Thromboembolism is well recognized as a major complication of cancer. Many tumor cells overexpress tissue factor (TF), which activates blood coagulation in cancer patients. Inflammatory cells expressing TF are also contributors to this activation. In prostate cancer, we believe that prostasomes may also be involved in the initiation of blood coagulation. Prostasomes are submicron secretory granules derived from the prostate gland. They are surrounded by membrane and their extracellular appearance and membrane architecture are complex. Seminal prostasomes are believed to be necessary for successful fertilization and act as protectors of the spermatozoa in the lower and upper female genital tract. Cells from prostate cancer and its metastases are able to produce and export prostasomes to the extracellular environment. These prostasomes may differ quantitatively rather than qualitatively from their normal counterparts with regard to protein composition and function. A majority of human prostate cancers have been found to overexpress TF, and we have demonstrated by various methods that prostasomes derived from prostate cancer cells express considerably higher levels of TF compared with prostasomes of nonmalignant cell origin. The mechanism related to thromboembolic disease generated by prostasomes in prostatic cancer patients may be the early release of prostasomes from prostate cancer cells into the blood circulation, where they will evoke their blood-clotting effects.

BACKGROUND. Prostasomes are secretory granules produced by the glandular epithelial cells of the prostate. Seminal prostasomes contain high amounts of Tissue Factor (TF) but no studies of TF on malignant cell prostasomes have been made. Here we compare the expression, phosphorylation, and function of TF on prostasomes of different origin. METHODS. TF was detected on prostasomes isolated from seminal fluid and human prostate cancer cell lines (PC-3, DU145, and LNCaP) using FACS and enzyme immunoassay (EIA). Incubation of prostasomes with radioactive ATP under conditions favoring protein kinase A activity led to phosphorylation of TF as detected by immunoprecipitation and SDS-PAGE. The prothrombotic effect of prostasomes was investigated in whole blood and recalcified plasma. Blocking experiments were performed using anti-TF antibodies and corn trypsin inhibitor. RESULTS. TF was expressed on all tested prostasome preparations with lowest values found for seminal ones. Prostasomal TF was the main endogenous substrate for prostasomal protein kinase A. All tested prostasome preparations greatly enhanced the rate of clot formation in a dose-dependent fashion, that is, the clotting capability of prostasomes seemed to be related to the extent of their expression of TF. In addition, the density of the clot varied between different prostasome preparations. When incubated in whole blood, prostasomes were found to associate to WBC thereby inducing them to express and release TF. CONCLUSIONS. These data show that TF is overexpressed and also subjected to phosphorylation by malignant cell prostasomes. This suggests major roles for prostasomes in thrombotic events that occur in some advanced cases of prostate cancer.

BACKGROUND: Angiogenesis is the formation of new blood vessels by capillary sprouting from pre-existing vessels. Tumor growth is angiogenesis-dependent and the formation of new blood vessels is associated with the increased expression of angiogenic factors. Prostasomes are secretory granules produced, stored and released by the glandular epithelial cells of the prostate. We investigated the expression of selected angiogenic and anti-angiogenic factors on the surface of prostasomes of different origins as well as the direct effect of prostasomes on angiogenesis. METHODS: VEGF, endothelin-1, endostatin, and thrombospondin-1 were determined on prostasomes from seminal fluid and human prostate cancer cell lines (DU145,PC-3,LNCaP) using different immunochemical techniques. Human dermal microvascular endothelial cells were incubated with seminal and DU145 cell-prostasomes and with radioactive thymidine. The effect of prostasomes on angiogenesis was judged by measuring the uptake of labeled thymidine. The presence of any deleterious effects of prostasomes on the endothelial cells was investigated using thymidine assay and confocal laser microscopy. RESULTS: VEGF and endothelin-1 were determined on malignant cell-prostasomes (no difference between cell lines) but not determined on seminal prostasomes. The same applies for the expression of endostatin but with much higher expression on malignant cell-prostasomes with obvious differences between them. Seminal and DU145 cell-prostasomes were found to have anti-angiogenic effect which was more expressed by DU145 cell-prostasomes. No deleterious effect of prostasomes on endothelial function was detected using either thymidine assay or microscopy. CONCLUSIONS: Prostasomes contain pro- and anti-angiogenic factors that function to counteract each other unless the impact from one side exceeds the other to bring about dysequilibrium.

