target conventional hemorrhagic neoplasms, full tissue diagnoses of all hemorrhagic CNS tumors are clearly warranted.

Biliary strictures caused by inflammation or fibrosis lead to jaundice and cholangitis which often make it difficult to distinguish malignant strictures. In cases when malignancy cannot be excluded, surgery is often performed. The concept of immunoglobulin G4 (IgG4)-related sclerosing cholangitis (SC) as a benign biliary stricture was recently proposed. The high prevalence of the disease in Asian countries has resulted in multiple diagnostic and treatment guidelines; however, there is need to formulate a standardized diagnostic strategy among various countries considering the utility, invasiveness, and cost-effectiveness. We evaluated accuracies of various diagnostic modalities for biliary strictures comparing pathology in the Delphi meetings which were held in Rochester, MN. The diagnostic utility for each modality was graded according to the experts, including gastroenterologists, endoscopists, radiologists, and pathologists from the United States and Japan. Diagnostic utility of 10 modalities, including serum IgG4 level, noninvasive imaging, endoscopic ultrasound, endoscopic retrograde cholangiopancreatography-related diagnostic procedures were advocated and the reasons were specified. Serum IgG4 level, noninvasive imaging, diagnostic endoscopic ultrasound and intraductal ultrasonography under endoscopic retrograde cholangiopancreatography were recognized as useful modalities for the diagnosis. The information in this article will aid in the diagnosis of biliary strictures particularly for distinguishing IgG4-SC from cholangiocarcinoma and/or primary SC.

We newly propose and experimentally investigate an InGaAs-channel high-electron-mobility transistor integrated with a unitraveling-carrier photodiode (UTC-PD) structure on its source side for an efficient optical-to-wireless carrier frequency downconversion utilizing its photonic double-mixing functionality. It is demonstrated that the double-mixing conversion gain is significantly enhanced by 20 dB compared with a standard HEMT, owing to the integration of the UTC-PD structure. The device operation principle expected from the device structure is confirmed through measured DC characteristics and photomixing/double-mixing characteristics in the millimeter-wave region. The feasibility of the device for practical use in future optical-wireless convergence networks is addressed.

Follicular T-cell lymphoma (FTCL), one of the nodal T-cell lymphomas with T follicular helper (TFH) phenotype, is an uncommon disease. The diagnosis of FTCL is challenging on the distinction from the morphological mimics mostly exemplified by follicular lymphoma. Here, we described a case of FTCL that mimicked lymphocyte-rich classic Hodgkin lymphoma (LRCHL). A 47-year-old male presented with cervical lymphadenopathy. The biopsy specimen demonstrated nodular lymphoid proliferation, which included scattered CD30+ CD15- CD20- PAX5 weakly+ Hodgkin and Reed-Sternberg (HRS)-like cells and a rich distribution of CD3+ CD4+ PD1+ T-cells. Epstein Barr virus was not detected in HRS-like cells, but it was detected in a small proportion of the scattered lymphocytes. The large cells were also negative for programmed cell death ligand 1, which appeared to be coincidental as described in our previous report of LRCHL. However, flow cytometry showed a CD3- CD4+ T-cell population that constituted 37.4% of all gated lymphocytes. A PCR analysis showed a clonal T-cell receptor-gamma gene rearrangement, but not a clonal immunoglobulin heavy chain gene rearrangement, and showed RHOA G17V mutation. The constellation of these findings led us to revise the diagnosis to FTCL. This result indicated that our case belonged to a relatively indolent subgroup of nodal peripheral T-cell lymphoma of TFH phenotype, which affects patients ≤60 years old, recently proposed by our group. This case report expands our understanding of the morphologic spectrum of FTCL and its clinicopathologic significance.

A mechanistic model for dryout and rewetting in boiling water reactors, is necessary in safety evaluations since it could be commonly applicable to various fuel assemblies and wider ranges of therm...

Segmental absence of the intestinal musculature (SAIM) can cause intestinal perforation in adults. However, its prevalence and clinicopathologic features have not been well-described. This study aimed to determine the prevalence of SAIM-associated perforation and characterize its clinicopathologic features. We retrospectively examined 109 cases of intestinal perforation that underwent surgical resection from January 2009 to December 2019. SAIM was defined as the complete absence of the muscularis propria without extensive inflammation and fibrinous exudation around the perforation. SAIM was the second most frequent cause of perforation (26 cases: 24%), the most frequent cause being related to diverticulitis (39 cases: 36%). The most common site was the sigmoid colon (12 cases: 46.2%). The younger group (aged below 65 y) exhibited more frequent perforation of the upper segments of the gastrointestinal tract (from the duodenum to the descending colon) than the older group (65 y and above) (P=0.0018). No patients developed recurrence. The most common gross features were well-defined circular or small punched-out lesions, and the histologic features were complete absence of the muscularis propria and absence of hemorrhage and necrosis around the area of perforation. The characteristic features of SAIM were unique and their prevalence was higher than previously reported. The precise recognition of SAIM can aid in understanding the cause of perforation and avoiding further unnecessary examinations.

