The Association between Patient Characteristics and Biochemical Recurrence after Radical Prostatectomy.

Background: Biochemical recurrence (BCR) represents the rise of prostate-specific antigen (PSA) levels after treatment with curative radical prostatectomy (RP) or radiation for prostate cancer. The objective of the current study was to test for the association between patient characteristics, namely age, body mass index (BMI), as well as prostate volume at surgery, and BCR after RP. Material and Methods: Within a tertiary care database, patients with prostate cancer treated with RP between January 2014 and June 2023 were included. Kaplan-Meier survival analyses and Cox regression models addressed BCR after RP according to patient characteristics. Results: Of 821 patients, the median age was 66 years (interquartile range [IQR] 61-71 years), BMI was 26.2 kg/m2 (IQR 24.3-28.8 kg/m2), and prostate volume was 40 cm3 (IQR 30-55 cm3). Median follow-up was 20 months. In survival analyses, the three-year BCR-free survival rates were 81 vs. 84 vs. 81% in patients aged ≤60 vs. 61-69 vs. 70 years (p = 0.1). In patients with BMI < 25.0 vs. 25.0-29.9 vs. ≥30.0 kg/m2, the three-year BCR-free survival rates were 84 vs. 81 vs. 84% (p = 0.7). In patients with prostate volume ≤40 vs. >40 cm3, the three-year BCR-free survival rates were 85 vs. 80% (p = 0.004). In multivariable Cox regression models accounting for patient and pathologic tumor characteristics and adjuvant radiation therapy, a higher prostate volume independently predicted BCR as continuous (hazard ratio 1.012, 95% confidence interval 1.005-1.019; p < 0.001), as well as categorized the variable based on the median (hazard ratio 1.66, 95% confidence interval 1.17-2.36; p = 0.005). Conversely, neither age nor BMI were significantly associated with BCR after RP. Conclusions: The higher prostate volume independently predicted BCR after RP, but not age or BMI at surgery. Consequently, patients with an elevated prostate volume should be considered for closer postoperative follow-up.

Transition from Transrectal to Transperineal MRI-Fusion Prostate Biopsy Does Not Comprise Detection Rates of Clinically Significant Prostate Cancer at a Tertiary Care Center.

BACKGROUND: A remarkable paradigm shift has emerged regarding the preferred prostate biopsy approach, favoring the transperineal (TP) over the transrectal (TR) approach due to the reduced risk of severe urinary tract infections. However, its impact on the detection of clinically significant prostate cancer (csPCa) remains unclear. MATERIALS AND METHODS: We relied on a prospectively maintained tertiary care database to identify patients who underwent either TP or TR prostate biopsy between 01/2014 and 12/2023. Of those, only patients with suspicious magnetic resonance imaging (MRI) PIRADS lesions (Likert-scale: 3,4,5) received MRI-targeted and systematic biopsies. Detection rates of csPCa (International Society of Urological Pathology [ISUP] ≥ 2) were compared between biopsy approach (TP vs. TR) according to index lesion. Subsequently, uni- and multivariable logistic regression models were applied to investigate the predictive status of the biopsy approach within each subcohort. RESULTS: Of 2063 patients, 1118 (54%) underwent combined MRI-guided and systematic prostate biopsy and were included in the final cohort. Of those, 127 (11%) and 991 (89%) underwent TP vs. TR. CsPCa rates, regardless of differences in patients' demographics and distribution of index PIRDAS lesions, did not differ statistically significantly and were 51 vs. 52%, respectively (p = 0.8). CsPCa detection rates for PIRDAS-3, PIRADS-4 and PIRADS-5 did not differ and were 24 vs. 23%, 48 vs. 51% and 72 vs. 76% for PIRADS-3, PIRADS-4 and PIRADS-5 subgroups for TP vs. TR, respectively (all p ≥ 0.9) Conclusions: The current results support the available data indicating that TP biopsy approach is comparable to transrectal biopsy approach regarding csPCa detection rates.

Biweekly vs Triweekly Cabazitaxel in Older Patients With Metastatic Castration-Resistant Prostate Cancer: The CABASTY Phase 3 Randomized Clinical Trial.