BACKGROUND: Prostasomes are secretory granules produced, stored, and released, by the glandular epithelial cells of the prostate. They express the glycosylphosphatidylinositol (GPI)-anchored complement regulatory protein CD59, which has been shown to be transferred to spermatozoa and erythrocytes.

METHODS: The CD59 content of prostasomes isolated from seminal fluid and malignant prostate cells (PC-3, DU145, and LNCaP) and the transfer of prostasomal CD59 to rabbit erythrocytes (RE) and to PIPLC-treated and unmanipulated cancer cells were investigated using FACS. All prostasomes were also incubated with RE and tested in a hemolytic assay.

RESULTS: Prostasomes from cancer cells had higher expression of CD59 than those of normal cells. Prostasomal CD59 of different origin could be transferred to RE, malignant cell lines stripped of CD59 by PIPLC, or unmanipulated LNCaP cells. Malignant cell prostasomes had an increased ability to inhibit complement-mediated lysis compared to those from non-malignant cells.

CONCLUSIONS: These results point to a novel mechanism by which prostasomes can protect prostatic malignant cells from complement attack.

BACKGROUND:

Prostasomes are secretory granules produced, stored, and released by the glandular epithelial cells of the prostate. They express numerous enzymes whose physiological roles have so far not been fully evaluated. In this study, we investigated the expression and function of prostasomal protein kinases and ATPase.

METHODS:

The protein kinase activities of prostasomes isolated from seminal fluid and malignant prostate cell lines (PC-3, DU145, and LNCaP) were investigated using the model phosphorylation substrates histone and casein, as well as the plasma proteins C3 and fibrinogen, in combination with specific protein kinase inhibitors. The prostasomal ATPase activity was also evaluated. The expression of protein kinases and ATPase on prostasomes was verified by flow cytometry.

RESULTS:

Prostasomes (intact or solubilized with octylglucoside or saponin) from prostate cancer cells had higher expression of protein kinases A, C, and casein kinase II compared to prostasomes isolated from seminal plasma, resulting in higher phosphorylation of both exogenous and endogenous substrates. Using intact prostasomes, it was found that prostasomes of metastatic origin had lower ATPase activity, resulting in higher residual ATP available for the phosphorylation reaction. Finally, complement component C3 and fibrinogen (two proteins whose activities are modulated by phosphorylation) were identified as physiologically relevant phosphorylation substrates.

CONCLUSIONS:

These results indicate that prostasomes are capable of modifying proteins possibly involved in the innate response by extracellular phosphorylation mediated by ecto-kinases. This is a novel mechanism by which prostatic malignant cells may interact with their environment.

Prostasomes are extracellularly occurring submicron, membrane-surrounded organelles produced by the epithelial cells of the prostate and present in semen after secretion. Even dedifferentiated prostate cancer cells have preserved their ability to produce and export prostasomes to the extracellular space. The precise physiological role of prostasomes is not known, although some of their properties assign them to important physiological and patho-physiological functions that could be exploited in prostate cancer growth and development. In this review, some new properties of seminal and malignant cell line (DU145, PC-3 and LNCaP) prostasomes will be discussed.

There are typical differences in the expressions and activities of prostasomal CD59, ATPase, protein kinases and tissue factor (TF) as well as in the transfer of prostasomal CD59 to CD59-deficient erythrocytes (rabbit and human PNH erythrocytes). CD59, protein kinases and TF exhibit characteristic patterns of overexpression by malignant cell prostasomes. A high ATPase activity is recognized on seminal prostasomes with minimal activity on malignant cell prostasomes resulting in more residual ATP available for phosphorylation reactions. Several proteins are phosphorylated by prostasomal protein kinases, namely, complement component C3, fibrinogen, vitronectin and E-cadherin. Furthermore, TF is identified as the main endogenous phosphorylation substrate on prostasomes. In addition, prothrombotic effects of prostasomes are demonstrated. DU145 and PC-3 cell-derived prostasomes exert a higher clotting effect on whole blood and plasma compared to LNCaP cell-derived and seminal prostasomes.

