Claudin 6 is associated with a short survival and a short recurrent free interval in non-small cell lung carcinoma.

We investigated the expression of claudin 6 in non-small-cell lung carcinomas (NSCLC) by immunohistochemistry. Samples of 164 patients with NSCLC were studied by immunohistochemistry. Claudin 6 was expressed in 42 % of cases. Its expression was significantly more frequent in adeno- than in squamous cell carcinoma (p = 0.002). There was no association between the TNM status and claudin 6 expression. Claudin 6 associated with a poor prognosis of the patients and with a short recurrence-free interval (p = 0.002, p < 0.001). The association with survival had independent prognostic value (p = 0.011). The results show that claudin 6 can be regarded as a marker of poor prognosis in lung cancer. This is different to some other cancers, such as breast and cervical carcinoma suggesting that claudin 6 probably induces other cellular pathways in neoplastic lung cells than in those tumors. In lung cancer, adenocarcinomas were most abundantly positive indicating a higher linkage of claudin 6 to glandular differentiation.

Prognostic significance of Twist, ZEB1 and Slug in peripheral T-cell lymphomas.

ABSTRACT Objectives: To investigate the protein expression of the epithelial-mesenchymal transition-inducing transcription factors (TFs) Twist, ZEB1 and Slug in peripheral T-cell lymphomas (PTCL) and their correlation with clinical parameters. Methods: The expression of these TFs was studied in 53 diagnostic biopsy specimens of several different PTCL subtypes with immunohistochemistry. Patient data were retrospectively collected from patient records and a statistical analysis was performed. Results: All three TFs were widely expressed. ZEB1 and Slug had correlations with clinical outcome. In all PTCL cases, high nuclear ZEB1 percentage correlated with a favorable progression-free survival (PFS) (3-year PFS: 70% vs. 34%; P = 0.010) and strong nuclear Slug intensity correlated with an unfavorable PFS (3-year PFS: 17% vs. 62%; P = 0.036). Discussion: The correlations between PFS and ZEB1 or Slug protein expression have not previously been established in PTCLs. The impact of ZEB1 and Slug expression on prognosis differed from our findings in DLBCL and the impact of ZEB1 expression was in line with current studies on mycosis fungoides and sézary syndrome. The findings may be explained by the roles these TFs play in hematopoiesis. Conclusion: ZEB1 and Slug may have potential clinical value for evaluating prognosis in PTCLs. The study size was small and heterogenous, and larger studies are warranted.

Cytoplasmic Mineralocorticoid Receptor Expression Predicts Dismal Local Relapse-free Survival in Non-triple-negative Breast Cancer.

BACKGROUND/AIM: The aim of the study was to investigate the prognostic role of androgen receptor (AR), mineralocorticoid receptor (MR) and glucocorticoid receptor ß (GRß) expression in HER-2 negative breast cancer patients. MATERIALS AND METHODS: The study population (n=152) was enriched with triple-negative breast cancers (TNBC) (n=96; 63.2%). The median follow-up time was 100 months. AR, MR and GRß immunocytochemical staining was compared with that of epithelial-mesenchymal transition (EMT) markers (vimentin, SIP1, ZEB1). RESULTS: High expression of cytoplasmic MR was associated with dismal local relapse-free survival (RR=13.923; 95%CI=1.071-181.045; p=0.044) in tumours with non-TNBC phenotype. AR and GRß were more frequently expressed in ER+/PR+/HER2- tumours, while cytoplasmic MR was more often expressed in TNBC tumours (for all, p<0.0005). GRß and AR were associated with decreased vimentin expression (p<0.005), indicating their association with attenuated EMT. CONCLUSION: Cytoplasmic MR expression is a strong predictor of local recurrence in non-metastatic breast cancer patients with non-TNBC tumour phenotype.

