Levels of Circulating TIMP-2 and MMP2-TIMP2 Complex Are Decreased in Squamous Cervical Carcinoma

Background. The role of matrix metalloproteinase-2 and -9 (MMP-2, MMP-9) in matrix degradation and metastasis has been described in various tumors. Their action is inhibited by their natural tissue inhibitor molecules TIMP-1 and -2. Methods. The study population consisted of 12 squamous cervical carcinoma patients and 27 healthy volunteer control patients. MMP-9, MMP-2-TIMP-2 complex, TIMP-1, and TIMP-2 were analyzed from serum samples using enzyme-linked immunoassay (ELISA). Results. The mean levels of serum TIMP-2 and of MMP-2-TIMP-2 complex were higher in healthy controls compared to patients with a malignant tumor. Serum TIMP-2 values decreased significantly from healthy controls (median 323 μg/l, range 305–342 μg/l) to malignant (median 136 μg/l, range 120–151 μg/l) squamous cervical carcinoma patients (P < .000). Also, serum proMMP2-TIMP2 complex values decreased from control patients to squamous cervical carcinoma patients (P < .006). Conclusion. This paper shows that the levels of circulating TIMP-2 and that of MMP-2-TIMP-2 complex are lower in squamous cervical carcinoma patients than in healthy women

The Sample Type used Affects the Levels of Gelatinases (MMP-2 and -9) and their Inhibitors (TIMP-1 and -2) in Circulating Blood of Healthy Controls and Breast Cancer Patients

New potential tumor markers such as matrix metalloproteinases and their inhibitors have been extensively studied during the last decades. The aim is to find prognostic markers that are measurable in easily available samples, such as serum or plasma. The proper sample type to use when measuring the levels of gelatinases and their inhibitors from blood samples is currently under critical evaluation. In this study, the effect of sample type is studied in 26 healthy controls, and the result is confirmed in a series of 80 breast carcinoma patients

Development and evaluation of a virtual microscopy application for automated assessment of Ki-67 expression in breast cancer

<p>Abstract</p> <p>Background</p> <p>The aim of the study was to develop a virtual microscopy enabled method for assessment of Ki-67 expression and to study the prognostic value of the automated analysis in a comprehensive series of patients with breast cancer.</p> <p>Methods</p> <p>Using a previously reported virtual microscopy platform and an open source image processing tool, ImageJ, a method for assessment of immunohistochemically (IHC) stained area and intensity was created. A tissue microarray (TMA) series of breast cancer specimens from 1931 patients was immunostained for Ki-67, digitized with a whole slide scanner and uploaded to an image web server. The extent of Ki-67 staining in the tumour specimens was assessed both visually and with the image analysis algorithm. The prognostic value of the computer vision assessment of Ki-67 was evaluated by comparison of distant disease-free survival in patients with low, moderate or high expression of the protein.</p> <p>Results</p> <p>1648 evaluable image files from 1334 patients were analysed in less than two hours. Visual and automated Ki-67 extent of staining assessments showed a percentage agreement of 87% and weighted kappa value of 0.57. The hazard ratio for distant recurrence for patients with a computer determined moderate Ki-67 extent of staining was 1.77 (95% CI 1.31-2.37) and for high extent 2.34 (95% CI 1.76-3.10), compared to patients with a low extent. In multivariate survival analyses, automated assessment of Ki-67 extent of staining was retained as a significant prognostic factor.</p> <p>Conclusions</p> <p>Running high-throughput automated IHC algorithms on a virtual microscopy platform is feasible. Comparison of visual and automated assessments of Ki-67 expression shows moderate agreement. In multivariate survival analysis, the automated assessment of Ki-67 extent of staining is a significant and independent predictor of outcome in breast cancer.</p

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.Peer reviewe

R-Bendamustine in the treatment of nodular lymphocyte-predominant Hodgkin lymphoma

Peer reviewe

Real-time monitoring of human blood-brain barrier disruption

Chemotherapy aided by opening of the blood-brain barrier with intra-arterial infusion of hyperosmolar mannitol improves the outcome in primary central nervous system lymphoma. Proper opening of the blood-brain barrier is crucial for the treatment, yet there are no means available for its real-time monitoring. The intact blood-brain barrier maintains a mV-level electrical potential difference between blood and brain tissue, giving rise to a measurable electrical signal at the scalp. Therefore, we used direct-current electroencephalography ( DC-EEG) to characterize the spatiotemporal behavior of scalp-recorded slow electrical signals during blood-brain barrier opening. Nine anesthetized patients receiving chemotherapy were monitored continuously during 47 blood-brain barrier openings induced by carotid or vertebral artery mannitol infusion. Left or right carotid artery mannitol infusion generated a strongly lateralized DC-EEG response that began with a 2 min negative shift of up to 2000 mu V followed by a positive shift lasting up to 20 min above the infused carotid artery territory, whereas contralateral responses were of opposite polarity. Vertebral artery mannitol infusion gave rise to a minimally lateralized and more uniformly distributed slow negative response with a posterior-frontal gradient. Simultaneously performed near-infrared spectroscopy detected a multiphasic response beginning with mannitol-bolus induced dilution of blood and ending in a prolonged increase in the oxy/deoxyhemoglobin ratio. The pronounced DC-EEG shifts are readily accounted for by opening and sealing of the blood-brain barrier. These data show that DC-EEG is a promising real-time monitoring tool for bloodbrain barrier disruption augmented drug delivery.Peer reviewe

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.Peer reviewe