In conclusion, malignant cell prostasomes show an increased ability to interact with the biological system in favor of prostate cancer cell promotion and survival. The roles played by prostasomes in this context may improve the understanding of the mechanisms that help the prostate cancer cells to avoid the complement attack (CD59 transfer and phosphorylation and inactivation of C3), to promote angiogenesis (TF) and to metastasize. It may also provide a better understanding of some of the complications usually seen in some terminal prostate cancer patients like thrombotic events and tendency to develop disseminated intravascular coagulation.

Prostasomes are extracellularly occurring submicron, membrane-surrounded organelles produced by the epithelial cells of the prostate and present in semen. Their precise physiological role is not known, although some of their properties assign them to important physiological and patho-physiological functions. In this thesis, some new properties of seminal and malignant cell line (DU145, PC-3 and LNCaP) prostasomes have been identified.

Differences in the expressions and activities of prostasomal CD59, ATPase, protein kinases and tissue factor (TF) have been characterized. The transfer of prostasomal CD59 to CD59-deficient erythrocytes (rabbit and human PNH erythrocytes) has been established. CD59, protein kinases and TF were overexpressed by malignant cell prostasomes. ATPase activity was highest on seminal prostasomes with minimal expression by malignant cell prostasomes resulting in more residual ATP available for phosphorylation reactions. Several proteins were phosphorylated by prostasomal protein kinases, viz. complement component C3, fibrinogen, vitronectin and E-cadherin. Furthermore, TF was identified as the main endogenous phosphorylation substrate on prostasomes. In addition, prothrombotic effects of prostasomes were established. DU145 and PC-3-derived prostasomes exerted a higher clotting effect on whole blood and plasma compared to LNCaP and seminal prostasomes.

In conclusion, malignant cell prostasomes showed higher ability to interact with the biological system in favor of prostate cancer cell promotion and survival. The roles played by prostasomes in this context may improve the understanding of the mechanisms that help the prostate cancer cells to avoid the complement attack (CD59 transfer and phosphorylation of C3), to promote angiogenesis (TF) and to metastasize. It may also provide a better understanding of some of the complications usually seen in some terminal prostate cancer patients like thrombotic events and tendency to develop disseminated intravascular coagulation.

OBJECTIVE:

Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, with a correlation between RA disease severity and lymphoma risk, most pronounced for diffuse large B cell lymphomas (DLBCLs), which also constitute the majority of RA-associated lymphomas. DLBCLs can be further subdivided into germinal center (GC)-like and non-GC-like subtypes, with different cellular origins and prognoses. This study was undertaken to investigate whether RA displays a specific association with any of the DLBCL subtypes.

METHODS:

We identified 139 patients with DLBCLs within a population-based case-control study of 378 RA patients with lymphoma. The DLBCLs were examined for CD10, Bcl-6, and interferon regulatory factor 4 expression patterns, subclassified into GC and non-GC subtypes, and then correlated with clinical parameters.

RESULTS:

We found a statistically significant predominance of the non-GC subtype (97 patients; 70% of all DLBCLs). These patients more often had an advanced stage of lymphoma at diagnosis and had a worse 5-year overall survival rate (16% versus 33%) compared with patients with the GC subtype. There was a strong association with RA disease activity in both subtypes, with >70% of the GC and non-GC cases occurring in RA patients with the highest overall disease activity scores.

CONCLUSION: These findings suggest that severe RA is particularly associated with the non-GC subtype of DLBCL, and indicate a critical role of activated peripheral B cells as the cells of origin in these lymphomas.

