Transition of an androgen-dependent human prostate cancer cell line into an androgen-independent subline is associated with increased angiogenesis

BACKGROUND: Androgen-independent prostate cancer is today an incurable disease, but increased understanding of the mechanisms for the transition into an androgen-independent state may increase the possibilities for more efficient strategies in the future. METHODS: An androgen-independent subline, LNCaP-19, to the androgen-dependent prostate cancer cell line LNCaP was developed in vitro under standard culture conditions. The characteristics of LNCaP-19 regarding androgen responsiveness, PSA, and VEGF secretion was studied in vitro. The growth in vivo and the microvessel density (MVD) of the tumors were studied after inoculation in nude mice. RESULTS: LNCaP-19 grows equally well in dextran-charcoal stripped FBS (DCC-FBS) as in normal FBS, and rapidly gives rise to tumors in both intact and castrated mice, indicating a true androgen-independent growth. The PSA secretion from LNCaP-19 cells was lower than from LNCaP cells, while the VEGF level was comparable to the secretion from LNCaP cells without androgen stimulation. The MVD was increased in the LNCaP-19 tumors, and the vessels also displayed a changed morphology with exclusively small microvessels without lumen. CONCLUSIONS: LNCaP-19 shows characteristics resembling those of androgen-independent prostate cancer. An increased MVD and changed vessel morphology in the tumor, makes it an interesting model system for studies regarding angiogenesis in the context of the acquisition of androgen independence.     

Treatment of overactive bladder in the older patient: pooled analysis of three phase III studies of darifenacin, an M3 selective receptor antagonist

AIM: To evaluate the efficacy, tolerability and safety of darifenacin, an M(3) selective receptor antagonist, in the subgroup of older patients from a pooled analysis of three phase III, multicentre, randomized, double-blind clinical trials in patients with overactive bladder (OAB). PATIENTS AND METHODS: 317 patients aged > or =65 years with OAB symptoms (urge incontinence, urgency and frequency) received up to 12 weeks' oral treatment with darifenacin 7.5 mg or 15 mg once daily or matching placebo. Efficacy was evaluated from daily electronic diary records. Safety endpoints included withdrawal rates and treatment-related adverse events. RESULTS: Darifenacin treatment of patients aged > or =65 years was associated with a dose-related, significant improvement of all the major symptoms of OAB. At week 12, the median reduction in incontinence episodes/week was greater with darifenacin 7.5 mg or 15 mg than in the corresponding placebo arms (66.7% vs. 34.8% and 75.9% vs. 44.8%, respectively, both p < 0.001). Both doses were also significantly superior to placebo in improving micturition frequency (both p < 0.001), bladder capacity (volume voided) (darifenacin 7.5 mg, p = 0.018, darifenacin 15 mg, p < 0.001), and the frequency of urgency episodes (both p < 0.001). Darifenacin was well tolerated. The most common treatment-related adverse events were dry mouth (7.5 mg, 20.6%; 15 mg, 30.9%; placebo, 4.5%) and constipation (7.5 mg, 18.6%; 15 mg, 23.6%; placebo, 6.4%), typically mild or moderate. Use of constipation remedies (laxatives, stool softeners or fibre supplements) was low and similar between groups (7.5 mg, 10.3%; 15 mg, 16.4%; placebo, 10.0%). There were few withdrawals due to treatment-related adverse events (7.5 mg, 1.0%; 15 mg, 9.1%; placebo, 2.7%), and no nervous system or cardiovascular safety concerns. CONCLUSIONS: The results demonstrate excellent efficacy, tolerability and safety with darifenacin 7.5 mg and 15 mg once-daily treatment for OAB in older patients.     

Intraoperative low-dose S-ketamine has no preventive effects on postoperative pain and morphine consumption after major urological surgery in children

BACKGROUND: Clinical studies suggest low-dose ketamine may have preemptive effects on postoperative pain in adults. The objective of this study was to determine whether intraoperative low-dose S-ketamine reduces postoperative pain and morphine consumption in children undergoing major urological surgery. MATERIALS: Thirty children scheduled for major urological surgery were included in this prospective study. Anesthesia was performed as total intravenous anesthesia (TIVA) with alfentanil and propofol. Fifteen patients additionally received an intravenous bolus of S-ketamine (0.2 mg.kg-1) followed by a continuous infusion of 5 microg.kg-1.min-1, which was stopped immediately after skin closure (Ketamine Group). Another 15 patients received an infusion of saline (Control group). After transfer to the PACU, pain intensity was evaluated using a numeric rating scale (NRS). First patient controlled analgesia (PCA) request, cumulative morphine consumption and pain intensities within the first 72 h were compared. RESULTS: Morphine consumption was not significantly different during the first 72 h (Control: 0.4 mg.kg-1, 0.24-0.51 mg.kg-1, Ketamine: 0.32 mg.kg-1, 0.19-0.61 mg.kg-1; median, 25-75% percentile; n.s.). However, differences were found in pain intensity during the first postoperative hour (Control: 4.0, 3.2-4.6, Ketamine: 2.5, 1.3-3.5; median, 25-75% percentile; P<0.05) and in the time to first PCA use (Control: 37, 28-46 min, Ketamine: 62, 38-68 min; median, 25-75% percentile; P<0.05). CONCLUSIONS: Intraoperative low-dose S-ketamine had no effect on morphine consumption during the first 72 h after surgery. The differences in pain intensity and time to first PCA use probably reflect additional sedation and antinociceptive effects of S-ketamine rather than a true 'prevention' of pain.     

