Lithium-ion Mobility in Li6 B18 (Li3 N) and Li Vacancy Tuning in the Solid Solution Li6 B18 (Li3 N)1-x (Li2 O)x.

All-solid-state batteries are promising candidates for safe energy-storage systems due to non-flammable solid electrolytes and the possibility to use metallic lithium as an anode. Thus, there is a challenge to design new solid electrolytes and to understand the principles of ion conduction on an atomic scale. We report on a new concept for compounds with high lithium ion mobility based on a rigid open-framework boron structure. The host-guest structure Li6 B18 (Li3 N) comprises large hexagonal pores filled with ∞ 1 [ ${{}_{{\rm { \infty }}}{}^{{\rm { 1}}}{\rm { [}}}$ Li7 N] strands that represent a perfect cutout from the structure of α-Li3 N. Variable-temperature 7 Li NMR spectroscopy reveals a very high Li mobility in the template phase with a remarkably low activation energy below 19 kJ mol-1 and thus much lower than pristine Li3 N. The formation of the solid solution of Li6 B18 (Li3 N) and Li6 B18 (Li2 O) over the complete compositional range allows the tuning of lithium defects in the template structure that is not possible for pristine Li3 N and Li2 O.

A study on pharmacokinetics, pharmacodynamics and safety of lixisenatide in children and adolescents with type 2 diabetes.

OBJECTIVE: The aim of this study was to investigate the pharmacokinetic, pharmacodynamic and safety profile of the glucagon-like peptide-1 receptor agonist, lixisenatide, for the treatment of type 2 diabetes (T2D) in pediatric individuals. MATERIALS AND METHODS: In this Phase 1, multicenter, randomized, double-blind, placebo-controlled, parallel-group, ascending repeated dose study (NCT02803918), participants aged ≥10 and < 18 years were randomized 3:1 to receive once-daily lixisenatide in 2-week increments of 5, 10, and 20 µg (n = 18) or placebo (n = 5) for 6 weeks. RESULTS: Mean lixisenatide concentrations generally increased with increasing doses irrespective of anti-drug antibody (ADA) status; however, mean lixisenatide concentrations and inter-subject variability were higher for participants with positive ADA status. Improvements in fasting plasma glucose, post-prandial glucose, AUC0-4.5 , HbA1c , and body weight were observed with lixisenatide. Overall, the safety profile was consistent with the known profile in adults, with no unexpected side effects and no treatment-emergent adverse events resulting in death or discontinuation. The most common events in the lixisenatide group were vomiting (11.1%) and nausea (11.1%). No symptomatic hypoglycemia was reported in either group. No clinically significant hematologic, biochemical or vital sign abnormalities were observed. CONCLUSIONS: Mean lixisenatide concentrations generally increased with increasing dose, irrespective of ADA status. Lixisenatide was associated with improved glycemic control and a trend in body weight reduction compared with placebo. The safety and tolerability profile of repeated lixisenatide doses of up to 20 µg per day in children and adolescents with T2D was reflective of the established safety profile of lixisenatide in adults.

Efficacy and safety of insulin glargine/lixisenatide fixed-ratio combination (iGlarLixi 1:1) in Japanese patients with type 2 diabetes mellitus inadequately controlled on oral antidiabetic drugs: A randomized, 26-week, open-label, multicentre study: The LixiLan JP-O2 randomized clinical trial.