Diffuse large B-cell lymphomas (DLBCL) can be subdivided into germinal centre (GC)-like and non-GC-like subtypes by CD10, BCL6 and MUM1/IRF4 status. We previously reported that patients with severe rheumatoid arthritis (RA) are at increased risk of non-GC DLBCL. This study examined a new GC-marker, human germinal-centre-associated lymphoma (HGAL) protein, in RA-DLBCL. Of 111, 38 (34%) DLBCL were HGAL-positive and showed less disseminated disease and a tendency toward improved overall survival compared to HGAL-negative cases. This supports that a majority of RA-DLBCL are of non-GC origin, indicating a specific role for activated peripheral B cells in the pathogenesis of RA-DLBCL.

During fetal development, the hippocampal structures are folded forming the hippocampal sulcus which penetrates into the temporal lobe and then the entity rotates.  During this process, the hippocampal sulcus will be closed and the inverted hippocampus takes a rounded form. After complete inversion, the hippocampus has an oval form in a plane perpendicular to its long axis. If this process has not been completed the hippocampus remains the rounded form. That condition is called incomplete hippocampal inversion (IHI).

The aims of this study was to evaluate the frequency of IHI in non-epileptic and epileptic children and adults and to explore the development of the hippocampal region by studying premature neonates and fetuses.

Magnetic resonance (MR) images of 201 epilepsy patients and 150 non-epileptic subjects were evaluated without knowing clinical data. IHI was found in 19 % in seizure free controls (20 left-sided and 8 bilateral). 30% of the 201 epilepsy patients had IHI (40 left-sided, 4 right-sided, 16 bilateral). The difference was statistically significant (p<0.02). 25% of the temporal lobe epilepsy patients had IHI. The frequency was not significantly higher than in controls. There is no causality between temporal lobe epilepsy and IHI. 44% of the Rolandic epilepsy patients and 57% of the cryptogenic generalized epilepsy patients had IHI. IHI can be a sign of possible disturbed cerebral development in other parts of the brain.

Cranial ultrasound examinations of 160 premature children were analyzed. The age at examination was 23-24 GW in 24 children, 25-28 GW in 72 children, and 29-36 GW in 64 children. IHI was found in 50%, 25% and 14%, respectively. The frequency difference between the children < 25 GW and > 25 GW was statistically significant (p< 0.001). From 25 GW onwards, the frequency and laterality of IHI is similar to that in the adult population.

MRIs of 63 fetuses without intracranial pathology were reviewed independently by two radiologists. Three MRIs were performed post mortem at gestation week (GW) 17-18 and 60 in utero at GW 19-35. The hippocampal sulcus was open, bi- or unilaterally, in 35 fetuses at GW 17-32. The oldest of them was at GW 32.  The sulcus was closed at GW 21 at the earliest, unilaterally, and always from GW 33 onwards bilaterally. In 26/63 fetuses (41%), the hippocampal development was asymmetric and in 23 fetuses, the right side had developed faster.

BACKGROUND AND PURPOSE: Hippocampal development is poorly understood. This study evaluated the normal development of the hippocampal region during the fetal period by using MR imaging.

MATERIALS AND METHODS: MR images of 63 fetuses without intracranial pathology were reviewed independently by 2 radiologists with no knowledge of the fetal GA. Three MR images were performed postmortem and 60 in vivo. The progress of hippocampal inversion was analyzed in coronal sections, and the left and right sides of the hippocampal region were compared in every case.

RESULTS: The fetuses in the postmortem examinations were at GWs 17-18 and in the in vivo examinations, at GWs 19-36. The hippocampal sulcus was open, bi- or unilaterally, in 39 fetuses. The oldest was at GW 32. The sulcus was closed at GW 21 at the earliest, unilaterally. In 26/63 fetuses (41%), the deepening or closure of the hippocampal sulcus or hippocampal inversion was asymmetric; in 23 fetuses, the right side developed faster. A shallow collateral sulcus was found earliest at GW 17. A deep collateral sulcus was visible earliest at GW 26 unilaterally, but in all fetuses from GW 31 onward, it was seen bilaterally. The orientation of the collateral sulcus was not related to the GA.

