Progression-free survival after front line, second line and third line in patients with follicular lymphoma treated in clinical practice.

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.

Cancer Patients' Social Relationships During 3 Years After Diagnosis-Generic and Cancer-Specific Social Networks.

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.

Primary central nervous system lymphoma high incidence and poor survival in Finnish population-based analysis.

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.

Impact of central nervous system (CNS) prophylaxis on the incidence of CNS relapse in patients with high-risk diffuse large B cell/follicular grade 3B lymphoma.

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.

Thioredoxin-1 as a biological predictive marker for selecting diffuse large B-cell lymphoma patients for etoposide-containing treatment.

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.

Risk of secondary haematological malignancies in patients with follicular lymphoma: an analysis of 1028 patients treated in the rituximab era.

Follicular lymphoma (FL) is the most common indolent lymphoma. Currently there are many comparable treatment options available for FL. When selecting the most optimal therapy it is important to consider possible late effects of the treatment as well as survival. Secondary haematological malignancy (SHM) is a severe late effect of treatments, but the incidence of SHMs is still largely unknown. The goal of the present study was to determine the incidence of SHMs and how therapeutic decisions interfere with this risk. The study included 1028 FL patients with a median follow-up time of 5·6 years. The 5-year risk of SHM was 1·1% and the risk was associated with multiple lines of treatment (P = 0·016). The 5-year risk of SHM was 0·5% after the first-line treatment and 1·6% after the second-line. The standardized incidence ratio (SIR) was 6·2 (95% confidence interval 3·4-10·5) for SHM overall. This retrospective study found that the risk of SHM was low after first-line treatment in FL patients from the rituximab era. However, the risk of SHM increases with multiple lines of treatment. Therapeutic approaches should aim to achieve as long a remission as possible with first-line treatment, thereby postponing the added risk of SHM.

Incidence of solid cancer in patients with follicular lymphoma.

Introduction: Patients with follicular lymphoma (FL) have classically had a higher risk of solid cancers than the general population, but there is little data available in patients diagnosed and treated with modern day regimens.Material and methods: We conducted a retrospective multicenter study assessing the cumulative incidence of solid cancers other than nonmelanoma skin cancer in patients with FL between 1997 and 2016 and determined the standardized incidence ratio (SIR) to compare the incidence of solid cancers with that of the general populationResults: Among 1002 FL patients with 7 years of median follow-up, we found 74 solid cancers (most common breast [n = 19], lung and colon [n = 9 each]). The cumulative incidence was 3.8% at 5 years (95%CI 2.6-5.2) from the time of diagnosis and 4.4% at 5 years (95%CI 3.1-5.9%) from the time of front-line treatment. Although a comparison of all front-line strategies did not reveal differences in the risk of solid cancers, patients treated with anthracycline-based regimens appeared to have a lower incidence than those treated with bendamustine-based strategies (2.8% vs. 6.9%). However, patients receiving the former regimen were younger than the latter. On multivariable analysis, older age was correlated with the incidence of solid cancer and bendamustine-based treatment was of borderline significance. SIR for any solid cancer was 1.22 (95%CI 0.91-1.64), indicating no increased risk of solid cancer in patients with FL over that of the general population. However, on subgroup analyses, female patients treated with bendamustine-based strategies appeared to have a greater risk (SIR 3.85 [95%CI 1.45-10.27])Discussion: The incidence of solid cancer in this cohort of patients with FL was low and not greater than in the general population. However, the risk may be greater in female patients treated with bendamustine.

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.

Promising treatment results with blood brain barrier disruption (BBBD) based immunochemotherapy combined with autologous stem cell transplantation (ASCT) in patients with primary central nervous system lymphoma (PCNSL).

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.

Biological subtyping of early breast cancer: a study comparing RT-qPCR with immunohistochemistry.

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.

Similar chemokine receptor profiles in lymphomas with central nervous system involvement - possible biomarkers for patient selection for central nervous system prophylaxis, a retrospective study.

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.

Antithrombin III is probably not a suitable biomarker for diagnosis of primary central nervous system lymphoma.

