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Purpose: Sinonasal tract diffuse large B‐cell lymphoma (SNT‐DLBCL), a rare extranodal lymphoma, is not well characterized. We performed a population‐based study to determine cell‐of‐origin, clinical presentation and impact of rituximab (R) and central nervous system (CNS) directed chemotherapy on survival. Patients and methods: Patients with SNT‐DLBCL were identified from pathology databases. Clinical information was collected and outcomes between different treatment modalities evaluated. Results: Thirty‐two percent of the patients had germinal centre B‐cell phenotype. Forty‐six patients were treated with curative intent using CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP‐like chemotherapy, 21 (46%) before and 25 (54%) in the R‐era. Additionally, 24 (52%) received CNS‐directed chemotherapy. Addition of R to chemotherapy reduced the risk of progression (RR = 0.368, 95% CI 0.138‐0.976, P = 0.045) and death (RR = 0.245, 95% CI 0.068‐0.883, P = 0.032), and translated into better survival (5‐year PFS, 67% vs 38%, P = 0.037; 5‐year OS, 81% vs 48%, P = 0.020). CNS‐directed chemotherapy reduced the risk of progression (RR = 0.404, 95% CI 0.159‐1.029, P = 0.057) and death (RR = 0.298, 95% CI 0.093‐0.950, P = 0.041), and translated into favorable survival (5‐year PFS, 67% vs 32%, P = 0.050; 5‐year OS 82% vs 43%, P = 0.030). Conclusion: Patients with SNT‐DLBCL benefit from rituximab and CNS‐directed chemotherapy. [ABSTRACT FROM AUTHOR]

Syndecan-1 is a multifunctional transmembrane heparan sulphate proteoglycan (HSPG) that is present on a variety of cell types. The extracellular syndecan domains can be shed from the cell surface in a highly regulated process called ectodomain shedding. We studied the influence of soluble syndecan-1 on outcome in 88 small cell lung cancer (SCLC) patients treated within the context of two randomised clinical trials with platinum-based therapy. Serum syndecan-1 concentrations were determined using enzyme-linked immunosorbent assay (ELISA) from sera taken prior to initiation of chemotherapy. Patients with the serum syndecan-1 level within the highest tertile (>212 μg/l) had only 38% 1-year and 3% 2-year survival, whereas 58% of those with a lower serum level survived for 1 year and 25% for 2 years following the diagnosis (P=0.0034). A high serum syndecan-1 level (>212 μg/l) was associated with a high pretreatment lactate dehydrogenase (LDH) level (P=0.0024) and a poor Karnofsky''s performance status (P=0.021), but not with the clinical stage or the presence of distant metastases at diagnosis. A high serum syndecan-1 level had independent influence on survival also in a multivariate analysis (the relative risk, RR, 1.68; 95% CI, 1.02–2.77; P=0.044) together with the clinical stage (RR, 1.72; 95% CI, 1.05–2.82; P=0.032). We conclude that high pretreatment serum syndecan-1 level is associated with poor prognosis in SCLC treated with platinum-based chemotherapy. [Copyright &y& Elsevier]

c-Jun/AP-1 activation has been implicated in various, often opposing cellular responses. For example, although there is considerable evidence that c-Jun activation can be a positive step in the events leading a cell towards apoptosis, there are also many reports stating the opposite: that under certain circumstances c-Jun can inhibit apoptosis and promote proliferation or differentiation instead – and that these responses are important for normal mammalian development. It is clear that the effects of c-Jun on cellular responses depend strongly on the cell type and the context of other regulatory influences that the cell is receiving. This review focuses on recent developments in understanding how activation of JNK and c-Jun contributes to different cellular responses. [ABSTRACT FROM AUTHOR]

The two MAP kinases JNK and ERK direct distinct cellular activities even though they share a number of common substrates, including several transcription factors. Here we have compared JNK and ERK signalling during PC12 cell differentiation and investigated how activation of c-Jun by the MAPKs contributes to this cellular response. Exposure to nerve growth factor, or expression of constitutively active MEK1—two treatments which cause differentiation of PC12 cells into a neuronal phenotype—result in activation of ERK-type MAP kinases and phosphorylation of c-Jun on several sites including Ser63 and Ser73. Constitutively activated c-Jun, which mimics the MAPK-phosphorylated form of the protein, can induce neuronal differentiation of PC12 cells independently of upstream signals. Conversely, expression of dominant-negative c-JunbZIP prevents neurite outgrowth induced by activated MEK1. Activation of MEKK1, which stimulates the JNK pathway, is not sufficient for PC12 cell differentiation but can induce apoptosis. However, neurite outgrowth is triggered when c-Jun is co-expressed with activated MEKK1 or SEK1. Consistently, MEK-induced ERK activation in PC12 cells induces c-Jun expression, while JNK signalling does not. Therefore, dual input of expression and phosphorylation of c-Jun provided by the ERK pathway is required to direct neuronal differentiation in PC12 cells. [ABSTRACT FROM AUTHOR]

Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT. The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II–IV mantle cell lymphoma, aged 18–65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m2 on day 1, intravenous doxorubicin 50 mg/m2 on day 1, intravenous vincristine 1·4 mg/m2 on day 1, and oral prednisone 100 mg on days 1–5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1–4, intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1–19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov , NCT02858258. Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84–92) versus 72% (67–79; hazard ratio 0·52 [one-sided 98·3% CI 0–0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67–79) versus 86% (82–91; hazard ratio 1·77 [one-sided 98·3% CI 0–3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3–5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3–5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238). Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined. Janssen and Leukemia & Lymphoma Society. [ABSTRACT FROM AUTHOR]

Outcomes for patients with non-Hodgkin's lymphoma (NHL) that proves refractory to treatment remain poor. Treatment of such patients is individualized and can include enrolment in a clinical trial of novel agents or use of one of a wide array of drug regimens. Initial treatment with anthracyclines such as doxorubicin limits options at later stages of treatment because of anthracycline-related cumulative cardiotoxicity. The aza-anthracenedione pixantrone was developed to reduce the likelihood of cardiotoxicity without compromising efficacy and is currently conditionally approved for use as monotherapy in patients with multiply-relapsed or refractory aggressive B cell NHL. The use of pixantrone in combination therapy, often to replace doxorubicin or mitoxantrone, has or is currently being investigated in numerous studies in patients with aggressive or indolent NHL and is the focus of this review. These include the R-CPOP regimen (rituximab, cyclophosphamide, pixantrone, vincristine, prednisone) for aggressive NHL in the first-line setting, including a study in elderly patients with limited cardiac function, and for patients with relapsed NHL with prior anthracycline exposure; the PSHAP regimen (pixantrone, cytarabine, prednisone, cisplatin), also in the latter setting; the PREBen/PEBen regimen (pixantrone, bendamustine and etoposide with or without rituximab) as salvage therapy; and pixantrone in combination with fludarabine, dexamethasone, and rituximab (FPD-R) for relapsed indolent NHL. [ABSTRACT FROM AUTHOR]

The article focuses on the intra-patient evolution of the tumor microenvironment (TME) in treatment-naive metastatic melanoma patients. Topics discussed include the heterogeneity of TME between primary and metastatic tumors, differential gene expression profiles, and the potential implications for predicting immunotherapy responsiveness.