Alterations in the expression of EMT-related proteins claudin-1, claudin-4 and claudin-7, E-cadherin, TWIST1 and ZEB1 in oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is a chronic T-cell-mediated inflammatory disease, which is associated with increased risk of developing oral squamous cell carcinoma. Epithelial-to-mesenchymal transition is a physiological phenomenon occurring during growth and organogenesis, but it has also an important role in tumorigenesis. In the present work, we studied the expression of known epithelial-to-mesenchymal transition markers in oral lichen planus. METHODS: In total, 54 oral lichen planus and 22 control samples were analyzed for epithelial-to-mesenchymal transition markers. Samples were immunohistochemically stained for claudin-1, claudin-4 and claudin-7, cadherin-1 (E-cadherin), Twist-related protein 1 (TWIST1) and zinc finger E-box-binding homeobox 1 (ZEB1). RESULTS: The expression of claudin-1, claudin-4 and E-cadherin was significantly weaker in oral lichen planus epithelium compared to controls (P < 0.001). The quantity of claudin-7-expressing cells (P < 0.001) and claudin-7 staining intensity (P < 0.05) in the stroma was greater in lichen planus than in control samples. TWIST1 and ZEB1 stainings were negative in the epithelium in both lichen planus and controls. The number of TWIST1-expressing cells in the stroma was higher in lichen planus than in controls (P < 0.001). There was a statistically significant difference in ZEB1 staining intensity in the stroma between lichen planus and control samples (P < 0.05). CONCLUSIONS: The data indicate that the expression of claudin-1, claudin-4 and E-cadherin is decreased in oral lichen planus. This may lead to disturbance in epithelial tight junctions, cell-cell connections and epithelial permeability, contributing to oral lichen planus pathogenesis. Based on the present study, the role of TWIST1 and ZEB1 in oral lichen planus remains unclear.

Nuclear factor erythroid 2-related factors 1 and 2 are able to define the worst prognosis group among high-risk diffuse large B cell lymphomas treated with R-CHOEP.

AIMS: Oxidative stress markers and antioxidant enzymes have previously been shown to have prognostic value and associate with adverse outcome in patients with diffuse large B cell lymphoma (DLBCL). Nuclear factor erythroid 2-related factor 1 (Nrf1) and factor 2 (Nrf2) are among the principal inducers of antioxidant enzyme production. Kelch ECH associating protein 1 (Keap1) is a negative regulator of Nrf2, and BTB (BR-C, ttk and bab) domain and CNC homolog 1 (Bach1) represses the function of both factors. Their significance in DLBCL prognosis is unknown. METHODS: Diagnostic biopsy samples of 76 patients with high-risk DLBCL were retrospectively stained with immunohistochemistry for Nrf1, Nrf2, Keap1 and Bach1, and correlated with clinical data and outcome. RESULTS: Nuclear Nrf2 and nuclear Bach1 expression were associated with adverse clinical features (anaemia, advanced stage, high IPI, high risk of neutropaenic infections), whereas cytoplasmic Nrf1 and Nrf2 were associated with favourable clinical presentation (normal haemoglobin level, no B symptoms, limited stage). None of the evaluated factors could predict survival alone. However, when two of the following parameters were combined: high nuclear score of Nrf2, low nuclear score of Nrf1, high cytoplasmic score of Nrf1 and low cytoplasmic score of Keap1 were associated with significantly worse overall survival. CONCLUSIONS: Nrf1 and Nrf2 are relevant in disease presentation and overall survival in high-risk DLBCL. Low nuclear expression of Nrf1, high cytoplasmic expression of Nrf1, high nuclear expression of Nrf2 and low cytoplasmic expression of Keap1 are associated with adverse outcome in this patient group.

Expression Levels of microRNAs miR-93 and miR-200a in Pancreatic Adenocarcinoma with Special Reference to Differentiation and Relapse-Free Survival.

