Kun aterooma ei ole aterooma

Teema : Hematologiset syövä

Lymfoomien luokitus tarkentuu

Lymfoomien alatyyppien yleisyystiedot ovat nyt saatavilla Suomen syöpärekisterin verkkosivuilla. Lymfoomat yleistyvät, mutta kuolleisuus non-Hodgkin-lymfoomiin on laskussa. Lymfoomat jaetaan nykyään B- ja T-solulymfoomiin, kun aiemmin jako tehtiin vain Hodgkinin ja non-Hodgkin-lymfoomiin. Laadukas ja kattava rekisteritieto on tärkeää harvinaissairauksien hoidon kehittämisen pohjaksi.Peer reviewe

Adverse prognostic impact of regulatory T-cells in testicular diffuse large B-cell lymphoma

Objectives Testicular diffuse large B-cell lymphoma (T-DLBCL) is a rare and aggressive extranodal lymphoma. We have previously shown that high content of tumor-infiltrating lymphocytes (TILs) and PD-1 expressing TILs associate with better survival in T-DLBCL. In this study, we have further characterized distinct TIL subtypes and their proportions in association with patient demographics and survival. Methods We used multiplex immunohistochemistry to characterize TIL phenotypes, including cytotoxic T-cells (CTLs; CD8(+), OX40(+), Granzyme B+, Ki-67(+), LAG-3(+), TIM-3(+), PD-1(+)), CD4(+)T-cells (CD3(+), CD4(+), TIM-3(+), LAG-3(+)), regulatory T-cells (Tregs; CD3(+), CD4(+), FoxP3(+)), and T helper 1 cells (Th1; CD3(+), CD4(+), T-bet(+)) in 79 T-DLBCLs, and correlated the findings with patient demographics and outcome. Results We observed a substantial variation in TIL phenotypes between the patients. The most prominent CD8(+)TILs were Ki-67(+)and TIM-3(+)CTLs, whereas the most prominent CD4(+)TILs were FoxP3(+)Tregs. Despite the overall favorable prognostic impact of high TIL content, we found a subpopulation of T-bet(+)FoxP3(+)Tregs that had a significant adverse impact on survival. Lower content of CTLs with activated or exhausted phenotypes correlated with aggressive clinical features. Conclusions Our results demonstrate significant variation in TIL phenotypes and emphasize the adverse prognostic impact of Tregs in T-DLBCL.Peer reviewe

Clinical Impact of Immune Cells and Their Spatial Interactions in Diffuse Large B-Cell Lymphoma Microenvironment

Purpose: Tumor-infiltrating immune cells have prognostic sig-nificance and are attractive therapeutic targets. Yet, the clinical significance of their spatial organization and phenotype in diffuse large B-cell lymphoma (DLBCL) is unclear. Experimental Design: We characterized T cells, macrophages, and their spatial interactions by multiplex IHC (mIHC) in 178 patients with DLBCL and correlated the data with patient demo-graphics and survival. We validated the findings on gene expression data from two external DLBCL cohorts comprising 633 patients. Results: Macrophage and T-cell contents divided the samples into T cell-inflamed (60%) and noninflamed (40%) subgroups. The T cell-inflamed lymphoma microenvironment (LME) was also rich in other immune cells, defining immune hot phenotype, which did not as such correlate with outcome. However, when we divided the patients according to T-cell and macrophage contents, LME char-acterized by high T-cell/low macrophage content or a correspond-ing gene signature was associated with superior survival [5-year overall survival (OS): 92.3% vs. 74.4%, P = 0.036; 5-year progres-sion-free survival (PFS): 92.6% vs. 69.8%, P = 0.012]. High pro-portion of PD -L1-and TIM3-expressing CD163- macrophages in the T cell-inflamed LME defined a group of patients with poor outcome [OS: HR = 3.22, 95% confidence interval (CI), 1.63-6.37, P-adj = 0.011; PFS: HR = 2.76, 95% CI, 1.44-5.28, P-adj = 0.016]. Furthermore, PD-L1 and PD-1 were enriched on macrophages interacting with T cells. Conclusions: Our data demonstrate that the interplay between macrophages and T cells in the DLBCL LME is immune checkpoint dependent and clinically meaningful.Peer reviewe

Prognostic Impact of Tumor-Associated Macrophages on Survival Is Checkpoint Dependent in Classical Hodgkin Lymphoma

