Development and Validation of a Risk-Adapted Scoring Model for Metachronous Upper Tract Urothelial Carcinoma following Radical Cystectomy.

PURPOSE: The incidence and risk factors for metachronous upper tract urothelial carcinoma (UTUC) following radical cystectomy (RC) remain incompletely defined, which has limited the ability to individualize postoperative surveillance. MATERIALS AND METHODS: A retrospective review of 2 institutional registries was performed to identify patients undergoing RC for urothelial carcinoma. Multivariable Cox proportional hazard models for metachronous post-RC UTUC were developed in one institutional data set and validated in the second institutional data set. A post-RC UTUC risk score was then developed from these models. RESULTS: A total of 3,170 RC patients were included from the training cohort and 959 RC patients from the validation cohort. At a median followup after RC of 4.6 years (IQR 2.1-8.7), 167 patients were diagnosed with UTUC. On multivariable analysis in the training cohort, risk factors for metachronous UTUC were the presence of positive urothelial margin (HR 2.60, p <0.01), history of bacillus Calmette-Guérin treatment prior to RC (HR 2.20, p <0.01), carcinoma in situ at RC (HR 2.01, p <0.01) and pre-RC hydronephrosis (HR 1.48, p=0.04). These factors had similar discriminative capacity in the training and validation cohorts (C-statistic 0.71 and 0.73, respectively). A UTUC risk score was developed with these variables which stratified patients into low (0 points), intermediate (1-3 points), and high risk (4+ points) for post-RC UTUC, with respective 5-year UTUC-free survivals of 99%, 96%, 89% in the training cohort and 98%, 96%, and 91% in the validation cohort. CONCLUSIONS: We developed and validated a risk score for post-RC UTUC that may optimize UTUC surveillance protocols after RC.

The current status of thermal ablation in the management of T1b renal masses.

The role of thermal ablation in the management of T1b renal masses is not well defined. The purpose of this review is to examine current evidence for cryoablation, radiofrequency ablation, and microwave ablation of T1b renal masses as well as review current AUA and EAU guidelines for thermal ablation of T1b masses. Given the size of these tumors, adjunctive maneuvers are often necessary to ensure patient safety and protect vital adjacent structures.

Immunotherapy in prostate cancer.

Immunotherapy for the treatment of malignant neoplasms has made significant progress over the last 20 years. Multiple molecular targets and clinical agents have been developed recently, particularly in the field of metastatic adenocarcinoma of the prostate. Sipuleucel-T is currently the only FDA approved immunotherapy for prostate cancer. PSA-TRICOM (Prostvac) currently has a phase III randomized trial underway after a phase II trial showed an improvement in overall survival. Interestingly, both these agents showed improvement in overall survival with no measurable change in disease state, leading to significant controversy as the utility of these agents in prostate cancer. Ipilimumab revealed a benefit for a sub-cohort of men in a post-docetaxel group and is currently undergoing investigation in a pre-docetaxel group. There are a number of other targets such as PD-1 which have shown effectiveness in other neoplasms that will likely be investigated in the future for use in prostate cancer.

Perioperative outcomes and hospital reimbursement by type of radical prostatectomy: results from a privately insured patient population.

BACKGROUND: With the increasing use of robotic surgery in the United States, the comparative effectiveness and differences in reimbursement of minimally invasive radical prostatectomy (MIRP) and open prostatectomy (ORP) in privately insured patients are unknown. Therefore, we sought to assess the differences in perioperative outcomes and hospital reimbursement in a privately insured patient population who were surgically treated for prostate cancer. METHODS: Using a large private insurance database, we identified 17,610 prostate cancer patients who underwent either MIRP or ORP from 2003 to 2010. The primary outcomes were length of stay (LOS), perioperative complications, 90-day readmissions rates and hospital reimbursement. Multivariable regression analyses were used to evaluate for differences in primary outcomes across surgical approaches. RESULTS: Overall, 8981 (51.0%) and 8629 (49.0%) surgically treated prostate cancer patients underwent MIRP and ORP, respectively. The proportion of patients undergoing MIRP markedly rose from 11.9% in 2003 to 72.5% in 2010 (P<0.001 for trend). Relative to ORP, MIRP was associated with a shorter median LOS (1.0 day vs 3.0 days; P<0.001) and lower adjusted odds ratio of perioperative complications (OR: 0.82; P<0.001). However, the 90-day readmission rates of MIRP and ORP were similar (OR: 0.99; P=0.76). MIRP provided higher adjusted mean hospital reimbursement compared with ORP (US $19,292 vs. US $17,347; P<0.001). CONCLUSIONS: Among privately insured patients diagnosed with prostate cancer, robotic surgery rapidly disseminated with over 70% of patients undergoing MIRP by 2009-2010. Although MIRP was associated with shorter LOS and modestly better perioperative outcomes, hospitals received higher reimbursement for MIRP compared with ORP.