OBJECTIVES: Protein levels of the transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2) and its inhibitor Kelch-like ECH-associated protein 1 (Keap1) have been proposed as prognostic factors in pancreatic ductal adenocarcinomas (PDACs). These cellular redox-state-regulating enzymes are targeted by several microRNAs, including miR-93 and miR-200a. METHODS: We assessed mRNA levels of Nrf2 and Keap1 and tissue expression of miR-93 and miR-200a in 51 patients with surgically treated PDAC. Expression levels were separately measured in malignant cells and adjacent benign cells. RESULTS: Keap1 and Nrf2 mRNA expression levels in cancer cells were lower than in adjacent benign tissue (Wilcoxon's test; p = 0.0015 and p = 0.000032, respectively). Conversely, miR-93 expression was higher in cancer cells than in adjacent benign tissue (p = 0.00082). Low levels of miR-93 and miR-200a in cancer cells were associated with poorer differentiation (p = 0.004 and p = 0.002, respectively). In univariate survival analysis, benign-tissue levels of miR-200a above the median predicted better relapse-free survival (RFS) (p = 0.045). CONCLUSIONS: High miR-93 and miR-200a levels in cancer cells of PDAC were associated with better differentiation, and miR-200a expression in benign tissue with excellent RFS. Keap1 and Nrf2 mRNA levels showed prominent down-regulation in cancerous versus benign tissue, but they were not associated with disease aggressiveness or outcome.

Mutation of TP53, translocation analysis and immunohistochemical expression of MYC, BCL-2 and BCL-6 in patients with DLBCL treated with R-CHOP.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with diverse outcomes. Concurrent translocation of MYC and BCL-2 and/or BCL-6, and concurrent immunohistochemical (IHC) high expression of MYC and BCL-2, have been linked to unfavorable treatment responses. TP53-mutated DLBCL has also been linked to worse outcome. Our aim was to evaluate the aforementioned issues in a cohort of 155 patients uniformly treated with R-CHOP-like therapies. We performed direct sequencing of TP53 exons 5, 6, 7 and 8 as well as fluorescence in-situ hybridization (FISH) of MYC, BCL-2 and BCL-6, and IHC of MYC, BCL-2 and BCL-6. In multivariate analysis, TP53 mutations in L3 and loop-sheet helix (LSH) associated with a risk ratio (RR) of disease-specific survival (DSS) of 8.779 (p = 0.022) and a RR of disease-free survival (DFS) of 10.498 (p = 0.011). In IHC analysis BCL-2 overexpression was associated with inferior DFS (p = 0.002) and DSS (p = 0.002). DLBCL with BCL-2 and MYC overexpression conferred inferior survival in all patients (DSS, p = 0.038 and DFS, p = 0.011) and in patients with non-GC phenotype (DSS (p = 0.013) and DFS (p = 0.010). Our results imply that in DLBCL, the location of TP53 mutations and IHC analysis of BCL-2 and MYC might have a role in the assessment of prognosis.

Small oral tongue cancers (≤ 4 cm in diameter) with clinically negative neck: from the 7th to the 8th edition of the American Joint Committee on Cancer.

One of the main changes in the 8th edition of the American Joint Committee on Cancer (AJCC) for staging of oral cancer is the inclusion of depth of invasion (DOI) in the T category. However, cancers in different oral subsites have variable behavior, with oral tongue squamous cell carcinoma (OTSCC) being the most aggressive one even at early stage. Thus, it is necessary to evaluate the performance of this new T category in homogenous cohort of early OTSCC. Therefore, we analyzed a large cohort of patients with a small (≤ 4 cm) OTSCC to demonstrate the differences in T stage between the AJCC 7th and 8th editions. A total of 311 early-stage cases (AJCC 7th) of OTSCC were analyzed. We used 5 mm and 10 mm DOI for upstaging from T1 to T2 and from T2 to T3 respectively, as in the AJCC 8th. We further reclassified the cases according to our own proposal suggesting 2 mm to upstage to T2 and 4 mm to upstage to T3. According to AJCC 7th, there were no significant differences in the survival analysis. When we applied the 8th edition, many cases were upstaged to T3 and thus associated with worse disease-specific survival (HR 2.37, 95% CI 1.12-4.99) and disease-free survival (HR 2.12, 95% CI 1.09-4.08). Based on our proposal, T3 cases were associated with even worse disease-specific survival (HR 4.19, 95% CI 2.27-7.74). The 8th edition provides better survival prediction for OTSCC than the 7th and can be further optimized by lowering the DOI cutoffs.

Elevated expression of hyaluronan synthase 2 associates with decreased survival in diffusely infiltrating astrocytomas.

