Baseline neutrophil-to-lymphocyte ratio as a predictive and prognostic biomarker in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel versus abiraterone or enzalutamide in the CARD study.

BACKGROUND: There is growing evidence that a high neutrophil-to-lymphocyte ratio (NLR) is associated with poor overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC). In the CARD study (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and OS versus abiraterone or enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative androgen-receptor-targeted agent (ARTA). Here, we investigated NLR as a biomarker. PATIENTS AND METHODS: CARD was a multicenter, open-label study that randomized patients with mCRPC to receive cabazitaxel (25 mg/m2 every 3 weeks) versus abiraterone (1000 mg/day) or enzalutamide (160 mg/day). The relationships between baseline NLR [< versus ≥ median (3.38)] and rPFS, OS, time to prostate-specific antigen progression, and prostate-specific antigen response to cabazitaxel versus ARTA were evaluated using Kaplan-Meier estimates. Multivariable Cox regression with stepwise selection of covariates was used to investigate the prognostic association between baseline NLR and OS. RESULTS: The rPFS benefit with cabazitaxel versus ARTA was particularly marked in patients with high NLR {8.5 versus 2.8 months, respectively; hazard ratio (HR) 0.43 [95% confidence interval (CI) 0.27-0.67]; P < 0.0001}, compared with low NLR [7.5 versus 5.1 months, respectively; HR 0.69 (95% CI 0.45-1.06); P = 0.0860]. Higher NLR (continuous covariate, per 1 unit increase) independently associated with poor OS [HR 1.05 (95% CI 1.02-1.08); P = 0.0003]. For cabazitaxel, there was no OS difference between patients with high versus low NLR (15.3 versus 12.9 months, respectively; P = 0.7465). Patients receiving an ARTA with high NLR, however, had a worse OS versus those with low NLR (9.5 versus 13.3 months, respectively; P = 0.0608). CONCLUSIONS: High baseline NLR predicts poor outcomes with an ARTA in patients with mCRPC previously treated with docetaxel and the alternative ARTA. Conversely, the activity of cabazitaxel is retained irrespective of NLR.

Filtration Markers, Cardiovascular Disease, Mortality, and Kidney Outcomes in Stable Kidney Transplant Recipients: The FAVORIT Trial.

Cystatin C and beta-2-microglobulin (B2M) are filtration markers associated with adverse outcomes in nontransplant populations, sometimes with stronger associations than for creatinine. We evaluated associations of estimated glomerular filtration rate from cystatin C (eGFRcys ), B2M (eGFRB2M ), and creatinine (eGFRcr ) with cardiovascular outcomes, mortality, and kidney failure in stable kidney transplant recipients using a case-cohort study nested within the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial. A random subcohort was selected (N = 508; mean age 51.6 years, median transplant vintage 4 years, 38% women, 23.6% nonwhite race) with enrichment for cardiovascular events (N = 306; 54 within the subcohort), mortality (N = 208; 68 within the subcohort), and kidney failure (N = 208; 52 within the subcohort). Mean eGFRcr , eGFRcys , and eGFRB2M were 46.0, 43.8, and 48.8 mL/min/1.73m2 , respectively. After multivariable adjustment, hazard ratios for eGFRcys and eGFRB2M <30 versus 60+ were 2.02 (95% confidence interval [CI] 1.09-3.76; p = 0.03) and 2.56 (1.35-4.88; p = 0.004) for cardiovascular events; 3.92 (2.11-7.31) and 4.09 (2.21-7.54; both p < 0.001) for mortality; and 9.49 (4.28-21.00) and 15.53 (6.99-34.51; both p < 0.001) for kidney failure. Associations persisted with additional adjustment for baseline eGFRcr . We conclude that cystatin C and B2M are strongly associated with cardiovascular events, mortality, and kidney failure in stable kidney transplant recipients.

Estimated GFR for Living Kidney Donor Evaluation.

All living kidney donor candidates undergo evaluation of GFR. Guidelines recommend measured GFR (mGFR), using either an endogenous filtration marker or creatinine clearance, rather than estimated GFR (eGFR), but measurement methods are difficult, time consuming and costly. We investigated whether GFR estimated from serum creatinine (eGFRcr) with or without sequential cystatin C is sufficiently accurate to identify donor candidates with high probability that mGFR is above or below thresholds for clinical decision making. We combined the pretest probability for mGFR thresholds <60, <70, ≥80, and ≥90 mL/min per 1.73 m(2) based on demographic characteristics (from the National Health and Nutrition Examination Survey) with test performance of eGFR (categorical likelihood ratios from the Chronic Kidney Disease Epidemiology Collaboration) to compute posttest probabilities. Using data from the Scientific Registry of Transplant Recipients, 53% of recent living donors had predonation eGFRcr high enough to ensure ≥95% probability that predonation mGFR was ≥90 mL/min per 1.73 m(2) , suggesting that mGFR may not be necessary in a large proportion of donor candidates. We developed a Web-based application to compute the probability, based on eGFR, that mGFR for a donor candidate is above or below a range of thresholds useful in living donor evaluation and selection.