CONCLUSIONS: There are wide individual temporal variations in the development and the inversion process of the hippocampal sulcus as well as in the formation of the collateral sulcus. Asymmetric development is common, and in most of the asymmetric cases, the right hippocampus develops faster.

INTRODUCTION: During fetal development, the hippocampal structures fold around the hippocampal sulcus into the temporal lobe. According to the literature, this inversion should be completed at gestation week (GW) 21. Thereafter, the hippocampal shape should resemble the adult shape. However, incomplete hippocampal inversion (IHI) is found in 19% of the common population. The aim of this study was to study fetal hippocampal development by examining neonates born preterm. METHODS: We analyzed cranial ultrasound examinations, performed as a part of the routine assessment of all preterm infants, over a 3-year period and excluded the infants with brain pathology. The final material consisted of 158 children born <35 GW. A rounded form (the ratio between the horizontal and vertical diameters of the hippocampal body <25 GW and >/=25 GW was statistically highly significant (p < 0.001). The frequency of bilateral IHI was highest in the youngest age group. In the other groups, the left-sided IHI was the most common. CONCLUSION: In about 50% of the neonates, hippocampal inversion is not completed up to GW 24; but from 25 GW onwards, the frequency and laterality of IHI is similar to that in the adult population.

Incomplete hippocampal inversion (IHI) has been described in patients with epilepsy or severe midline malformations but also in nonepileptic subjects without obvious developmental anomalies. We studied the frequency of IHI in different epilepsy syndromes to evaluate their relationship. Three hundred patients were drawn from the regional epilepsy register. Of these, 99 were excluded because of a disease or condition affecting the temporal lobes or incomplete data. Controls were 150 subjects without epilepsy or obvious intracranial developmental anomalies. The coronal MR images were analysed without knowledge of the clinical data. Among epilepsy patients, 30% had IHI (40 left-sided, 4 right-sided, 16 bilateral). Of controls, 18% had IHI (20 left-sided, 8 bilateral). The difference was statistically significant (P < 0.05). Of temporal lobe epilepsy (TLE) patients, 25% had IHI, which was not a significantly higher frequency than in controls (P = 0.34). There was no correlation between EEG and IHI laterality. A total of 44% of Rolandic epilepsy patients and 57% of cryptogenic generalised epilepsy patients had IHI. The IHI frequency was very high in some epileptic syndromes, but not significantly higher in TLE compared to controls. No causality between TLE and IHI could be found. IHI can be a sign of disturbed cerebral development affecting other parts of the brain, maybe leading to epilepsy.

Incomplete inversion of the hippocampus, an imperfect fetal development, has been described in patients with epilepsy or severe midline malformations. We studied this condition in a nonepileptic population without obvious developmental anomalies. We analyzed the coronal MR images of 50 women and 50 men who did not have epilepsy. Twenty of them were healthy volunteers and 80 were patients without obvious intracranial developmental anomalies, intracranial masses, hydrocephalus or any condition affecting the temporal lobes. If the entire hippocampus (the head could not be evaluated) were affected, the incomplete inversion was classified as total, otherwise as partial. Incomplete inversion of the hippocampus was found in 19/100 subjects (9 women, 10 men). It was unilateral, always on the left side, in 13 subjects (4 women, 9 men): 9 were of the total type, 4 were partial. It was bilateral in six subjects (five women, one man): four subjects had total types bilaterally, two had a combination of total and partial types. The collateral sulcus was vertically oriented in all subjects with a deviating hippocampal shape. We conclude that incomplete inversion of the hippocampus is not an unusual morphologic variety in a nonepileptic population without other obvious intracranial developmental anomalies.

