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Abstract: The purpose of the study was to analyse the generalisability and geographic transportability of survival estimates produced by commonly used prognostic factors. We compared the influence of tumour size, histologic grade, axillary nodal status, oestrogen and progesterone receptor contents, age at diagnosis and two prognostication schemes (the Nottingham Prognostic Index and St. Gallen criteria) in two nationwide cohorts of patients diagnosed with breast cancer in 1991–2, the FinProg (n =2923, Finland) and the SEER series (n =43,249, the United States (US)). Eight-year estimates of breast cancer-specific (84% versus 80%), relative (86% versus 83%), and overall (70% versus 69%) survival were slightly more favourable in the SEER than in the FinProg series, respectively. Despite differences in demographic variables and the frequency of use of adjuvant therapies and mammography screening between the series, the prognostic factors examined produced close to overlapping survival curves with similar shapes. The results suggest that quantitative survival estimates based on frequently used prognostic factors and prognostication schemes are generalisable and transportable between large, unselected cohorts of breast cancer patients. [Copyright &y& Elsevier]

Context Selection of systemic adjuvant therapies for women diagnosed as having breast cancer is based on risk estimations for cancer recurrence. In such estimations, tumors detected by mammography screening are considered to be associated with a similar risk of recurrence as tumors of similar size found by other methods. Objective To compare the risk of recurrence and survival among women with cancerous tumors detected by mammography screening compared with other methods (outside of screening). Design, Setting, and Patients Retrospective study comparing clinical, histopathological, and biological features of cancerous tumors detected by mammography screening compared with tumors detected outside of screening. Women diagnosed as having breast cancer in 1991 or 1992 were identified from the Finnish Cancer Registry (n = 2842). The median follow-up time was 9.5 years. Cancer biological variables were analyzed from tumor tissue microarrays using immunohistochemistry or in situ hybridization and included ERBB2, TP53, and MK167 expression and ERBB2 amplification data. Main Outcome Measures Univariate and multivariate analyses of potential risk factors for distant recurrence of breast cancer and 10-year survival. Results Of the 1983 women with unilateral invasive breast cancer, data on tumor diameter were available for 1918 women. Women with cancerous tumors detected by mammography screening had better estimated 10-year distant disease-free survival than women with tumors found outside of screening (tumor size of ≤10 mm [n = 386] 92% vs 85% [P = .04]; 11-20 mm [n = 808] 88% vs 76% [P<.001]; 21-30 mm [n = 409] 86% vs 63% [P = .008]; > 30 mm [n = 315] 68% vs 50% [P = .12], respectively). In a Cox multivariate model that included cancer biological factors, the relative hazard ratio for distant recurrence among women with tumors detected outside of screening (HR, 1.90; 95% confidence interval, 1.15-3.11) was significantly higher than among women with tumors det... [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

It has been demonstrated that diffuse large B-cell lymphoma (DLBCL) is especially sensitive to ferroptosis. Currently, confirming the presence of ferroptosis requires flow cytometry, which is a time consuming and labor-intensive task. Blistering of the cell membrane has been shown to be a ferroptosis-specific morphological change. In this study we developed a deep convolutional neural network to detect the blistering of cell membrane. Buthionine sulfoximine treatment increased the percentage of blistering cells from 2 % to 38 % (p < 0.001) when glutathione was deprived from the culture media. Ferrostatin-1 treatment completely reversed the effect. Imidazole ketone erastin (IKE) and auranofin treatment increased blistering cells gradually in dose response manner from 5.4 % to 18.1 % (p < 0.05) and 6.1-50.1 % (p < 0.0001) respectively. We also tested malignant melanoma and breast cancer cell lines to confirm that the blistering phenomena can also be observed in adherent cell lines. We used fluorescence-activated cell sorting to measure the lipid peroxidation associated with ferroptosis and found a significant increase of bodiby-C11 oxidized mean compared to DMSO controls for IKE (345 vs 462, p < 0.01) and auranofin (345 vs 686.5, p < 0.05)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pyry Kotkaranta reports financial support was provided by Terttu Foundation. Mikko Chan reports financial support was provided by Terttu Foundation. Milla E.L Kuusisto reports financial support was provided by Terttu Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background/aim: Central nervous system (CNS) involvement in aggressive B-cell lymphoma, either as a primary or secondary event to systemic disease, portends a poor prognosis. This study sought to identify patients at high risk for CNS relapse by analyzing their human leukocyte antigen (HLA) genotypes., Patients and Methods: We retrospectively examined the HLA genotypes of 164 patients with systemic lymphoma, primary CNS lymphoma, and CNS relapse of systemic lymphoma. Patient records were analyzed, and HLA typing was performed by the Finnish Red Cross Blood Service. After excluding patients who received CNS prophylaxis, 131 patients were included in the final analysis., Results: A strong association was found between the HLA-A*31 genotype and CNS disease (p=0.001). Additionally, various HLA genotypes were linked to lactate dehydrogenase levels, extranodal disease, International Prognostic Index score, and disease stage., Conclusion: The patient's genetic constitution, rather than solely disease-related factors, plays a role in the tropism of lymphoma for the CNS. If confirmed in a larger study, defining the HLA genotype of a lymphoma patient could provide valuable information for predicting CNS relapse., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Importance: The standard adjuvant treatment for patients with ERRB2-positive breast cancer is chemotherapy plus 1 year of trastuzumab. Shorter durations of trastuzumab administration improve cardiac safety, but more information is needed about their effect on survival., Objective: To compare survival outcomes after 9-week vs 1-year administration of trastuzumab with the same adjuvant chemotherapy., Design, Setting, and Participants: This post hoc secondary analysis of an open-label, multicenter, noninferiority-design randomized clinical trial included women aged 18 years or older with early ERBB2-positive, axillary node-negative or axillary node-positive breast cancer who were enrolled from January 3, 2008, to December 16, 2014, at 65 centers in 7 European countries. The current exploratory analysis was conducted after achieving the maximum attainable follow-up data when the last patient enrolled had completed the last scheduled visit in December 2022., Intervention: Chemotherapy consisted of 3 cycles of docetaxel administered at 3-week intervals followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide at 3-week intervals. Trastuzumab was administered in both groups for 9 weeks concomitantly with docetaxel. In the 9-week group, no further trastuzumab was administered after chemotherapy, whereas in the 1-year group, trastuzumab was continued after chemotherapy to complete 1 year of administration., Main Outcomes and Measures: The primary objective was disease-free survival (DFS). Distant DFS and OS were secondary objectives. Survival between groups was compared using the Kaplan-Meier method and log-rank test or univariable Cox proportional hazards regression., Results: Among the 2174 women analyzed, median age was 56 years (IQR, 48-64 years). The median follow-up time was 8.1 years (IQR, 8.0-8.9 years); 357 DFS events and 176 deaths occurred. Trastuzumab for 9 weeks was associated with shorter DFS compared with trastuzumab for 1 year (hazard ratio [HR], 1.36; 90% CI, 1.14-1.62); 10-year DFS was 80.3% in the 1-year group vs 78.6% in the 9-week group. The 5-year and 10-year OS rates were comparable between the 9-week and 1-year groups (95.0% vs 95.9% and 89.1% vs 88.2%, respectively; HR for all time points, 1.20; 90% CI, 0.94-1.54). In multivariable analyses, 9-week treatment was associated with shorter DFS compared with 1-year treatment (HR for recurrence or death, 1.36; 95% CI, 1.10-1.68; P = .005), but there was no between-group difference in OS (HR, 1.22; 95% CI, 0.90-1.64; P = .20). Only 4 patients (0.2%) died of a cardiac cause., Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, 1-year vs 9-week adjuvant trastuzumab was associated with improved DFS among patients with ERRB2-positive breast cancer receiving chemotherapy, but there was no significant difference in OS between the groups., Trial Registration: ClinicalTrials.gov Identifier: NCT00593697.