Comparative Diagnostic Utility of Low‐Dose Breast‐Specific Gamma Imaging to Current Clinical Standard

To retrospectively compare low‐dose (7–10 mCi) to high‐dose (15–30 mCi) breast‐specific gamma imaging (BSGI) in the detection of breast cancer. A retrospective review of 223 consecutive women who underwent BSGI exam between February 2011 and August 2013 with subsequent pathologic analysis was performed. Women were divided into low‐dose and high‐dose groups. The results of BSGI and pathology were compared, and the sensitivity, positive predictive value (PPV), and negative predictive value (NPV) were determined. A subgroup analysis was performed to evaluate specificity using benign follow‐up imaging to establish true‐negative results. There were 223 women who met inclusion criteria with 109 patients with 153 lesions in the low‐dose group and 114 patients with 145 lesions in the high‐dose group. Pathologic correlation demonstrates sensitivities of 97.6% (95% CI = 90.9–99.6%) and 94.6% (95% CI = 84.2–98.6%; p = 0.093), PPVs of 62.1% (95% CI = 53.2–70.3%) and 50.5% (95% CI = 40.6–60.3%, p = 0.089), and NPVs of 90.5% (95% CI = 68.2–98.3%) and 92.5% (95% CI = 78.5–98.0%, p = 0.781) in the low‐dose and high‐dose groups, respectively. Subgroup analysis included 72 patients with 98 lesions in the low‐dose group and 116 patients with 132 lesions in the high‐dose group, with a specificity of 53.7% (95% CI = 39.7–67.1%) and 66.3% (95% CI = 56.2–75.2%%, p = 0.143), respectively. Low‐dose BSGI demonstrated high sensitivity and NPV in the detection of breast cancer comparable to the current standard dose BSGI, with moderate specificity and PPV in a limited subgroup analysis, which was associated with a substantial number of false‐positives.     

DAA‐based antiviral treatment of patients with chronic hepatitis C in the pre‐ and postkidney transplantation setting

DAA‐based regimens for chronic hepatitis C infection encourage treatment of “difficult‐to‐treat” cohorts. This study investigated efficacy and safety of DAA‐based regimens in HCV patients on dialysis or postkidney or liver/kidney transplantation. Twenty‐five patients treated with DAA combinations were evaluated: 10 were on dialysis (eight: hemodialysis, two: peritoneal dialysis), eight were kidney transplant recipients, and seven were liver/kidney transplant recipients. Except for one patient treated with daclatasvir ([DCV]/60 mg/QD)/simeprevir ([SMV]/150 mg/QD), the others received sofosbuvir‐based regimens ([SOF];400 mg/QD) combined with SMV:eight, DCV:13 or either ledipasvir ([LDV]90 mg/QD), ribavirin ([RBV];weight based) or pegylated interferon/RBV. HCV‐RNA was determined by Abbott RealTime (LLOQ]:12 IU/ml) or Roche AmpliPrep/COBAS TaqMan assay (LLOQ:15 IU/ml); treatment response evaluated every 4 weeks, at the end of treatment, and 4 and 12 weeks thereafter. Twenty‐four (96%) patients achieved SVR 12/24 (ITT‐analysis). Mean treatment duration was 15.1 ± 5.1 weeks (±SD), and two patients terminated prematurely – both reached SVR12. Six patients were hospitalized due to complications of underlying disease. One patient achieved SVR24 but was re‐infected (week 27). Kidney function remained stable; serum creatinine increased in only one patient – SOF was reduced to 400 mg/48 h. Treatment with DAA combinations in renally impaired HCV patients is highly effective and well tolerated. These findings call for further controlled trials and data from real‐life cohorts.     

Osteonecrosis of jaw in patient with hormone-refractory prostate cancer treated with zoledronic acid

Intravenous bisphosphonates are widely used in the management of metastatic bone disease, as well as osteoporosis. Recent published reports have documented a possible link between treatment with intravenous bisphosphonates and osteonecrosis of the jaw. We report a case of osteonecrosis of the jaw in 1 patient with prostate cancer receiving both chemotherapy and intravenous zoledronic acid (Zometa). Bisphosphonates have been demonstrated to alter the normal bone microenvironment and appear to have direct effects on tumors as well. These changes may contribute to the development of osteonecrosis of the jaw, particularly after tooth extractions or other invasive dental procedures.     