Antithrombin III (AT III) in cerebrospinal fluid (CSF) has been suggested to have high specificity and sensitivity in separating primary central nervous system (CNS) lymphoma from other neurological conditions. We measured with ELISA CSF and serum AT III and albumin levels in 12 lymphoma patients with CNS involvement, 30 lymphoma patients without CNS involvement, and 41 patients with non-neoplastic neurological diseases. AT III immunostaining was also carried out, in lymphoma patients. Both CSF AT III and albumin levels were higher in lymphoma patients with CNS involvement. AT III/albumin ratio in CSF was the most sensitive and specific measure for diagnosis. Lowest it was in patients with known CNS lymphoma. Serum AT III levels were lower both in CNS lymphoma and systemic lymphoma. CSF AT III levels were shown to be higher in lymphoma patients with CNS involvement, when AT III/albumin ratios were lower. This was probably a result of lowered serum AT III levels, indicating that high levels of AT III in CSF might reflect only leakage of the blood-brain barrier. Thus, AT III fails to be a specific marker for diagnosis of lymphoma CNS involvement.

Constant pattern of relapse in primary central nervous lymphoma patients treated with high-dose methotrexate combinations. A Finnish retrospective study.

BACKGROUND: 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 is poor. MATERIAL AND METHODS: We performed a hospital-based retrospective analysis to evaluate the long-term results of the Nordic type of Bonn chemotherapy regimen in PCNSL patients. The study included 54 patients with newly diagnosed PCNSL who received chemotherapy with curative intent as their first-line treatment. RESULTS: We found promising response rates, 76% of the patients achieving CR and 22% patients achieving PR, with corresponding two-year EFS 53% and OS 76%. However, with longer follow-up a constant pattern of relapses was observed with only one patient remaining in primary remission after 60 months. DISCUSSION: The finding suggests that basic biological differences exist between PCNSL and systemic diffuse large B-cell lymphoma and there is a need for consolidation or maintenance therapy after achieving a remission in patients with PCNSL.

Oxidative stress markers and mitochondrial antioxidant enzyme expression are increased in aggressive Hodgkin lymphomas.

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.

2-Weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial.

BACKGROUND: Docetaxel administered every 3 weeks is a standard treatment for castration-resistant advanced prostate cancer. We hypothesised that 2-weekly administration of docetaxel would be better tolerated than 3-weekly docetaxel in patients with castration-resistant advanced prostate cancer, and did a prospective, multicentre, randomised, phase 3 study to compare efficacy and safety. METHODS: Eligible patients had advanced prostate cancer (metastasis, a prostate-specific-antigen test result of more than 10·0 ng/mL, and WHO performance status score of 0-2), had received no chemotherapy (except with estramustine), had undergone surgical or chemical castration, and had been referred to a treatment centre in Finland, Ireland, or Sweden. Enrolment and treatment were done between March 1, 2004, and May 31, 2009. Randomisation was done centrally and stratified by centre and WHO performance status score of 0-1 vs 2. Patients were assigned 75 mg/m(2) docetaxel intravenously on day 1 of a 3-week cycle, or 50 mg/m(2) docetaxel intravenously on days 1 and 15 of a 4-week cycle. 10 mg oral prednisolone was administered daily to all patients. The primary endpoint was time to treatment failure (TTTF). We assessed data in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00255606. FINDINGS: 177 patients were randomly assigned to the 2-weekly docetaxel group and 184 to the 3-weekly group. 170 patients in the 2-weekly group and 176 in the 3-weekly group were included in the analysis. The 2-weekly administration was associated with significantly longer TTTF than was 3-weekly administration (5·6 months, 95% CI 5·0-6·2 vs 4·9 months, 4·5-5·4; hazard ratio 1·3, 95% CI 1·1-1·6, p=0·014). Grade 3-4 adverse events occurred more frequently in the 3-weekly than in the 2-weekly administration group, including neutropenia (93 [53%] vs 61 [36%]), leucopenia (51 [29%] vs 22 [13%]), and febrile neutropenia (25 [14%] vs six [4%]). Neutropenic infections were reported more frequently in patients who received docetaxel every 3 weeks (43 [24%] vs 11 [6%], p=0·002). INTERPRETATION: Administration of docetaxel every 2 weeks seems to be well tolerated in patients with castration-resistant advanced prostate cancer and could be a useful option when 3-weekly single-dose administration is unlikely to be tolerated. FUNDING: Sanofi.