Importance: Many patients 65 years or older with metastatic castration-resistant prostate cancer (mCRPC) are denied taxane chemotherapy because this treatment is considered unsuitable. Objective: To determine whether biweekly cabazitaxel (CBZ), 16 mg/m2 (biweekly CBZ16), plus prophylactic granulocyte colony-stimulating factor (G-CSF) at each cycle reduces the risk of grade 3 or higher neutropenia and/or neutropenic complications (eg, febrile neutropenia, neutropenic infection, or sepsis) compared with triweekly CBZ, 25 mg/m2 (triweekly CBZ25), plus G-CSF (standard regimen). Design, Setting, and Participants: A total of 196 patients 65 years or older with progressive mCRPC were enrolled in this prospective phase 3 randomized clinical trial conducted in France (18 centers) and Germany (7 centers) between May 5, 2017, and January 7, 2021. All patients had received docetaxel and at least 1 novel androgen receptor-targeted agent. Interventions: Patients were randomly assigned 1:1 to receive biweekly CBZ16 plus G-CSF and daily prednisolone (experimental group) or triweekly CBZ25 plus G-CSF and daily prednisolone (control group). Main Outcome and Measures: The primary end point was the occurrence of grade 3 or higher neutropenia measured at nadir and/or neutropenic complications. Results: Among 196 patients (97 in the triweekly CBZ25 group and 99 in the biweekly CBZ16 group), the median (IQR) age was 74.6 (70.4-79.3) years, and 181 (92.3%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median (IQR) follow-up duration was 31.3 (22.5-37.5) months. Relative dose intensities were comparable between groups (median [IQR], 92.7% [83.7%-98.9%] in the triweekly CBZ25 group vs 92.8% [87.0%-98.9%] in the biweekly CBZ16 group). The rate of grade 3 or higher neutropenia and/or neutropenic complications was significantly higher with triweekly CBZ25 vs biweekly CBZ16 (60 of 96 [62.5%] vs 5 of 98 [5.1%]; odds ratio, 0.03; 95% CI, 0.01-0.08; P < .001). Grade 3 or higher adverse events were more common with triweekly CBZ25 (70 of 96 [72.9%]) vs biweekly CBZ16 (55 of 98 [56.1%]). One patient (triweekly CBZ25 group) died of a neutropenic complication. Conclusions and Relevance: In this randomized clinical trial, compared with the standard regimen, biweekly CBZ16 plus G-CSF significantly reduced by 12-fold the occurrence of grade 3 or higher neutropenia and/or neutropenic complications, with comparable clinical outcomes. The findings suggest that biweekly CBZ16 regimen should be offered to patients 65 years or older with mCRPC for whom the standard regimen is unsuitable. Trial Registration: ClinicalTrials.gov Identifier: NCT02961257.

Changes in the expression of cancer- and metastasis-related genes and proteins after metformin treatment under different metabolic conditions in endometrial cancer cells.

Research question: Hyperinsulinemia and elevated estrogen levels are known risk factors for endometrial cancer (EC) development and are associated with obesity, type 2 diabetes mellitus (T2DM), insulin resistance, among others. Metformin, an insulin-sensitizing drug, displays anti-tumor effects in cancer patients, including EC, but the mechanism of action is still not completely understood. In the present study, the effects of metformin on gene and protein expression were investigated in pre- and postmenopausal EC in vitro models in order to identify candidates that are potentially involved in the drug's anti-cancer mechanism. Design: After treating the cells with metformin (0.1 and 1.0 mmol/L), changes in the expression of >160 cancer- and metastasis-related gene transcripts were evaluated with RNA arrays. A total of 19 genes and 7 proteins were selected for a follow-up expression analysis, including further treatment conditions, in order to evaluate the influence of hyperinsulinemia and hyperglycemia on metformin-induced effects. Results: Changes in the expression of BCL2L11, CDH1, CDKN1A, COL1A1, PTEN, MMP9 and TIMP2 were analyzed on gene and protein level. The consequences resulting from the detected expression changes as well as the influence of varying environmental influences are discussed in detail. With the presented data, we contribute to a better understanding of the direct anti-cancer activity of metformin as well as its underlying mechanism of action in EC cells. Conclusions: Although further research will be necessary to confirm the data, the influence of different environmental settings on metformin-induced effects could be highlighted with the presented data. Additionally, gene and protein regulation were not similar in the pre- and postmenopausal in vitro models.