Background: Social relationships are important health resources and may be investigated as social networks. We measured cancer patients' social subnetworks divided into generic social networks (people known to the patients) and disease-specific social networks (the persons talked to about the cancer) during 3 years after diagnosis., Method: Newly diagnosed patients with localized breast cancer (n = 222), lymphoma (n = 102), and prostate cancer (n = 141) completed a questionnaire on their social subnetworks at 2-5 months after diagnosis and 9, 18, and 36 months thereafter. Generic and cancer-specific numbers of persons of spouse/partner; other family; close relatives, in detail; and friends were recorded as well as cancer-specific numbers of persons in acquaintances; others with cancer; work community; healthcare professionals; and religious, hobby, and civic participation. The data was analyzed with regression models., Results: At study entry, most patients had a spouse/partner, all had close relatives (the younger, more often parents; and the older, more often adult children with families) and most also friends. The cancer was typically discussed with them, and often with acquaintances and other patients (74-86%). Only minor usually decreasing time trends were seen. However, the numbers of distant relatives and friends were found to strongly increase by the 9-month evaluation (P < 0.001)., Conclusion: Cancer patients have multiple social relationships and usually talk to them about their cancer soon after diagnosis. Most temporal changes are due to the natural course of life cycle. The cancer widened the patients' social networks by including other patients and healthcare professionals and by an increased number of relatives and friends., (© 2024. The Author(s).)

Background: The modern-day therapeutic landscape for follicular lymphoma (FL) includes a number of highly effective therapies., Patients and Methods: We set out to determine progression-free survival (PFS) after front line, second line, and third line of therapy on the basis of relevant biological characteristics and therapeutic choices. Patients (n = 743, 51% females, median 60 years old) diagnosed with grade 1-2 FL between 1997 and 2016 in nine institutions were included., Results: The median PFS1, PFS2, and PFS3 were 8.1 years (95% confidence interval [CI]: 7-9.3 years), 4.2 years (95% CI: 2.8-5.6 years) and 2.2 years (95% CI 1.7-2.8 years). We found longer PFS1 for (1) females, (2) younger age, (3) lower-risk follicular lymphoma international prognostic index (FLIPI), (4) standard intensity (over low intensity) regimens and (5) immunochemotherapy strategies and (6) maintenance rituximab. We found a shorter PFS2 for patients who received front-line immunochemotherapy. Older age at diagnosis correlated with a shorter PFS3. Intensity of front-line chemotherapy, maintenance, or POD24 status did not correlate with PFS2 or PFS3 in this dataset., Interpretation: With current immunochemotherapy strategies, the natural course of FL is characterized by shorter-lasting remissions after each relapse. It will be interesting to see whether new therapies can alter this pattern.

Background: Rituximab-based combinations are the standard of care in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Despite being on market for over 20 years, some of the adverse effects associated with the use of rituximab are not well known. Drug-induced interstitial pneumonitis (DIP) is a potentially fatal complication of the treatment. Granulocyte colony-stimulating factors (G-CSF) are supportive agents commonly used to prevent neutropenic infections. G-CSF are reported to have pulmonary toxicity, but the risk of DIP is greater when used in combination with other potentially pulmotoxic agents., Methods: In this retrospective study, we reported the G-CSF use and risk of DIP in 234 DLBCL patients and 87 FL patients receiving R-CHOP-type immunochemotherapy., Results: In 72% of patients, the treatment included a G-CSF support. The overall incidence of treatment-induced pneumonitis was 6.9% in this patient group. All the DIP cases (n = 16) were among patients receiving G-CSF support (p = 0.03). Older age (over 60 years) and higher disease stage (Ann Arbor 3-4) also increased the risk of DIP., Conclusions: These findings suggest that the use of G-CSF increases the risk of DIP, when used in combination with rituximab-containing regimen., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: We report here the first population-based incidence rates and prognosis of primary central nervous system lymphoma (PCNSL) in Finland., Methods: Finnish Cancer Registry data by histological diagnosis and tumor location (2007-2017) for cases with diffuse large B-cell lymphoma., Results: During 2007-2017, 392 new cases of PCNSL were reported (195 males, 197 females). The average age-adjusted incidence was 0.68/100,000 person-years. Incidence for males was 0.74/100,000 and for females 0.63/100,000, respectively. The incidence was highest, 2.93/100,000, among people aged 75-79 years. Concerning all cases in 2007-2017 the 2-year age-adjusted relative survival rate was 33% and the corresponding 5-year survival rate was 26%. Among patients under the age of 70, the age-adjusted 5-year relative survival rate increased from 36% in 2007-2012 to 43% for 2013-2017. Among patients aged 70+ the corresponding survival rates were poor, 7 and 9%., Conclusions: PCNSL incidence in Finland is among the highest reported in the world. The annual increase in incidence was 2.4%. The prognosis is still dismal, especially in elderly patients., (© 2022. The Author(s).)

Follicular T-cell lymphoma (FTCL) is a rare subtype of mature T-cell lymphoma. It was recently recognized as a separate lymphoma entity in the 2017 revised fourth edition of the World Health Organization classification. The main goals of the present study were to gain better knowledge of the incidence and histopathological and clinical features of FTCL in Finland. In this study, we reviewed all angioimmunoblastic T-cell (AITL) and peripheral T-cell lymphomas, not otherwise specified, from the patient records in three hospital districts in Finland over a 10-year period, to identify FTCL cases and estimate its incidence. Five patients rediagnosed with FTCL and 34 with AITL were analyzed. Hodgkin/Reed-Sternberg (HRS)-like cells were observed in 24 of the 34 AITL cases and four of the five FTCL cases. We found that the main features that differentiated FTCL from AITL were rosetting of T-cells around HRS-like cells, the absence of clear cells, follicular dendritic cell meshwork and T-cell monoclonality. Our estimated incidence of FTCL is 0.20 per 100,000 people in Finland., (Copyright © 2021. Published by Elsevier Inc.)

