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1.
Hinyokika Kiyo ; 67(8): 395-398, 2021 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-34472323

RESUMO

A 56-year-old man visited a clinic with the chief complaint of frequent micturition and residual sensation of urine. He was referred to our hospital for close examination. Cystoscopy showed a tumor protruding toward the bladder neck from the prostate with stones and debris on the surface. Magnetic resonance imaging showed an encapsulated tumor of iso-intensity in the prostate in T2-weighed images. Prostate specific antigen was 0.88 mg/dl. Transurethral resection of prostate was performed under the diagnosis of benign prostate hyperplasia. During the operation, a solid tumor with mucus deposit was observed. Intraoperative rapid pathological diagnosis was mucinous adenocarcinoma. A radical cystectomy was performed. Pathologically, mucinous adenocarcinoma was distributed in the bladder neck, the prostate and surrounding tissue, but the prostatic urethra was intact. The surgery was assessed to be curative. Neither neoadjuvant nor adjuvant chemotherapy was performed, since the effectiveness of chemotherapy for mucinous adenocarcinoma arising from urothelial epithelium has not been established.


Assuntos
Adenocarcinoma Mucinoso , Neoplasias da Próstata , Ressecção Transuretral da Próstata , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adenocarcinoma Mucinoso/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/cirurgia , Bexiga Urinária
2.
J Natl Cancer Inst ; 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34524427

RESUMO

BACKGROUND: About 20% of lung adenocarcinoma (LUAD) is negative for the lineage-specific oncogene Thyroid transcription factor 1 (TTF-1) and exhibits worse clinical outcome with a low frequency of actionable genomic alterations. To identify molecular features associated with TTF-1-negative LUAD, we compared the transcriptomic and proteomic profiles of LUAD cell lines. SRGN, a chondroitin sulfate proteoglycan Serglycin, was identified as a markedly overexpressed gene in TTF-1-negative LUAD. We therefore investigated the roles and regulation of SRGN in TTF-1-negative LUAD. METHODS: Proteomic and metabolomic analyses of 41 LUAD cell lines were done using mass spectrometry. The function of SRGN was investigated in 3 TTF-1-negative and 4 TTF-1-positive LUAD cell lines and in a syngeneic mouse model (n = 5 to 8 mice per group). Expression of SRGN in was evaluated in 94 and 105 surgically resected LUAD tumor specimens using immunohistochemistry. All statistical tests were two-sided. RESULTS: SRGN was markedly overexpressed at mRNA and protein levels in TTF-1-negative LUAD cell lines (P < .001 for both mRNA and protein levels). Expression of SRGN in LUAD tumor tissue was associated with poor outcome (hazard ratio = 4.22, 95% confidential interval = 1.12 to 15.86; likelihood ratio test, P = .03), and with higher expression of Programmed cell death 1 ligand 1 (PD-L1) in tumor cells and higher infiltration of Programmed cell death protein 1 (PD-1)-positive lymphocytes. SRGN regulated expression of PD-L1, as well as proinflammatory cytokines including Interleukin-6 (IL-6), Interleukin-8 (IL-8), and C-X-C motif chemokine 1 (CXCL1) in LUAD cell lines, and increased migratory and invasive properties of LUAD cells and fibroblasts, and enhanced angiogenesis. SRGN was induced by DNA de-methylation resulting from Nicotinamide N-methyltransferase (NNMT)-mediated impairment of methionine metabolism. CONCLUSION: Our findings suggest that SRGN plays a pivotal role in tumor-stromal interaction and reprogramming into an aggressive and immunosuppressive tumor microenvironment in TTF-1-negative LUAD.

3.
J Clin Exp Hematop ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34511582

RESUMO

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.

4.
J Clin Exp Hematop ; 61(3): 173-179, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34511545

RESUMO

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.


Assuntos
Doença de Hodgkin/diagnóstico , Linfócitos/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Diagnóstico Diferencial , Evolução Fatal , Feminino , Infecções por HTLV-I/complicações , Doença de Hodgkin/etiologia , Doença de Hodgkin/metabolismo , Doença de Hodgkin/terapia , Humanos , Imuno-Histoquímica , Síndromes de Imunodeficiência/complicações , Linfócitos/metabolismo , Células de Reed-Sternberg/patologia , Evasão Tumoral/imunologia
5.
Am J Surg Pathol ; 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34534136

RESUMO

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<0.001 and P=0.002, respectively). In conclusion, we evaluated 3 types of PA-DLBCL and found that each had unique clinical, pathologic, and prognostic features. Our results suggested that immune senescence, iatrogenic immunodeficiency, and immune evasion contribute to the development of PA-DLBCL.