Drug-induced pneumonitis risk in diffuse large B-cell/follicular lymphoma patients treated with R-CHOP-like regimen is associated with the use of granulocyte colony-stimulating growth factors.

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.

Biological roles and prognostic values of the epithelial-mesenchymal transition-mediating transcription factors Twist, ZEB1 and Slug in diffuse large B-cell lymphoma.

AIMS: To evaluate the biological roles and prognostic significance of the epithelial-mesenchymal transition (EMT)-mediating transcription factors (TFs) Twist, ZEB1 and Slug in patients with diffuse large B-cell lymphoma (DLBCL). EMT has been shown to enhance solid tumour metastasis, invasion, and proliferation. METHODS AND RESULTS: Expression of Twist, ZEB1 and Slug was evaluated immunohistochemically in eight samples from reactive lymphoid tissues and in diagnostic samples from 102 DLBCL patients treated with curative intent with R-CHOP-type chemotherapy. ZEB1 and Slug expression correlated with adverse disease presentation. However, cytoplasmic Slug expression was linked to a favourable disease outcome, whereas nuclear expression of ZEB1 indicated an adverse outcome. CONCLUSIONS: This study shows that an EMT-like process occurs in lymphomas. Of the TFs investigated, ZEB1 seems to be the main one associated with adverse clinical presentation and clinical outcome. Surprisingly, Slug expression in cytoplasm was linked to a favourable prognosis. Further studies are needed to evaluate whether inhibition of ZEB1 could serve as a therapeutic target.

Circulating matrix metalloproteinase MMP-9 and MMP-2/TIMP-2 complex are associated with spontaneous early pregnancy failure.

BACKGROUND: Trophoblast cell (CTB) invasion into the maternal endometrium plays a crucial role during human embryo implantation and placentation. This invasion is facilitated by the activity of matrix metalloproteinases, which are regulated by tissue inhibitors of MMPs (TIMPs). METHODS: This study compares the serum levels of MMP-9, MMP-2/TIMP-2 complex, TIMP-1 and TIMP-2 in 129 patients with ongoing pregnancy (n = 40) or spontaneous early pregnancy failure (n = 89). RESULTS: MMP-9 was markedly (p < 0.0001) elevated in missed abortions, as was MMP-2/TIMP-2 complex (p < 0.0005). However, the serum levels of TIMP-1 and TIMP-2 were markedly elevated (p < 0.0001) in ongoing pregnancies. CONCLUSIONS: Human placentation is mediated by fetal trophoblastic cells that invade the maternal uterine endometrium. Trophoblast invasion requires a precisely regulated secretion of specific proteolytic enzymes able to degrade the endometrial basement membrane and extracellular matrix. The elevated levels of MMP-9 and MMP-2/TIMP-2 complex may play a role in spontaneous termination of pregnancy.

Cell cycle regulation score predicts relapse-free survival in non-germinal centre diffuse large B-cell lymphoma patients treated by means of immunochemotherapy.

OBJECTIVES: The cell cycle is under strict regulation by the retinoblastoma, p53 and p27 pathways, and the disruption of these pathways is an important characteristic of diffuse large B-cell lymphoma (DLBCL). In this study, we wanted to assess the function and prognostic significance of these pathways in DLBCL patients. METHODS: Tissue samples from 120 DLBCL patients treated by means of R-CHOP-type chemotherapy were stained for the cell cycle-regulating proteins p16, p21, p27 and p53, and the germinal centre (GC) phenotype was determined according to Hans' algorithm. Based on the number of impaired cell cycle-regulating pathways a predictive score was obtained, covering three different prognostic groups: a 'favourable' group with damage in 0-1 of the studied pathways, a 'poor' group with damage in all three pathways and an 'intermediate' group comprising the rest of the patients. RESULTS: The prognosis of non-GC DLBCL patients was significantly poorer vs. GC phenotype patients (P = 0.015). The prognostic score proved especially useful among non-GC phenotype patients, with 3-yrs relapse-free survival of 100% vs. 62.6% vs. 24.3% in the 'favourable-', 'intermediate-' and 'poor prognosis' groups, respectively (P = 0.003). CONCLUSION: The prognosis of non-GC DLBCL patients is progressively impaired with the accumulation of damage in different cell cycle-regulating pathways.