In vitro assessment of synergistic effects in combinations of a temoporfin-based photodynamic therapy with glutathione peroxidase 1 inhibitors.

BACKGROUND: Due to an increased elimination of reactive oxygen species (ROS), in particular hydrogen peroxide (H2O2), overexpression of glutathione peroxidase 1 (GPX1) can lead to an attenuation of apoptosis and development of resistance in cancer cells, thereby promoting tumor cell survival. Consequently, GPX1 inhibitors have the potential to be used in cancer therapy as they support oxidative stress in cancer cells. Similarly, photodynamic therapy (PDT) induces oxidative stress in cancer cells by the formation of ROS upon illumination. Thus, both methods of treatment might act in synergy when used in combination. METHODS: To investigate this hypothesis, combinations of the known GPX1 inhibitors 9-chloro-6-ethyl-6H-[1,2,3,4,5]pentathiepino[6,7-b]indole (CEPI) or mercaptosuccinic acid (MSA) with PDT induced by the photosensitizer (PS) temoporfin (5,10,15,20-tetra(m-hydroxyphenyl)chlorin, mTHPC) were studied in vitro. This new combinatory approach was intended to accumulate ROS formed during PDT via blockage of GPX1-catalyzed H2O2 degradation, and thus to enhance PDT-induced phototoxicity. Five human cancer cell lines from tumor origins treatable with PDT were utilized to investigate ROS generation, apoptosis induction, and cell cycle distribution. RESULTS: Synergy was identified with both GPX1 inhibitors, but not in all cell lines. ROS levels were increased after combined treatment with mTHPC and CEPI, but not MSA, in some cell lines, indicating that oxidative stress and ROS accumulation were enhanced by CEPI. Surprisingly, enhanced apoptosis induction was also observed with MSA afterwards, suggesting that other pathways contributed to the initiation of apoptosis. Cell cycle analysis confirmed apoptosis induction via the detection of DNA fragmentation. CONCLUSION: A combination of GPX1 inhibitors with mTHPC-PDT has the potential to generate synergistic effects and to increase overall phototoxicity, but the success of this combination approach was dependent on cancer type, and even antagonistic effects can occur.

Changes in protein expression due to metformin treatment and hyperinsulinemia in a human endometrial cancer cell line.

The incidence of endometrial cancer (EC) has increased over the past years and mainly affects women above the age of 45 years. Metabolic diseases such as obesity and type II diabetes mellitus as well as associated conditions like polycystic ovary syndrome (PCOS), insulin resistance and hyperinsulinemia lead to elevated levels of circulating estrogens. Increased estrogen concentrations, in turn, further trigger the proliferation of endometrial cells and thus promote EC development and progression, especially in the absence of progesterone as seen in postmenopausal women. Elevated blood glucose levels in diabetic patients further contribute to the risk of EC development. Metformin is an insulin-sensitizing biguanide drug, commonly used in the treatment of type II diabetes mellitus, especially in obese patients. Besides its effects on glucose metabolism, metformin displayed anti-cancer effects in various cancer types, including EC. Direct anti-cancer effects of metformin target signaling pathways that are involved in cellular growth and proliferation, e.g. the AKT/PKB/mTOR pathway. Further proteins and pathways have been suggested as potential targets, but the underlying mechanism of action of metformin's anti-cancer activity is still not completely understood. In the present study, the effects of metformin on protein expression were investigated in the human EC cell line HEC-1A using an affinity proteomic approach. Cells were treated with 0.5 mmol/L metformin over a period of 7 days and changes in the expression pattern of 1,300 different proteins were compared to the expression in untreated control cells as well as insulin-treated cells. Insulin treatment (100 ng/mL) was incorporated into the study in order to implement a model for insulin resistance and associated hyperinsulinemia, conditions that are often observed in obese and diabetic patients. Furthermore, the culture medium was supplemented with 10 nmol/L ß-estradiol (E2) during treatments to mimic increased estrogen levels, a common risk factor for EC development. Based on the most prominent and significant changes in expression, a set of 80 proteins was selected and subjected to a more detailed analysis. The data revealed that metformin and insulin targeted similar pathways in the present study and mostly acted on proteins related to proliferation, migration and tumor immune response. These pathways may be affected in a tumor-promoting as well as a tumor-suppressing way by either metformin treatment or insulin supplementation. The consequences for the cells resulting from the detected expression changes were discussed in detail for several proteins. The presented data helps identify potential targets affected by metformin treatment in EC and allows for a better understanding of the mechanism of action of the biguanide drug's anti-cancer activity. However, further investigations are necessary to confirm the observations and conclusions drawn from the presented data after metformin administration, especially for proteins that were regulated in a favorable way, i.e. AKT3, CCND2, CD63, CD81, GFAP, IL5, IL17A, IRF4, PI3, and VTCN1. Further proteins might be of interest, where metformin counteracted unfavorable effects that have been induced by hyperinsulinemia.