Menopause denotes the end of the reproductive period in a woman's life and is characterized by gradually declining plasma levels of ovarian hormones. Mounting evidence suggests that prepulse inhibition (PPI) is sensitive to fluctuations in estradiol and progesterone. Deficits in PPI are associated with conditions characterized by increased levels of ovarian steroids, such as the mid-luteal phase of the menstrual cycle and the third trimester of pregnancy. The aim of the current study was to further elucidate ovarian steroid-related effects on PPI by examining 43 women with regular menstrual cycles, 20 healthy postmenopausal women without hormone replacement treatment (HRT) and 21 healthy postmenopausal women with ongoing estradiol-only or estradiol and progesterone therapy (EPT). Cycling women were tested during the late luteal phase of the menstrual cycle while postmenopausal women were tested on any arbitrary day. The PPI was measured by electromyography. Cycling women exhibited lower levels of PPI than postmenopausal women (p<0.05). There were no differences in PPI between postmenopausal HRT users and non-users. However, postmenopausal women with estradiol serum concentrations in the cycling range had lower PPI than postmenopausal women with low estradiol concentrations (groupxPPI interaction, p<0.05). In conclusion, the results further suggest a role for the ovarian steroids in PPI regulation as PPI is increased in postmenopausal women in comparison to regularly menstruating women examined during the late luteal phase. Furthermore, postmenopausal women with estradiol levels in the cycling range had lower PPI than postmenopausal women with low estradiol levels.

A total 71 male athletes (weight lifters, wrestlers, orienteers, and ice-hockey players) and 21 non-athletes were randomly selected, for a baseline MRI study. After 15 years all the participants at baseline were invited to take part in a follow-up examination, including a questionnaire on back pain and a follow-up MRI examination. Thirty-two athletes and all non-athletes had disc height reduction at one or several disc levels. Disc degeneration was found in more than 90% of the athletes and deterioration had occurred in 88% of the athletes, with the highest frequency in weight lifters and ice-hockey players. 78% of the athletes and 38% of the non-athletes reported previous or present history of back pain at baseline and 71 and 75%, respectively at follow-up. There was no statistically significant correlation between back pain and MRI changes. In conclusion, athletes in sports with severe or moderate demands on the back run a high risk of developing disc degeneration and other abnormalities of the spine on MRI and they report high frequency of back pain. The study confirmed our hypothesis, i.e. that most of the spinal abnormalities in athletes seem to occur during the growth spurt, since the majority of the abnormalities demonstrated at follow-up MRI after the sports career were present already at baseline. The abnormalities found at young age deteriorated to a varying degree during the 15-year follow-up, probably due to a combination of continued high load sporting activities and normal ageing. Preventive measures should be considered to avoid the development of these injuries in young athletes.

Several studies have been published on disc degeneration among young athletes in sports with great demands on the back, but few on competitive divers; however, there are no long-term follow-up studies. Twenty elite divers between 10 and 21 years of age, with the highest possible national ranking, were selected at random without knowledge of previous or present back injuries or symptoms for an MRI study of the thoraco-lumbar spine in a 5-year longitudinal study. The occurrence of MRI abnormalities and their correlation with back pain were evaluated. Eighty-nine percent of the divers had a history of back pain and the median age at the first episode of back pain was 15 years. Sixty-five percent of the divers had MRI abnormalities in the thoraco-lumbar spine already at baseline. Only one diver without abnormalities at baseline had developed abnormalities at follow-up. Deterioration of any type of abnormality was found in 9 of 17 (53%) divers. Including all disc levels in all divers, the total number of abnormalities increased by 29% at follow-up, as compared to baseline. The most common abnormalities were reduced disc signal, Schmorl's nodes, and disc height reduction. Since almost all divers had previous or present back pain, a differentiated analysis of the relationship between pain and MRI findings was not possible. However, the high frequency of both back pain and MRI changes suggests a causal relationship. In conclusion, elite divers had high frequency of back pain at young ages and they run a high risk of developing degenerative abnormalities of the thoraco-lumbar spine, probably due to injuries to the spine during the growth spurt.