Tumor microenvironment and immune escape affect pathogenesis and survival in classical Hodgkin lymphoma (cHL). While tumor-associated macrophage (TAM) content has been associated with poor outcomes, macrophage-derived determinants with clinical impact have remained undefined. Here, we have used multiplex immunohistochemistry and digital image analysis to characterize TAM immunophenotypes with regard to expression of checkpoint molecules programmed cell death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO-1) from the diagnostic tumor tissue samples of 130 cHL patients, and correlated the findings with clinical characteristics and survival. We show that a large proportion of TAMs express PD-L1 (CD68+, median 32%; M2 type CD163+, median 22%), whereas the proportion of TAMs expressing IDO-1 is lower (CD68+, median 5.5%; CD163+, median 1.4%). A high proportion of PD-L1 and IDO-1 expressing TAMs from all TAMs (CD68+), or from CD163+ TAMs, is associated with inferior outcome. In multivariate analysis with age and stage, high proportions of PD-L1+ and IDO-1+ TAMs remain independent prognostic factors for freedom from treatment failure (PD-L1+CD68+/CD68+, HR = 2.63, 95% CI 1.17–5.88, p = 0.019; IDO-1+CD68+/CD68+, HR = 2.48, 95% CI 1.03–5.95, p = 0.042). In contrast, proportions of PD-L1+ tumor cells, all TAMs or PD-L1− and IDO-1− TAMs are not associated with outcome. The findings implicate that adverse prognostic impact of TAMs is checkpoint-dependent in cHL

Clinical findings in 25 patients with sinonasal or nasopharyngeal extramedullary plasmacytoma in a four-decade single-centre series

Objectives: Extramedullary plasmacytoma in the sinonasal tract or nasopharynx is rare. The aim of the study was to review data on symptoms, clinical findings, treatment and follow-up of plasmacytomas in the sinonasal and nasopharyngeal regions in order to delineate the main clinical characteristics and the optimal management. Method: Twenty-five patients with sinonasal or nasopharyngeal plasmacytoma, diagnosed and treated at the Helsinki University Hospital during a 39-year period from 1975 to 2013 were retrospectively reviewed. Results: There were 18 males and 7 females with a median age of 66 years (range, 36-80). Sixty-eight percent received only radiotherapy or (chemo)radiotherapy. Forty-seven percent of them had a complete response to primary radiotherapy and one patient had a complete response after receiving additional brachytherapy. Four patients were treated primarily with surgery only. Two of them had a local recurrence, but were then successfully treated with radiotherapy. Altogether, four patients received a combination of surgery and (chemo)radiotherapy. Forty-four percent were alive with no evidence of disease after a median follow-up time of 78 months. Forty percent died of their disease and 16% died of other causes. Conclusions: Our study supports radiotherapy as a treatment of choice, but for small tumours surgery alone or in combination with radiotherapy may also be considered. Chinese abstractPeer reviewe

Checkpoint protein expression in the tumor microenvironment defines the outcome of classical Hodgkin lymphoma patients

Emerging evidence indicates a major impact for the tumor microenvironment (TME) and immune escape in the pathogenesis and clinical course of classical Hodgkin lymphoma (cHL). We used gene expression profiling (n = 88), CIBERSORT, and multiplex immunohistochemistry (n = 131) to characterize the immunoprofile of cHL TME and correlated the findings with survival. Gene expression analysis divided tumors into subgroups with T cell-inflamed and -noninflamed TME. Several macrophage-related genes were upregulated in samples with the non-T cell-inflamed TME, and based on the immune cell proportions, the samples clustered according to the content of T cells and macrophages. A cluster with high proportions of checkpoint protein (programmed cell death protein 1, PD-1 ligands, indoleamine 2,3 dioxygenase 1, lymphocyte-activation gene 3, and T-cell immunoglobulin and mucin domain containing protein 3) positive immune cells translated to unfavorable overall survival (OS) (5-year OS 76% vs 96%; P = .010) and remained an independent prognostic factor for OS in multivariable analysis (HR, 4.34; 95% CI, 1.05-17.91; P = .043). cHL samples with high proportions of checkpoint proteins overexpressed genes coding for cytolytic factors, proposing paradoxically that they were immunologically active. This checkpoint molecule gene signature translated to inferior survival in a validation cohort of 290 diagnostic cHL samples (P < .001) and in an expan-sion cohort of 84 cHL relapse samples (P = .048). Our findings demonstrate the impact of T cell-and macrophage-mediated checkpoint system on the survival of patients with cHL.Peer reviewe