Effectiveness and Distribution of Testosterone Levels within First Year of Androgen Deprivation Therapy in a Real-World Setting: Results from the Non-Interventional German Cohort LEAN Study.

BACKGROUND: Observational studies generate information on real-world therapy and complement data from prospective randomized trials. LEAN is an open-label, non-interventional, multi-centre, German cohort study on leuprorelin in routine clinical practice. OBJECTIVES: To extend knowledge on the use, effectiveness, and tolerability of HEXAL/Sandoz leuprorelin (in this article, the term Leuprone® HEXAL® covers Leuprorelin Sandoz® as well) solid implant in patients with prostate cancer (PCa) in a real-world setting. METHODS: 959 PCa patients scheduled for androgen deprivation therapy (ADT) received leuprorelin acetate implant. Metabolism, serum prostate-specific antigen (PSA), and testosterone data, if available, were collected at baseline and follow-up visits for ≥12 months. RESULTS: Of 694 patients in the modified full analysis set, 26.4% received GnRH analogues ≤6 months before enrolment. Fifty-one percent of patients were treated for locally advanced or metastatic PCa. In 19.6% of patients, ADT was used in neoadjuvant or adjuvant settings and in 28.5% with rising PSA after definite therapy. Testosterone levels <0.5 ng/mL were achieved in >90% of patients. Safety profile was in line with the summary of product characteristics. Therapy was well tolerated, with patient-triggered therapy discontinuation in 3.6%. CONCLUSIONS: This interim analysis confirmed previous efficacy findings for leuprorelin implant in a real-world setting. This contemporary cohort showed a shift in the use of ADT to non-metastatic PCa stages.

[Advanced prostate cancer: sequence of androgen receptor-targeted substances and chemotherapy determines long-term survival]. / Fortgeschrittenes Prostatakarzinom: Sequenz aus androgenrezeptorgerichteten Substanzen und Chemotherapie entscheidet über das Langzeitüberleben.

The treatment of advanced prostate cancer is changing. New study data and the resulting new therapeutic options have led to increasingly differentiated treatment decisions. Despite the changing therapy landscape, taxane-based chemotherapy-being a life-prolonging treatment-remains an indispensable therapeutic component for chemotherapy-fit patients in the metastatic setting. The current results of the randomized study CARD show that cabazitaxel has a higher oncological effectiveness, including a significant survival benefit and no negative impact on quality of life parameters, compared to a second androgen receptor targeted agent (ARTA) in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after treatment with docetaxel and an androgen receptor-targeted agent (ARTA). In mCNPC the combination therapies of ADT (androgen deprivation therapy) plus docetaxel or of ADT plus ARTA have been established. In addition, three ARTAs tested in recent phase III studies in a clinical setting for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) showed that their use significantly prolongs metastasis-free survival and overall survival. The potential early use of ARTAs also has implications for the treatment of mCNPC. The aim of this publication is to provide guidance for clinical routine and to develop criteria for individual therapy decisions with a special focus on the use of chemotherapy.

Pharmacological characterization of high-affinity σ1 receptor ligands with spirocyclic thienopyran and thienofuran scaffold.