BACKGROUND: Diffusely infiltrating astrocytomas originate from astrocytic glial cells or their precursor cells and are the most common type of brain tumors in adults. In this retrospective study, we investigated the content of hyaluronan, its cell surface receptor, CD44 and the expression of hyaluronan metabolizing enzymes, in these aggressive tumors. Hyaluronan is the main component of extracellular matrix in the brain. In many tumors, aberrant hyaluronan metabolism implicates aggressive disease progression and metastatic potential. METHODS: Our material consisted of 163 diffusely infiltrating astrocytomas (WHO grades II-IV). Tumor samples were processed into tissue microarray (TMA) blocks. The TMA sections were stained for hyaluronan, CD44, hyaluronan synthases 1-3 (HAS1-3) and hyaluronidase 2 (HYAL2). The immunostaining results were compared with χ2 -test or with Kruskal-Wallis test for correlation with clinicopathological parameters and survival analyses were done with Kaplan-Meier log rank test and Cox regression. RESULTS: Hyaluronan and CD44 were strongly expressed in astrocytic gliomas but their expression did not correlate with WHO grade or any other clinicopathological parameters whereas high HAS2 staining intensity was observed in IDH1 negative tumors (p = 0.003). In addition, in non-parametric tests increased HAS2 staining intensity correlated with increased cell proliferation (p = 0.013) and in log rank test with decreased overall survival of patients (p = 0.001). In the Cox regression analysis HAS2 expression turned out to be a significant independent prognostic factor (p = 0.008). CONCLUSIONS: This study indicates that elevated expression of HAS2 is associated with glioma progression and suggests that HAS2 has a prognostic significance in diffusely infiltrating astrocytomas.

Proteins of the retinoblastoma pathway, FEN1 and MGMT are novel potential prognostic biomarkers in pancreatic adenocarcinoma.

BACKGROUND: We studied the expression of some major proteins involved in cell-cycle regulation and DNA repair, the roles of which are not well known in pancreatic ductal adenocarcinoma (PDAC), but which have a significant impact on carcinogenesis of many other cancers. METHODS: We immunohistochemically assessed expression levels of the cell-cycle regulators Rb1, p16 and cyclin-dependent kinase 4 (CDK4), and the DNA repair enzymes O6-methylguanine-DNA-alkyltransferase (MGMT) and flap endonuclease-1 (FEN1) separately in malignant tissue and benign tissue from resection margins in 102 cases of PDAC. Nearly all (95.1%) patients had undergone pancreaticoduodenectomy. RESULTS: The studied proteins showed wide but somewhat variable expression in both benign and malignant pancreatic tissues. Strong CDK4 expression in islets of Langerhans predicted poor relapse-free survival (RFS) (HR 2.874; 95% CI 1.261-6.550; p = .012) and within T3-4 tumors CDK4 expression in adenocarcinoma cells also predicted poor disease-free survival (DFS) (RR 2.148; 95% CI 1.081-4.272; p = .029). Strong MGMT expression was associated in N1 patients with weak local relapse-free survival (RFS), DFS and overall survival; all significantly in Cox regression analysis. FEN1 was also an independent predictor of decreased DFS (in the whole study population) and worse RFS (in the patients with T3-4 tumors). CONCLUSIONS: Major cell-cycle regulator also have predictive significance, but further studies are required to evaluate this.

KDM4D Predicts Recurrence in Exocrine Pancreatic Cells of Resection Margins from Patients with Pancreatic Adenocarcinoma.

BACKGROUND/AIM: The role of histone demethylators, such as Jumonji domain 2 (JMJD2/KDM4) proteins, and histone deacetylases, such as sirtuins (SIRT) is poorly characterized in pancreatic carcinomas while they have a major role in the carcinogenesis of several other tumours. MATERIALS AND METHODS: We assessed retrospectively with immunohistochemistry the expressions of KDM4A, KDM4B and KDM4D in 81 and SIRT1-4 in 102 pancreatic adenocarcinomas. Immunostaining was evaluated separately in benign pancreatic tissues and in malignant cells. RESULTS: High nuclear KDM4D expression in benign pancreatic tissue from resection margins associated with dismal disease-free survival (DFS) (OR=8.00; 95%CI=1.87-33.9; p=0.005), even more significantly than tumour size and lymph node involvement. High cytoplasmic SIRT2 expression in benign pancreatic tissues also associated with a shorter DFS, but only in univariate analysis (p=0.026). CONCLUSION: Nuclear KDM4D and SIRT2 expression deviated from that of benign pancreatic tissue thus putatively influencing gene expression of tumor cells. Regardless, none of the enzymes studied had a decisive role in the spread of pancreatic cancer. A high nuclear expression of KDM4D in samples of pancreatic resection margins significantly and independently predicted an earlier recurrence and could thus be used in the assessment of risk of relapse in clinical practice.