MAPK-dependent activation of AP-1 protein c-Jun is involved in PC12 cell differentiation and apoptosis. However, the role of other AP-1 proteins and their connection to MAPKs during growth, differentiation and apoptosis has remained elusive. Here we studied the activation of AP-1 proteins in response to ERK, JNK, and p38 signaling upon NGF, EGF and anisomycin exposures. All treatments caused different kinetics and strength of MAPK and AP-1 activities. NGF induced persistent ERK and AP-1 activities, whereas upon EGF and anisomycin exposures, their activities were only weakly and transiently induced. The sustained AP-1 activity was associated with concomitant c-Fos and c-Jun expression and phoshorylation, which were JNK and ERK dependent. While inhibition of the ERK, JNK, and p38 activities partially prevented AP-1 activity and suppressed differentiation, none of them was required for anisomycin-induced apoptosis. The importance of c-Fos and c-Jun as mediators of differentiation was demonstrated by the findings that the corresponding siRNAs suppressed NGF-induced neurite outgrowth. However, the capacity of c-Fos to promote differentiation required cooperation with Jun proteins. In contrast, Fra-2 expression was not required for the differentiation response. Together, the results show that sustained c-Jun and c-Fos activities mediate MAPK signaling and are essential for differentiation of PC12 cells. J. Cell. Physiol. 210: 538–548, 2007. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Simple Summary: Testicular diffuse large B-cell lymphoma (T-DLBCL) is a rare and aggressive lymphoma entity that mainly affects elderly men. It has a high relapse rate with especially the relapses of the central nervous system associating with dismal outcome. T-DLBCL has a unique biology with distinct genetic characteristics and clinical presentation, and the increasing knowledge on the tumor microenvironment of T-DLBCL highlights the significance of the host immunity and immune escape in this rare lymphoma, presenting in an immune-privileged site of the testis. This review provides an update on the latest progress made in T-DLBCL research and summarizes the clinical perspectives in T-DLBCL. Primary testicular lymphoma is a rare lymphoma entity, yet it is the most common testicular malignancy among elderly men. The majority of the cases represent non-germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL) with aggressive clinical behavior and a relatively high relapse rate. Due to the rareness of the disease, no randomized clinical trials have been conducted and the currently recognized standard of care is based on retrospective analyses and few phase II trials. During recent years, the tumor microenvironment (TME) and tumor-related immunity have been the focus of many tumor biology studies, and the emergence of targeted therapies and checkpoint inhibitors has significantly modulated the field of cancer therapies. Testicular DLBCL (T-DLBCL) is presented in an immune-privileged site of the testis, and the roles of NF-κB pathway signaling, 9p24.1 aberrations, and tumor-infiltrating immune cells, especially immune checkpoint expressing lymphocytes and macrophages, seem to be unique compared to other lymphoma entities. Preliminary data on the use of immune checkpoint inhibitors in the treatment of T-DLBCL are promising and more studies are ongoing. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The epigenome plays a key role in cancer heterogeneity and drug resistance. Hence, a number of epigenetic inhibitors have been developed and tested in cancers. The major focus of most studies so far has been on the cytotoxic effect of these compounds, and only few have investigated the ability to revert the resistant phenotype in cancer cells. Hence, there is a need for a systematic methodology to unravel the mechanisms behind epigenetic sensitization. Results: We have developed a high-throughput protocol to screen non-simultaneous drug combinations, and used it to investigate the reprogramming potential of epigenetic inhibitors. We demonstrated the effectiveness of our protocol by screening 60 epigenetic compounds on diffuse large B-cell lymphoma (DLBCL) cells. We identified several histone deacetylase (HDAC) and histone methyltransferase (HMT) inhibitors that acted synergistically with doxorubicin and rituximab. These two classes of epigenetic inhibitors achieved sensitization by disrupting DNA repair, cell cycle, and apoptotic signaling. The data used to perform these analyses are easily browsable through our Results Explorer. Additionally, we showed that these inhibitors achieve sensitization at lower doses than those required to induce cytotoxicity. Conclusions: Our drug screening approach provides a systematic framework to test non-simultaneous drug combinations. This methodology identified HDAC and HMT inhibitors as successful sensitizing compounds in treatment-resistant DLBCL. Further investigation into the mechanisms behind successful epigenetic sensitization highlighted DNA repair, cell cycle, and apoptosis as the most dysregulated pathways. Altogether, our method adds supporting evidence in the use of epigenetic inhibitors as sensitizing agents in clinical settings. [ABSTRACT FROM AUTHOR]

The article presents a study which examined the therapeutic efficacy of allogeneic haemotopoietic stem cell transplantation (allo-SCT) in patients with cutaneous T-cell lymphomas (CTCL). The variables considered include demographic data and previous treatments, media age of the patients, and the number of patients who received grafts. The possibility of death or chronic graft-versus-host disease (GVHD) in patients treated with allo-SCT is discussed.