OBJECTIVES: In this study, the pharmacological properties of six spirocyclic piperidines 1-6 showing very high σ1 receptor affinity (Ki  = 0.2-16 nm) were investigated. METHODS: In vitro receptor binding studies, retinal ganglion assay and in vivo capsaicin assay were used to determine the affinity, selectivity and activity. Influence on human tumour cell growth (cell lines A427, LCLC-103H, 5637 and DAN-G) was determined in different assays. The effect on the ergosterol and cholesterol biosynthesis was determined by GLC/MS analysis. KEY FINDINGS: Receptor binding studies demonstrated high selectivity for the σ1 receptor. The increased Ca2+ influx mediated by 2 and the analgesic activity of 1, 4, 5 and 6 confirm σ1 receptor antagonistic activity. Inhibition of human tumour cell growth further supports the σ1 antagonistic effects. Treatment of A427 tumour cells with 2 led to cell detachment and cell degradation. Whereas the ergosterol biosynthesis was not affected, the sterol C14-reductase, a key enzyme in the cholesterol biosynthesis, was weakly inhibited. CONCLUSIONS: Due to the high selectivity, off-target effects are not expected. The antiallodynic activity underlines the clinical potential of the spirocyclic piperidines for the treatment of neuropathic pain. Due to the antiproliferative activity, the spirocyclic σ1 antagonists represent promising antitumour agents.

Comparison of Cellular Death Pathways after mTHPC-mediated Photodynamic Therapy (PDT) in Five Human Cancer Cell Lines.

One of the most promising photosensitizers (PS) used in photodynamic therapy (PDT) is the porphyrin derivative 5,10,15,20-tetra(m-hydroxyphenyl)chlorin (mTHPC, temoporfin), marketed in Europe under the trade name Foscan®. A set of five human cancer cell lines from head and neck and other PDT-relevant tissues was used to investigate oxidative stress and underlying cell death mechanisms of mTHPC-mediated PDT in vitro. Cells were treated with mTHPC in equitoxic concentrations and illuminated with light doses of 1.8-7.0 J/cm2 and harvested immediately, 6, 24, or 48 h post illumination for analyses. Our results confirm the induction of oxidative stress after mTHPC-based PDT by detecting a total loss of mitochondrial membrane potential (Δψm) and increased formation of ROS. However, lipid peroxidation (LPO) and loss of cell membrane integrity play only a minor role in cell death in most cell lines. Based on our results, apoptosis is the predominant death mechanism following mTHPC-mediated PDT. Autophagy can occur in parallel to apoptosis or the former can be dominant first, yet ultimately leading to autophagy-associated apoptosis. The death of the cells is in some cases accompanied by DNA fragmentation and a G2/M phase arrest. In general, the overall phototoxic effects and the concentrations as well as the time to establish these effects varies between cell lines, suggesting that the cancer cells are not all dying by one defined mechanism, but rather succumb to an individual interplay of different cell death mechanisms. Besides the evaluation of the underlying cell death mechanisms, we focused on the comparison of results in a set of five identically treated cell lines in this study. Although cells were treated under equitoxic conditions and PDT acts via a rather unspecific ROS formation, very heterogeneous results were obtained with different cell lines. This study shows that general conclusions after PDT in vitro require testing on several cell lines to be reliable, which has too often been ignored in the past.

Evaluation for Synergistic Effects by Combinations of Photodynamic Therapy (PDT) with Temoporfin (mTHPC) and Pt(II) Complexes Carboplatin, Cisplatin or Oxaliplatin in a Set of Five Human Cancer Cell Lines.

The platinum(II) complexes carboplatin (CBDCA), cisplatin (CDDP) and oxaliplatin (1-OHP) are used as anticancer drugs in a large number of tumour chemotherapy regimens. Many attempts have been made to combine Pt(II)-based chemotherapy with alternative treatment strategies. One such alternative anticancer approach is known as photodynamic therapy (PDT), where a non-toxic photosensitizer (PS) produces oxidative stress via the formation of reactive oxygen species (ROS) after local illumination of the affected tissue. A very promising PS is 5,10,15,20-tetra(m-hydroxyphenyl)chlorin (mTHPC, Temoporfin), which is approved for the treatment of head and neck cancer in Europe. In the present study, a combination of mTHPC-mediated PDT and either CBDCA, CDDP, or 1-OHP was applied to five human cancer cell lines from different tumour origins. Cytotoxicity was determined by the MTT assay and synergistic effects on cytotoxicity were evaluated by calculation of Combination Indices (CI). Synergy was identified in some of the combinations, for example, with 1-OHP in three of the tested cell lines but antagonism was also observed for a number of combinations in certain cell lines. In cases of synergy, elevated ROS levels were observed after combination but apoptosis induction was not necessarily increased compared to a treatment with a single compound. Cell cycle analysis revealed a formation of apoptotic subG1 populations and S phase as well as G2/M phase arrests after combination. In conclusion, pre-treatment with mTHPC-PDT has the potential to sensitize some types of tumour cells towards Pt(II) complexes, in particular 1-OHP but synergy is highly dependent on the type of cancer.