NRF2, DJ1 and SNRX1 and their prognostic impact in astrocytic gliomas.

Nuclear factor erythroid 2-related factor 2 (NRF2), DJ1 and sulfiredoxin 1 (SRXN1) are transcription factors which protect cells from the oxidative damage caused by reactive oxygen species and, on the other hand, are associated with resistance to cancer treatments. The immunohistochemical expression of NRF2, DJ1 and SRNX1 was assessed in human grade II-IV astrocytic gliomas. Their association to clinicopathologic and essential molecular factors was evaluated. The RNA expression levels and genetic alterations were analyzed from publicly available datasets. All studied molecules were commonly expressed. The cytoplasmic NRF2 expression was higher in tumors with a higher malignancy grade, whereas the nuclear and cytoplasmic DJ1 expression was associated with a lower grade. The presence of the isocitrate dehyrdogenase 1 mutation (IDH1) was associated with an increasing cytoplasmic and nuclear expression of NRF2 and a nuclear DJ1 expression. When primary grade IV astrocytomas were compared to secondary glioblastomas, nuclear DJ1 was associated with secondary tumors. In grade II-IV tumors, the cytoplasmic NRF2 expression was associated with a poor prognosis, whereas nuclear NRF2 and both cytoplasmic and nuclear DJ1 were associated with a better patient prognosis. Recurrent homozygous deletions of DJ1 were observed, especially in the IDH wild-type samples. When only the glioblastomas were evaluated, nuclear NRF2 and SRNX1 predicted better survival. As a conclusion, NRF2, DJ1 and SNXR1 can be used as prognosticators in gliomas.

High-level cytoplasmic claudin 3 expression is an independent predictor of poor survival in triple-negative breast cancer.

BACKGROUND: The subtype of claudin-low breast cancer can be reliably determined only by gene-expression profiling. Attempts have been made to develop immunohistochemical surrogates, which nearly always focus on membranous claudin expression. METHODS: We assessed the immunohistochemical expression of both membranous and cytoplasmic claudins 3, 4 and 7 in a series of 197 non-metastatic breast cancers, enriched with triple-negative breast cancers (TNBCs; 60%). The expression of epithelial-to-mesenchymal transition-regulating transcription factors Sip1, Zeb1 and vimentin had previously been determined in the same material. RESULTS: In multivariate analysis, strong cytoplasmic claudin 3 expression was associated with poor relapse-free survival (RFS), disease-free survival, distant disease-free survival, breast cancer-specific survival and overall survival among TNBC patients (for RFS, RR 5.202, 95% CI 1.210-22.369, p = 0.027, vs. T-class, RR 0.663, 95% CI 0.168-2.623, p = 0.558, and N-class, RR 3.940, 95% CI 0.933-16.631, p = 0.062). Cytoplasmic claudin 3 expression was also associated with strong nuclear Sip1 expression (p = 0.000053), TNBC phenotype (p = 0.012) and within them, non-basal-like phenotype (p = 0.026). Cytoplasmic claudin 7 was associated with dismal RFS (RR 6.328, 95% CI 1.401-28.593, p = 0.016, vs. T-class, RR 0.692, 95% CI 0.242-1.982, p = 0.493, and N-class, RR 2.981, 95% CI 1.1016-8.749, p = 0.047). Low cytoplasmic expression of claudins 3, 4 and 7 together also predicted poor RFS (RR 6.070, 95% CI 1.347-27.363, p = 0.019, vs. T-class, RR 0.677, 95% CI 0.237-1.934, p = 0.467, and N-class, RR 3.167, 95% CI 1.079-9.290, p = 0.036). CONCLUSIONS: Immunohistochemical expression levels of cytoplasmic claudins 3 and 7 appear to be novel prognostic factors in TNBC.