Although treatment for diffuse large B-cell lymphoma (DLBCL) has taken some notable steps in the 2000s, there are still subgroups of patients suffering from high mortality and relapse rates. To further improve treatment outcomes, it is essential to discover new mechanisms of chemotherapy resistance and create new treatment approaches to overcome them. In the present study, we analyzed the expression of chemokines and their ligands in systemic and testicular DLBCL. From our biopsy sample set of 21 testicular and 28 systemic lymphomas, we were able to demonstrate chemokine profile differences and identify associations with clinical risk factors. High cytoplasmic CXCL13 expression had correlations with better treatment response, lower disease-related mortality, and limited stage. This study suggests that active CXCR5/CXCL13 signaling could overtake the CXCR4/CXCL12 axis, resulting in a better prognosis.

The application of positron emission tomography (PET)-computed tomography (CT) in treatment response evaluation has increased in diffuse large B-cell lymphoma (DLBCL), although its predictive value is controversial. We retrospectively analyzed the rate of false-positive PET-CTs performed as interim (n = 94) and end-of-treatment (n = 8) assessments among 102 DLBCL patients treated during 2010-2017 at Oulu University Hospital. In PET-CT Deauville score ≥4 was regarded as positive. A biopsy was performed on 35 patients, and vital lymphoma tissue was detected from nine patients. Positive biopsy findings were associated with poor disease outcomes in this study. This difference was statistically significant: 2-year failure-free survival (FFS) was 44% in patients with a positive biopsy versus 83% for those with a negative biopsy (p = 0.003). The corresponding overall survival (OS) rates were 53% versus 95% (p = 0.010). In the multivariate analyses, a negative biopsy was an independent protective factor in FFS (Hazard Ratio (HR) 0.093 (95% confidence interval [CI] 0.017-0.511); p = 0.006) unrelated to the International Prognostic Index (IPI) (HR 1.139 [95% CI 0.237-5.474] p = 0.871) or stage (HR 1.365 [95% CI 0.138-13.470]; p = 0.790). There was no statistically significant difference in OS according to the PET results, but the FFS rate was significantly higher in patients with a negative PET. The value of PET-CT as an evaluation method suffers from a high false-positive rate, and it is inadequate alone for the justification of treatment decisions. Biopsy results provide more reliable prognostic information for the evaluation of treatment response and outcome and should be used to assess patients with positive PET-CT scans., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

DLBCL is the most common type of non-Hodgkin lymphoma with a substantial group of patients suffering a poor prognosis. Therefore more specific markers are required for better understanding of disease biology and treatment. This study demonstrates that testis-specific antioxidant enzymes TXNDC2, TXNDC3, and TXNDC6 alongside oxidative stress marker 8-OHdG are expressed in both testicular and systemic DLBCL, and their presence or absence has correlations with clinical risk factors such as the number of extranodal effusion, the appearance of B-symptoms, and treatment response. Biopsy samples were collected from 28 systemic and 21 testicular male DLBCL patients. The samples were histostained with TXNDC2, TXNDC3, TXNDC6, and 8-OHdG, then graded by a hematopathologist blinded to clinical data. Immunoelectron microscopy was used as a second method to confirm the reliability of the acquired immunohistochemistry data. The absence of nuclear TXNDC2 expression in testicular DLBCL cells correlated with worse primary treatment response, cytoplasmic TXNDC3 expression in testicular and systemic DLBCL associated with lower frequency of B-symptoms, and TXNDC6 expression in cytoplasm in systemic DLBCL had a clinical significance with higher LD levels suggesting a role in the biological nature of these lymphomas. Overall, TXNDC3 cytoplasmic expression is correlated with a more positive outcome in both testicular and systemic DLBCL, while TXNDC6 cytoplasmic expression is associated with a negative outcome in systemic DLBCL., Competing Interests: No potential conflict of interest was reported by the authors., (Copyright © 2021 Mikko C. Chan et al.)

Although overall survival in diffuse large B cell lymphomas (DLBCL) has improved, central nervous system (CNS) relapse is still a fatal complication of DLBCL. For this reason, CNS prophylaxis is recommended for patients at high risk of CNS disease. However, no consensus exists on definition of high-risk patient and optimal CNS prophylaxis. Systemic high-dose methotrexate in combination with R-CHOP has been suggested as a potential prophylactic method, since methotrexate penetrates the blood-brain barrier and achieves high concentration in the CNS. In this retrospective analysis, we report treatment outcome of 95 high-risk DLBCL/FL grade 3B patients treated with R-CHOP or its derivatives with (N = 57) or without (N = 38) CNS prophylaxis. At a median follow-up time (51 months), CNS relapses were detected in twelve patients (12.6%). Ten out of twelve (83%) of CNS events were confined to CNS system only. Median overall survival after CNS relapse was 9 months. Five-year isolated CNS relapse rates were 5% in the prophylaxis group and 26% in the group without prophylaxis. These findings suggest that high-dose methotrexate-containing prophylaxis decreases the risk of CNS failure.

Objective: In diffuse large B-cell lymphoma (DLBCL), there is an unmet medical need to select patients who would benefit from intensified frontline treatments such as adding etoposide to an R-CHOP regimen., Methods: The present work included a retrospective clinical analysis of two patient cohorts and an in vitro study. Primary biopsy samples from DLBCL patients treated with an etoposide-containing high-dose regimen (n = 37) and etoposide-containing frontline treatment (n = 69, R-CHOEP) were studied using immunohistochemical thioredoxin-1 (Trx1) staining. Two DLBCL cell lines expressing Trx1 were cultured, and their expression was silenced using the small interfering RNA knockdown technique. Chemoresistance was tested with doxorubicin, etoposide, vincristine, prednisolone and carboplatin., Results: Thioredoxin-1 knockdown sensitised DLBCL cells to doxorubicin (P < .0001) but decreased etoposide-induced cell death (P < .00001). In DLBCL patients who received etoposide-containing frontline treatment, low cytoplasmic Trx1 expression was associated with inferior 5-year overall survival (46% vs 76%, P = .026) and disease-specific survival (68% vs 90%, P = .026)., Conclusions: Strong Trx1 expression appears to increase drug resistance to doxorubicin but sensitises cells to etoposide. This implies that Trx1 expression might be the first predictive biological marker to select the patients who might benefit from adding etoposide to R-CHOP immunochemotherapy., (© 2020 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

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., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Primary central nervous system lymphoma (PCNSL) is a rare brain tumour with a dismal prognosis. Several phase II studies with high-dose methotrexate-based regimens have shown promising early results, but in all hospital-based data published so far, the disease outcome has been poor. Patients with relapsed or refractory disease have a dismal prognosis. We performed retrospective analysis to evaluate results and tolerabilities of BBBD therapy in combination with high-dose therapy supported by autologous stem cell transplantation. We analysed 25 patients (age range: 40-71 years) who were treated in first or second line with BBBD therapy. When we started BBBD treatment, patients had relapsed or refractory PCNSL or they did not tolerate Bonn-like therapy. In recent years, some of the patients were treated in first line. We found promising response rates. Altogether 19 (76 %) of the patients achieved a complete response (CR). Two-year progression-free survival (PFS) and overall survival (OS) rates were 61 and 57 % respectively and the five-year OS was 47 %. Patients who were treated with a five-drug therapy had a very promising prognosis. The CR rate was 100 % in first-line therapy and 60 % in relapsed cases. These findings suggest that BBBD is a promising therapy for PCNSL, especially for patients in first line, but also for patients with relapsed or refractory disease after conventional chemotherapy, who commonly have a very poor prognosis. Treatment-related toxicity was generally manageable. Thus, BBBD followed by ASCT could be a treatment of choice in transplant-eligible patients with PCNSL.