Presentation of a method at the Exploration Stage according to IDEAL: Percutaneous nephrolithotomy (PCNL) under local infiltrative anesthesia is a feasible and effective method - retrospective analysis of 439 patients.

INTRODUCTION: This study addresses minimally invasive anesthesiologic and analgetic approaches for stone surgery in the upper urinary tract. Aim of this retrospective analysis is to compare feasibility, safety and complication rates of percutaneous nephrolithotomy (PCNL) under local infiltration anesthesia alone (Group I) and additive intravenous analgetics and/or sedative medications (Group II). MATERIAL AND METHODS: This is a single center study. A total of 439 patients have been included from November 2003 until March 2012. A total of 226 patients were assigned to Group I receiving local infiltration anesthesia alone, whereas 213 patients were assigned to Group II receiving additive intravenous analgetics and/or sedative medications. Demographic characteristics and stone characteristics have been evaluated to determine feasibility, complication rates for safety, and stone-free rates for effectiveness. The study and the reported technique have then been retrospectively analysed according to the IDEAL stages of surgical innovation. RESULTS: All included patients who accepted local infiltration anesthesia underwent PCNL successfully. The mean American Society of Anesthesiologists score (ASA) of the included patients was 2.15 ±0.37 (range, 1-4). PCNL was indicated in 138 patients due to pelvic calculi, in 171 patients due to renal calculi, in 66 patients due to partial staghorn, in 48 patients due to complete staghorn and in 16 patients due to upper ureteral stones. The total stone free rate in our patients was 78.4% over all stone localizations. Compared to the possibility of using additive intravenous analgetics and/or sedative medications we could show differences in the median age (p=0.005) suggesting that older patients did better tolerate the infiltration anesthesia than patients at younger ages. We did also remark not statistically significant differences in Group I and Group II as for number of tracts, operation duration, hemoglobin drop, fever, transfusion rate, and stone free rate, but not for severe complications such as perirenal hematoma, colon perforation, pleura perforation, AV fistula, skin fistula, and mortality rate. CONCLUSION: PCNL performed under local infiltration anesthesia is a feasible method. It provides satisfactory positive clinical outcomes. Younger age seems to predispose to conversion to extended anesthesiologic procedures. When retrospectively applying the IDEAL criteria, the method can be assigned to the E level or stage 2b.

Quality of life and pain relief in men with metastatic castration-resistant prostate cancer on cabazitaxel: the non-interventional 'QoLiTime' study.

OBJECTIVE: To examine health-related quality of life (QoL) in men with metastatic castration-resistant prostate cancer (mCRPC) on cabazitaxel. PATIENTS AND METHODS: Men with mCRPC receiving cabazitaxel (25 mg/m², every 3 weeks) and 10 mg/day oral prednis(ol)one were enrolled (2011-2014) in the non-interventional prospective 'QoLiTime' study. Primary outcome was change in QoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item) with respect to prostate-specific antigen (PSA) response after four cycles of cabazitaxel. Secondary outcomes included occurrence of adverse events (AEs). RESULTS: Of 527 men, 348 received four cycles of cabazitaxel and 266 had the necessary PSA level measurements. After four cycles, 92 (34.6%) men had a PSA level decrease ≥50% (responders). QoL remained stable throughout the study (P = 0.62). Change in QoL did not differ between responders and non-responders (P = 0.69). Change in PSA level and global health status between baseline and four cycles showed an inversely proportional relationship (correlation coefficient -0.14; 95% confidence interval -0.26 to -0.01; P = 0.03), with increasing PSA level corresponding to lower health status. Responders showed no change in physical functioning vs baseline (-1.75, P = 0.12); non-responders showed a reduction vs baseline (-7.00, P < 0.001) and responders (P = 0.05). Responders showed an improvement in pain vs baseline (-7.61, P = 0.05) and vs non-responders (P = 0.01). AEs occurred in 292 patients (55.4%), most commonly anaemia (16.5%), fatigue (12.3%) and diarrhoea (11.8%). Neutropenia and febrile neutropenia were reported in 3.8% and 3.6% of patients, respectively. CONCLUSION: Prostate-specific antigen level response was associated with stable physical functioning and improvement in pain. Symptom increases were seen in areas typical of chemotoxicity, but QoL was maintained.