7.
J Clin Exp Hematop ; 61(2): 97-101, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33716241

RESUMO

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.


Assuntos
Doença de Hodgkin/diagnóstico , Linfoma Folicular/diagnóstico , Linfoma de Células T/diagnóstico , Rearranjo Gênico da Cadeia gama dos Receptores de Antígenos dos Linfócitos T , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patologia , Linfoma de Células T/genética , Linfoma de Células T/patologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/patologia
8.
Cancer Sci ; 112(4): 1614-1623, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33506575

RESUMO

We previously reported that ROR1 is a crucial downstream gene for the TTF-1/NKX2-1 lineage-survival oncogene in lung adenocarcinoma, while others have found altered expression of ROR1 in multiple cancer types. Accumulated evidence therefore indicates ROR1 as an attractive molecular target, though it has yet to be determined whether targeting Ror1 can inhibit tumor development and growth in vivo. To this end, genetically engineered mice carrying homozygously floxed Ror1 alleles and an SP-C promoter-driven human mutant EGFR transgene were generated. Ror1 ablation resulted in marked retardation of tumor development and progression in association with reduced malignant characteristics and significantly better survival. Interestingly, gene set enrichment analysis identified a hypoxia-induced gene set (HALLMARK_HYPOXIA) as most significantly downregulated by Ror1 ablation in vivo, which led to findings showing that ROR1 knockdown diminished HIF-1α expression under normoxia and clearly hampered HIF-1α induction in response to hypoxia in human lung adenocarcinoma cell lines. The present results directly demonstrate the importance of Ror1 for in vivo development and progression of lung adenocarcinoma, and also identify Ror1 as a novel regulator of Hif-1α. Thus, a future study aimed at the development of a novel therapeutic targeting ROR1 for treatment of solid tumors such as seen in lung cancer, which are frequently accompanied with a hypoxic tumor microenvironment, is warranted.


Assuntos
Adenocarcinoma de Pulmão/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Hipóxia/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Oncogenes/genética , Transdução de Sinais/genética , Fator Nuclear 1 de Tireoide/genética , Microambiente Tumoral/genética
9.
Asia Pac J Clin Oncol ; 17(3): 238-244, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32970933

RESUMO

AIM: To date, the optimal sequencing of life-prolonging therapies for patients with metastatic castration-resistant prostate cancer (mCRPC) remains unclear owing to a lack of prospective trials. This study aimed to evaluate the efficacy and safety of cabazitaxel (CBZ) treatment and examine the prognostic factors for oncological outcomes in patients with mCRPC who received CBZ after docetaxel (DOC). METHODS: This multi-institutional retrospective study included 44 patients with mCRPC who received CBZ. All enrolled patients had histologically confirmed prostate cancer (PCa) with distant metastases and had received DOC before CBZ administration. The primary endpoint was the oncological outcomes, including the overall (OS) and progression-free survival (PFS). The secondary endpoints were adverse events due to CBZ and rates of ≥30% reduction in prostate-specific antigen (PSA) levels. RESULTS: The median follow-up period was 9.2 months (range, 0.2-34 months). During this time, 34 patients (77%) died of PCa. The median OS and PFS were 12.2 (range, 0.2-34 months) and 1.4 months (range, 0.4-17 months), respectively. According to the PSA decline rate, patients who achieved a ≥30% reduction in PSA levels had significantly longer OS than those who showed a <30% reduction in PSA levels (P = 0.002). Regarding the number of cycles of CBZ, patients who received ≥4 cycles of CBZ showed significantly longer OS than those who received <4 cycles of CBZ (P < 0.001). Patients who had visceral metastasis showed significantly shorter OS than those without visceral metastasis (P = 0.012). CONCLUSION: This study demonstrated that CBZ was effective and safe in Japanese local patients in a real-world setting. Patients with mCRPC who received ≥4 cycles of CBZ showed a ≥30% reduction in the serum PSA levels, and did not have visceral metastasis might achieve longer OS.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Taxoides/uso terapêutico , Idoso , Humanos , Masculino , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
10.
Neuropathology ; 41(2): 99-108, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33269495

RESUMO

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.