Kateenkorvan epiteelilähtöiset syövät

Vertaisarvioitu. English summaryKateenkorvan kasvaimet ovat monimuotoinen joukko harvinaisia syöpiä, jotka ovat yleensä parannet­ta vissa leikkauksella. Tietokonetomografia (TT) on perustutkimus arvioitaessa kateenkorvan syöpien levinneisyyttä. Erotusdiagnostiset vaihtoehdot on syytä huomioida ja asianmukaisesti diagnosoida ennen hoitopäätösten tekoa. Kateenkorvan syöpien hoitosuunnitelma tehdään moniammatillisessa hoitokokouksessa. Mikäli kasvain ei ole suoraan leikattavissa, voidaan säde­ ja solunsalpaajahoidolla pienentää kasvainmassaa ja mahdollistaa paranemista tavoitteleva leikkaus. Edenneen kateenkorvan syövän hoidossa solunsalpaajat pienentävät usein tautitaakkaa ja lievittävät syövän aiheuttamia oireita. Lisääntyvä kateenkorvan syöpien biologian tuntemus mahdollistanee tulevaisuudessa myös geeni­muutoksiin kohdennetut hoidot.Peer reviewe

T-cell inflamed tumor microenvironment predicts favorable prognosis in primary testicular lymphoma

Primary testicular lymphoma is a rare lymphoid malignancy, most often, histologically, representing diffuse large B-cell lymphoma. The tumor rnicroenvi.ro.nrnent and limited immune surveillance have a major impact on diffuse large B-cell lymphoma pathogenesis and. survival, but the impact on primary testicular lymphoma is unknown. Here, the purpose of the study was to characterize the tumor microenvironme.nt in primary testicular lymphoma, and associate the findings with outcome. We profiled the expression of 730 immune response enes in 60 primary testicular lymphomas utilizing the Nanostring platorm, and used multiplex imrnunohistochemistry to characterize the immune cell phenotypes in the tumor tissue. We identified a gene signature enriched for T-lymphocyte markers differentially expressed. between the patients. Low expression of the signature predicted poor outcome independently of the International Prognostic Index (progression -free survival: HR=2.810, 95%CI: 1.228-6.431, P=0.014; overall survival: HR=3.267, 95`)/0' CI: 1.406-7.590, P=0.006). The T-lymphocyte signature was associated with outcome also in an independent diffuse large B-cell lymphoma cohort (n=96). Multiplex immunohistochemistry revealed that poor survival of primary testicular lymphoma patients correlated with low percentage of CD3'CD4' and CD3+CD8' tumor-infiltrating lymphocytes (PPeer reviewe

PD-L1(+) tumor-associated macrophages and PD-1(+) tumor-infiltrating lymphocytes predict survival in primary testicular lymphoma

Primary testicular lymphoma is a rare and aggressive lymphoid malignancy, most often representing diffuse large B-cell lymphoma histologically. Tumor-associated macrophages and tumor-infiltrating lymphocytes have been associated with survival in diffuse large B-cell lymphoma, but their prognostic impact in primary testicular lymphoma is unknown. Here, we aimed to identify macrophages, their immunophenotypes and association with lymphocytes, and translate the findings into survival of patients with primary testicular lymphoma. We collected clinical data and tumor tissue from 74 primary testicular lymphoma patients, and used multiplex immunohistochemistry and digital image analysis to examine macrophage markers (CD68, CD163, and c-Maf), T-cell markers (CD3, CD4, and CD8), B-cell marker (CD20), and three checkpoint molecules (PD-L1, PD-L2, and PD-1). We demonstrate that a large proportion of macrophages (median 41%, range 0.08-99%) and lymphoma cells (median 34%, range 0.1-100%) express PD-L1. The quantity of PD-L1+CD68+ macrophages correlates positively with the amount of PD-1+ lymphocytes, and a high proportion of either PD-L1+CD68+ macrophages or PD-1+CD4+ and PD-1+CD8+ T-cells translates into favorable survival. In contrast, the number of PD-L1+ lymphoma cells or PD-L1- macrophages do not associate with outcome. In multivariate analyses with IPI, PD-L1+CD68+ macrophage and PD-1+ lymphocyte contents remain as independent prognostic factors for survival. In conclusion, high PD-L1+CD68+ macrophage and PD-1+ lymphocyte contents predict favorable survival in patients with primary testicular lymphoma. The findings implicate that the tumor microenvironment and PD-1. PD-L1 pathway have a significant role in regulating treatment outcome. They also bring new insights to the targeted therapy of primary testicular lymphoma.Peer reviewe