Photosensitizers for Photodynamic Therapy: Photochemistry in the Service of Oncology.

The combined use of a photosensitizing agent, light and dioxygen for the treatment of diseases has become known as photodynamic therapy (PDT) and was first discovered more than one hundred years ago. Over the years, PDT has proven its potential for the treatment of malignant and non-malignant lesions in addition to classical cancer therapy in numerous clinical studies, but application as a routine method is still limited. In this review, the development of modern PDT since the beginning of the twentieth century is briefly portrayed. The underlying mechanisms of phototoxicity are explained, and the requirements for ideal photosensitizers (PS) are underlined. Selected PS are introduced and examples of some of the many attempts made at the optimization of PDT by developing new PS with improved chemical and phototoxic properties, are reviewed. Promising 3rd generation PS are introduced and newer approaches to increasing tumor selectivity and efficacy of PDT, such as with nanoparticles, are discussed.

Rigidity versus Flexibility: Is This an Issue in σ1 Receptor Ligand Affinity and Activity?

Stereoisomeric 2,5-diazabicyclo[2.2.2]octanes 14 and 15 were prepared in a chiral-pool synthesis starting from (S)- or (R)-aspartate. The key step in the synthesis was a Dieckmann-analogous cyclization of (dioxopiperazinyl)acetates 8, which involved trapping of the intermediate hemiketal anion with Me3SiCl. The σ1 affinity was tested using membrane preparations from animal (guinea pig) and human origin. The binding of bicyclic compounds was analyzed by molecular dynamics simulations based on a 3D homology model of the σ1 receptor. The good correlation between Ki values observed in the σ1 assays and calculated free binding energy, coupled with the identification of four crucial ligand/receptor interactions, allowed the formulation of structure-affinity relationships. In an in vitro antitumor assay with seven human tumor cell lines, the bicyclic compounds inhibited selectively the growth of the cell line A427, which is due to induction of apoptosis. In this assay, the compounds behave like the known σ1 receptor antagonist haloperidol.

Transcriptional profiling of human monocytes identifies the inhibitory receptor CD300a as regulator of transendothelial migration.

Local inflammatory responses are characterized by the recruitment of circulating leukocytes from the blood to sites of inflammation, a process requiring the directed migration of leukocytes across the vessel wall and hence a penetration of the endothelial lining. To identify underlying signalling events and novel factors involved in these processes we screened for genes differentially expressed in human monocytes following their adhesion to and passage through an endothelial monolayer. Functional annotation clustering of the genes identified revealed an overrepresentation of those associated with inflammation/immune response, in particular early monocyte to macrophage differentiation. Among the gene products so far not implicated in monocyte transendothelial migration was the inhibitory immune receptor CD300a. CD300a mRNA and protein levels were upregulated following transmigration and engagement of the receptor by anti-CD300a antibodies markedly reduced monocyte transendothelial migration. In contrast, siRNA mediated downregulation of CD300a in human monocytes increased their rate of migration. CD300a colocalized and cosedimented with actin filaments and, when activated, caused F-actin cytoskeleton alterations. Thus, monocyte transendothelial migration is accompanied by an elevation of CD300a which serves an inhibitory function possibly required for termination of the actual transmigration.

Idiopathic giant abdominal lymph cyst: a case report.