11.
J Virol ; 95(4)2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33087465

RESUMO

Toward development of a dual vaccine for human immunodeficiency virus type 1 (HIV-1) and tuberculosis infections, we developed a urease-deficient bacillus Calmette-Guérin (BCG) strain Tokyo172 (BCGΔurease) to enhance its immunogenicity. BCGΔurease expressing a simian immunodeficiency virus (SIV) Gag induced BCG antigen-specific CD4+ and CD8+ T cells more efficiently and more Gag-specific CD8+ T cells. We evaluated its protective efficacy against SIV infection in cynomolgus monkeys of Asian origin, shown to be as susceptible to infection with SIVmac251 as Indian rhesus macaques. Priming with recombinant BCG (rBCG) expressing SIV genes was followed by a boost with SIV gene-expressing LC16m8Δ vaccinia virus and a second boost with SIV Env-expressing Sendai virus. Eight weeks after the second boost, monkeys were repeatedly challenged with a low dose of SIVmac251 intrarectally. Two animals out of 6 vaccinees were protected, whereas all 7 control animals were infected without any early viral controls. In one vaccinated animal, which had the most potent CD8+ T cells in an in vitro suppression activity (ISA) assay of SIVmac239 replication, plasma viremia was undetectable throughout the follow-up period. Protection was confirmed by the lack of anamnestic antibody responses and detectable cell-associated provirus in various organs. Another monkey with a high ISA acquired a small amount of SIV, but it later became suppressed below the detection limit. Moreover, the ISA score correlated with SIV acquisition. On the other hand, any parameter relating anti-Env antibody was not correlated with the protection.IMPORTANCE Because both AIDS and tuberculosis are serious health threats in middle/low-income countries, development of a dual vaccine against them would be highly beneficial. To approach the goal, here we first assessed a urease-deficient bacillus Calmette-Guérin (BCG) for improvement of immunogenicity against both Mycobacterium tuberculosis and SIV. Second, we demonstrated the usefulness of Asian-origin cynomolgus monkeys for development of a preclinical AIDS vaccine by direct comparison with Indian rhesus macaques as the only validated hosts that identically mirror the outcomes of clinical trials, since the availability of Indian rhesus macaques is limited in countries other than the United States. Finally, we report the protective effect of a vaccination regimen comprising BCG, the highly attenuated vaccinia virus LC16m8Δ strain, and nontransmissible Sendai virus as safe vectors expressing SIV genes using repeated mucosal challenge with highly pathogenic SIVmac251. Identification of CD8+ T cells as a protective immunity suggests a future direction of AIDS vaccine development.


Assuntos
Vacinas contra a AIDS/imunologia , Síndrome de Imunodeficiência Adquirida/prevenção & controle , Vacina BCG/imunologia , Linfócitos T CD8-Positivos/imunologia , Vetores Genéticos/imunologia , Tuberculose/prevenção & controle , Animais , Linfócitos T CD8-Positivos/citologia , Linhagem Celular , Cricetinae , Modelos Animais de Doenças , HIV-1/imunologia , Humanos , Macaca mulatta , Camundongos , Camundongos Endogâmicos C57BL , Coelhos , Vacinas contra a SAIDS/imunologia , Vírus Sendai/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/imunologia , Vacinação , Vírus Vaccinia/imunologia
12.
Virchows Arch ; 478(3): 541-552, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32803453

RESUMO

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.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Herpesvirus Humano 4/isolamento & purificação , Linfonodos/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Feminino , Humanos , Imunossenescência , Japão , Linfonodos/patologia , Linfonodos/virologia , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral
13.
Ann Thorac Surg ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33242433

RESUMO

BACKGROUND: Invasive mucinous adenocarcinoma (IMA) is a rare subtype of invasive lung adenocarcinoma. However, the clinical course and prognostic outcomes following IMA resection, particularly postoperative recurrence, remain unclear. METHODS: We pathologically reevaluated 1362 lung adenocarcinoma resections performed at our institution, categorizing cases into the IMA group (72 cases) and non-IMA group (1290 cases). The IMA group was further classified into pneumonia and nodular types based on preoperative computed tomography. RESULTS: Overall, the IMA group had lower carcinoembryonic antigen levels (3 vs 8 ng/mL; P < .01), fewer lymph node metastasis (4% vs 24%; P < .01), and more KRAS mutations (56% vs 7%; P < .01) than the non-IMA group. Although postoperative recurrence rates did not differ between both groups (32% vs 27%; P = 0.35), lung recurrence occurred more frequently in the IMA group (83% vs 17%; P < .01). Propensity score-matched pair analysis showed that the IMA group had fewer lymph node metastasis (3% vs 35%; P < .01), more KRAS mutations (56% vs 9%; P < .01), and higher intrapulmonary recurrence rate (84% vs 31%; P < .01) than the non-IMA group. The 5-year overall survival rates did not differ between both groups (74% vs 81%; P = 0.26). However, among patients with intrapulmonary recurrence, those in the IMA group had significantly worse prognosis than those in the non-IMA group (35% vs 77%; P < .01). CONCLUSIONS: Intrapulmonary recurrence, which induced significantly worse prognosis, was more likely to occur in the IMA than non-IMA group.