Motivation DNA methylation aberrations are common in many cancer types. A major challenge hindering comparison of patient-derived samples is that they comprise of heterogeneous collection of cancer and microenvironment cells. We present a computational method that allows comparing cancer methylomes in two or more heterogeneous tumor samples featuring differing, unknown fraction of cancer cells. The method is unique in that it allows comparison also in the absence of normal cell control samples and without prior tumor purity estimates, as these are often unavailable or unreliable in clinical samples. Results We use simulations and next-generation methylome, RNA and whole-genome sequencing data from two cancer types to demonstrate that the method is accurate and outperforms alternatives. The results show that our method adapts well to various cancer types and to a wide range of tumor content, and works robustly without a control or with controls derived from various sources. Availability and implementation The method is freely available at https://bitbucket.org/anthakki/dmml. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Sinonasally located lymphoid malignancies are rare lesions with first symptoms similar to other obstructive conditions. Additionally, they often coexist with nasal inflammation and mucosal necrosis. Therefore, time from the first symptoms to diagnosis tends to be long. Awareness and early diagnosis of this disease entity could improve treatment outcome. Altogether, 142 patients with sinonasal or nasopharyngeal (i.e. sinonasal tract, SNT) lymphoid malignancies, diagnosed and treated at the Helsinki University Hospital, during a 39-year period from 1975 to 2013, were retrospectively reviewed. There were 90 males (63 %) and 52 females (37 %) with a median age of 64 years (range 26-92). Eighty-four percent of the patients had primary diseases and 16 % had relapses of lymphoid malignancies primarily diagnosed at other locations. The mean duration of symptoms prior to diagnosis was 4.8 months (range 0.5-24). The most common histological entity was diffuse large B-cell lymphoma (43 %), followed by plasmacytoma (18 %). The most common location was nasopharynx (58 %) followed by nasal cavity (44 %) and paranasal sinuses (35 %). Sixty-nine percent of the lesions were at a single anatomic location of the sinonasal tract. Fifty-two percent of the cases were of Ann Arbor Stage I. Lymphoid malignancies form an important and diverse group in the differential diagnosis of SNT tumours. They most often present with general obstructive nasal symptoms due to tumour location. Most of them are primary lesions, highlighting the importance of an accurate diagnosis as early as possible. [ABSTRACT FROM AUTHOR]

The article offers information on the identification of homozygous deletion in aggrecan (ACAN gene) and other candidate variants in classical Hodgkin lymphoma by exome sequencing. Topics discussed include aetiology of classical Hodgkin lymphoma (CHL), role in CHL tumourigenesis, and association of Epsteinâ€Barr virus (EBV) infection with CHL.

We evaluated the predictive value of interim positon emission tomography (I-PET) after one course of chemoimmunotherapy in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). One hundred and twelve patients with DLBCL were enrolled. All patients had PET/computed tomography (CT) scans performed after one course of chemotherapy (PET-1). I-PET scans were categorized according to International Harmonization Project criteria (IHP), Deauville 5-point scale (D 5PS) with scores 1-3 considered negative (D 5PS > 3) and D 5PS with scores 1-4 considered negative (D 5PS = 5). Ratios of tumor maximum standardized uptake value (SUVmax) to liver SUVmax were also analyzed. We found no difference in progression-free survival (PFS) between PET-negative and PET-positive patients according to IHP and D 5PS > 3. The 2-year PFS using D 5PS = 5 was 50.9% in the PET-positive group and 84.8% in the PET-negative group ( p = 0.002). A tumor/liver SUVmax cut-off of 3.1 to distinguish D 5PS scores of 4 and 5 provided the best prognostic value. PET after one course of chemotherapy was not able to safely discriminate PET-positive and PET-negative patients in different prognostic groups. [ABSTRACT FROM AUTHOR]

Translocations affecting both MYC and BCL2 are associated with a poor prognosis in diffuse large B-cell lymphomas. We have examined genetic aberrations combined with analyses of protein expression of respective gene products. Fluorescence in situ hybridization (FISH) for translocations of BCL2 and MYC and del17p13 was performed. Immunohistochemistry analyses included BCL2, MYC and TP53 protein expression. Sixty-seven patients with high-risk DLBCL participating in a prospective multicenter study were included. Six patients with simultaneous translocations of BCL2 and MYC had impaired overall (OS) ( p = 0.009) and progression-free survival (PFS) ( p = 0.009). Six patients with high coexpression of MYC and BCL2 proteins also had impaired OS ( p = 0.004) and PFS ( p = 0.002). Combining these groups identified nine patients with impaired OS ( p = 0.004) and PFS ( p = 0.005). Sixteen patients had double-hit translocation or protein expression and/or del17p13 and/or high TP53. This combined endpoint was associated with impaired OS ( p = 0.008) and PFS ( p = 0.036), and identified 70% of all deaths. [ABSTRACT FROM AUTHOR]