The biological subtype of breast cancer influences the selection of systemic therapy. Distinction between luminal A and B cancers depends on consistent assessment of Ki-67, but substantial intra-observer and inter-observer variability exists when immunohistochemistry (IHC) is used. We compared RT-qPCR with IHC in the assessment of Ki-67 and other standard factors used in breast cancer subtyping. RNA was extracted from archival breast tumour tissue of 769 women randomly assigned to the FinHer trial. Cancer ESR1, PGR, ERBB2 and MKI67 mRNA content was quantitated with an RT-qPCR assay. Local pathologists assessed ER, PgR and Ki-67 expression using IHC. HER2 amplification was identified with chromogenic in situ hybridization (CISH) centrally. The results were correlated with distant disease-free survival (DDFS) and overall survival (OS). qPCR-based and IHC-based assessments of ER and PgR showed good concordance. Both low tumour MKI67 mRNA (RT-qPCR) and Ki-67 protein (IHC) levels were prognostic for favourable DDFS [hazard ratio (HR) 0.42, 95 % CI 0.25-0.71, P = 0.001; and HR 0.56, 0.37-0.84, P = 0.005, respectively] and OS. In multivariable analyses, cancer MKI67 mRNA content had independent influence on DDFS (adjusted HR 0.51, 95 % CI 0.29-0.89, P = 0.019) while Ki-67 protein expression had not any influence (P = 0.266) whereas both assessments influenced independently OS. Luminal B patients treated with docetaxel-FEC had more favourable DDFS and OS than those treated with vinorelbine-FEC when the subtype was defined by RT-qPCR (for DDFS, HR 0.52, 95 % CI 0.29-0.94, P = 0.031), but not when defined using IHC. Breast cancer subtypes approximated with RT-qPCR and IHC show good concordance, but cancer MKI67 mRNA content correlated slightly better with DDFS than Ki-67 expression. The findings based on MKI67 mRNA content suggest that patients with luminal B cancer benefit more from docetaxel-FEC than from vinorelbine-FEC.

Redox state-regulating enzymes may have roles in chemoresistance and also in lymphomagenesis, but there have been only a limited number of studies on this topic in lymphomas. Our aim was to assess expression of the redox state-regulating enzymes peroxiredoxins (Prxs) I-VI and thioredoxin (Trx) and the oxidative stress marker nitrotyrosine in follicular lymphomas (FLs). We immunohistochemically assessed Prxs I-VI, Trx and nitrotyrosine in a cohort of 76 histologically confirmed, untreated FLs. We also studied the localisation of Prxs I, II, III, V and VI by means of immunoelectron microscopy (IEM). Immunohistochemistry results were correlated with disease-specific survival (DSS), progression-free survival (PFS), overall survival (OS) and clinical prognostic factors. When all Prx expression intensities were grouped as a single variable, we discovered that high total Prx intensity correlated with favourable DSS (p = 0.024) and OS (p = 0.035) but not with PFS. No deaths due to lymphoma were recorded amongst patients with high total Prx expression during the median follow-up period of 7.6 years. IEM results were in line with earlier ones demonstrating wide subcellular localisation of Prx isoenzymes. In conclusion, our results demonstrate an association between high total Prx expression and prolonged survival and suggest that Prxs may have a protective role in FL that cannot be compensated by other antioxidant mechanisms.

Central nervous system (CNS) relapse occurs in around 5% of diffuse large B-cell lymphoma (DLBCL) cases. No biomarkers to identify high-risk patients have been discovered. We evaluated the expression of lymphocyte-guiding chemokine receptors in systemic and CNS lymphomas. Immunohistochemical staining for CXCR4, CXCR5, CCR7, CXCL12, and CXCL13 was performed on 89 tissue samples, including cases of primary central nervous system lymphoma (PCNSL), secondary CNS lymphoma (sCNSL), and systemic DLBCL. Also, 10 reactive lymph node samples were included. Immunoelectron microscopy was performed on two PCNSLs, one sCNSL, one systemic DLBCL, and one reactive lymph node samples, and staining was performed for CXCR4, CXCR5, CXCL12, and CXCL13. Chi-square test was used to determine correlations between clinical parameters, diagnostic groups, and chemokine receptor expression. Strong nuclear CXCR4 positivity correlated with systemic DLBCL, whereas strong cytoplasmic CXCR5 positivity correlated with CNS involvement (P = 0.003 and P = 0.039). Immunoelectron microscopy revealed a nuclear CXCR4 staining in reactive lymph node, compared with cytoplasmic and membranous localization seen in CNS lymphomas. We found that CNS lymphoma presented a chemokine receptor profile different from systemic disease. Our findings give new information on the CNS tropism of DLBCL and, if confirmed, may contribute to more effective targeting of CNS prophylaxis among patients with DLBCL., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: Diffuse large B-cell lymphoma (DLBCL) is an aggressive and potentially fatal disease. Prediction of risk of relapse is based on clinical markers. There is a need for more accurate biomarkers to select patients for more aggressive first-line treatments. Peroxiredoxins (Prxs) are a family of potent antioxidant proteins. Their prognostic role in DLBCL is unknown., Methods: Altogether, 103 diagnostic biopsy samples from patients with DLBCL were immunohistochemically stained for Prxs I, II, III, V and VI., Results: Strong Prx VI expression was associated with the presence of B-symptoms. There were no other significant associations with traditional risk factors. Five-year disease-specific survival was 68.6% in patients with high cytoplasmic Prx VI intensity vs 97.0% in those with low intensity. In multivariate analysis, high Prx VI expression (HR 12.846, 95% CI 1.722 to 95.807, p=0.013) was an independent risk factor of lymphoma-associated death not related to International Prognostic Index score (HR 2.514, 95% CI 1.040 to 6.073, p=0.041)., Conclusions: High intensity of cytoplasmic Prx VI expression in pretreatment DLBCL samples predicts worse outcome in patients with DLBCL. Whether Prx VI is associated with chemoresistance, and therefore a poorer outcome, needs to be evaluated. If Prx VI is a predictive marker and it proves causality, it would be crucial to study Prx VI ability to become a target enzyme for treatment., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Aims: Hodgkin lymphoma treatments are largely based on the generation of reactive oxygen species, but increased expression of antioxidant enzymes may contribute to chemoresistance. The aims of this study were: to define the extent and prognostic value of oxidative stress marker and antioxidant enzyme expression in Hodgkin lymphomas; and to investigate a potential association between antioxidant enzymes and chemoresistance., Methods and Results: We immunohistochemically assessed expression of peroxiredoxin (Prx) II, Prx III, Prx V, Prx VI, manganese superoxide dismutase (MnSOD), 8-hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine in 99 cases of uniformly treated Hodgkin lymphoma. Localization of 8-OHdG was assessed using transmission electron microscopy, which demonstrated expression in the cytosol and mitochondria. 8-OHdG expression in Reed-Sternberg (RS) cells was associated with advanced stage (P = 0.006) and a lower International Prognostic Score (P = 0.004). Prx III expression in reactive cellular infiltrate was associated with advanced stage (P = 0.002) and B-symptoms (P = 0.0006). Strong cytoplasmic Prx V immunostaining was associated with a low rate of complete response to chemotherapy (P = 0.043). MnSOD immunostaining in RS cells was related to advanced stage (P = 0.031) and to poorer relapse-free survival (RFS) (P = 0.033). Low 8-OHdG expression in the nuclei of RS cells was a predictor of poorer RFS (P = 0.038). Both 8-OHdG and MnSOD were also significant RFS predictors in multivariate analysis., Conclusions: Our results suggest that significant oxidative stress exists in Hodgkin lymphomas, both in RS cells and in reactive cellular infiltrates. Mitochondrial antioxidant enzymes are induced in the most aggressive forms of the disease, and they may play some part in chemoresistance., (© 2014 John Wiley & Sons Ltd.)