The programmed cell death 1 (PD1)/PD1 ligand (PD-L1) axis plays an important role in tumor cell escape from immune control and has been most extensively investigated for therapeutic purposes. However, PD-L1 immunohistochemistry is still not used widely for diagnosis. We review the diagnostic utility of PD-L1 (by clone SP142) immunohistochemistry in large-cell lymphomas, mainly consisting of classic Hodgkin lymphoma (CHL) and diffuse large B-cell lymphoma (DLBCL). Neoplastic PD-L1 (nPD-L1) expression on Hodgkin and Reed-Sternberg cells is well-established among prototypic CHL. Of note, EBV+ CHL often poses a challenge for differential diagnosis from peripheral T-cell lymphoma with EBV+ non-malignant large B-cells; their distinction is based on the lack of PD-L1 expression on large B-cells in the latter. The nPD-L1 expression further provides a good diagnostic consensus for CHL with primary extranodal disease conceivably characterized by a combined pathogenesis of immune escape of tumor cells and immunodeficiency. Compared with CHL, the nPD-L1 expression rate is much lower in DLBCL, highlighting some specific subgroups of intravascular large B-cell lymphoma, primary mediastinal large B-cell lymphoma, and EBV+ DLBCL. They consist of nPD-L1-positive and -negative subgroups, but their clinicopathological significance remains to be elucidated. Microenvironmental PD-L1 positivity on immune cells may be associated with a favorable prognosis in extranodal DLBCL. PD-L1 (by SP142) immunohistochemistry has helped us to understand the immune biology of lymphoid neoplasms possibly related by immune escape and/or immunodeficiency. However, knowledge of these issues remains limited and should be clarified for diagnostic consensus in the future.

Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNS-DLBCL) is rare. Thirty-nine patients consecutively diagnosed as having PCNS-DLBCL were analyzed to highlight the prognostic value of the expression of programmed cell death ligand-1 (PD-L1) by neoplastic cells and immune cells in the microenvironment. They were positive for CD20 in all (100%), CD5 in two (5%), CD10 in nine (23%), BCL-2 in 27 (69%), BCL-6 in 34 (87%), and MUM-1 in 37 (95%). Only one case was positive for neoplastic PD-L1, with an unexpectedly long clinical course of 92 months. The remaining 38 cases were further divided into three groups based on the percentage of PD-L1+ cells among microenvironmental immune cells. Cutoffs of < 5%, 5-40%, and ≥ 40% successfully stratified mean prognoses with three-year overall survival (OS) of 21%, 63%, and 100% (P = 0.009), respectively. Progression-free survival (PFS) and OS were different between the groups with and without methotrexate (MTX)-containing chemotherapy (P = 0.007 and P < 0.001, respectively). Multivariate analysis identified three independent adverse factors of OS: PD-L1 negativity (< 5%) on microenvironmental immune cells (P = 0.027), deep structure involvement (P = 0.034), and performance status (PS) 2-4 (P = 0.009). The study showed that PD-L1 expression on immune cells in the microenvironment was associated with prognosis among patients with PCNS-DLBCL.

Hodgkin lymphomas (HLs) are lymphoid neoplasms derived from B cells and consist histologically of large neoplastic cells known as Hodgkin and Reed–Sternberg cells and abundant reactive bystander cells. HLs include two main types, classic HL (CHL) and nodular lymphocyte predominant HL (NLPHL). Recent molecular analyses have revealed that an immune evasion mechanism, particularly the PD-1/PD-L1 pathway, plays a key role in the development of CHL. Other highlighted key pathways in CHL are NF-κB and JAK/STAT. These advances have dramatically changed the treatment for CHL, particularly relapsed/refractory CHL. For example, PD-1 inhibitors are now widely used in relapsed/refractory CHL. Compared with CHL, NLPHL is more characterized by preserved B cell features. Overlapping morphological and molecular features between NLPHL and T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) have been reported, and biological continuity between these two entities has been highlighted. Some THRLBCLs are considered to represent progression from NLPHLs. With considerable new understanding becoming available from molecular studies in HLs, therapies and classification of HLs are continually evolving. This paper offers a summary of and update on the pathological and molecular features of HLs for a better understanding of the diseases.