Background: Despite improved survival for the patients with diffuse large B-cell lymphoma (DLBCL), the prognosis after relapse is poor. The aim was to identify molecular events that contribute to relapse and treatment resistance in DLBCL. Methods: We analysed 51 prospectively collected pretreatment tumour samples from clinically high risk patients treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis with high resolution array comparative genomic hybridization (aCGH) and gene expression microarrays. Major finding was validated at the protein level immunohistochemically in a trial specific tissue microarray series of 70, and in an independent validation series of 146 patients. Results: We identified 31 genes whose expression changes were strongly associated with copy number aberrations. In addition, gains of chromosomes 2p15 and 18q12.2 were associated with unfavourable survival. The 2p15 aberration harboured COMMD1 gene, whose expression had a significant adverse prognostic impact on survival. Immunohistochemical analysis of COMMD1 expression in two series confirmed the association of COMMD1 expression with poor prognosis. Conclusion: COMMD1 is a potential novel prognostic factor in DLBCLs. The results highlight the value of integrated comprehensive analysis to identify prognostic markers and genetic driver events not previously implicated in DLBCL. Trial Registration: ClinicalTrials.gov NCT01502982 [ABSTRACT FROM AUTHOR]

Objectives To determine whether serum vascular endothelial growth factor (s- VEGF) levels and VEGF gene expression in tumor tissue predict survival of diffuse large B-cell lymphoma ( DLBCL) patients treated with chemoimmunotherapy. Methods VEGF levels were measured in serum samples from 102 patients <65 yrs with high-risk DLBCL using a quantitative sandwich enzyme immunoassay technique. Exon array data set of tumor tissues from 32 patients was concurrently used to determine VEGF-A exon and gene expression. All patients were treated in a Nordic phase II study with six dose-dense chemoimmunotherapy courses followed by systemic central nervous system prophylaxis. Results After a median follow-up time of 40 months, 3-yr progression-free survival ( PFS) was inferior in patients with high s- VEGF levels compared to those with low levels (59% vs. 83%, P = 0.005). The relative risk of progression or relapse was 3.1-fold (95% confidence interval 1.34-6.91, P = 0.008). The predictive capacity of s- VEGF levels on PFS was most pronounced in the DLBCLs of non-germinal center subtype. In contrast to serum data, VEGF mRNA expression in the lymphoma tissue did not predict outcome, and no correlation was found between s- VEGF levels and lymphoma VEGF expression. Conclusion Pretreatment s- VEGF level is a predictor of PFS after chemoimmunotherapy and may help to further stratify high-risk DLBCL patients into low- and high-risk groups. [ABSTRACT FROM AUTHOR]

Male gender is an adverse prognostic factor in Hodgkin's lymphoma, but no such association has yet been established in non-Hodgkin lymphomas. Here, we have evaluated whether gender has prognostic impact on the survival of patients with B-cell non-Hodgkin lymphoma in the postrituximab era of lymphoma therapies. The study populations consisted of 217 diffuse large B-cell lymphoma (DLBCL) and 110 follicular lymphoma (FL) patients treated with immunochemotherapy. Hundred and sixty chemotherapy-treated DLBCL patients served as a control group. According to Kaplan-Meier analyses, female patients had a significantly better progression-free survival than men both in DLBCL (4 yr PFS 75% vs. 60%; P = 0.013) and in FL (4 yr PFS 68% vs. 52%, P = 0.036) patients treated with immunochemotherapy. In chemotherapy-treated DLBCL patients, no difference in survival between the genders was found. The results support the idea that women seem to respond better to rituximab. [ABSTRACT FROM AUTHOR]

Background: Tumour-infiltrating mast cells (MCs) can remodel tumour microenvironment and growth by suppressing immune responses and potentiating angiogenesis. Furthermore, accumulation of MCs in follicular lymphoma (FL) correlates with unfavourable prognosis after immunochemotherapy. Here we investigated whether tumour vascularity is associated with MC content and outcome in FL patients treated with immunochemotherapy. Patients and methods: Microvessel density (MVD) and MC content were determined immunohistochemically from pretreatment samples of 95 FL patients using CD31, CD34 and mast cell tryptase antibodies. Gene expression data from a separate set of 24 FL patients were analysed for comparison. All patients were treated with the combination of rituximab (R) and cyclophoshamide-doxorubicin–vincristine–prednisone (CHOP) chemotherapy. Results: Increased CD31+ MVD correlated positively with the number of tumour infiltrating MCs and CD34+ vessels, and negatively with the outcome. Overall survival and progression-free survival were significantly better among patients with low CD31+ MVDs. In multivariate analyses, CD31+ MVD had prognostic value independently of Follicular Lymphoma Prognostic Index but not of MC content. Consistent with the immunohistochemical data, high CD31/PECAM1 mRNA levels were associated with adverse outcome. Conversely, a positive prognostic impact of VEGF mRNA expression on the outcome was found. Conclusion: Vascularity is associated with MC content and outcome in R-CHOP-treated FL patients. [Copyright &y& Elsevier]