14.
J Cell Mol Med ; 24(20): 11949-11959, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32902157

RESUMO

Sphingolipids constitute a class of bio-reactive molecules that transmit signals and exhibit a variety of physical properties in various cell types, though their functions in cancer pathogenesis have yet to be elucidated. Analyses of gene expression profiles of clinical specimens and a panel of cell lines revealed that the ceramide synthase gene CERS6 was overexpressed in non-small-cell lung cancer (NSCLC) tissues, while elevated expression was shown to be associated with poor prognosis and lymph node metastasis. NSCLC profile and in vitro luciferase analysis results suggested that CERS6 overexpression is promoted, at least in part, by reduced miR-101 expression. Under a reduced CERS6 expression condition, the ceramide profile became altered, which was determined to be associated with decreased cell migration and invasion activities in vitro. Furthermore, CERS6 knockdown suppressed RAC1-positive lamellipodia/ruffling formation and attenuated lung metastasis efficiency in mice, while forced expression of CERS6 resulted in an opposite phenotype in examined cell lines. Based on these findings, we consider that ceramide synthesis by CERS6 has important roles in lung cancer migration and metastasis.


Assuntos
Movimento Celular , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Esfingosina N-Aciltransferase/metabolismo , Animais , Sequência de Bases , Linhagem Celular Tumoral , Ceramidas/metabolismo , Humanos , Masculino , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Biológicos , Metástase Neoplásica , Pseudópodes/metabolismo , Resultado do Tratamento
15.
Pediatr Int ; 62(12): 1315-1331, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32657507

RESUMO

The Japan Pediatric Helicobacter pylori Study Group published the first guidelines on childhood H. pylori infection in 1997. They were later revised by the Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition (JSPGHAN). The H. pylori eradication rates, when employing triple therapy with amoxicillin and clarithromycin, currently recommended as the first-line therapy of H. pylori infection in Japan, have substantially decreased, creating an important clinical problem worldwide. In Japanese adults, the "test-and-treat" strategy for H. pylori infection is under consideration as an approach for gastric cancer prevention. However, the combined North American and European pediatric guidelines have rejected such a strategy for asymptomatic children. As risk for gastric cancer development is high in Japan, determining whether the "test-and-treat" strategy can be recommended in children has become an urgent matter. Accordingly, the JSPGHAN has produced a second revision of the H. pylori guidelines, which includes discussion about the issues mentioned above. They consist of 19 clinical questions and 34 statements. An H. pylori culture from gastric biopsies is recommended, not only as a diagnostic test for active infection but for antimicrobial susceptibility testing to optimize eradication therapy. Based upon antimicrobial susceptibility testing of H. pylori strains (especially involving clarithromycin), an eradication regimen including use of the antibiotics to which H. pylori is susceptible is recommended as the first-line therapy against H. pylori-associated diseases. The guidelines recommend against a "test-and-treat" strategy for H. pylori infection for asymptomatic children to protect against the development of gastric cancer because there has been no evidence supporting this strategy.


Assuntos
Antibacterianos/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/isolamento & purificação , Inibidores da Bomba de Prótons/uso terapêutico , Adolescente , Amoxicilina/uso terapêutico , Biópsia/métodos , Criança , Pré-Escolar , Claritromicina/uso terapêutico , Técnica Delfos , Farmacorresistência Bacteriana , Quimioterapia Combinada , Gastroenterologia , Infecções por Helicobacter/diagnóstico , Humanos , Lactente , Japão , Testes de Sensibilidade Microbiana/métodos , Neoplasias Gástricas/epidemiologia
16.
J Clin Exp Hematop ; 60(2): 30-36, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32565530

