Differential response of human ovarian cancer cells to induction of apoptosis by vitamin E Succinate and vitamin E analogue, alpha-TEA.

A vitamin E derivative, vitamin E succinate (VES; RRR-alpha-tocopheryl succinate), and a vitamin E analogue, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid (alpha-TEA), induce human breast, prostate, colon, lung, cervical, and endometrial tumor cells in culture to undergo apoptosis but not normal human mammary epithelial cells, immortalized, nontumorigenic breast cells, or normal human prostate epithelial cells. Human ovarian and cervical cancer cell lines are exceptions, with alpha-TEA exhibiting greater proapoptotic effects. Although both VES and alpha-TEA can induce A2780 and subline A2780/cp70 ovarian cancer cells to undergo DNA synthesis arrest within 24 h of treatment, only alpha-TEA is an effective inducer of apoptosis. VES or alpha-TEA treatment of cp70 cells with 5, 10, or 20 microg/ml for 3 days induced 5, 6, and 19% versus 9, 36, and 71% apoptosis, respectively. Colony formation data provide additional evidence that cp70 cells are more sensitive to growth inhibition by alpha-TEA than VES. Differences in stability of the ester-linked succinate moiety of VES versus the ether-linked acetic acid moiety of alpha-TEA were demonstrated by high-performance liquid chromatography analyses that showed alpha-TEA to remain intact, whereas VES was hydrolyzed to the free phenol, RRR-alpha-tocopherol. Pretreatment of cp70 cells with bis-(p-nitrophenyl) phosphate, an esterase inhibitor, before VES treatment, resulted in increased levels of intact VES and apoptosis. Taken together, these data show alpha-TEA to be a potent and stable proapoptotic agent for human ovarian tumor cells and suggest that endogenous ovarian esterases can hydrolyze the succinate moiety of VES, yielding RRR-alpha-tocopherol, an ineffective apoptotic-inducing agent.     

Features of the renin-angiotensin system in ascites and pleural effusion during severe ovarian hyperstimulation syndrome

Purpose: The purpose of this work was to investigate the ovarian renin-angiotensin system (RAS) during severe ovarian hyperstimulation syndrome (OHSS) with ascites and pleural effusion. Methods: Two patients who developed severe OHSS after ovarian stimulation for in vitro fertilization were investigated. Both patients presented ascites and pleural effusion. Blood, ascites, and pleural fluid were simultaneously sampled during therapeutic paracentesis and thoracocentesis. Renin activity, active renin, prorenin, and angiotensin II immunoreactivity (Ang II-ir) were measured simultaneously in plasma, ascites, and pleural fluid. Results: Prorenin, renin activity, active renin, and Ang II-ir levels were much higher than normal plasmatic laboratory norms in the three compartments. Prorenin and Ang II-ir levels were the highest in the ascites, while they were in the same range in the pleural fluid and in the plasma. Conclusions: The present findings provide additional evidence for the ovarian origin of the prorenin and Ang II-ir in the ascites of severe OHSS.     

Induction of CYP1A in the beagle dog by an inhibitor of kinase insert domain-containing receptor: differential effects in vitro and in vivo on mRNA and functional activity.

Compound I [3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2-one] is a potent inhibitor of human kinase insert domain-containing receptor (KDR kinase), which is under investigation for the treatment of cancer. Bile duct-cannulated male beagle dogs were administered 6 mg/kg compound I q.d. for 14 days. There was an approximately 2.5-fold decrease in the mean plasma area under the curve of I on days 7 and 14 (approximately 11.3 microM . h), relative to day 1 (28.2 microM . h). In the dog, compound I was eliminated by metabolism, with a major pathway being aromatic hydroxylation and subsequent sulfation to form the metabolite M3. Metabolic profiling suggested that the pathway leading to the formation of the sulfated conjugate M3 was induced upon multiple dosing of I. Studies conducted in vitro suggested that CYP1A1/2 was responsible for the formation of the hydroxylated metabolite, which is sulfated to yield M3. Additional studies confirmed induction of CYP1A protein and activity in the livers of dogs treated with I. However, studies in a dog hepatocyte model of induction showed a surprising decrease both in CYP1A mRNA and enzymatic activity in the presence of I, emphasizing the need to consider the results from a variety of in vitro and in vivo studies in deriving an understanding of the metabolic fate of a drug candidate. It is concluded that the autoinduction observed after multiple treatments with compound I occurs since compound I is both an inducer and a substrate for dog CYP1A.     