We have previously shown that expression of CD40 has a favorable prognostic impact in diffuse large B-cell lymphoma (DLBCL) after anthracycline-based chemotherapy. Here we examined the prognostic value of immunohistochemically defined CD40 expression in 95 patients with DLBCL treated with both anthracycline-based chemotherapy and rituximab. Using a 10% cut-off level, 77% of the patients had CD40-positive tumors and showed a superior overall survival ( p = 0.02 log-rank, hazard ratio 0.35, 95% CI 0.14–0.88, p = 0.03 Cox regression). When adjusted for International Prognostic Index in multivariate analysis, CD40 was not an independent prognostic factor (hazard ratio 0.39, 95% CI 0.15–1.04, p = 0.06 Cox regression). However, even after the introduction of immunochemotherapy, CD40 has a potential prognostic impact in DLBCL. Additional and larger studies are necessary, regarding the immunohistochemical robustness of CD40 and the biological mechanisms that contribute to the superior prognosis in CD40-expressing DLBCL. [ABSTRACT FROM AUTHOR]

Objectives: Non-germinal center (non-GC) phenotype, high level expression of the transcription factor forkhead box protein P1 (FOXP1) and anti-apoptotic protein Bcl-2 have been identified as unfavorable prognostic factors for diffuse large B-cell lymphoma (DLBCL) patients treated with chemotherapy. Our aim was to re-evaluate the prognostic impact of these biologic factors on the survival of the patients treated with immunochemotherapy. Methods: Expression of Bcl-2 and FOXP1, and cell of origin based on the Hans algorithm were determined immunohistochemically from samples of 117 de novo DLBCL patients treated with R-CHOP and R-CHOEP regimens, and correlated with clinical data. Results: Consistent with our previous studies, no significant difference in 2-yr survival rates between the GC- and non-GC phenotypes was found. Both FOXP1 and Bcl-2 expression were associated with the non-GC phenotype. For all patients, no prognostic impact of FOXP1 positivity on survival was observed. However, Bcl-2 negative patients had a better survival as compared to Bcl-2 positive patients [failure free survival (FFS) 97% vs. 71%, P = 0.001 and overall survival (OS) 97% vs. 82%, P = 0.034]. When Bcl-2 related survival was analyzed in the GC- and non-GC subgroups, a significant prognostic effect of Bcl-2 on FFS was seen only in the non-GC group of patients (positive 65% vs. negative 100%, P = 0.011). A trend for the difference in OS was also observed (positive 84% vs. negative 100%, P = 0.082). Conclusions: The data demonstrate that expression of Bcl-2 and FOXP1 is associated with the non-GC phenotype, but only Bcl-2 expression continues to be of prognostic significance in DLBCL patients treated with immunochemotherapy. [ABSTRACT FROM AUTHOR]

EGF-R regulates cell proliferation, migration, and invasion in fibroblasts. However, the connection of EGF-R with downstream signaling pathways mediating these responses has remained elusive. Here we provide genetic and biochemical evidence that EGF-R- and AP-1-mediated signals are required for MMP expression and collagen contraction in fibroblasts. In EGF-R (-/-) mouse embryonal fibroblasts, basal and inducible expression of several MMPs, including MMP-2, -3, and -14 is impaired in comparison to wild-type counterparts. The loss of MMP expression is associated with a suppression of EGF-induced Erk and Jnk activities, and AP-1 DNA-binding and transactivation capacities. While inhibition of Jnk mainly prevents EGF-induced phosphorylation of c-Jun, inhibition of Erk pathway suppresses both the expression and phosphorylation of c-Jun and c-Fos proteins. Moreover, the expression of MMP-3 and -14, and collagen contraction is partially prevented by Mek/Erk and Jnk inhibitors. However, Jnk inhibitor also suppresses cell growth independently of EGF-R activity. The central role of AP-1 as a mediator of EGF-R signaling in fibroblasts is emphasized by the finding that expression of a dominant negative c-Jun downregulates the expression of MMP-3. Conversely, expression of a constitutively active Mek1 can induce MMP-3 expression independently of upstream signals. The results indicate that ERK pathway and AP-1 are downstream effectors of the EGF-R-mediated MMP-3 expression and collagen contraction in fibroblasts. J. Cell. Physiol. 212: 489–497, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Rituximab in combination with chemotherapy (immunochemotherapy) is one of the most effective treatments available for follicular lymphoma (FL). This study aimed to determine whether differences in gene expression in FL tissue correlate with outcome in response to rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy (R–CHOP). We divided 24 patients into long- [time to treatment failure (TTF) >35 months] and short-term (TTF <23 months) responders, and analysed the gene expression profiles of lymphoma tissue using oligonucleotide microarrays. We used a supervised learning technique to identify genes correlating with outcome, and confirmed the expression of selected genes with quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Among the transcripts with a high correlation between microarray and qPCR analyses, we identified EPHA1, a tyrosine kinase involved in transepithelial migration, SMAD1, a transcription factor and a mediator of bone morphogenetic protein and transforming growth factor- β signalling, and MARCO, a scavenger receptor on macrophages. According to Kaplan–Meier estimates, high EPHA1, and low SMAD1 and MARCO expression were associated with better progression-free survival (PFS). Immunohistochemistry showed that EphA1 was primarily localised in granulocytes. In addition, both EphA1 and Smad1 were expressed in vascular endothelia. However, no difference in vasculature was detected between long- and short-term responders. In a validation set of 40 patients, a trend towards a better PFS was observed among patients with high EphA1 expression. We conclude that gene expression in non-malignant cells contributes to clinical outcome in R–CHOP-treated FL patients. [ABSTRACT FROM AUTHOR]