Primary central nervous system lymphoma (PCNSL) is sensitive to both chemotherapy and radiation, but the blood-brain barrier limits the usefulness of the most effective chemotherapeutic agents. On the other hand radiation therapy carries along serious long term adverse events. In BBBD-therapy the blood-brain barrier is opened with intra-arterial mannitol infusion thus permitting both the chemotherapeutics and antibodies to enter through blood-brain barrier. So far 17 patients have started the therapy in our clinics. Ten patients have reached a complete response and 8 of these responses are ongoing with follow-up times of 6-62 months.

Tissue inhibitors of metalloproteinases are important regulators of metalloproteinase activity, and the balance of active enzyme and inhibitor is a critical determinant of tumor cell invasiveness. This study aimed to evaluate the prognostic and clinical implications of the two main inhibitors of matrix metalloproteinases, TIMP-1 and TIMP-2, in endometrial carcinoma. The material consisted of 241 patients with primary endometrial carcinoma. The median follow-up time was 77 months. Expressions of TIMP-1 and TIMP-2 proteins were examined in paraffin-embedded tumor sections by immunohistochemical methods. Positive staining for TIMP-1 and -2 was observed in 88% and 86% of the primary tumors, respectively. The Kaplan-Meier analysis showed that the 5-year cancer-specific survival rate of the patients with TIMP-2 positive immunostaining was 89% and that of the TIMP-2 negative patients 78%. Positive immunoreaction for TIMP-2 correlated with favorable cancer-specific and overall survival. When including only endometrioid adenocarcinomas, a similar trend towards favorable survival was seen. Excluding stage IA carcinomas, the difference became again statistically significant. For TIMP-1, there was no statistically significant association with overall or cancer-specific survival. The Cox regression analysis showed stage, grade and TIMP-2 to be significant predictors of survival. We suggest that TIMP-2 may have a more important role in endometrial carcinoma progression than TIMP-1 and might serve as a potential marker for favorable prognosis in this type of cancer.

The objective of this immunohistochemical study was to explore the roles of Ki67 and p53 in conjunction with matrix metalloproteinase-2 and matrix metalloproteinase-9, tissue inhibitors of metalloproteinase-1 and tissue inhibitors of metalloproteinase-2 in a series of 157 cases of skin melanomas. Elevated Ki67 expression and positive staining for p53 correlated to the propensity to metastasize (P = .016) and to declined disease-specific survival, as well as to shortened recurrence-free survival. In patients with a high immunoreaction for Ki67, the 10-year disease-specific survival was 39% compared with 73% in patients with a low Ki67 expression (P = .03). In cases with a positive p53 expression in melanoma cells, the 10-year disease-specific survival was 59% compared with 76% in patients with a negative immunoreaction for p53 (P = .005). Overexpression of the matrix metalloproteinase 2 protein in conjunction with overexpression of Ki67 characterized melanomas with high metastatic potential and was associated with declined survival with a 10-year disease-specific survival of 33% compared with 85% in the cases with low matrix metalloproteinase-2 and low Ki-67 levels (P = .002). Similarly, in cases with overexpression of matrix metalloproteinase-2 and a positive immunoreaction for p53, the 10-year disease-specific survival was only 42% compared with 80% in patients with matrix metalloproteinase-2 less than 20% and a negative immunostaining for p53 (P < .001). The presence of all 3 adverse prognostic factors was prognostically more significant than any marker alone with a 10-year survival of only 28%. This combination of determining matrix metalloproteinase 2, Ki67, and p53 immunoreactive proteins could be beneficial in the selection of high-risk melanoma patients for future adjuvant trials., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Oxidative stress markers and peroxiredoxins are connected to cancer. A large set of urinary bladder carcinomas were studied for the expression of nitrotyrosine and 8-hydroxydeguanosine (8OHdG), two markers indicating oxidative damage. Serum and urine 8-OHdG were assessed in a subset of patients. We also analysed immunohisto-chemically the expression of nrf2, keap1, all six peroxiredoxins (prx) and thioredoxin (trx) in these tumors. 15 % of the cases showed 8OHdG and 36 % nitrotyrosine positivity. Expression of nitrotyrosine and 8OHdG associated with a poor prognosis (p=0.050, p=0.011, respectively). Peroxiredoxin positivity ranged from 39 % to 84 % lowest expression being for prx 4 and highest for prx 3. Prx 4 expression associated with a poor prognosis (p=0.025) with high grade (p=0.044) and larger tumors (p=0.023). Cytoplasmic trx positivity was seen in 91 % and nuclear in 59 % of tumors. Nuclear and cytoplasmic trx associated with each other (p<0.001), and nuclear trx associated with prx 6 (p=0.001), prx 2 (p<0.001), and prx 5 (p<0.001). 8OHdG associated with nuclear trx positivity (p=0.002), inversely with prx 1 (p=0.025) and with keap1 (p=0.020). Nuclear nrf2 was associated with nitrotyrosine (p=0.042). The results show that the amount of oxidative stress in urinary bladder tumors affects the prognosis of the patients. Of antioxidative enzymes, prx4 associated with an unfavourable prognosis. Selective inhibition of prx4 expression might then be one additional option of treatment of bladder cancer.