Office Systems and Their Influence on Mammography Use in Rural and Urban Primary Care

CONTEXT: Breast cancer screening rates are lower in rural communities. Although studies have addressed barriers to mammography for rural residents, physician practice barriers have received less attention. PURPOSE: Controlled clinical trials have shown that the use of office reminder systems in primary care practices is related to increased clinical care rates. Therefore, we compared office systems use in primary care practices located in rural and urban communities and assessed the impact of these systems on rural-urban differences in mammography utilization. METHODS: We identified female Kansas Medicare beneficiaries aged 65 to 79 from Medicare claims data (N = 24,030) and determined which beneficiaries received a mammogram between April 1, 1999, and March 31, 2001. We linked beneficiaries to their primary care providers and obtained surveys from 180 primary care practices on their use of office reminder systems. FINDINGS: Mammography rates ranged from 20% to 92% (mean = 65%) among the 180 practices. Flowsheets with a mammography prompt were used by 33% of the practices, 38% utilized nonphysician staff to identify women due for mammograms, and 15% used computerized reminder systems. Urban practices used flowsheets more often than rural practices (44% versus 16%, P < 0.001). A multivariable regression model demonstrated higher mammography rates in urban practices, group practices, and practices using mammography flowsheets. CONCLUSIONS: Despite success in randomized controlled trials, reminder systems are not used often by primary care providers and are used even less often in rural compared to urban practices. Consistent implementation may be a major barrier to the successful adaptation of flowsheets by primary care offices.     

Chronic oral treatment with 13-cis-retinoic acid (isotretinoin) or all-trans-retinoic acid does not alter depression-like behaviors in rats.

Oral treatment with the anti-acne drug Accutane (isotretinoin, 13-cis-retinoic acid) has been associated with suicide ideation and depression. Here, depression-like behaviors (i.e., behavioral despair and anhedonia) were quantified in adult Sprague-Dawley rats gavaged daily beginning at postnatal day (PND) 82 with 13-cis-RA (7.5 or 22.5 mg/kg) or all-trans-retinoic acid (10 or 15 mg/kg ). Tested at PND 130-131 in the Forced Swim Test, 7.5 mg/kg 13-cis-RA marginally decreased immobility and slightly increased climb/struggle durations whereas neither all-trans-retinoic acid group differed from controls. Voluntary saccharin solution (0.03%) intake at PND 102-104 and PND 151-153 was not different from controls in any treated group, although all RA-treated groups had lower intakes. Swim speed in a water maze at PND 180 was similar across groups, indicating no RA-induced differences in physical ability. Open field activity was mildly decreased at PND 91 in 7.5 mg/kg-treated males only, but it was within the control range at PND 119, 147, and 175. Thus, at serum levels similar to those in humans receiving the drug, chronic 13-cis-RA treatment did not severely affect depression-like behaviors in rats. These data do not substantiate the hypothesis of 13-cis-RA-induced depression.     

Resistance of tumor interstitial pressure to the penetration of intraperitoneally delivered antibodies into metastatic ovarian tumors.

PURPOSE: Despite evidence that regional chemotherapy improves the treatment of metastatic peritoneal ovarian carcinoma, monoclonal antibodies have not shown significant success in i.p. delivery. The present study was designed to address the hypothesis that convective penetration of macromolecular antineoplastic agents depends on a positive pressure difference between the i.p. therapeutic solution and the tumor. EXPERIMENTAL DESIGN: Nude rats with human ovarian xenografts implanted in the abdominal wall were used in experiments to facilitate in vivo measurement of tumor pressure and the treatment of the tumor with i.p. solutions at high pressures. Penetration of (125)I-labeled trastuzumab was measured with quantitative autoradiography. RESULTS: Tumor pressure profiles showed peak pressures of 32 mm Hg with mean pressures (+/- SD, mm Hg) in 12 SKOV3 tumors of 9.7 +/- 8.3 and in 15 OVCAR3 tumors of 12.5 +/- 7.0. I.p. therapeutic dwells at 6 to 8 mm Hg (maximum feasible pressure) showed significantly less penetration of trastuzumab than in adjacent normal muscle. To establish a driving force for convection into the tumor, various maneuvers were attempted to reduce tumor pressure, including treatment with taxanes or prostaglandin E(1), elimination of tumor circulation, and removal of the tumor capsule. Tumor decapsulation decreased the pressure to zero but did not enhance the penetration of antibody. Binding to specific trastuzumab receptors on each tumor was shown to be not a significant barrier to antibody penetration. CONCLUSIONS: The results only partially support our hypothesis and imply that the microenvironment of the tumor is in itself a major barrier to delivery of charged macromolecules.     