Abstract: Mitogen-activated protein kinases (MAPKs) have been implicated as regulators of cellular differentiation. The biological effect of MAPK signaling in the nucleus is achieved by signal-responsive transcription factors. Here, we have investigated the connection of MAPKs, transcription factor AP-1, and α2β1 integrin expression in K562 cells undergoing differentiation along the megakaryocytic pathway. We report that three distinct MAPKs, ERK, JNK, and p38, are activated during the TPA-induced megakaryocytic differentiation. Activation of MAPK pathways is followed by acquisition of the AP-1 DNA-binding and transactivation capacities. AP-1 DNA-binding activity consists primarily of JunD, c-Fos, and Fra-1, and is accompanied with the increased expression and phosphorylation of these subunits. While inhibition of JNK mainly prevents expression and phosphorylation of JunD and c-Jun, inhibition of the ERK pathway suppresses both phosphorylation and expression of Jun proteins, and expression of c-Fos and Fra-1. Furthermore, only the activity of the ERK pathway is essential for the differentiation response, as determined by expression of α2β1 (CD49b) integrin. The importance of AP-1 as a mediator ERK signaling during differentiation is demonstrated by the findings that expression of c-fos siRNA and dominant negative AP-1/c-JunbZIP downregulate the TPA- and ERK-induced expression of α2β1 integrin mRNAs and proteins. Conversely, coexpression of JunD or c-Jun and c-Fos can induce α2β1 integrin expression independently of upstream signals. Taken together, the results show that AP-1 is a nuclear target of the ERK-pathway and mediates α2β1 integrin expression during megakaryocytic differentiation of K562 cells. [Copyright &y& Elsevier]

Simple Summary: Soluble forms of checkpoint protein PD-1 and its ligand PD-L1 can be measured from circulation, but their source, function, and clinical impact in cancer remain incompletely understood. In this study, we used serum samples collected during a conduction of a prospective immunochemotherapy trial in patients with high-risk diffuse large B-cell lymphoma (DLBCL) and assessed their clinical significance. Our results demonstrate that sPD-1 levels in the peripheral blood at the time of diagnosis correlate with the quantities of tumor infiltrating PD1+ T cells and translate to inferior survival. To our knowledge, this is the first study to identify sPD-1 as a prognostic factor, providing interesting perspectives on future clinical trials in DLBCL, including patients' stratification associated with checkpoint blockade. Interaction of checkpoint receptor programmed death 1 (PD-1) with its ligand 1 (PD-L1) downregulates T cell effector functions and thereby leads to tumor immune escape. Here, we aimed to determine the clinical significance of soluble PD-1 (sPD-1) and soluble PD-L1 (sPD-L1) in patients with diffuse large B-cell lymphoma (DLBCL). We included 121 high-risk DLBCL patients treated in the Nordic NLG-LBC-05 trial with dose-dense immunochemotherapy. sPD-1 and sPD-L1 levels were measured from serum samples collected prior to treatment, after three immunochemotherapy courses, and at the end of therapy. sPD-1 and sPD-L1 levels were the highest in pretreatment samples, declining after three courses, and remaining low post-treatment. Pretreatment sPD-1 levels correlated with the quantities of PD1+ T cells in tumor tissue and translated to inferior survival, while no correlation was observed between sPD-L1 levels and outcome. The relative risk of death was 2.9-fold (95% CI 1.12–7.75, p = 0.028) and the risk of progression was 2.8-fold (95% CI 1.16–6.56, p = 0.021) in patients with high pretreatment sPD-1 levels compared to those with low levels. In conclusion, pretreatment sPD-1 level is a predictor of poor outcome after dose-dense immunochemotherapy and may be helpful in further improving molecular risk profiles in DLBCL. [ABSTRACT FROM AUTHOR]