Gleason grading after neoadjuvant hormonal therapy retains prognostic value for systemic progression following radical prostatectomy.

BACKGROUND: The Gleason grading system in prostatectomy specimens following receipt of neoadjuvant therapy has been considered inaccurate. However, with continuing expansion of novel therapeutics, it is important to understand whether the Gleason system can be effectively utilized in this setting. The aim of this study was to assess the ability of the Gleason grading system to predict systemic progression among prostatectomy specimens treated with neoadjuvant hormone therapy (NHT). METHODS: This was a single-institution retrospective analysis from 1987 to 2009 of 13,427 patients who underwent radical prostatectomy (RP) without NHT and 1148 patients with NHT. NHT consisted of leuprolide alone (n = 415), antiandrogen therapy alone (n = 400) and combined treatment (n = 333). Kaplan-Meier analysis estimated 15-year systemic progression-free survival among NHT and non-NHT patients. Cox proportional hazard regression models estimated risk of systemic progression following RP according to NHT use and nonuse. RESULTS: Median duration of NHT was 3 months (interquartile range (IQR) 2-4) whereas median follow-up after RP was 8.3 years (IQR 5-10.8). NHT patients were more likely to be D'Amico high risk, have locally advanced pathologic T stage (≥ pT3), pathologic Gleason scores (GS) of 8-10 and lymph node involvement (P<0.0001 for all). NHT use was associated with lower rates of positive surgical margins, more downgrading to pT0 and less GS upgrading from biopsy (P ≤ 0.001 for all). GS could not be assigned to only 3% of NHT patients. On multivariate analysis, pathologic GS remained a predictor of systemic progression (SP) following NHT (hazard ratio (HR) 1.6, P = 0.005), but the association was less strong compared with non-NHT patients (HR 2.9, P < 0.0001). CONCLUSIONS: Utilization of the Gleason system appears feasible among hormonally pretreated prostatectomy specimens and shows continued prognostication for systemic progression. Confirmatory investigations are needed before the Gleason system can be reliably applied in the setting of neoadjuvant therapy.

Specialty bias in treatment recommendations and quality of life among radiation oncologists and urologists for localized prostate cancer.

BACKGROUND: Given the importance of physician attitudes about different treatments and the quality of life (QOL) in prostate cancer, we performed a national survey of specialists to assess treatment recommendations and perceptions of treatment-related survival and QOL. METHODS: We mailed a self-administered survey instrument to a random sample of 1366 specialists in the U.S. Respondents were asked for treatment recommendations and survival that varied by PSA levels and Gleason scores and estimate QOL outcomes. Pearson's chi-square and multivariable regression models were used to test for differences in each outcome. RESULTS: Response rates were similar for radiation oncologists (52.6%) and urologists (52.3%; P=0.92). Across all risk strata, urologists were more likely to recommend surgery than were radiation oncologists, for conditions ranging from PSA>20 and Gleason score 8-10 (35.2 vs. 0.2%; P<0.001) to PSA 4-10 and Gleason score 7 (87.5 vs. 20.9%; P<0.001). Radiation oncologists were also more likely to recommend radiation therapy relative to urologists (all P<0.001). From low- to high-risk prostate cancer, radiation oncologists and urologists perceived their treatment as being better for improving survival (all P<0.001). Each specialty also viewed their treatment as having less urinary incontinence (all P<0.001). CONCLUSIONS: Radiation oncologists and urologists both prefer the treatment modalities they offer, perceive them to be more effective and to lead to a better QOL. Patients may be receiving biased information, and a truly informed consent process with shared decision-making may be possible only if they are evaluated by both specialties before deciding upon a treatment course.