Background: Potential tissue and serum biomarkers were assessed for predicting efficacy of bevacizumab in ovarian cancer (OC)., Patients and Methods: Twenty patients with OC received chemotherapy alone (control group) or in combination with bevacizumab (study group) in this non-randomised study. Pre- and post-treatment serum concentrations of vascular endothelial growth factor (VEGF), 8-hydroxydeoxyguanosine (8-OHdG) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured in all patients. In addition, immunohistochemical expressions VEGF receptors (R1, R2), hypoxia-inducible factor 1alpha (HIF-1 alpha), matrix metalloproteinases (-2, -9) and TIMP-2 were analysed in tumours from bevacizumab-treated patients., Results: 8-OHdG and HIF-1alpha immunostainings were more highly expressed among patients with progression-free survival (PFS) >23 months than in patients with PFS <12 months. Similarly, MMP-9 was more frequently highly expressed in those with long versus short PFS. Serum VEGF concentrations decreased substantially in all bevacizumab-treated patients versus only 20% of the control group., Conclusion: Our results indicate differences in MMP-9 and HIF-1alpha expression in relation to duration of PFS and effects on serum VEGF when bevacizumab is used in combination with chemotherapy.

Background: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a key role in extracellular matrix (ECM) turnover and remodeling. Changes in their expression levels have been observed in various tumor types. However, their clinical significance and prognostic importance in the progression of endometrial carcinoma is still unclear. This study aimed to evaluate the circulating levels of gelatinases and tissue inhibitors of gelatinases, and to study their relationships with the clinical behavior of endometrial cancer., Materials and Methods: Pretreatment serum levels of MMP-2, MMP-9, TIMP-1, TIMP-2 and MMP-2/TIMP-2 complex were quantitatively measured by enzyme-linked immunosorbent assay (ELISA) in 93 patients presenting with primary endometrioid endometrial adenocarcinoma. The study population was divided into low-risk and high-risk patient groups as determined by conventional prognostic criteria., Results: Elevated serum levels of TIMP-1 at diagnosis were found in the high-risk patient group (p=0.018). The median follow-up time was 101 months. A cut-off value of 536 ng/ml was used to divide the serum values of TIMP-1 into two groups. A high serum concentration of TIMP-1 was associated with shortened relapse-free (p=0.036) and cancer-specific survival (p=0.029)., Conclusion: The results suggest that the preoperative serum TIMP-1 level predicts the behavior of endometrial cancer. However, in multivariate analysis TIMP-1 was not an independent prognostic factor.

Background: [corrected] The purpose of this study was to explore whether changes in matrix metalloproteinase-9 (MMP-9) are involved in the progression of urinary bladder cancer and whether they have any prognostic value., Patients and Methods: Overexpression of MMP-9 was evaluated in the primary tumor of 87 urinary bladder cancer cases with immunohistochemical staining., Results: Of the urinary bladder carcinomas, 38% showed an overexpression (>25%) of MMP-9 immunoreactive protein. Increased positivity for MMP-9 correlated with favorable overall survival of the urinary bladder cancer patients. The 5-year overall survival and relapse-free survival was 68% and 36% in patients showing high MMP-9 expression and 48% and 19% in patients with low (<25%) or negative MMP-9 expression (p=0.006, p=0.08, respectively). In multivariate analysis, MMP-9 overexpression seems to retain its independent prognostic value., Conclusion: This study shows that MMP-9 expression in urinary bladder carcinoma is associated with better prognosis.

Previously, gelatinases matrix metalloproteinase (MMP)-2 and MMP-9 have been shown to be involved in melanoma invasion and progression. Also, overexpression of MMP-2 has been suggested to be linked to hematogenous metastasis in melanoma. This study was conducted to study the prognostic value of MMP-2 and MMP-9 in human melanoma. The expression of MMP-2 and MMP-9 immunoreactive protein was evaluated in 157 cases of primary melanomas. An immunohistochemical analysis using specific monoclonal antibodies for MMP-2 and MMP-9 on paraffin-embedded tissues was performed, and the immunostaining results were compared with the clinical course of melanoma. Overexpression of MMP-2 (>20% of malignant cells positive) was an independent prognostic marker for melanoma related death, with odds ratio of 2.6 (95% confidence interval, 1.32-5.07). The 10-year disease-specific survival rate was only 51% in patients with overexpression of MMP-2 protein compared with 79% in patients with a primary melanoma with low expression for MMP-2 (P = .001). Interestingly, male patients with a melanoma with overexpression of MMP-2 showed a 10-year disease-specific survival of only 41% compared with 77% in other male patients (P = .003). It is notable that the immunoreactive protein for MMP-9 in primary melanoma was not found to be of any prognostic importance. In the future, MMP-2 could be acknowledged as a new prognostic factor in melanoma. MMP-9, on the other hand, was not associated with the clinical course of melanoma. Based on the current data, MMP-2 could be evaluated as an inclusion factor for adjuvant studies especially in male melanoma patients.

Background: Matrix metalloproteinase-2 (MMP-2) (gelatinase A) and MMP-9 (gelatinase B) have the ability to degrade several extracellular matrix components. This study aimed to evaluate whether matrix metalloproteinases (MMP-2, MMP-9, MMP-2-TIMP-2 complex) or their tissue inhibitors (TIMP-1, TIMP-2) could be used as preoperative serum markers in differentiating between low malignant potential (LMP) and malignant ovarian tumours., Patients and Methods: The study population consisted of 61 patients with ovarian neoplasms (28 benign, 11 LMP and 22 malignant). MMP-2, MMP-9, MMP-2-TIMP-2 complex, TIMP-1 and TIMP-2 were analysed from serum samples using enzyme-linked immunoassay (ELISA)., Results: Serum TIMP-1 values significantly increased from benign (median 250 microg/l, range 137-616 microg/l) to LMP (median 357 microg/l, range 63-587 microg/l) and further to malignant (median 443 microg/l, range 199-983 microg/l) ovarian neoplasms (p<0.001). There was a significant difference in the ratios of TIMP-1 to MMP-2 and TIMP-1 to MMP-2-TIMP-2 complex between the patients with benign vs. malignant and an LMP vs. malignant tumour., Conclusion: The value of circulating TIMP-1 and the ratios of TIMP-1 to MMP-2 and TIMP-1 to MMP-2-TIMP-2 complex may be valuable for differentiating between LMP and malignant ovarian tumours.

Objectives: To examine whether the circulating TIMP-2 or MMP-2:TIMP-2 complex associate with disease-free or cause-specific survival in bladder cancer patients., Design and Methods: Levels of circulating TIMP-2 and MMP-2:TIMP-2 complex from 50 patients and 44 healthy volunteers were measured by ELISA and compared with the clinical data., Results: In cancer patients the levels of TIMP-2 and MMP-2:TIMP-2 complex were significantly lower than in healthy volunteers (p= or <0.0001). Low TIMP-2 levels and low MMP-2:TIMP-2 complex levels correlated significantly with poor prognosis (p=0.0032, p=0.0022, respectively). The 5-year cause-specific survival rate was 67% and 60% in patients with a high serum level for TIMP-2 and MMP-2:TIMP-2 versus 18% and 20% in those with low levels of TIMP-2 and MMP-2:TIMP-2 complex., Conclusions: The results indicate that TIMP-2 and MMP-2:TIMP-2 complex associate with favorable clinical course and could be used as a novel prognostic indicators in bladder cancer.