AIMS: To assess efficacy and safety of 26-week treatment with insulin glargine/lixisenatide fixed-ratio combination (iGlarLixi) compared with insulin glargine U100 (iGlar) in Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on oral antidiabetic drugs (OADs). MATERIALS AND METHODS: This phase 3, multicentre, open-label, 1:1 randomized, parallel-group study compared efficacy of iGlarLixi and iGlar in patients with T2DM, HbA1c of ≥7.5% to ≤9.5% and fasting plasma glucose ≤10.0 mmol/L (180 mg/dL). The primary endpoint was change in HbA1c from baseline to week 26. RESULTS: Patients were randomized to iGlarLixi (n = 260) or iGlar (n = 261) (mean age 59.7 years, baseline BMI 26.04 kg/m2 , and HbA1c 8.04% [64.4 mmol/mol]). HbA1c reduction was significantly greater with iGlarLixi (-1.40% [-15.3 mmol/mol]) than with iGlar (-0.76% [-8.3 mmol/mol]). Significantly more iGlarLixi patients reached HbA1c <7% at week 26 (71.5% vs 38.5%, P < .0001), with significantly lower weight gain (LS mean difference -1.06 kg, P < .0001). Documented symptomatic hypoglycemia (plasma glucose ≤3.9 mmol/L [70 mg/dL]) was recorded in 14.2% of patients with iGlarLixi and 12.3% with iGlar. No severe hypoglycemia was reported in either group. Other than the expected gastrointestinal issues associated with glucagon-like peptide 1 receptor agonists, we found no major difference in the incidence of TEAEs. CONCLUSIONS: HbA1c reduction was significantly greater with iGlarLixi than with iGlar; significantly more patients achieved HbA1c <7%, with no additional risk of hypoglycemia and without weight gain. iGlarLixi (1:1) provided an effective treatment option for Japanese patients with T2DM inadequately controlled on OADs. Clinical Trial Number: NCT02752828.

Efficacy and Safety of 1:1 Fixed-Ratio Combination of Insulin Glargine and Lixisenatide Versus Lixisenatide in Japanese Patients With Type 2 Diabetes Inadequately Controlled on Oral Antidiabetic Drugs: The LixiLan JP-O1 Randomized Clinical Trial.

OBJECTIVE: To assess the efficacy and safety of a 1:1 fixed-ratio combination of insulin glargine and lixisenatide (iGlarLixi) versus lixisenatide (Lixi) in insulin-naive Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on oral antidiabetic drugs (OADs). RESEARCH DESIGN AND METHODS: In this phase 3, open-label, multicenter trial, 321 patients with HbA1c≥7.5 to ≤10.0% (58-86 mmol/mol) and fasting plasma glucose (FPG) ≤13.8 mmol/L (250 mg/dL) were randomized 1:1 to iGlarLixi or Lixi for 52 weeks. The primary end point was change in HbA1c at week 26. RESULTS: Change in HbA1c from baseline to week 26 was significantly greater with iGlarLixi (-1.58% [-17.3 mmol/mol]) than with Lixi (-0.51% [-5.6 mmol/mol]), confirming the superiority of iGlarLixi (least squares [LS] mean difference -1.07% [-11.7 mmol/mol], P < 0.0001). At week 26, significantly greater proportions of patients treated with iGlarLixi reached HbA1c <7% (53 mmol/mol) (65.2% vs. 19.4%; P < 0.0001), and FPG reductions were greater with iGlarLixi than Lixi (LS mean difference -2.29 mmol/L [-41.23 mg/dL], P < 0.0001). Incidence of documented symptomatic hypoglycemia (≤3.9 mmol/L [70 mg/dL]) was higher with iGlarLixi (13.0% vs. 2.5%) through week 26, with no severe hypoglycemic events in either group. Incidence of gastrointestinal events through week 52 was lower with iGlarLixi (36.0% vs. 50.0%), and rates of treatment-emergent adverse events were similar. CONCLUSIONS: This phase 3 study demonstrated superior glycemic control and fewer gastrointestinal adverse events with iGlarLixi than with Lixi, which may support it as a new treatment option for Japanese patients with T2DM that is inadequately controlled with OADs.

Efficacy and safety of insulin glargine/lixisenatide fixed-ratio combination (iGlarLixi) in Japanese patients with type 2 diabetes mellitus inadequately controlled on basal insulin and oral antidiabetic drugs: The LixiLan JP-L randomized clinical trial.