RESUMO

Nodal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (CTL) is a primary nodal peripheral T-cell lymphoma (PTCL) characterized by a cytotoxic phenotype and EBV on the tumor cells. This disease reportedly accounts for 21% of PTCL not otherwise specified (NOS). However, few nodal EBV+ lymphomas have been documented in detail. Nodal EBV+ CTL and nasal-type NK/T-cell lymphoma (NKTL) both exhibit cytotoxic molecule expression and EBV positivity on the tumor cells; however, nodal EBV+ CTL is characterized as a systemic disease without nasopharyngeal involvement, and exhibits a CD8+/CD56- phenotype distinct from NKTL. The clinicopathological uniqueness of nodal EBV+ CTL is further supported by its T-cell origin in most reported cases. In the 2008 WHO classification, it was unclear whether nodal EBV+ CTL should be classified as PTCL or NKTL. However, based on additional data, the 2017 revision classifies nodal EBV+ CTL as PTCL. In the present review, we focus on the clinicopathological characteristics of nodal EBV+ CTL, discuss the relationship between chronic active EBV infection and nodal EBV+ lymphoma, and highlight future perspectives regarding the treatment of this disease.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Linfoma de Células T Periférico/classificação , Linfoma de Células T Periférico/virologia , Linfócitos T Citotóxicos/patologia , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/terapia , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/isolamento & purificação , Humanos , Imunofenotipagem , Linfoma Extranodal de Células T-NK/classificação , Linfoma Extranodal de Células T-NK/patologia , Linfoma Extranodal de Células T-NK/terapia , Linfoma Extranodal de Células T-NK/virologia , Linfoma de Células T Periférico/patologia , Linfoma de Células T Periférico/terapia , Linfócitos T Citotóxicos/virologia , Organização Mundial da Saúde
17.
Pathol Int ; 70(8): 481-492, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32367595

RESUMO

Epstein-Barr virus (EBV) is prevalent among healthy individuals, and is implicated in numerous reactive and neoplastic processes in the immune system. The authors originally identified a series of senile or age-related EBV-associated B-cell lymphoproliferative disorders (LPD) bearing a resemblance to immunodeficiency-associated ones. These LPDs may be associated with immune senescence and are now incorporated into the revised 4th edition of 2017 WHO lymphoma classification as EBV-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS). These EBV+ B-cells often have a Hodgkin/Reed-Sternberg (HRS)-like appearance and are shared beyond the diagnostic categories of mature B-cell neoplasms, mature T-cell neoplasms, classic Hodgkin lymphoma, and immunodeficiency-associated LPD. In addition, peculiar new diseases, such as EBV+ mucocutaneous ulcer and EBV+ DLBCL affecting the young, were recognized. On the other hand, lymphoma classification is now evolving in accord with deeper understanding of the biology of programmed death ligand 1 (PD-L1). Assessing PD-L1 positivity by staining with the anti-PD-L1 monoclonal antibody SP142 provides new insight by discriminating between immune evasion and senescence or immunodeficiency. The aim of the present review is to briefly summarize the diagnostic use of immunostaining with SP142 in malignant lymphomas and/or LPDs that feature tumor and nonmalignant large B-cells harboring EBV.


Assuntos
Linfócitos B , Antígeno B7-H1/imunologia , Infecções por Vírus Epstein-Barr , Transtornos Linfoproliferativos , Envelhecimento , Anticorpos/sangue , Linfócitos B/patologia , Linfócitos B/virologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Doença de Hodgkin/diagnóstico , Humanos , Evasão da Resposta Imune , Linfoma/diagnóstico , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia
18.
Cancer Med ; 9(13): 4768-4776, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32367674

RESUMO

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare form of diffuse large B-cell lymphoma (DLBCL) arising in extranodal sites. PD-L1 expression of tumor cells has been reported in IVLBCL cells, but its clinicopathological relevance remains to be elucidated. AIMS: This study was aimed to reveal the characteristics of PD-L1+ IVLBCL. METHODS AND RESULTS: Neoplastic PD-L1 expression was examined in 34 cases of IVLBCL and clinicopathological characteristics between patients with PD-L1+ and PD-L1- IVLBCL were compared. We assessed PD-L1 expression with SP142 antibody. Twelve (35%) of 34 cases showed positivity for PD-L1. The PD-L1+ group had significantly lower survival rates compared to the PD-L1- group. The PD-L1+ IVLBCL group also had a significantly lower age distribution and a lower frequency of patients older than 60 years compared to the PD-L1- group. Very recently, we speculate that there is possible link between PD-L1+ IVLBCL and PD-L1+ extranodal DLBCL-NOS (eDLBCL) because features of the two groups showed overlapping. Therefore, we compared the clinicopathological characteristics of the PD-L1+ IVLBCL and PD-L1+ eDLBCL. There were no significant differences in clinicopathological parameters and prognosis. CONCLUSION: The worse prognosis of the PD-L1+ group might be caused by immune evasion mechanisms, which are linked to PD-L1 expression. Therefore, PD-L1+ IVLBCL cases might be regarded as good candidates for targeted immunotherapy. We also highlighted the overlapping features of PD-L1+ IVLBCL and PD-L1+ eDLBCL. This result suggests that they should be regarded as one entity, immune evasion-related extranodal large B-cell lymphoma.