Plasma cell differentiation (PCD) is frequently observed in some entities of non-Hodgkin B cell lymphoma, including both low-grade and high-grade lymphomas. However, except for plasmablastic lymphoma and primary effusion lymphoma, EBV+ B cell lymphoproliferative disorder (LPD) with PCD has not been well addressed due to its rarity. We clinicopathologically examined five cases of nodal EBV+ polymorphic B cell LPD with PCD (PBLPD-PCD) initially diagnosed as polymorphic EBV+ diffuse large B cell lymphoma, not otherwise specified (DLBCL-NOS) with PCD (n = 3) and methotrexate-associated B cell LPD (MTX-associated B-LPD) (n = 2). One case had a concomitant brain lesion which was clinically diagnosed as EBV-related encephalitis. This patient received therapy with vidarabine, and both the brain lesion and the nodal EBV+ PBLPD-PCD lesions disappeared. Another case was characterized by Mott cell differentiation. This case was the first reported case of EBV+ B cell lymphoma or LPD with Mott cell differentiation. The two cases of MTX-associated B cell LPD which arose in patients with rheumatoid arthritis spontaneously regressed after MTX cessation. TCRγ and IGH PCR analysis was performed in four cases. Two cases had TCRγ rearrangements, but no IGH rearrangements. The other two cases had no rearrangements in these genes. We concluded that nodal EBV+ PBLPD-PCD is rare, with heterogeneous characteristics. PCR analysis revealed that nodal EBV+ PBLPD-PCD may have only TCR clonality and no IGH clonality. Considering the partial or complete loss of CD20 expression on the tumor cells, this result may be confusing for accurate diagnosis of EBV+ PBLPD-PCD, and pathologists need to be aware of this phenomenon to avoid misdiagnosis.

Recent studies of tumor microenvironments have revealed that clonal B cells reacting to tumor-derived antigens play an important role in anti-tumor immunity. We report a case of a 72-year-old Japanese man with a complaint of fever for 1 month. Computed tomography revealed a 48 mm mass in his right kidney. The patient underwent a right nephrectomy and histology revealed clear cell renal cell carcinoma (ccRCC) of Fuhrman Grade 4 with rhabdoid morphology. Focally, marked plasmacytoid cell infiltration was detected in the carcinoma. These plasmacytoid cells were immunohistochemically positive for immunoglobulin (Ig) G, and kappa light chain restriction was confirmed using mRNA in situ hybridization. Programmed death-ligand 1 (PD-L1) immunostaining and RNA in situ hybridization of transforming growth factor beta (TGF-β) revealed that both PD-L1 and TGF-β were highly expressed in the area with clonal plasmacytoid cell infiltration. The patient developed bone metastasis 3 months after surgery, and plasmacytoma was not detected during the observation period. We identified a potential link between an immunosuppressive microenvironment and clonal B cell proliferation. The latter posed a differential diagnosis problem between reactive and neoplastic clonal B cell proliferation vis-a-vis a plasmacytoma complicating carcinoma.

The programmed death 1 (PD1)/PD1 ligand (PD-L1) axis plays an important role in the pathogenesis of Epstein-Barr virus-positive diffuse large B cell lymphoma, not otherwise specified (EBV+ DLBCL, NOS). Here, we describe PD-L1 expression by EBV+ DLBCL, NOS in order to evaluate its possible contribution to the pathogenesis of this tumor. The study included 57 cases of EBV+ DLBCL, NOS. The median patient age was 69 years and 95% (n = 54) were aged > 45. Extranodal lesions were present in 39 (69%) at initial diagnosis. PD-L1 expression (mAb SP142-positive staining) was present in more than 5% of tumor cells in only six cases (11%), in clear contrast to the 77% reported in cases aged under 45 years. Among the PD-L1+ cases, three were nodal lesions. All six PD-L1+ cases progressed in the 3 years after diagnosis and four of the six patients died of the disease within 2 years. PD-L1+ cases had significantly shorter PFS (P = 0.002) and relatively short OS (P = 0.26), compared with PD-L1− cases. EBV+ DLBCL, NOS in the elderly infrequently expressed PD-L1 and had poor prognosis. PD-L1 expression in EBV+ DLBCL, NOS of the elderly sheds light on the pathogenetic role of immune senescence.