The association of tumor volume with mortality following radical prostatectomy.

BACKGROUND: Data regarding the prognostic significance of tumor volume (TV) in prostate cancer are conflicting. Herein, we evaluated the association of TV with prostate cancer mortality following radical prostatectomy (RP), and assessed the additive prognostic value of TV to an established predictive model. METHODS: We identified 13,687 patients who underwent RP without preoperative therapy between 1987 and 2009. TV was estimated using the prolate ellipsoid formula. Survival was estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazard regression models were used to evaluate the association of TV with mortality. The ability of TV to enhance the performance of an established prognostic model (Mayo Clinic GPSM (Gleason, PSA, seminal vesicle and margin status) score) was assessed using the c-index. RESULTS: Median TV was 1.57 cm(3) (interquartile range (IQR) 0.48-4.19). Increasing TV was associated with significantly higher risks of seminal vesicle invasion (hazard ratio (HR) 1.58; P<0.0001), positive surgical margins (HR 1.28; P<0.0001) and lymph node involvement (HR 1.26; P<0.0001). Median postoperative follow-up was 9.4 years (IQR 5.0-14.5). Patient grouping into quartiles according to TV resulted in a significant stratification of outcome, as the 15-year cancer-specific survival by TV quartile was 99%, 98%, 95% and 88%, respectively (P<0.0001). Moreover, on multivariate analysis, greater TV remained associated with significantly increased risks of systemic progression (HR 1.27; P<0.0001), death from prostate cancer (HR 1.29; P<0.0001) and all-cause mortality (HR 1.05; P<0.0001). Meanwhile, addition of TV to the GPSM score increased the c-index for the model's prediction of prostate cancer mortality from 0.803 to 0.822. CONCLUSIONS: TV is associated with survival following RP, and enhances, although modestly, the performance of an established prediction model. As such, TV warrants continued assessment in risk stratification tools.

Association of T-cell co-regulatory protein expression with clinical outcomes following radical cystectomy for urothelial carcinoma of the bladder.

PURPOSE: Expression of T-cell co-regulatory proteins has been associated with worse outcomes in patients with UCB. We aimed to confirm these findings. MATERIALS AND METHODS: The study comprised tissue microarrays from 302 consecutive UCB patients treated with RC and lymphadenectomy between 1988 and 2003, 117 matched lymph nodes, and 50 cases of adjacent normal urothelium controls, which were evaluated for B7-H1, B7-H3, and PD-1 protein expression by immunohistochemistry. RESULTS: B7-H3 and PD-1 expression were increased in cancers compared to adjacent normal urothelium (58.6% vs 6% and 65% vs 0%, respectively; both p values < 0.001). Meanwhile, B7-H1 was expressed in 25% of cancers (n = 76). Expression of B7-H3, B7-H1, and PD-1 were highly correlated between the primary tumors and metastatic nodes, with concordance rates of 90%, 86%, and 78% for B7H3, B7H1 and PD-1, respectively. Expression was not associated with clinicopathologic features, disease recurrence, cancer-specific or overall mortality. However, for the subgroup of patients with organ-confined disease (n = 96), B7-H1 expression was associated with an increased risk of overall mortality (p = 0.02) on univariate and trended toward an association on multivariate analyses (p = 0.06). CONCLUSIONS: B7-H1, B7-H3 and PD-1 are altered in a large proportion of UCB. B7-H1 and PD-1 expression are differentially upregulated in cancer versus normal urothelium. High correlation between expression in LN and expression in RC specimens was observed. While expression was not associated with clinicopathologic features or standard outcomes in all patients, B7-H1 expression predicted overall mortality after RC in the subset of patients with organ-confined UCB.

Investigation and management of chronic cough using a probability-based algorithm.