Prognostic impact of tumour-stroma ratio in early-stage oral tongue cancers.

AIMS: Oral tongue squamous cell carcinoma (OTSCC) has a relatively poor outcome, and there is a need to identify better prognostic factors. Recently, tumour-stroma ratio (TSR) has been associated with prognosis in several cancers. The aim of this multi-institutional study was to evaluate the prognostic value of TSR from original haematoxylin and eosin (HE)-stained tumour-resection slides in a series of early-stage (cT1-2N0) OTSCC patients. METHODS AND RESULTS: A TSR cutoff value of 50% was used to divide the patients into stroma-rich (≥50%) and stroma-poor (<50%) groups. The relationships between TSR and clinicopathological characteristics of 311 early-stage OTSCC cases were analysed. The prognostic value of TSR in OTSCC was calculated separately and in combination with a previously published cancer cell budding and depth of invasion (BD) prognostic model. A total of 89 cases (28.6%) belonged to the stroma-rich group. In a multivariate analysis, the stroma-rich group had worse disease-free survival, with a hazard ratio (HR) of 1.81 [95% confidence interval (CI) 1.17-2.79, P = 0.008], and higher cancer-related mortality (HR 1.71, 95% CI 1.02-2.86, P = 0.03). The combination of the highest-risk parameter scores of TSR and the BD model showed significant correlations with recurrence rate (HR 3.42, 95% CI 1.71-6.82, P = 0.004) and cancer-related mortality (HR 11.63, 95% CI 3.83-35.31, P < 0.001). CONCLUSIONS: We conclude that TSR is a simple histopathological feature that is useful for prognostication of early-stage OTSCC, and suggest that TSR analyses in association with BD score could be included in routine clinical pathology reports for HE-stained slides.

Evaluation of the budding and depth of invasion (BD) model in oral tongue cancer biopsies.

It is of great clinical importance to identify simple prognostic markers from preoperative biopsies that could guide treatment planning. Here, we compared tumor budding (B), depth of invasion (D), and the combined scores (i.e., budding and depth of invasion (BD) histopathologic model) in preoperative biopsies and the corresponding postoperative specimens of oral tongue squamous cell carcinoma (OTSCC). Tumor budding and depth of invasion were evaluated in the pre- and postoperative samples from 100 patients treated for OTSCC. Sensitivity and specificity statistics were used. Our results showed statistically significant (P < 0.001) relationship between pre- and postoperative BD scores. There was an agreement between the pre- and postoperative BD model scores in 83 cases (83%) with 57.1% sensitivity (95% CI 39.4 to 73.7%) and 96.9% specificity (95% CI 89.3 to 99.6%). Our findings suggest that the BD model, analyzed from representative biopsies, could be used for the treatment planning of OTSCC.

Strong Prolyl Hydroxylase Domain 1 Expression Predicts Poor Outcome in Radiotherapy-treated Patients with Classical Hodgkin's Lymphoma.

BACKGROUND: Hypoxia-inducible factors (HIFs) and prolyl hydroxylase domain (PHD) proteins control cellular oxygen homeostasis and a wide range of other processes. MATERIALS AND METHODS: We immunohistochemically assessed the expression of HIF1α, HIF2α, PHD1, PHD2 and PHD3 in 115 cases of classical Hodgkin's lymphoma, all treated in the first line with doxorubicin, bleomycin, vinblastine and darcabazine (ABVD) chemotherapy. RESULTS: In advanced-stage patients treated with involved-field radiotherapy (IFRT), nuclear HIF1α expression in reactive cellular infiltrate predicted prolonged relapse-free survival (RFS) (p=0.026). Strong cytoplasmic PHD1 expression in Reed-Sternberg cells was associated with poor RFS among patients treated with IFRT and advanced-stage patients treated with ABVD and IFRT (p=0.0028 and p=0.0058, respectively). In Cox regression analysis, PHD1 was a more significant predictor of relapse (risk ratio=18.383; 95% confidence interval(CI)=1.521-222.246; p=0.022) than the International Prognostic Score. CONCLUSION: HIF and PHD expression appear to be novel prognostic biomarkers in classical Hodgkin's lymphoma.