High Cortical Bone Mass Phenotype in Betacellulin Transgenic Mice Is EGFR Dependent

Signaling through the epidermal growth factor receptor (EGFR) by ligands such as epidermal growth factor (EGF), transforming growth factor α (TGFA), and amphiregulin (AREG) has been reported to have effects on skeletal growth. The role of betacellulin (BTC), another EGFR ligand, in skeletal development and bone metabolism is unknown. In previous experiments, transgenic mice overexpressing BTC ubiquitously under the control of the chicken β‐actin promoter (BTC‐tg) exhibited stunted growth and disproportionately sized long bones. In this study, we performed a detailed phenotypic analysis of BTC‐tg mice at 3, 6, and 9 wk of age. Osteoblastic cells from transgenic mice showed strong expression of BTC as determined by Western blots and by immunohistochemistry on bone sections. In femurs of male and female BTC‐tg mice, we found reduced longitudinal bone growth and a pronounced increase in total volumetric BMD. The increased femoral BMD was mainly caused by augmented endocortical bone apposition and subsequent cortical bone thickening. In contrast, vertebral BMD was reduced in BTC‐tg mice of both sexes. An overall similar phenotype was found in 6‐mo‐old BTC‐tg mice. The increase in cortical bone mass in the appendicular skeleton of BTC‐tg mice was largely blocked when they were crossed into the Egfr^Wa5 background characterized by a dominant negative EGFR. Our study showed that overexpression of BTC results in an EGFR‐dependent upregulation of cortical bone mass in the appendicular skeleton of mice, uncovering a potential novel anabolic pathway for cortical bone.     

Improved Performance of Hip DXA Using a Novel Region of Interest in the Upper Part of the Femoral Neck: In Vitro Study Using Bone Strength as a Standard of Reference

We tested the hypothesis that bone mineral density (BMD) and bone mineral content (BMC) in proximal human femur specimens in the upper neck region of interest (ROI) and femoral neck axis length (FNAL) provide a significantly better prediction of femoral bone strength than standard ROIs in vitro. BMD and BMC were measured in 110 proximal femur specimens using a standard dual-energy X-ray absorptiometry (DXA) scanner. The analysis included a new ROI in the upper neck as well as the standard ROIs. FNAL was obtained from the scan images. The specimens' failure-load was measured in a mechanical loading device, simulating a fall on the greater trochanter. For the standard ROIs, correlations between failure-load and BMD ranged from R2 = 0.64 (shaft ROI) to R2 = 0.70, p < 0.001 (femoral neck). Prediction of strength by BMD did not significantly differ from those of BMC (R2 ranging from 0.65 to 0.75, p < 0.001). In the upper neck ROI, for both BMD and BMC correlations with failure-load were higher (R2 = 0.76 and 0.81, respectively; p < 0.001). A lower, yet still significant, correlation was found between FNAL and bone strength (R2 = 0.23, p < 0.001). Normalization of failure-load with respect to FNAL did not significantly increase the correlations with densitometric measures. This study provides in vitro evidence indicating that among the ROIs of the proximal femur the newly defined upper neck ROI provides the best prediction of bone strength. Only a weak association was observed between failure load and FNAL.     

Results of gastric bypass plus resection of the distal excluded gastric segment in patients with morbid obesity

Surgical treatment is the procedure of choice for morbidly obese patients. Gastric bypass with a long limb Roux-en-Y anastomosis is the "gold standard" technique for these patients. We sought to determine the early and late results of open gastric bypass with resection of the distal excluded stomach in patients with morbid obesity. We included in this prospective study 400 patients who were seen from September 1999 through August 2003 (311 women and 89 men; mean age, 38.5 years). The mean body mass index of the patients was 46 kg/m2. All underwent 95% distal gastrectomy, with resection of the bypassed stomach, leaving a small gastric pouch of 15 to 20 ml. An end-to-side gastrojejunostomy was performed with circular stapler No. 25. The length of the Roux-en-Y loop was 125 to 150 cm. In all patients, a biopsy was taken from the liver and routine cholecystectomy was performed. Follow-up was as long as 36 months. A barium study was performed in all patients at 5 days after surgery. Mortality and postoperative morbidity rates were 0.5% and 4.75%, respectively, mainly due to anastomotic leak in 10 patients (2.5%). Hospital length of stay was 7 days for 95% of the patients. Follow-up data for longer than 12 months were available in 184 patients. There was excess body weight loss of 70% at 24 and 36 months, and there was an inverse correlation among preoperative body mass index and the loss of weight. Anemia was present in 10%, and incisional hernia was present in 10.2%. At 1 year after surgery, the BAROS index demonstrated very good or excellent index in 96.6% of the patients. Gastric bypass with resection of the distal excluded segment has results very similar to those of gastric bypass alone but eliminates the potential risks of gastric bypass such as anastomotic ulcer, gastrogastric fistula, postoperative bleeding due to peptic ulcer and gastritis, and the eventual future development of gastric cancer. It is also possible to perform via laparoscopy, as we started to do recently.