Background: Gelatinases and tissue inhibitors of metalloproteinases (TIMPs) are involved in tumour invasion and metastasis. High pre-operative TIMP-1 serum values have been previously found to correlate to aggressive features in ovarian cancer patients. This study has examined the clinical value of sequential serum measurements of gelatinases and TIMPs during ovarian cancer treatment., Patients and Methods: Serum gelatinase and TIMP values were measured in 48 patients receiving cytotoxic chemotherapy for ovarian cancer. The serum values were analysed by enzyme-linked immunosorbent assay (ELISA) in the third and sixth chemotherapy cycles, and compared to the treatment response., Results: Increased MMP-9 (matrix metalloproteinase-9), TIMP-2 and MMP-2 mean serum values were observed in optimally operated patients with a complete response to treatment, compared to those with a partial response. No significant differences were found in the change of circulating TIMP-1 values in the different chemotherapy response groups., Conclusion: Measuring the serum values of gelatinases or TIMP-2 sequentially during chemotherapy might be beneficial for response evaluation in optimally operated patients, whereas the serum TIMP-1 values might not contribute to an evaluation of the treatment response.

Malignant tumors that are capable of invading surrounding structures and metastasizing possess certain capacities to cross tissue barriers. Matrix metalloproteinases (MMPs), especially gelatinases and their inhibitor molecules, are known to affect the extracellular matrix turnover, and the proteolytic imbalance due to the abnormal expression of these enzymes eventually leads to cancer progression. This has been well documented at the tissue level. In this study, the different forms of the circulating MMP-2 have been studied in the preoperative sera of 71 patients with breast carcinoma. A quantitative enzyme-linked immunosorbent assay was performed for total proMMP-2, proMMP-2-tissue inhibitor of metalloproteinase 2 (TIMP-2) complex, and free active MMP-2. It is shown here, for the first time, that the total proMMP-2 levels in the serum correlate inversely with node positivity, high stage of the disease, and high nuclear grade of the breast tumor. An association with the levels of lower free active MMP-2 and tumor recurrence is also demonstrated. Interestingly, the tumor tissue expression of MMP-2 had an inverse correlation with proMMP-2-TIMP-2 complex levels in the serum. In conclusion, the levels of the total proMMP-2 correlate inversely with tumor burden, whereas free active MMP-2 might be associated with survival. This could indicate that the prognostic value of the circulating forms of MMP-2 is not congruent with the prognostic information obtained from tissue expression. This is further supported by the inverse correlation of the proMMP-2-TIMP-2 complex and MMP-2 tissue expression in the tumor. Therefore, the different forms of circulating metalloproteinases need to be evaluated further to explore their full potential for clinical use.

Useful markers showing biological aggressiveness of head and neck squamous cell carcinoma (HNSCC) are needed to predict the outcome of the disease. MMP-2 is associated with aggressive behavior of several solid cancers. In this study, the clinical significance of tumor tissue and circulating immunoreactive proteins for MMP-2 and TIMP-2 was assessed in HNSCC. The study group consisted of 74 patients with HNSCC and 44 healthy controls. Expression of MMP-2 and TIMP-2 was examined in paraffin-embedded tumor sections by immunohistochemical methods using specific antibodies. The pretreatment serum levels of MMP-2, TIMP-2 and MMP-2:TIMP-2 complex were quantitatively measured by ELISA assay. The results were compared with the clinicopathological factors of the disease and the patients' outcome. Immunohistochemical overexpression of MMP-2 in tumor was found to be prognostic for shortened survival in HNSCC, the 5-year cumulative relapse-free survival being 42% in patients with high positivity for MMP-2 in tumor vs 61% in cases with a negative or only weakly MMP-2-positive tumor (P=0.045). Tissue MMP-2 positivity was also strongly connected with later lymph node or hematogenic relapses and associated to the cause-specific survival (P=0.055). Similarly, the 5-year cause-specific survival was significantly poorer in patients with extensive positive immunostaining for tumor TIMP-2 than in those with a TIMP-2-negative tumor (40 vs 64%, P=0.038). Patients with a TIMP-2-positive tumor also had an unfavorable 5-year relapse-free survival rate (43 vs 60%, respectively, P=0.071). Additionally, the overexpression of TIMP-2 was a powerful predictor of later lymph node or hematogenous metastases in HNSCC. Serum levels of MMP-2, TIMP-2 or MMP-2:TIMP-2 complex failed to associate with the clinical behavior of HNSCC in this material. The results of this study provide evidence that MMP-2 and TIMP-2 immunoreactive protein in tumor tissue of HNSCC patients, but not when assayed from preoperative serum samples, are prognostic in estimation of the aggressive clinical course of HNSCC.

Matrix metalloproteinase-2 (MMP-2), a member of the zinc-dependent metalloproteinase gene family, plays an important role in cancer invasion and metastasis. The current study aimed to evaluate whether the expression of MMP-2 is associated with survival in patients with endometrial endometrioid adenocarcinoma. The MMP-2 immunoreactive protein was evaluated from endometrioid adenocarcinoma of the endometrium in 112 patients treated at Oulu University Hospital, Finland. The median follow-up time was 88 months. The expression of MMP-2 was studied immunohistochemically in paraffin-embedded tissue samples from the primary tumours by using a specific monoclonal antibody to MMP-2. The MMP-2 protein was found in 80% of the primary tumours, including all histological grades. All grade 3 tumors were MMP-2-positive. At the end of the study period, 21 of the 22 (95%) patients presenting MMP-2-negative immunostaining were alive, whereas the corresponding figure for those with MMP-2-positive tumours was 78 out of 90 (87%). These data suggest that MMP-2 immunostaining negativity might be linked with a favourable prognosis in endometrial endometrioid adenocarcinoma.

The aim of this study was to determine whether serum matrix metalloproteinase-9 (MMP-9) could predict cause-specific and relapse-free survival in patients with squamous cell carcinoma of head and neck. Furthermore, this study was designed to investigate whether there is an association between MMP-9 immunohistochemical staining and serum MMP-9 levels. Pretreatment serum levels of MMP-9 were quantitatively measured by ELISA assay in 67 patients presenting with a primary head and neck squamous cell carcinoma. The results were compared with the corresponding immunohistochemical staining results, clinical data and the patients' outcome. The follow-up time for all of the patients was at least 5 years. There was a statistically significant correlation between circulating MMP-9 and MMP-9 immunohistochemical staining in the corresponding tumors (p = 0.028). The cause-specific and relapse-free survival rates were clearly lower among patients with high MMP-9 serum levels (> 73 ng/ml). The 5-year cause-specific survival-rate was 40% in a patient group with high serum MMP-9, and 69% for patients with a low MMP-9 level (p = 0.027). In the same follow-up period, the cumulative relapse-free survival rate was 36% in patients presenting with a high serum MMP-9 and 66% in those with a low MMP-9 level. No correlation was found between MMP-9 serum levels and the traditional clinical or histopathologic factors. The results suggest for the first time that pretreatment serum MMP-9 level could serve as a prognostic factor in head and neck squamous cell carcinoma.