AIMS: To assess efficacy and safety of fixed-ratio (1:1) combination insulin glargine and lixisenatide (iGlarLixi) compared to insulin glargine U100 (iGlar), with metformin, in Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on basal insulin and oral antidiabetic drugs (OADs). MATERIALS AND METHODS: This 26-week, randomized, open-label study compared iGlarLixi to iGlar, both with metformin in adult Japanese patients with T2DM and hemoglobin (Hb) A1c ≥7.5% to ≤9.5%, treated with basal insulin and 1 or 2 OADs. Five hundred and twelve patients were randomized after a 12-week run-in, when iGlar was introduced and/or further titrated and OADs other than metformin were stopped. The primary endpoint was change in HbA1c from baseline to week 26. RESULTS: iGlarLixi (n = 255) demonstrated significantly greater reductions in HbA1c (-1.27%) than iGlar (n = 257, -0.53%) (LS mean difference: -0.74%, P < .0001) at week 26, confirming the superiority of iGlarLixi. Significantly, more iGlarLixi patients reached target HbA1c <7% at week 26 (51.8% vs 16.0% for iGlar). iGlarLixi patients lost weight in contrast to iGlar patients (-0.51 kg vs +0.55 kg). Documented symptomatic hypoglycemia (plasma glucose ≤ 3.9 mmol/L) was observed in 18.8% of iGlarLixi patients vs 16.7% of iGlar patients. iGlarLixi patients had more gastrointestinal-related adverse events than iGlar patients (33.3% vs 8.6%), primarily nausea (16.9% vs 0.8%). However, the treatment was generally well-tolerated. CONCLUSIONS: A once-daily injection of iGlarLixi with metformin is an effective, well-tolerated, and simple therapeutic intervention providing significant improvement in glycemic control in Japanese patients with T2DM inadequately controlled on basal insulin and up to two OADs. Clinical Trial Number: NCT02752412.

Proteolysis of mature HIV-1 p6 Gag protein by the insulin-degrading enzyme (IDE) regulates virus replication in an Env-dependent manner.

There is a significantly higher risk for type II diabetes in HIV-1 carriers, albeit the molecular mechanism for this HIV-related pathology remains enigmatic. The 52 amino acid HIV-1 p6 Gag protein is synthesized as the C-terminal part of the Gag polyprotein Pr55. In this context, p6 promotes virus release by its two late (L-) domains, and facilitates the incorporation of the viral accessory protein Vpr. However, the function of p6 in its mature form, after proteolytic release from Gag, has not been investigated yet. We found that the mature p6 represents the first known viral substrate of the ubiquitously expressed cytosolic metalloendopeptidase insulin-degrading enzyme (IDE). IDE is sufficient and required for degradation of p6, and p6 is approximately 100-fold more efficiently degraded by IDE than its eponymous substrate insulin. This observation appears to be specific for HIV-1, as p6 proteins from HIV-2 and simian immunodeficiency virus, as well as the 51 amino acid p9 from equine infectious anaemia virus were insensitive to IDE degradation. The amount of virus-associated p6, as well as the efficiency of release and maturation of progeny viruses does not depend on the presence of IDE in the host cells, as it was shown by CRISPR/Cas9 edited IDE KO cells. However, HIV-1 mutants harboring IDE-insensitive p6 variants exhibit reduced virus replication capacity, a phenomenon that seems to depend on the presence of an X4-tropic Env. Furthermore, competing for IDE by exogenous insulin or inhibiting IDE by the highly specific inhibitor 6bK, also reduced virus replication. This effect could be specifically attributed to IDE since replication of HIV-1 variants coding for an IDE-insensitive p6 were inert towards IDE-inhibition. Our cumulative data support a model in which removal of p6 during viral entry is important for virus replication, at least in the case of X4 tropic HIV-1.

[Safety monitoring of cell-based medicinal products (CBMPs)]. / Überwachung der Sicherheit von Zelltherapeutika (CBMPs).

Cell-based medicinal products (CBMPs), a category of advanced-therapy medicinal products (ATMPs), are authorised for the European market by the European Commission by means of the centralized marketing authorisation. By conforming to the German Medicinal Products Act (Sec. 4b AMG), national authorisation can be granted by the Paul-Ehrlich-Institut in Germany exclusively for ATMPs not based on a routine manufacturing procedure. In both procedures, quality, efficacy, and safety are evaluated and the risk-benefit balance is assessed. For the centralised procedure, mainly controlled clinical trial data must be submitted, whereas the requirements for national procedures could be modified corresponding to the stage of development of the ATMP. After marketing authorization, the marketing authorization/license holder is obligated to report all serious adverse reactions to the competent authority and to provide periodic safety update reports. If necessary, post-authorization safety studies could be imposed. On the basis of these regulatory measures, the safety of advanced therapies can be monitored and improved.