Chronic cough is a common and distressing symptom. A novel algorithm has been developed for the management of chronic cough, in which an assessment of clinical probability of disease determines the need to proceed to investigation. In this study, the performance of this algorithm in clinical practice was prospectively evaluated. A total of 131 consecutively referred patients (86 females) whose principal presenting symptom was a cough of duration >8 weeks were studied. Their age (median (range)) was 60 (16-88) yrs and cough duration 5.9 (0.2-65) yrs. A cause of cough was established in 93% of cases. The most frequent diagnoses were asthma (24% of cases), gastro-oesophageal disease (22%), post-viral cough (8%), bronchiectasis (8%) and interstitial lung disease (8%). Primary pulmonary disease was significantly more likely in patients with a productive cough and in patients with an abnormal chest radiograph. Only a small proportion (<8%) of patients had multiple causes of cough. The probability of treatment started on the basis of a high clinical suspicion of either asthma, gastro-oesophageal disease or rhinitis being successful was 74%. Overall, 26% of the patients were managed successfully without the need for any form of investigation other than chest radiography and spirometry. Use of the algorithm resulted in identification of the cause of cough and successful treatment in the large majority of cases. It is concluded that this protocol has the potential to improve management by providing a structured approach, reducing the number of investigations performed, and minimising unnecessary delays in treatment.

Spatial, cellular and temporal basis of vasopressin potentiation of norepinephrine-induced cAMP formation.

This study investigated the spatial distribution of vasopressin V(1) and beta(1)-adrenoceptors within hippocampal subfields and lamina in an attempt to localize the site(s) of interaction between these two receptor systems. In addition, the cell types, neuronal and glial, in which the vasopressin-induced neuromodulation occurs, were identified. Lastly, the temporal constraints of the potentiation induced by vasopressin were investigated. Results of these analyses demonstrated multiple sites within the hippocampus where the interaction between vasopressin and norephinephrine could occur. Moreover, vasopressin-induced potentiation of adrenergic stimulated cyclase occurred in both hippocampal neurons and glia whereas it did not occur in undifferentiated neurons. Analysis of the temporal constraints of vasopressin-induced potentiation revealed that pre-activation of the vasopressin V(1) receptor for 1 min yielded greater potentiation than simultaneous exposure to vasopressin and norepinephrine. These data provide insights into the spatial and temporal characteristics for the interaction between the vasopressin receptor and adrenoceptor systems and provide a cellular and biochemical rationale for the behavioral findings of Kovács and De Wied.

Reinforcement of compliance with respiratory treatment in a child with cystic fibrosis.

An 8-year-old boy with cystic fibrosis (CF), mental retardation, and autism exhibited noncompliance with respiratory treatments that were essential for the management of his CF. A treatment involving shaping cooperation while still allowing escape for aggression and avoidance behavior resulted in increases compliance with respiratory treatments and decreases in problem behavior. Treatment gains were maintained over 3 months.

Research on children's behavior after hospitalization: a review and synthesis.

Despite the presence of considerable research on techniques for reducing distress associated with childhood hospitalization, few studies have examined the more basic issue of whether the event negatively affects children after discharge. A meta-analysis was conducted of studies using the Posthospital Behavior Questionnaire (the most commonly used method of examining posthospital behavior) to determine whether hospitalization results in negative behavioral change, the duration of this reaction, if detected, and factors potentially related to its strength. The mean weighted effect size was +.29 (Confidence interval .95 = +/- .07). Thus, in the absence of interventions, negative behavior tends to increase significantly after discharge (z = +3.99; p < .00006). However, this response diminishes with time and has largely disappeared after 2 weeks. Contrary to expectations, neither age of subjects nor their medical condition was related to their degree of upset. Subjects hospitalized for periods of 2 to 3 days exhibited more behavioral distress than did those hospitalized for either shorter or longer periods.

Research on the effect of experimental interventions on children's behavior after hospitalization: a review and synthesis.

Despite continued interest in ameliorating the posthospital psychological effects of hospitalization on children, there have been no analytic reviews of the research on this topic. The present study synthesized all known research that evaluated experimental interventions through the use of the Posthospital Behavior Questionnaire (PHBQ), by far the most commonly used method of examining posthospital behavior. The mean weighted effect size (ES) was +.44, Confidence Interval (CI).95 = +/- .10. Thus, on the average, children who received experimental interventions tended to change their behavior in the direction of psychological upset less than children who did not (z = +4.81; p < .00006). Analyses of ES moderators indicated significant variations (p < .05) associated with (1) the year of the report, (2) questionnaire format, (3) study design, (4) variations in experimental treatment, (5) subject's age, and (6) length of hospitalization. Psychoeducational preparation was not effective with younger children. The benefits of experimental interventions persisted up to 4 weeks after discharge.

Separation of pairs of C-24 epimeric sterols by glass capillary gas liquid chromatography.