Expression of cyclooxygenase-2 (COX-2) and matrix metalloproteinase-2 (MMP-2) associates with reduced survival in human breast cancer. COX-2 may be directly involved with mammary carcinogenesis, since expression of COX-2 is sufficient for formation of breast tumors in transgenic mice, and COX-2 selective inhibitors can suppress tumorigenesis in rodent models of breast cancer. MMP-2 is an extracellular matrix degrading proteolytic enzyme that bas been linked to invasion and metastasis. A direct link between COX-2 and MMP-2 may exist, since inhibition of COX-2 activity can result in reduction of MMP-2 expression and activity. In this study we analyzed protein expression of COX-2 and MMP-2 in tissue array specimens of 278 invasive breast cancers by immunohistochemistry. Immunopositivity of these two markers was correlated with each other and with various clinicopathological parameters including survival. We found high COX-2 expression in 30% and high MMP-2 expression in 83% of the breast cancer specimens, and there was a positive association between the expression of these two factors (p = 0.003). It was especially evident that whenever COX-2 expression was high, MMP-2 expression was almost invariably high (95%). Furthermore, high expression of either COX-2 or MMP-2 associated with decreased disease specific survival when compared with the COX-2 or MPP-2 low group (p = 0.026 and p = 0.021, respectively). Taken together, our results indicate that expression of COX-2 protein is associated with expression of MMP-2 protein in human breast cancer and that both COX-2 and MMP-2 are markers of poor prognosis in breast cancer.

The amount of the immunoreactive protein for the tissue inhibitor of the matrix metalloproteinase-1 (TIMP-1) was studied prospectively from the pretreatment sera of 71 breast carcinoma patients using an enzyme-linked immunoassay (ELISA). The study consisted of patients with a primary breast carcinoma diagnosed between 1988 and 1991. The median follow-up time was more than 10 years, and routine adjuvant treatment was not used in the primary treatment. High TIMP-1 (> 196 ng/ml) was found to correlate with a poor relapse-free survival (RFS) in primary node-negative breast carcinoma. After 10 years of the follow-up only 42% of the patients with a high preoperative serum TIMP-1-level were free of the relapse, whereas 82% of the patients with a low serum TIMP-1 enjoyed a long RFS-time (log rank p =0.009). High serum TIMP-1 also indicated poor RFS (p = 0.02) and overall survival (p = 0.05) in stage I breast carcinoma. In Kaplan-Meier analysis the RFS was 89% in patients with a low serum level of TIMP-1 compared to 52% in patients with a high serum concentration of TIMP-1. In conclusion, preoperative high serum TIMP-1 levels predict poor outcome in primary breast carcinoma. In multivariate analysis preoperative high serum TIMP-1 increases the risk of relapse 3.4-fold during the first 10 years of follow-up in primary node-negative breast carcinoma.

Background: Matrix metalloproteinases (MMPs) are involved with tumour invasion and metastasis. Controversial data exists concerning the prognostic value of MMP-9 in breast carcinoma. We examined, here, whether the MMP-9 immunoreactive protein would correlate with--the prognosis in breast carcinoma treated with hormonal adjuvant therapy., Materials and Methods: The MMP-9 status was determined immunohistochemically from primary tumour specimens in 168 postmenopausal breast cancer patients with a locally advanced (N+) disease treated with antiestrogen for three years after the primary therapy., Results: A positive immunostaining for MMP-9 was found in 61.3% of 168 primary tumours without any significant correlation to clinical stage, histology or hormone receptor status. MMP-9 immunoreactivity did not correlate with the survival when the entire study population was included in the analysis. There was, however, a compromised disease-free survival in a subgroup of patients presenting with an estrogen receptor-negative and MMP-9-positive tumour. The 5-year disease-free survival was only 37% in those patients, when it was 63% in the patients with a tumour negative for both estrogen receptor and MMP-9., Conclusion: We suggest that the prognostic value of MMP-9 immunoreactivity in the primary tumour is not generally strong in breast carcinoma, but it might correlate with the clinical benefit of an antiestrogen therapy, since MMP-9 positivity seemed to correlate with early recurrence in patients with an estrogen receptor-negative primary tumour.

Purpose: To assess the relative importance of 10 prognostic factors in pT1N0M0 breast cancer (< or =2 cm in diameter, node negative)., Experimental Design: Women diagnosed with breast cancer in Finland from 1991 to 1992 were identified from the files of the Finnish Cancer Registry, and individual clinicopathological data were collected from the hospital case records of women living in five regions comprising about one-half of the Finnish population. Of the women with minimum required information available (n = 2842), 852 had unilateral pT(1)N(0)M(0) cancer. The median follow-up time was 9.5 years, and only 5% had received systemic adjuvant therapy. Estrogen receptor (ER), progesterone receptor, erbB2, p53, and Ki-67 expression was determined from tumor tissue microarrays using immunohistochemistry, and the erbB2 (HER-2) amplification status was determined using chromogenic in situ hybridization., Results: Primary tumor size < or =5 mm and histological grade 1 were associated with 100 and 95% (95% confidence interval, 92-98%) 9-year distant disease-free survival, respectively, whereas strong erbB2 expression or the presence of >20% Ki-67-positive cells was associated with >20% risk. ER and progesterone receptor values obtained from the hospital case records or tumor microarrays showed weaker association with outcome than the erbB2 status. Small (< or =10 mm) erbB2-negative cancers were associated with >90% 9-year distant disease-free survival, irrespective of histological grade., Conclusions: Prognosis of pT(1)N(0)M(0) breast cancer is generally well defined by the histological grade and primary tumor size. The erbB2 status was superior to ER as a prognostic factor in these tumors.

Node-negative breast carcinoma is associated with favorable prognosis in breast carcinoma. Despite therapy some early stage breast carcinoma patients still die of metastatic disease. Prognostic factors are needed to define patients for new treatment modalities. Matrix metalloproteinase-2 (MMP-2) has been shown to be associated with tumor invasiveness and MMP-2 negativity has been linked with favorable prognosis in node-positive breast carcinoma. Here, the prognostic value of MMP-2 in node-negative, T(1-2) breast carcinoma patients was evaluated in 137 cases. Expression of MMP-2 was studied in paraffin-embedded tissue sections from primary tumors using a specific monoclonal antibody for MMP-2 in an avidin-biotin-peroxidase immunohistochemical staining. Postoperative survival rates were analyzed by the Kaplan-Meier method and the differences between the survival were compared by means of log-rank test. All MMP-2 negative patients were alive during the 10 years' follow-up, compared to the 87% survival in the MMP-2 positive group. MMP-2 negativity seemed to improve the prognosis in the estrogen receptor negative group. The differences did not achieve statistical significance due to few events in the node-negative group. In conclusion, we suggest that MMP-2 negativity may be linked with a favorable prognosis in node-negative breast carcinoma.