Antiviral activity of the proteasome inhibitor VL-01 against influenza A viruses.

The appearance of highly pathogenic avian influenza A viruses of the H5N1 subtype being able to infect humans and the 2009 H1N1 pandemic reveals the urgent need for new and efficient countermeasures against these viruses. The long-term efficacy of current antivirals is often limited, because of the emergence of drug-resistant virus mutants. A growing understanding of the virus-host interaction raises the possibility to explore alternative targets involved in the viral replication. In the present study we show that the proteasome inhibitor VL-01 leads to reduction of influenza virus replication in human lung adenocarcinoma epithelial cells (A549) as demonstrated with three different influenza virus strains, A/Puerto Rico/8/34 (H1N1) (EC50 value of 1.7 µM), A/Regensburg/D6/09 (H1N1v) (EC50 value of 2.4 µM) and A/Mallard/Bavaria/1/2006 (H5N1) (EC50 value of 0.8 µM). In in vivo experiments we could demonstrate that VL-01-aerosol-treatment of BALB/c mice with 14.1 mg/kg results in no toxic side effects, reduced progeny virus titers in the lung (1.1 ± 0.3 log10 pfu) and enhanced survival of mice after infection with a 5-fold MLD50 of the human influenza A virus strain A/Puerto Rico/8/34 (H1N1) up to 50%. Furthermore, treatment of mice with VL-01 reduced the cytokine release of IL-α/ß, IL-6, MIP-1ß, RANTES and TNF-α induced by LPS or highly pathogen avian H5N1 influenza A virus. The present data demonstrates an antiviral effect of VL-01 in vitro and in vivo and the ability to reduce influenza virus induced cytokines and chemokines.

Leptin expression in primary trophoblast cells in response to incubation with the serum of preeclamptic women.

OBJECTIVE: We investigated whether the increase of leptin expression in preeclamptic placentas is additionally influenced by soluble maternal factors under hypoxic and nonhypoxic conditions. METHODS: Term trophoblast cells were isolated and stimulated with sera from preeclamptic women under normoxic or hypoxic conditions. Levels of leptin mRNA and protein were evaluated by real-time RT-PCR or ELISA and Western blot analysis. RESULTS: Leptin concentrations were increased in the serum of patients with preeclampsia and gestational diabetes. Hypoxia, insulin, and dexamethasone induced leptin expression in trophoblast cells. The incubation with sera from preeclamptic women led to a small, though, significant, increase of leptin gene expression. The effect of preeclamptic serum on leptin gene expression in trophoblast cells was lost under hypoxia. The serum of women with gestational diabetes did not increase leptin expression neither in normoxic nor hypoxic primary trophoblast cells. CONCLUSION: Our results can not exclude a soluble maternal factor in the serum of women with preeclampsia accounting for increased leptin expression in placental tissue in addition to hypoxia. However, an important biological role of this small increase in nonhypoxic conditions does not seem very likely.

Relapse after radical prostatectomy correlates with preoperative PSA velocity and tumor volume: results from a screening population.

OBJECTIVES: To evaluate, in a screening population, the impact of tumor volume and prostate volume on prostate-specific antigen (PSA) velocity (PSAV) and to find predictors of biochemical failure after radical prostatectomy. Longitudinal PSA changes in men with prostate cancer have been reported to be significantly different from those without prostate cancer. METHODS: PSAV was assessed in 102 men undergoing radical retropubic prostatectomy. The pathologic findings of specimens obtained at radical retropubic prostatectomy and pelvic lymph node dissection were analyzed separately for all patients. RESULTS: The median preoperative PSA in the 102 patients was 6.4 ng/mL, the median prostate volume was 32.8 cm3, and the median tumor volume was 1.27 cm3. The PSAV correlated significantly with tumor volume (P <0.05) but not with prostate volume (P = 0.142). The median tumor volume in men with biochemical progression after radical retropubic prostatectomy was 2.55 cm3 versus 0.94 cm3 in men who were free of disease 5 years after surgery. The median PSAV in the year before diagnosis in men with relapse after radical prostatectomy was 1.98 ng/mL/yr versus 1.05 ng/mL/yr in men who had no evidence of disease. CONCLUSIONS: The results of our study have shown that the main factor contributing to the PSAV in patients with prostate cancer is cancer load and that prostate volume is not significantly associated with the PSAV. Men with a PSAV of more than 2 ng/mL/yr in the year before cancer diagnosis are at a high risk of relapse. The PSAV may be helpful in identifying patients with small tumors and thus increase the detection rate of potentially curable prostate cancers.