The MRE11, RAD50, and NBS1 genes encode proteins of the MRE11-RAD50-NBS1 (MRN) complex critical for proper maintenance of genomic integrity and tumour suppression; however, the extent and impact of their cancer-predisposing defects, and potential clinical value remain to be determined. Here, we report that among a large series of approximately 1000 breast carcinomas, around 3%, 7% and 10% tumours showed aberrantly reduced protein expression for RAD50, MRE11 and NBS1, respectively. Such defects were more frequent among the ER/PR/ERBB2 triple-negative and higher-grade tumours, among familial (especially BRCA1/BRCA2-associated) rather than sporadic cases, and the NBS1 defects correlated with shorter patients' survival. The BRCA1-associated and ER/PR/ERBB2 triple-negative tumours also showed high incidence of constitutively active DNA damage signalling (gamma H2AX) and p53 aberrations. Sequencing the RAD50, MRE11 and NBS1 genes of 8 patients from non-BRCA1/2 breast cancer families whose tumours showed concomitant reduction/loss of all three MRN-complex proteins revealed two germline mutations in MRE11: a missense mutation R202G and a truncating mutation R633STOP (R633X). Gene transfer and protein analysis of cell culture models with mutant MRE11 implicated various destabilization patterns among the MRN complex proteins including NBS1, the abundance of which was restored by re-expression of wild-type MRE11. We propose that germline mutations qualify MRE11 as a novel candidate breast cancer susceptibility gene in a subset of non-BRCA1/2 families. Our data have implications for the concept of the DNA damage response as an intrinsic anti-cancer barrier, various components of which become inactivated during cancer progression and also represent the bulk of breast cancer susceptibility genes discovered to date.

The addition of oral capecitabine to docetaxel improves response rate, time to progression (TTP) and overall survival in anthracycline-pretreated metastatic breast cancer (MBC). This phase II study evaluates the efficacy and safety of a 21-day cycle of oral capecitabine (1000 mg m(-2) twice daily, days 1-14) plus i.v. paclitaxel (175 mg m(-2), day 1) in anthracycline-pretreated advanced/MBC. In all, 73 patients were enrolled at 13 Swedish and Spanish centres. The objective response rate was 52% (95% confidence interval (CI): 40-63%) in the intent-to-treat population, including complete responses in 11%. Disease was stabilised in a further 29%. The median time to disease progression (TTP) was 8.1 months and the median overall survival was 16.5 months. The combination was generally well tolerated with a predictable safety profile. The most common treatment-related nonhaematological adverse events were hand-foot syndrome (42%), alopecia (30%) and diarrhoea (26%). The only treatment-related Grade 3/4 adverse events occurring in >5% of patients were alopecia (22%) and hand-foot syndrome (11%). Grade 3/4 neutropenia and lymphocytopenia were reported in 12 and 14% of patients, respectively. Capecitabine plus paclitaxel is highly active with a favourable safety profile in anthracycline-pretreated MBC.

The clinical utility of a human epidermal growth factor receptor 2 (HER2)-targeting Affibody molecule for detection and characterization of HER2-positive lesions was investigated in patients with recurrent metastatic breast cancer. METHODS: Three patients received (111)In- or (68)Ga-labeled DOTA(0)-Z(HER2:342-pep2) (ABY-002). gamma-Camera, SPECT, or PET/CT images were compared with earlier (18)F-FDG PET/CT results. RESULTS: Administration of radiolabeled ABY-002 was well tolerated. Blood kinetics of radiolabeled ABY-002 showed a first half-life of 4-14 min, second half-life of 1-4 h, and third half-life of 12-18 h. Radiolabeled ABY-002 detected 9 of 11 (18)F-FDG-positive metastases as early as 2-3 h after injection. CONCLUSION: Molecular imaging using (111)In- or (68)Ga-labeled ABY-002 has the potential to localize metastatic lesions in vivo, adds qualitative information not available today by conventional imaging techniques, and may allow the HER2 status to be determined for metastases not amenable to biopsy. To our knowledge, this is the first report on clinical imaging data obtained with a non-immunoglobulin-based scaffold protein.