INTRODUCTION: Giant lymph cysts are a relatively frequent complication after surgical procedures in the abdomen, often after kidney transplantation, but there are also cases after pelvic surgery such as lymphadenectomy and others. In the recent literature, there have been no reported cases of idiopathic giant lymphocyst. CASE PRESENTATION: We present the case of a 76-year-old Caucasian man who had a lymph cyst he had known of for more than 15 years. Laparoscopic treatment was necessary because of hydronephrosis of the left kidney. CONCLUSION: This case shows that laparoscopic drainage and partial resection of the lymph cyst is a safe and effective treatment.

Transcriptional profiling of human monocytes reveals complex changes in the expression pattern of inflammation-related genes in response to the annexin A1-derived peptide Ac1-25.

Annexin A1 is a glucocorticoid-regulated, anti-inflammatory protein, which plays an important role as an endogenous regulator of the inflammatory response. Many of these anti-inflammatory properties are retained in the N-terminal annexin A1 peptide Ac1-25, which is released from the full-length protein by a neutrophil elastase. To elucidate whether the anti-inflammatory activity of the bioactive peptide is solely a result of immediate post-translational effects, which include the shedding of L-selectin or also involve transcriptional changes affecting leukocyte function, we recorded global gene expression changes in human monocytes stimulated with exogenously applied Ac1-25. Applying stringent selection criteria, we show that approximately 100 genes are up-regulated, and approximately 230 are down-regulated by a factor of at least two in the Ac1-25-treated monocytes. It is important that the profiling reveals that Ac1-25 induces an anti-inflammatory phenotype by down-regulating proinflammatory and up-regulating anti-inflammatory mediators. These effects, elicited by exogenously applied Ac1-25, depend, to different extents, on ERK1/2 and p38 signaling pathways. This identifies the annexin A1 N-terminal peptide as a stimulus, eliciting not only short-term, post-translational effects in human monocytes but also transcriptional changes, defining a more anti-inflammatory profile.

The diabetes-prone NZO/Hl strain. Proliferation capacity of beta cells in hyperinsulinemia and hyperglycemia.

New Zealand Obese (NZO) male mice develop a polygenic juvenile-onset obesity and maturity onset hyperinsulinemia. Approximately 50% transit to chronic hyperglycemia. Here we report on the proliferation of beta cells in relation to both the individual's metabolic status and structural parameters of the endocrine pancreas. Proliferating beta cells were quantified in pancreas sections by immunoenzymatic double staining of Ki-67 protein, as a marker for proliferating cells, and endocrine non-beta cells in order to distinguish them from beta cells. In normoglycemic NZO/Hl males Ki-67 labelling indices (IKi-67) of beta cells varied between 0.14 and 1.5%, and correlated significantly with both serum insulin levels and beta cell size. There was no correlation with the glycemic status. In diabetic males, beta cell size was increased. IKi-67 varied between 1 and 3%. The data suggest that the secretory activity of beta cells triggered by glucose, entailed changes in both beta cell hypertrophy and proliferation. As shown by morphometric measurements, beta cell expansion in diabetic mice was limited, in spite of high IKi-67 values. This suggested increased death rates of beta cells.

An annexin 1 N-terminal peptide activates leukocytes by triggering different members of the formyl peptide receptor family.

The human N-formyl peptide receptor (FPR) is a key modulator of chemotaxis directing granulocytes toward sites of bacterial infections. FPR is the founding member of a subfamily of G protein-coupled receptors thought to function in inflammatory processes. The other two members, FPR-like (FPRL)1 and FPRL2, have a greatly reduced affinity for bacterial peptides or do not bind them at all, with FPRL2 being considered an orphan receptor so far. In this study we show that a peptide derived from the N-terminal domain of the anti-inflammatory protein annexin 1 (lipocortin 1) can activate all three FPR family members at similar concentrations. The annexin 1 peptide initiates chemotactic responses in human monocytes that express all three FPR family members and also desensitizes the cells toward subsequent stimulation with bacterial peptide agonists. Experiments using HEK 293 cells stably expressing a single FPR family member reveal that all three receptors can be activated and desensitized by the N-terminal annexin 1 peptide. These observations identify the annexin 1 peptide as the first endogenous ligand of FPRL2 and indicate that annexin 1 participates in regulating leukocyte emigration into inflamed tissue by activating and desensitizing different receptors of the FPR family.