Vascular resistance in the prostate evaluated by colour Doppler ultrasonography: is benign prostatic hyperplasia a vascular disease?

OBJECTIVE: To evaluate prostatic vascular resistance by measuring the resistive index (RI), and flow velocity using colour Doppler ultrasonography (CDUS), in normal prostates and in patients with benign prostatic hyperplasia (BPH) or prostate cancer, as BPH is considered to be a result of urogenital ageing and studies suggest that hyperplasia in the stromal and glandular compartments might be induced by stromal growth secondary to hypoxia, which in turn results from abnormal blood flow patterns. PATIENTS, SUBJECTS AND METHODS: Ninety-two men (22 with normal prostates, 45 with BPH and 25 with prostate cancer; mean age 56 years) were prospectively evaluated by CDUS. The RI values for the peripheral, central and transition zones were assessed by one investigator. The diagnosis of BPH and prostate cancer was established from histological findings. RESULTS: The mean (sd) RI in the transition zone was significantly higher only in patients with BPH, at 0.77 (0.05), vs 0.65 (0.05) in the other two groups. In the peripheral and central zones there was no significant difference in the RI among the three groups. Arterial CDUS flow velocity was increased in the transition zone of patients with BPH, but not in the peripheral and central zones. CONCLUSIONS: The present results support the hypothesis that an age-related impairment of blood supply to the lower urinary tract might have a role in the development of BPH. Although prostate cancer cannot be excluded by measuring RI, high RI values (>0.75) in the transition zone are indicative of BPH.

Hypoxia-induced leptin production in human trophoblasts does not protect from apoptosis.

OBJECTIVE: The ob-gene product, leptin, is an important regulator of placental and fetal development during pregnancy. Leptin, being induced by hypoxia in the placenta, is a known pro-apoptotic molecule in adipose tissue but is also known to inhibit apoptosis in other tissues like neuroblastoma cells. Based on these findings, we investigated if leptin has a pro- or anti-apoptotic effect on a trophoblastic cell line (JAr cells) in the presence or absence of oxygen. METHODS AND RESULTS: Measurement of leptin in the supernatant by using ELISA showed hypoxia-induced leptin production in JAr cells in vitro. This could be confirmed by a leptin-specific RT-PCR. By analyzing leptin and/or hypoxia exposed cells with FACS cytometry we found that JAr cells can cope with hypoxia down to oxygen tensions of 1%. At this level, only a small number of cells underwent apoptosis. Interestingly, leptin added to the culture medium in high concentrations was not able to interfere with the rate of proliferation or apoptosis in these cells independent of the oxygen tension. Finally, an anti-caspase-3 and anti-caspase-9 Western blot was performed. Again, no difference in the expression of caspase-3 and -9 under the conditions tested was seen. CONCLUSIONS: These results show that leptin, produced by placental cells after hypoxia in vitro, has no influence on the rate of proliferation of these cells. Furthermore, it does not influence apoptotic pathways in the trophoblastic cell line tested under hypoxic and non-hypoxic conditions.

Longitudinal PSA changes in men with and without prostate cancer: assessment of prostate cancer risk.

