Validation of the Decipher genomic classifier in patients receiving salvage radiotherapy without hormone therapy after radical prostatectomy - an ancillary study of the SAKK 09/10 randomized clinical trial.

BACKGROUND: The Decipher genomic classifier (GC) has shown to independently prognosticate outcomes in prostate cancer. The objective of this study was to validate the GC in a randomized phase III trial of dose-escalated salvage radiotherapy (SRT) after radical prostatectomy. PATIENTS AND METHODS: A clinical-grade whole-transcriptome assay was carried out on radical prostatectomy samples obtained from patients enrolled in Swiss Group for Clinical Cancer Research (SAKK) 09/10, a phase III trial of 350 men with biochemical recurrence after radical prostatectomy randomized to 64 Gy versus 70 Gy without concurrent hormonal therapy or pelvic nodal RT. A prespecified statistical plan was developed to assess the impact of the GC on clinical outcomes. The primary endpoint was biochemical progression; secondary endpoints were clinical progression and time to hormone therapy. Multivariable analyses adjusted for age, T-category, Gleason score, postradical prostatectomy persistent prostate-specific antigen (PSA), PSA at randomization, and randomization arm were conducted, accounting for competing risks. RESULTS: The analytic cohort of 226 patients was representative of the overall trial, with a median follow-up of 6.3 years (interquartile range 6.1-7.2 years). The GC (high versus low-intermediate) was independently associated with biochemical progression [subdistribution hazard ratio (sHR) 2.26, 95% confidence interval (CI) 1.42-3.60; P < 0.001], clinical progression (HR 2.29, 95% CI 1.32-3.98; P = 0.003), and use of hormone therapy (sHR 2.99, 95% CI 1.55-5.76; P = 0.001). GC high patients had a 5-year freedom from biochemical progression of 45% versus 71% for GC low-intermediate. Dose escalation did not benefit the overall cohort, nor patients with lower versus higher GC scores. CONCLUSIONS: This study represents the first contemporary randomized controlled trial in patients treated with early SRT without concurrent hormone therapy or pelvic nodal RT that has validated the prognostic utility of the GC. Independent of standard clinicopathologic variables and RT dose, high-GC patients were more than twice as likely than lower-GC patients to experience biochemical and clinical progression and receive of salvage hormone therapy. These data confirm the clinical value of Decipher GC to personalize the use of concurrent systemic therapy in the postoperative salvage setting.

Technical note: Near infrared reflectance spectroscopy to predict fecal indigestible neutral detergent fiber for dairy cows.

In vitro and in situ procedures performed to estimate indigestible neutral detergent fiber (iNDF) in forage or fecal samples are time consuming, costly, and limited by intrinsic factors. In contrast, near infrared reflectance spectroscopy (NIRS) has become widely recognized as a valuable tool for accurately determining chemical composition and digestibility parameters of forages. The aim of this study was to build NIRS calibrations and equations for fecal iNDF. In total, 1,281 fecal samples were collected to build a calibration data set, but only 301 were used to develop equations. Once dried, samples were ground and chemically analyzed for crude protein, ash, amylase and sodium sulfite-treated NDF corrected for ash residue (aNDFom), acid detergent fiber, acid detergent lignin, and in vitro digestion at 240 h to estimate iNDF (uNDF240). Each fecal sample was scanned using a NIRSystem 6500 instrument (Perstorp Analytical Inc., Silver Spring, MD). Spectra selection was performed, resulting in 301 sample spectra used to develop regression equations with good accuracy and low standard error of prediction. The standard error of calibration (SEC), cross validation (SECV), and coefficients of determination for calibration (R2) and for cross validation (1 - VR, where VR = variance ratio) were used to evaluate calibration and validation results. Moreover, the ratio performance deviation (RPD) and ratio of the range of the original data to SECV (range/SECV; range error ratio, RER) were also used to evaluate calibration and equation performance. Calibration data obtained on fiber fractions aNDFom (R2 = 0.92, 1 - VR = 0.87, SEC = 1.48, SECV = 1.89, RPD = 2.80, and RER = 20.19), uNDF240 (R2 = 0.92, 1 - VR = 0.86, SEC = 1.65, SECV = 2.24, RPD = 2.57, and RER = 14.30), and in vitro rumen aNDFom digestibility at 240 h (R2 = 0.90, 1 - VR = 0.85, SEC = 2.68, SECV = 3.43, RPD = 2.53, and RER = 14.0) indicated the predictive equations had good predictive value.

Plasma parameters related to energy and lipid metabolism in periparturient Modenese and Italian Friesian cows.

The aim of this work was to compare energy and lipid metabolism during the peripartum period between Modenese (MO) and Italian Friesian (IF) cows. The study was carried out on 33 pluriparous pregnant cows, 19 IF and 14 MO, reared together in the same herd and kept under equal conditions of management and nutrition. Blood was sampled from jugular vein starting 4 week before expected calving date until 4 week post-calving, once weekly. Plasma was analysed for glucose, NEFA, BHBA, triglycerides and cholesterol concentrations. Body condition score (BCS) was assessed weekly after blood sampling. Data from antepartum (a.p.) and post-partum (p.p.) periods were separately analysed as repeated measures by a linear mixed models with the effect of breed, time and their interaction as main factors and random cow within breed. The energy status differed between the two breeds during the peripartum period. We observed higher BCS a.p. and p.p. and lower BCS variations p.p. in MO compared to IF group. Modenese cows showed lower glucose and cholesterol concentrations (p < 0.001), but higher NEFA values, NEFA to cholesterol and NEFA to albumin ratios (p < 0.001) during a.p.; on the contrary, IF cows had higher (p < 0.05) cholesterol, NEFA, BHBA levels and NEFA to albumin ratio than MO ones during p.p. The differences observed between the two breeds suggest how MO cows are subjected to lipid mobilization during late gestation; on the contrary, IF cows are predisposed to mobilize their lipid reserves at the beginning of lactation to support high production. The results indicate a diverse ability to cope with metabolic stress and suggest the hypothesis that the differences in concentrations of plasma parameters and their variation amplitude around the calving period might depend on the different genetic merit for milk production between the two breeds.