Assuntos
Antígeno B7-H1/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Evasão da Resposta Imune , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Rituximab/uso terapêutico , Taxa de Sobrevida , Evasão Tumoral/imunologia
19.
Pathol Int ; 70(8): 513-522, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32424876

RESUMO

Inhibitors of programmed cell-death 1 (PD-1) and programmed cell-death ligand 1 (PD-L1) have revolutionized cancer therapy. Nodal cytotoxic T-cell lymphoma (CTL) is characterized by a poorer prognosis compared to nodal non-CTLs. Here we investigated PD-L1 expression in 50 nodal CTL patients, with and without EBV association (25 of each). We identified seven patients (14%) with neoplastic PD-L1 (nPD-L1) expression on tumor cells, including three males and four females, with a median age of 66 years. One of the seven cases was TCRαß type, three were TCRγδ type and three were TCR-silent type. Six of the seven cases exhibited a lethal clinical course despite multi-agent chemotherapy, of whom four patients died within one year of diagnosis. Morphological findings were uniform, with six cases showing centroblastoid appearance. Among nPD-L1+ cases, two of three examined had structural variations of PD-L1 disrupting 3'-UTR region. Notably, all of the TCRγδ-type nodal CTL cases showed nPD-L1 or miPD-L1 positivity (3 and 10 cases, respectively). TCRγδ-type cases comprised 42% of nPD-L1+ cases (P = 0.043 vs. PD-L1- ), and 35% of miPD-L1+ cases (P = 0.037 vs. PD-L1- ). The results indicate that PD-L1+ nodal CTL cases, especially of the TCRγδ type, are potential candidates for anti-PD-1/PD-L1 therapies.


Assuntos
Antígeno B7-H1/metabolismo , Linfoma de Células T Periférico , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/patologia , Feminino , Humanos , Linfoma de Células T/diagnóstico , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
20.
Eur J Radiol ; 127: 108990, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32304929

RESUMO

PURPOSE: This study aimed to compare the efficacy and safety of image-guided core needle biopsy (CNB) with those of surgical excision biopsy (SEB) for the diagnosis of lymphoma, and to clarify the indication of CNB in clinical practice. METHOD: This retrospective study included 263 image-guided CNB cases and 108 SEB cases that were performed at our institution between January 2014 and December 2018. The rate of patients with performance status of grade 1-4 was higher in the CNB group than in the SEB group (43.7% vs. 24.1%, P <  0.01). Waiting time to biopsy and diagnosis was shorter for CNB group than for SEB group (4 days vs. 7 days, 13 days vs. 15 days, P <  0.01). The rate of biopsy at the deep sites was higher in the CNB group than in the SEB group (53.2% vs. 8.3%, P <  0.01). Successful biopsy and complication rates were compared between the 2 groups. RESULTS: There were no significant differences between the CNB and SEB groups in successful biopsy rates (89.0% vs. 93.5%, P =  0.25). The grade 3 complication rate was significantly lower for CNB group than for SEB group (0% vs. 4.6%, P <  0.01), although there was no significant difference in overall complication rates (4.9% vs. 6.5%, respectively, P =  0.61). CONCLUSIONS: CNB showed high diagnostic yield comparable to SEB for suspected lymphoma. CNB was especially recommended to the cases with low-PS, lesions in the deep sites, and requiring early pathological diagnosis.


Assuntos
Linfoma/diagnóstico por imagem , Linfoma/patologia , Ultrassonografia de Intervenção/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia com Agulha de Grande Calibre , Feminino , Humanos , Biópsia Guiada por Imagem , Linfoma/cirurgia , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto Jovem
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