BACKGROUND: To determine longitudinal PSA changes over a period of 10 years in patients with and without prostate cancer. METHODS: Serial PSA measurements performed over 10 years were evaluated in 353 men who eventually developed prostate cancer and in 2.462 participants of a screening program without prostatic malignancy. RESULTS: In men with cancer, mean tPSA increased from 2.28 ng/ml at 10 years before diagnosis to 6.37 ng/ml at the time of postive biopsy (PSA velocity: 0.409 ng/ml/year). PSA velocity was significantly associated with Gleason scores and pathologic stage. In the benign group (n=2.462), mean tPSA increased from 1.18 to 1.49 ng/ml over a period of 10 years (PSA velocity of 0.03 ng/ml/year). Of the subjects with tPSA levels of 2 ng/ml or less, 2 years prior to cancer diagnosis, 11.4% had tPSA values of more than 4 ng/ml at the time of biopsy. Of the 972 men with tPSA below 1 ng/ml 2 years before the most recent measurement was obtained, 966 (99.4%) had no evidence of prostate cancer 2 years later, while six were found to have malignancies (0.6%). CONCLUSIONS: Longitudinal PSA changes in men with and without prostate cancer are significantly different. Annual testing may not be required in men with baseline tPSA levels of 1 ng/ml or below, whereas in patients with levels higher than 1 ng/ml, it seems to be indicated because of the significant percentage of men presenting with tPSA levels of more than 4 ng/ml two years later.

Clinical and pathologic features of prostate cancer detected after repeat false-negative biopsy in a screening population.

BACKGROUND: The present study was designed to investigate whether the clinical or pathologic features of prostate cancer (PCa) are related to the number of repeat biopsies required to establish the diagnosis of PCa. METHODS: Between February 1993 and August 2000, 653 patients were evaluated in this retrospective study. All patients underwent transrectal ultrasound-guided biopsy of the prostate prior to radical retropubic prostatectomy. The pathologic findings of specimens obtained at radical prostatectomy and pelvic lymph node dissection as well as PSA levels, findings on DRE, prostate volumes, transition zone volumes, and age were analyzed separately for all PCa patients diagnosed at the first set of biopsies (group A) and compared with the data of those diagnosed at the 2nd-5th set of biopsies (group B). In a second step, we compared the results obtained from patients diagnosed at the 2nd set of biopsies (group B1) with those of patients diagnosed at the 3rd to 5th set of biopsies (group B2). RESULTS: Gleason scores, pathologic tumor stages, and tumor volumes in group B were found to be significantly decreased compared to group A. But from the 2nd to 5th serial biopsy no further decrease in pathologic stage, Gleason score, or tumor volume was observed. On the contrary, there was a tendency towards higher tumor stages and Gleason scores. Of the tumors detected after the second false-negative set of biopsies almost 70% were lesions with Gleason scores of 6 or higher. CONCLUSIONS: False-negative results at the first needle biopsy are predictive of a lower pathologic stage and grade as well as smaller tumor volumes of PCa diagnosed at repeat sets of biopsies. False-negative results on repeat biopsy, however, have no prognostic significance for the tumor stage of PCas detected at subsequent sets of biopsies.

Safer transurethral resection of the prostate: coagulating intermittent cutting reduces hemostatic complications.

PURPOSE: Transurethral resection of the prostate (TURP) is still the gold standard for the surgical treatment of symptomatic benign prostatic hyperplasia. However, the associated morbidity and blood loss remain concerns. A coagulating intermittent cutting (CIC) device with constant voltage pulses and controlled pulse intervals was recently developed. The impact of CIC on bleeding and blood transfusion rates as well as the occurrence of the TUR syndrome were investigated. MATERIALS AND METHODS: From January 2000 to July 2002, 271 consecutive patients with symptomatic benign prostatic hyperplasia underwent TURP with the CIC device. In addition to blood transfusion rates, serum hemoglobin and electrolytes were determined in all patients immediately before and after TURP. RESULTS: The mortality rate in the 271 patients subjected to TURP was 0.0%. Mean decrease in hemoglobin after TURP was 1.08 mg/dl. Intraoperative and postoperative blood transfusions were required in 7 patients (2.6%), and clinical signs of the transurethral resection syndrome were noted in 1.1% of patients. CONCLUSIONS: Coagulating intermittent cutting dramatically improves the safety of TURP by decreasing intraoperative and postoperative blood loss, and the rate of blood transfusions. With this blood sparing device we anticipate a lower incidence of hemostatic complications from TURP.

Early detection of prostate cancer with low PSA cut-off values leads to significant stage migration in radical prostatectomy specimens.