Primary mediastinal large B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL) accounting for 2% to 4% of all non-Hodgkin lymphomas. We report a family of 3 siblings with PMBCL and their cousin with extranodal DLBCL. The histopathological characteristics of lymphomas of all 4 patients are similar, implying post-germinal center differentiation and growth deregulation by other mechanisms than BCL2-mediated inhibition of apoptosis and suggesting a shared biological background. We aimed to identify the genetic defect underlying lymphorna susceptibility in this family using exome sequencing and linkage analysis. The only variant segregating in all 4 patients and not reported in genetic databases was 5533C>A (His1845Asn) in the MLL gene. To our knowledge, this is the first time when familial clustering of PMBCL is reported. Although we propose MLL as a candidate predisposition gene for this condition, this finding needs to be validated in additional cases. [ABSTRACT FROM AUTHOR]

Low absolute lymphocyte counts (ALC) and high absolute monocyte counts (AMC) are associated with poor survival in patients with diffuse large B-cell lymphoma (DLBCL). We studied the prognostic impact of the ALC and AMC in patients with testicular DLBCL (T-DLBCL). T-DLBCL patients were searched using Southern Finland University Hospital databases and the Danish lymphoma registry. The progression free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox proportional hazards methods. We identified 178 T-DLBCL patients, of whom 78 (44%) had a low ALC at diagnosis. The ALC did not correlate with survival in the whole cohort. However, among the patients treated with rituximab (R) containing regimen, a pre-therapeutic low ALC was associated with an increased risk of progression (HR 1.976, 95% CI 1.267–3.086, p = 0.003). Conversely, intravenous (iv) CNS directed chemotherapy translated to favorable outcome. In multivariate analyses, the advantage of an iv CNS directed chemotherapy was sustained (PFS, HR 0.364, 95% CI 0.175–0.757, p = 0.007). The benefit of R and intravenous CNS directed chemotherapy was observed only in non-lymphopenic patients. The AMC did not correlate with survival. A low ALC is an adverse prognostic factor in patients with T-DLBCL. Alternative treatment options for lymphopenic patients are needed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Peripheral T-cell lymphomas (PTCL) are a heterogeneous, and often aggressive group of non-Hodgkin lymphomas. Recent advances in the molecular and genetic characterization of PTCLs have helped to delineate differences and similarities between the various subtypes, and the JAK/STAT pathway has been found to play an important oncogenic role. Here, we aimed to characterize the JAK/STAT pathway in PTCL subtypes and investigate whether the activation of the pathway correlates with the frequency of STAT gene mutations. Patient samples from AITL (n = 30), ALCL (n = 21) and PTCL-NOS (n = 12) cases were sequenced for STAT3, STAT5B, JAK1, JAK3, and RHOA mutations using amplicon sequencing and stained immunohistochemically for pSTAT3, pMAPK, and pAKT. We discovered STAT3 mutations in 13% of AITL, 13% of ALK+ ALCL, 38% of ALK− ALCL and 17% of PTCL-NOS cases. However, no STAT5B mutations were found and JAK mutations were only present in ALK- ALCL (15%). Concurrent mutations were found in all subgroups except ALK+ ALCL where STAT3 mutations were always seen alone. High pY-STAT3 expression was observed especially in AITL and ALCL samples. When studying JAK-STAT pathway mutations, pY-STAT3 expression was highest in PTCLs harboring either JAK1 or STAT3 mutations and CD30+ phenotype representing primarily ALK− ALCLs. Further investigation is needed to elucidate the molecular mechanisms of JAK-STAT pathway activation in PTCL. [ABSTRACT FROM AUTHOR]