Paris of C-24 epimeric sterols have been very difficult to separate by physical emthods. We report here the partial or complete separation of the trimethylsilyl ethers of nine pairs of C-24 epimeric sterols by gas liquid chromatography on a glass capillary column coated with SP-2340. The trimethylsilyl ethers of the epimeric pairs of sterols with saturated side chains and a pair with two double bonds in the side chain were completely separated from each other by GLC. The epimeric pairs with a double bond at C-22 showed partial separation. The 24ß-epimer with a saturated side chain eluted before the corresponding 24α-epimer. This order was reversed for pairs of C-24 epimeric sterol trimethylsilyl ethers containing a double bond in the side chain at C-22.

A long term study of root retention in the treatment of maxillary molars with furcation involvement.

A study was done to evaluate long-term results of treating 387 maxillary molars with furcation involvement in 100 patients with chronic destructive periodontal disease. Results showed a favorable long term functional survival rate of 341 teeth (88%) 5 to 24 years after treatment, despite the fact that many teeth had at least one root with 50% or less of bone support before treatment. Of the 46 teeth (12%) that were ultimately extracted, 25 were present for a significant length of time (6 to 18 years) before extraction. The radiographs of 292 teeth (75%) showed no significant change in bone support 5 to 24 years after treatement, while those of 8 teeth (2%) suggested improvement. There was perceptible increase in bone loss in 41 teeth (11%). Forty-six (12 %) were extracted. All periodontally involved teeth in each patient of the study were treated. Specific treatment for maxillary molars with furaction involvement included soft tissue therapy; coronal reshaping, if indicated; and instruction in home care. Considerable emphasis was placed on improving occlusal function. In no case was root amputation, hemisection, osseous surgery, or reshaping of the cervical area of the tooth done. A total of 366 (94%) of the teeth did not have endodontic therapy before, during, or after the study. Therefore endodontic therapy was not a significant factor in retention of the 341 teeth.

Hypothalamic dysfunction in secondary amenorrhea associated with simple weight loss.

We tested hypothalamic, pituitary and endocrine function in 19 patients with secondary amenorrhea associated with simple weight loss who did not have anorexia nervosa to evaluate the effects of weight loss on these systems. Thermoregulation at 10 degrees C and 49 degrees C was abnormal and correlated with the percentage below ideal body weight (r = 0.62, P less than 0.02, and r = 0.55, P less than 0.05, respectively). Partial diabetes insipidus was found in 27 per cent of patients with simple weight loss. They had delayed peak plasma luteinizing hormone levels after 10 microgram of luteinizing-hormone-releasing factor, which was correlated with percentage below ideal body weight (r = 0.49, P less than 0.05). Delayed peak plasma thyrotropin levels after 500 microgram of thyrotropin-releasing factor were found. No prolactin, pituitary, thyroid or adrenal abnormalities were present. These findings are qualitatively similar to results of studies in 29 patients with anorexia nervosa, but less severe and less frequently present. We conclude that hypothalamic dysfunction may be caused by weight loss per se.

The copper status of beef cattle in Northern Ireland.

1. Serum caeruloplasmin (ferroxidase I;EC 1.16.3.1) activity has been used as an indicator of copper status of cattle to survey beef herds in Northern Ireland. 2. The main survey covered some 20 000 cows on 1200 farms. 3. The results are reported in the form of a map showing area where herds of low and very-low Cu status predominate. Clinical signs of Cu deficiency in calves were encountered in only two areas.

Role of pentose-phosphate pathway in haemolytic crisis of chronic copper toxicity of sheep.

Although the rise in blood copper is associated with onset of the acute haemolytic crisis of chronic copper poisoning in sheep, the sudden fall in erythrocyte glutathione is apparently not due to a direct action of the copper. Moreover the reduced glutathione of the red cells is converted to some form that is not capable of regeneration by the pentose-phosphate mechanism. Only negligible inhibition of the pentose-phosphate enzymes occurs. As the haemolysis proceeds, there is a rapid recovery of erythrocyte glutathione levels, and a marked increase in pentose-phosphate enzyme activity, consistent with influx of young red cells. It seems that the release of copper into blood from liver at the haemolytic crisis is associated with an increase of the oxidative state of the blood, possibly by simultaneous release of other components from the liver.