BACKGROUND: The introduction of prostate-specific antigen (PSA) contributed to a shift in tumor stage at diagnosis in patients with prostate cancer. The aim of the present study was to evaluate the effects of PSA screening with low PSA cut-off values on mean total and percent-free PSA levels in patients with prostate cancers at the time of diagnosis as well as on pathologic stage and mean Gleason scores in positive biopsies and radical prostatectomy specimens. METHODS: Data of 875 patients who were diagnosed with prostate cancers between 1996 and 2001 were analyzed. Patients were stratified into six groups according to the year of biopsy. Annual changes in total and percent-free PSA values, in Gleason scores of biopsies and radical prostatectomy specimens, and in pathologic stages of radical prostatectomy specimens were assessed. RESULTS: Mean PSA of patients diagnosed with prostate cancer decreased from 13.11 ng/ml (percent-free PSA: 11.89%) in 1996 to 7.33 ng/ml (percent-free PSA: 12.58%) in 2001 (P < 0.05). The percentage of organ-confined prostatectomy specimens increased from 64.3% in 1996 to 81.5% in 2001 (P < 0.05). However, mean Gleason scores increased from 5.23 to 6.33 over the 6 years (P < 0.05). The percentage of patients with biopsy-proven prostate cancers and PSA values below 4 ng/ml increased from 14.0% in 1996 to 39.2% in 2001. In the group with PSA values below 4 ng/ml organ-confined cancers were found in 80.0-95.2% of patients. CONCLUSIONS: PSAg screening with low cut-off levels has led to a significant reduction of mean baseline PSA levels in prostate cancer patients and to a significant increase in the percentage of organ-confined radical prostatectomy specimens, whereas mean Gleason scores have remained relatively constant.

Periprostatic administration of local anesthesia during transrectal ultrasound-guided biopsy of the prostate: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: To evaluate the effect of periprostatic infiltration with local anesthesia on the level of discomfort associated with transrectal ultrasound-guided needle biopsy of the prostate. Transrectal ultrasound-guided needle biopsy of the prostate is the standard procedure to diagnose prostate cancer. METHODS: A prospective, randomized, double-blind study was performed on 100 men referred for biopsy of the prostate. Fifty subjects were randomized to periprostatic injection of 10 mL of 2% lidocaine solution without epinephrine, and 50 were randomized to injection of placebo (10 mL of 0.9% NaCl). Each subject completed three 10-point visual analog scales for pain after a series of 15 needle biopsies. Pain was rated during the biopsy, diagnostic investigation, and injection of lidocaine. RESULTS: Patients who received local anesthesia had significantly lower visual analog scale scores compared with the group without lidocaine during the biopsy (mean score 0.76 versus 3.62, P <0.001) and diagnostic examination (mean score 1.08 versus 1.86, P = 0.025). Lidocaine injection caused no adverse effects. CONCLUSIONS: Periprostatic injection of lidocaine represents a simple and safe procedure that significantly reduces discomfort during probe manipulation and biopsy. We recommend this procedure in men undergoing transrectal ultrasound-guided prostate biopsy.

Transurethral microwave thermotherapy (TUMT) with the Targis System: a single-centre study on 78 patients with acute urinary retention and poor general health.

OBJECTIVES: To evaluate the Targis System in men presenting with acute urinary retention, high prostate volume and high operative risk. MATERIALS AND METHODS: Between August 1997 and March 2001, a total of 78 patients in poor general health status presenting with large prostate glands and acute urinary retention secondary to BPH were treated with the Targis TUMT device. Mean age, mean prostate volume, and the percentage of patients who were able to urinate spontaneously after the procedure as well as mean peak and average flow rates and mean residual urine volume were evaluated. RESULTS: 68 (87.1%) of the 78 patients were able to urinate spontaneously three months after the procedure. In 5 (7.3%) of the 68 patients urinary retention recurred within two years. Following treatment, the mean peak flow rate in the 68 successfully treated patients was 11.1 ml/s, while the mean postvoid residual volume was 46 ml. CONCLUSION: Based on these data we recommend transurethral thermotherapy using the Targis System for patients in poor general health presenting with urinary retention and prostate volumes of more than 35 cc in whom TURP is not possible.