An audit of prostate-specific antigen and clinical symptoms in general practice.

The objective was to devise local guidelines for the referral of patients with suspected prostatic carcinoma following evaluation by a retrospective audit of the value of the prostate-specific antigen concentration, together with age, urological symptoms, and digital rectal examination in the diagnosis of carcinoma of the prostate. Relevant details were collected from the notes of 582 patients from general practice and hospital. The significant diagnostic factors were ascertained by stepwise logistic regression. Prostate-specific antigen concentration, digital rectal examination and significant terminal dribbling were the most powerful factors in the diagnosis of carcinoma of the prostate. When prostate-specific antigen concentration was considered in isolation, a value of 6.5 ng/ml appeared appropriate for referral. Age was not significant, perhaps due to the narrow patient age range. The significant diagnostic factors were built into an algorithm calculating the probability of carcinoma of the prostate. This algorithm, together with prostate-specific antigen concentration results and digital rectal examination findings, forms the basis of the referral guidelines and a subsequent prospective study.

Elemental composition of secretory granules in pancreatic islets of Langerhans.

We have characterized, by electron probe microanalysis, rapidly frozen cultured rat islets at the level of individual secretory granules. Elemental analysis of thin, dried cryosections showed that beta granules could be distinguished by high Zn, Ca, and S, whereas non-beta (mainly alpha) granules contained elevated P and Mg. Although a single granule type predominated in a particular cell, some rebel granules were found in A cells that had the compositional fingerprint of B cell granules. Zn, which was found in millimolar concentrations in B cell granules, was considered a marker for the insulin storage complex. The data indicate that non-B islet cells in the adult pancreas may produce insulin-containing organelles and that, when glucagon and insulin are coexpressed, these hormones are packaged in separate granules.

Effects of serotonin and carbachol on glial and neuronal rubidium uptake in leech CNS.

Effects of serotonin (5-HT) and carbachol on Rb uptake (used as a K marker) in leech neuron and glia were studied by electron probe microanalysis (EPMA). Hirudo medicinalis ganglia were perfused 60 s in 4 mM Rb substituted normal leech Ringer's with and without 5-HT (dosage range 5-500 microM) or carbachol (range 10-1000 microM), quench frozen cryosectioned, and subjected to EPMA to determine elemental mass fractions and cell water content. Both 5-HT and carbachol altered leech neuron and glial cell elemental distribution and water content. In glial cells, a dose-dependent increase in Rb uptake was observed following 5-HT (control: 26 +/- 2 microM; 5 microM: 47 +/- 4; 50 microM: 62 +/- 4; 500 microM: 82 +/- 11 mmol/kg dry wt. +/- S.E.M.) and carbachol (10 microM: 35 +/- 3; 100 microM: 52 +/- 3; 1000 microM: 68 +/- 3 mmol/kg dry wt. +/- S.E.M.). In neurons, 5-HT and carbachol had small effects. 5-HT decreased glial and neuronal cell water content. Carbachol decreased neuronal (but not glial) water content by approximately the same amount (mean decrease 9%) regardless of dose. Both 5-HT and carbachol affected glial cell K-accumulating properties, providing evidence that certain neurotransmitters may modulate invertebrate glial cells' K clearance function.

Preferential uptake of rubidium from extracellular space by glial cells compared to neurons in leech ganglia.

Glial cells play a significant role in maintaining extracellular space (ECS) potassium (K) by temporarily buffering or accumulating excess ECS K and then returning that K to neurons. Yet, little is known about the relative affinity of neurons or glial cells for K when both cells are simultaneously exposed to the same ECS K, in situ. Also, the process by which glial cells return K to neurons remains unknown. Therefore, electron probe X-ray microanalysis was used to measure rubidium (Rb) uptake, as a K tracer, into leech packet neurons and glial cells, and to measure the distribution of cell water content, K, Na and Cl. When ECS Rb was increased from 4 mM to 20 mM, there was a clear preferential Rb uptake into glial cells compared to neurons. At 4 mM extracellular Rb there was only a small difference between uptake velocity of neurons and glial cells (maximum mean uptake velocity at 4 mM Rb was 1.09 for glia, and 0.41 mmol Rb/kg dry wt/s for neurons), whereas at 20 mM extracellular Rb, glial uptake velocity was dramatically greater than of neurons (max. mean Rb uptake velocity for glia was 4.3 compared to 1.47 mmol Rb/kg dry wt/s for neurons). Glial Rb uptake velocity was enhanced by low temperature (max. mean Rb uptake velocity at 20 mM ECS Rb at 6 degrees C was 6.04 for glia compared to 0.78 mmol Rb/kg dry wt/s for neurons) and by substitution of Cl with isethionate (max. mean Rb uptake velocity was 10.6 for glia compared to 1.33 mmol Rb/kg dry wt/s for neurons).(ABSTRACT TRUNCATED AT 250 WORDS)

Personal-computer-based system for electron beam X-ray microanalysis of biological samples.

