Background: Prostate Cancer (PC) is a common and highly variable disease. Using current diagnostic methods, the prostate specific antigen (PSA) blood test and histological grading of prostate tissue needle biopsies, it is often difficult to evaluate whether the patient has a PC that requires active treatment or not. The absolute majority of all 10,000 cases of PCs diagnosed annually in Sweden have tumours graded as Gleason score (GS) 6-7 and a PSA value in blood below 10. Many of these are harmless and can be left without active treatment and hence spared problematic post-therapy side-effects, others are highly malignant and require early diagnosis and treatment. Better prognostic markers are needed and the aim of this study was to evaluate prognostic markers and to test if these markers could identify patients with indolent tumours. Methods: We have studied tumour material from 419 men consecutively diagnosed with PC at transurethral resection (1975-1990). The majority of these patients (295) had no metastasis at diagnosis and was not given any curative treatment and only hormonal treatment upon symptoms from metastatic progression. Standard histological sections and tissue microarrays (TMA) from these tumours and surrounding normal prostate tissue were stained and evaluated for cell proliferation (Ki67), blood vessels (endoglin and von Willebrand factor, vWf) and the extracellular matrix component hyaluronan (HA). An orthotopic rat PC model was used to explore hyaluronan staining, hyaluronic acid synthase (HAS)-1 mRNA levels and the effect of local HA treatment on tumour growth. Results: Tumour cell proliferation (Ki67) and the density of intra-tumoural endoglin stained blood vessels were independent prognostic markers (i.e. they added prognostic information to the conventional prognostic markers; clinical stage and GS). None of the GS 6 patients with low staining for both Ki67 and endoglin died of PC within 15 years of follow-up. High HA staining in the tumour epithelium and stroma was a negative prognostic marker of cancer specific survival but they were not independent of GS. High HA staining and high vascular density in the stroma of the surrounding morphologically normal prostate were prognostic for short cancer specific survival. Implantation of tumour cells in the normal rat prostate resulted in an increase in HA and HAS-1 mRNA levels in the prostate tissue surrounding prostate tumours. Concurrently intra-prostatic injection of HA also stimulated tumour growth. Conclusions: By evaluating both tumour cell proliferation (Ki67) and vascular density, it is possible to identify patients with very low risk of cancer specific death in the absence of active treatment. Prostate tumours influence the surrounding non-malignant prostate tissue, for example they cause an increased angiogenesis and synthesis of hyaluronan. Such responses can possibly be used to diagnose PC and to evaluate PC aggressiveness.

Le CD81 est une molécule de surface appartenant à la superfamille des tetraspanines. Son rôle pronostique a été précédemment étudié dans les pathologies lymphoïdes, dont le myélome multiple où son expression est associée à un pronostic péjoratif. A ce jour, ce marqueur n'a pas été étudié dans les leucémies aiguës myéloïdes (LAM). Nous avons étudié l'expression membranaire du CD81 sur les blastes de LAM au diagnostic, son association aux autres caractéristiques des LAM et sa potentielle influence sur la survie des patients sur une cohorte de 134 patients traités par chimiothérapie intensive.Le CD81 a été retrouvé chez 92 patients sur 134 (69%). Les patients exprimant ce marqueur avaient une leucocytose initiale plus élevée (p=0.02) et présentaient une cytogénétique intermédiaire ou défavorable (p<0.001). L'expression du CD81 avait un impact négatif sur la survie des patients (survie sans évènements (EFS), survie globale (OS), survie sans rechute (RFS)) en analyse uni- (p<0.001) et multivariées (p=0.003, 0.002 and <0.001 respectivement).De plus, le CD81 avait un impact négatif sur l'OS des patients avec une mutation de NPM1 (p=0.01) et chez les patients du groupe cytogénétique favorable (p=0.002) selon la classification ELN.Les anomalies du cycle cellulaire étant associées à la chimiorésistance, la croissance tumorale et l'agressivité de la pathologie, nous avons étudié l'expression du Ki67 sur les blastes de LAM au diagnostic. Ainsi, 10 prélèvements médullaires de patients avec une faible expression du CD81 par les blastes (moins de 20% de positivité) et 10 prélèvements avec une forte expression du marqueur ont été étudiés. Nous avons pu démontrer une expression significativement inférieure du Ki67 sur les blastes CD81 positifs par rapport aux blastes CD81 négatifs (p<0.001), suggérant ainsi un rôle potentiel du CD81 dans le contrôle du cycle cellulaire. De plus, nous nous sommes intéressés au rôle du CD81 dans la chimiorésistance et sur les différentes voies de signalisation cellulaire en étudiant le profil d'expression génique.En conclusion, le CD81 semble être un nouveau marqueur pronostique des LAM ainsi qu'une cible potentielle de traitement de ces pathologies. / CD81 is a cell surface protein which belongs to the tetraspanin family. While in multiple myeloma its expression on plasma cells is associated with worse prognosis, this has not yet been explored in acute myeloid leukemia (AML). We measured membrane expression of CD81 on AML cells at diagnosis, evaluated its association with AML characteristics and its influence on patient outcome after intensive chemotherapy in a cohort of 134 patients. CD81 was detected in 92/134 (69%) patients. Patients with AML expressing CD81 had elevated leukocyte count (p=0.02) and were more likely classified as intermediate or adverse-risk by cytogenetics (p<0.001). CD81 expression had a negative impact on survival (event-free [EFS], overall [OS] and relapse-free survival [RFS]) in univariate (p<0.001) and in multivariate analyses (p=0.003, 0.002 and <0.001, respectively). CD81 has a negative impact on OS in patients with NPM1 mutation (p=0.01) and in favorable risk patients by European Leukemia Net (ELN) classification (p=0.002).Since aberrations in cell cycle signaling can cause drug resistance, tumor growth and aggressiveness we measured Ki67 on primary blast cells from AML patients. We considered 10 bone marrow samples from AML patients with either weak CD81 expression (less than 20% of blast cells) or 10 bone marrow samples with strong CD81 expression on blasts. We found a significant lower ki67 expression on blast cells from CD81 positive patients compared with those from CD81 negative patients (p<0.001), indicating a potential role of CD81 in cell cycle control. Furthermore, we investigated the role of CD81 in chemotherapy resistance and investigated potentially implicated signaling pathways by gene expression profiling.In conclusion, the cell surface marker CD81 may be a new prognostic marker for diagnostic risk classification and a new potential therapeutic target for drug development in AML.

In breast cancer therapeutic decisions are based on the expression of estrogen (ER), progesterone (PR), the human epidermal growth factor 2 (HER2) receptors and the proliferation marker Ki67. However, only little is known concerning heterogeneity between the primary tumor and axillary lymph node metastases (LNM) in the primary site. We retrospectively analyzed receptor profiles of 215 early breast cancer patients with axillary synchronous LNM. Of our cohort, 69% were therapy naive and did not receive neoadjuvant treatment. Using immunohistochemistry, receptor status and Ki67 were compared between core needle biopsy of the tumor (t-CNB) and axillary LNM obtained during surgery. The discordance rates between t-CNB and axillary LNM were 12% for HER2, 6% for ER and 20% for PR. Receptor discordance appears to already occur at the primary site. Receptor losses might play a role concerning overtreatment concomitant with adverse drug effects, while receptor gains might be an option for additional targeted or endocrine therapy. Hence, not only receptor profiles of the tumor tissue but also of the synchronous axillary LNM should be considered in the choice of treatment.