Low Rap1-interacting factor 1 and sirtuin 6 expression predict poor outcome in radiotherapy-treated Hodgkin lymphoma patients.

Sirtuins (SIRTs) are a family of histone deacetylases, which widely regulate cellular metabolism and are also involved in DNA repair. Rap1-interacting factor 1 (Rif1) and O6-alkylguanine DNA alkyltransferase (MGMT) are DNA-repair enzymes, which may potentially be involved in resistance to treatment of classical Hodgkin lymphoma (HL). We assessed the expression levels of (previously unstudied) SIRT1, SIRT4, SIRT6, Rif1, and MGMT immunohistochemically in 85 patients with untreated classical HL. Aberrant distributions of SIRT1, SIRT4, and SIRT6 were detected in Hodgkin neoplastic Reed-Sternberg (RS) cells compared with reactive elements. Low-level expression of both Rif1 and SIRT6 predicted dismal relapse-free survival in radiotherapy-treated patients (multivariate analysis; HR 8.521; 95% CI 1.714-42.358; p = .0088). Expression levels of SIRT1, 4, and 6 were abnormally distributed in RS cells, suggesting a putative role of aberrant acetylation in classical HL carcinogenesis. Rif1 and SIRT6 may also have substantial prognostic and even predictive roles in classical HL.

Integrin alpha 10, CD44, PTEN, cadherin-11 and lactoferrin expressions are potential biomarkers for selecting patients in need of central nervous system prophylaxis in diffuse large B-cell lymphoma.

Central nervous system (CNS) relapse is a devastating complication that occurs in about 5% of diffuse large B-cell lymphoma (DLBCL) patients. Currently, there are no predictive biological markers. We wanted to study potential biomarkers of CNS tropism that play a role in adhesion, migration and/or in the regulation of inflammatory responses. The expression levels of ITGA10, CD44, PTEN, cadherin-11, CDH12, N-cadherin, P-cadherin, lactoferrin and E-cadherin were studied with IHC and IEM. GEP was performed to see whether found expressional changes are regulated at DNA/RNA level. IHC included 96 samples of primary CNS lymphoma (PCNSL), secondary CNS lymphoma (sCNSL) and systemic DLBCL (sDLBCL). IEM included two PCNSL, one sCNSL, one sDLBCL and one reactive lymph node samples. GEP was performed on two DLBCL samples, one with and one without CNS relapse. CNS disease was associated with enhanced expression of cytoplasmic and membranous ITGA10 and nuclear PTEN (P < 0.0005, P = 0.002, P = 0.024, respectively). sCNSL presented decreased membranous CD44 and nuclear and cytoplasmic cadherin-11 expressions (P = 0.001, P = 0.006, P = 0.048, respectively). In PCNSL lactoferrin expression was upregulated (P < 0.0005). IEM results were mainly supportive of the IHC results. In GEP CD44, cadherin-11, lactoferrin and E-cadherin were under-expressed in CNS disease. Our results are in line with previous studies, where gene expressions in extracellular matrix and adhesion-related pathways are altered in CNS lymphoma. This study gives new information on the DLBCL CNS tropism. If further verified, these markers might become useful in predicting CNS relapses.

Reactive Oxygen Species-Mediated Mechanisms of Action of Targeted Cancer Therapy.

Targeted cancer therapies, involving tyrosine kinase inhibitors and monoclonal antibodies, for example, have recently led to substantial prolongation of survival in many metastatic cancers. Compared with traditional chemotherapy and radiotherapy, where reactive oxygen species (ROS) have been directly linked to the mediation of cytotoxic effects and adverse events, the field of oxidative stress regulation is still emerging in targeted cancer therapies. Here, we provide a comprehensive review regarding the current evidence of ROS-mediated effects of antibodies and tyrosine kinase inhibitors, use of which has been indicated in the treatment of solid malignancies and lymphomas. It can be concluded that there is rapidly emerging evidence of ROS-mediated effects of some of these compounds, which is also relevant in the context of drug resistance and how to overcome it.