A system based on a personal computer has been developed which provides a relatively inexpensive way to equip an electron microscopy laboratory for quantitative elemental analyses of cryosectioned biological samples. This system demonstrates the feasibility of making an X-ray analyser from a personal computer, together with commercially available hardware and software components. Hardware and software have been assembled to drive the beam in a scanning electron microscope, collect and analyse X-ray spectra, and save, retrieve, and analyse data. Our software provides a menu-controlled user interface to direct spectra acquisition and analysis. Spot analyses, video images, and quantitative elemental images may be obtained and results transferred in ASCII format to other computers. Wet weight, as well as dry weight, concentrations are calculated, if measurements were made of areas of the hydrated sample before it was freeze-dried. Grey-level copies of video and quantitative elemental images may be made on a laser printer.

Using self-help support groups: a framework for nursing practice and research.

Social support groups are receiving increased attention in professional literature and the media and the number of groups is growing. Nurses are often urged to utilize social support groups as part of client care. These groups cannot be effectively used by nurses unless they are approached from the framework of the nursing process. This approach helps assure individualization of referrals and evaluation of the support group in relation to the client's needs. Based on the literature reviewed and the proposed nursing process framework, many research questions are identified.

Carcinoma of the prostate masquerading as rectal carcinoma. Report of 3 cases and review of the literature.

We present 3 patients with prostatic tumours who presented with symptoms of rectal stenosis. In all 3 cases digital examination of the rectum revealed a mass suggestive of rectal carcinoma, but carcinoma of the prostate was suspected because of other clinical features and this was confirmed by biopsy. Treatment by hormonal manipulation resulted in a dramatic improvement in symptoms. The diagnostic and management difficulties associated with this unusual presentation of carcinoma of the prostate are described, together with a review of the literature.

Health visitors as educators.

This paper describes some models of health education as a context for considering data from a recent study of mothers' and health visitors' perspectives on good child health care. Most health visitors favoured an individualistic top-down approach aimed at changing mothers' behaviour. Mothers preferred a dialogue which started from their own priorities.

Characteristics of cadaveric renal allograft recipients developing chronic rejection.

As the early results of renal transplantation improve, chronic rejection is increasing in relative importance as a cause of graft loss. The aetiology of the condition is unknown. In order to identify possible predisposing factors, the characteristics of 22 patients with chronic rejection were compared with those of 50 patients with stable graft function 2 years or more after transplantation. Patients with chronic rejection had significantly more acute rejection episodes in the first 6 months after transplant (P less than 0.01), a higher incidence of acute rejection with vascular features (P less than 0.01), and longer ischaemic times (P less than 0.05) compared to patients with stable graft function. In a logistic regression analysis both frequency and severity of acute rejection episodes were significantly associated with the subsequent development of chronic rejection. Thus chronic rejection is associated with early injury to the transplanted kidney.

The increasing importance of chronic rejection as a cause of renal allograft failure.

A consequence of reducing early graft failure due to acute rejection has been that more patients are at risk of chronic rejection, something which has become an increasingly important cause of graft loss. We examine the graft survival rates and reasons for failure in our unit from 1981 to 1986. Patients were divided into two series according to treatment of acute rejection episodes. From 1983 onwards, by treating acute vascular (poor prognosis) episodes with antilymphocyte globulin (ALG), we have significantly improved the 6-month actuarial graft survival rate. However, the percentage of total graft failure due to chronic rejection in this second series has significantly increased. The need for greater understanding of the aetiology of chronic rejection, together with its present unsatisfactory treatment, is discussed.

Early experience of the gittes "no-incision" pubovaginal suspension for stress urinary incontinence.

A series of 20 women with stress urinary incontinence underwent bladder neck suspension according to the method in which there are no suprapubic or vaginal incisions and no buttresses. Follow-up was between 9 weeks and 8 months. Twelve patients (60%) were cured, 2 (10%) were significantly improved and 6 (30%) were not improved; 3 patients had pre-operative detrusor instability; when they were excluded the failure rate fell to 23%. These results are inferior to those obtained in this unit using the Stamey procedure, although the difference is not significant. The operation is quick and easy to perform and was well tolerated with minimal complications; we believe it is worthy of further evaluation.