Identifying patients at risk for significant versus clinically insignificant postoperative prostate-specific antigen failure.

PURPOSE: We evaluated whether men at risk for significant versus clinically insignificant prostate-specific antigen (PSA) failure after radical prostatectomy could be identified using information available at diagnosis. PATIENTS AND METHODS: A prospective prostate cancer screening study that enrolled, diagnosed, and treated 1,011 men with radical prostatectomy at Barnes-Jewish Hospital (St Louis, MO) from January 1, 1989, to June 1, 2002, for localized prostate cancer formed the study cohort. Preoperative predictors of a postoperative PSA doubling time (DT) of less than 3 months and more than 12 months or no PSA failure were identified using logistic regression. RESULTS: A preoperative PSA velocity more than 2.0 ng/mL/yr (P = .001) and biopsy Gleason score 7 (P = .006) or 8 to 10 (P = .003) were significantly associated with having a postoperative PSA DT less than 3 months. A PSA level less than 10 ng/mL (P = .005), a nonpalpable cancer (P = .001) with a Gleason score < or = 6 (P = .0002), and a preoperative PSA increase that did not exceed 0.5 ng/mL/yr (P = .03) were significantly associated with a postoperative PSA DT of at least 12 months or no PSA failure. Most men with these preoperative characteristics and a postoperative PSA DT of 12 months or more had a persistent postoperative PSA level of at least 0.2 ng/mL that did not exceed 0.25 ng/mL after a median follow-up of 3.6 years. CONCLUSION: A postoperative PSA DT less than 3 months is associated with a preoperative PSA velocity more than 2.0 ng/mL/yr and high-grade disease. Select men with a postoperative PSA DT more than 12 months may not require salvage radiation therapy.     

Sexual dysfunction damages: A legal database review

IntroductionProcedural specialties are at higher risk for malpractice claims than non-procedural specialties. Previous studies have examined common damages and malpractice lawsuits resulting from specific procedures. Our goal was to analyze urological interventions that led to sexual dysfunction (SD) claims.MethodsThe Casetext legal research platform was queried using search terms for medical malpractice and common men’s health procedures between 1993 and 2020. In total, 236 cases were found, and 21 cases met the inclusion criteria: malpractice cases against a urologist or urology group, clearly stated legal outcome, and allegation of sexual dysfunction from an intervention that directly caused damages.ResultsA total of 42 damages were cited in 21 lawsuits. The top three damages claimed were erectile dysfunction (ED) (14/42, 33.3%), genital pain syndrome (7/42, 16.7%), and urinary incontinence (5/42, 11.9%). The most commonly cited treatments were urinary catheter placement or removal (3/21, 14.3%), robotic-assisted laparoscopic radical prostatectomy (RALP) (3/21, 14.3%), circumcision (3/21, 14.3%), and penile implant (3/21, 14.3%). In 19 of 21 suits (90.4%), the outcome favored the defendant. Two cases favored the plaintiff: penile implant (failure to prove the patient was permanently, organically impotent prior to the procedure; missed urethral injury at time of surgery, $300 000) and vasectomy (damage to vasculature resulting in loss of testicle, $300 000).ConclusionsMost suspected malpractice cases resulting in SD favored the defendant urologist. Interestingly, urinary catheter placement is as likely to result in litigation as other operative interventions, such as RALP, inflatable penile prosthesis, and circumcision. It is possible that thorough preoperative counselling and increased responsiveness to patients’ postoperative concerns may have avoided litigation in several cases.