BACKGROUND AND AIMS: In a retrospective study using stereotactic body radiotherapy (SBRT) in medically inoperable patients with stage I NSCLC we previously reported a local control rate of 88% utilizing a median dose of 15Gyx3. This report records the toxicity encountered in a prospective phase II trial, and its relation to coexisting chronic obstructive pulmonary disease (COPD) and cardio vascular disease (CVD). MATERIAL AND METHODS: Sixty patients were entered in the study between August 2003 and September 2005. Fifty-seven patients (T1 65%, T2 35%) with a median age of 75 years (59-87 years) were evaluable. The baseline mean FEV1% was 64% and median Karnofsky index was 80. A total dose of 45Gy was delivered in three fractions at the 67% isodose of the PTV. Clinical, pulmonary and radiological evaluations were made at 6 weeks, 3, 6, 9, 12, 18, and 36 months post-SBRT. Toxicity was graded according to CTC v2.0 and performance status was graded according to the Karnofsky scale. RESULTS: At a median follow-up of 23 months, 2 patients had relapsed locally. No grade 4 or 5 toxicity was reported. Grade 3 toxicity was seen in 12 patients (21%). There was no significant decline of FEV1% during follow-up. Low grade pneumonitis developed to the same extent in the CVD 3/17 (18%) and COPD 7/40 (18%) groups. The incidence of fibrosis was 9/17 (53%) and pleural effusions was 8/17 (47%) in the CVD group compared with 13/40 (33%) and 5/40 (13%) in the COPD group. CONCLUSION: SBRT for stage I NSCLC patients who are medically inoperable because of COPD and CVD results in a favourable local control rate with a low incidence of grade 3 and no grade 4 or 5 toxicity.

OBJECTIVE: To investigate the prevalence of urogenital symptoms and vaginal atrophy in postmenopausal breast cancer patients on adjuvant endocrine therapy. STUDY DESIGN: A population-based, cross-sectional study on postmenopausal breast cancer patients on adjuvant endocrine treatment and age-matched control subjects. Vaginal atrophy was assessed by gynecologic examination and atrophy-related symptoms by validated questionnaires. RESULTS: In all, 57.6% of aromatase inhibitor-treated and 32.4% of tamoxifen-treated breast cancer patients rated at least 1 vaginal atrophy symptom as moderate/severe, which was significantly more common than in control subjects (P < .01). Aromatase inhibitor-treated patients more often had moderate or severe vaginal atrophy (P < .05), a more atrophic cytohormonal evaluation, and significantly higher vaginal pH (P < .05) than all control subjects, irrespective of hormonal use. CONCLUSION: Our findings indicate that the frequency of vaginal atrophy symptoms, particularly in aromatase inhibitor-treated women, might have been underestimated in previous clinical trials.

Successful clinical xenotransplantation, i.e., transplantation between species, would eliminate the shortage of donor organs. In order to study the acute cellular rejection reaction following discordant xenogeneic transplantation, an experimental pig-to- mouse islet xenotransplantation model was established. Further, immunological processes were evaluated using genetically deficient (knock-out) recipient mice and pharmacological agents exerting cytokine-modulatory actions.

Xenogeneic islet transplantation persists in mice deficient in antibodies, interleukin-6, perforin or granzyme B, suggesting that neither xenoreactive antibodies or interleukin-6 nor granule-mediated lysis are of critical importance to the rejection process. Instead, the immune response following pig-to-mouse islet xenotransplantation bears a close morphological resemblance to a T helper (Th) 1-dependent delayed-type hypersensitivity-reaction with a massive infiltration of macrophages and comparatively small amounts of peripherally accumulated T cells. It may be speculated that islet xenograft destruction is a macrophage-mediated process regulated by T cells. Indeed, Th1-associated cytokines with macrophage-activating properties (interferon-γ and tumor necrosis factor-α) and interleukin-2 seem to be important to islet xenograft rejection, even though other cytokines eventually substitute for the lack of those in a majority of animals.

Key words: xenotransplantation, porcine, islet, in vivo, knock-out mouse,immunohistochemistry, CsA, MDL 201,449A, Ig, FcR, IL-6, perforin, granzyme B,macrophage, eosinophilic granulocyte, T cell, TCR, IFN- g, TNF- a, IL-2.