Plasma osteopontin as a biomarker of prostate cancer aggression: relationship to risk category and treatment response.

BACKGROUND: High plasma osteopontin (OPN) has been linked to tumour hypoxia, metastasis, and poor prognosis. This study aims to assess whether plasma osteopontin was a biomarker of increasing progression within prostate cancer (PCa) prognostic groups and whether it reflected treatment response to local and systemic therapies. METHODS: Baseline OPN was determined in men with localised (n=199), locally recurrent (n=9) and castrate-resistant, metastatic PCa (CRPC-MET; n=37). Receiver-operating curves (ROC) were generated to describe the accuracy of OPN for distinguishing between localised risk groups or localised vs metastatic disease. We also measured OPN pre- and posttreatment, following radical prostatectomy, external beam radiotherapy (EBRT), androgen deprivation (AD) or taxane-based chemotherapy. RESULTS: The CRPC-MET patients had increased baseline values (mean 219; 56-513 ng ml(-1); P<0.0001) compared with the localised, non-metastatic group (mean 72; 12-438 ng ml(-1)). The area under the ROC to differentiate localised vs metastatic disease was improved when OPN was added to prostate-specific antigen (PSA) (0.943-0.969). Osteopontin neither distinguished high-risk PCa from other localised PCa nor correlated with serum PSA at baseline. Osteopontin levels reduced in low-risk patients after radical prostatectomy (P=0.005) and in CRPC-MET patients after chemotherapy (P=0.027), but not after EBRT or AD. CONCLUSION: Plasma OPN is as good as PSA at predicting treatment response in CRPC-MET patients after chemotherapy. Our data do not support the use of plasma OPN as a biomarker of increasing tumour burden within localised PCa.

Independent Monte-Carlo dose calculation for MLC based CyberKnife radiotherapy.

This work aims to develop, implement and validate a Monte Carlo (MC)-based independent dose calculation (IDC) framework to perform patient-specific quality assurance (QA) for multi-leaf collimator (MLC)-based CyberKnife® (Accuray Inc., Sunnyvale, CA) treatment plans. The IDC framework uses an XML-format treatment plan as exported from the treatment planning system (TPS) and DICOM format patient CT data, an MC beam model using phase spaces, CyberKnife MLC beam modifier transport using the EGS++ class library, a beam sampling and coordinate transformation engine and dose scoring using DOSXYZnrc. The framework is validated against dose profiles and depth dose curves of single beams with varying field sizes in a water tank in units of cGy/Monitor Unit and against a 2D dose distribution of a full prostate treatment plan measured with Gafchromic EBT3 (Ashland Advanced Materials, Bridgewater, NJ) film in a homogeneous water-equivalent slab phantom. The film measurement is compared to IDC results by gamma analysis using 2% (global)/2 mm criteria. Further, the dose distribution of the clinical treatment plan in the patient CT is compared to TPS calculation by gamma analysis using the same criteria. Dose profiles from IDC calculation in a homogeneous water phantom agree within 2.3% of the global max dose or 1 mm distance to agreement to measurements for all except the smallest field size. Comparing the film measurement to calculated dose, 99.9% of all voxels pass gamma analysis, comparing dose calculated by the IDC framework to TPS calculated dose for the clinical prostate plan shows 99.0% passing rate. IDC calculated dose is found to be up to 5.6% lower than dose calculated by the TPS in this case near metal fiducial markers. An MC-based modular IDC framework was successfully developed, implemented and validated against measurements and is now available to perform patient-specific QA by IDC.

Blood parameters in fattening pigs fed whole-ear corn silage and housed in group pens or in metabolic cages.

The aim of this work was to evaluate the effects of the inclusion of whole-ear corn silage (WECS) in diets for advanced fattening heavy pigs (substitution for part of the dry corn and wheat bran) allocated or not in metabolic cages on the main blood parameters. The high-moisture shelled corn is largely used in pig feeding while WECS is less often used despite the fact that it increases the DM crop yield. Three experimental diets were fed to 27 barrows (Italian Large White × Italian Duroc), with an average BW of 98.2 (±5.6) kg at the start of the trial, and randomly allotted to 3 experimental groups including a control diet (CON) containing cereal meals (corn, barley, and wheat, 80.2% DM in total), soybean meal (9% DM), wheat bran (8% DM), minerals and supplements (2.8% DM), and 2 diets containing WECS (15 or 30% DM referred to as 15WECS and 30WECS, respectively) in partial or complete substitution for wheat bran and corn meal. The pigs were randomly housed in 9 pens with 3 animals per pen and 3 pens per dietary treatment. Six pigs per each of the 3 treatments were moved from the pens to individual metabolic cages for 3 consecutive periods (2 pigs per treatment per period). Each period lasted 14 d, and blood was collected at the start and at the end of the periods. Blood was drawn from the jugular vein before feed distribution in the morning, at 14 d intervals, and analyzed for hematological, metabolic, and serum protein profiles. The effect of the metabolic cage housing was included in the statistical model to compare the results obtained in the 2 different environments of restrained and group-housed barrows. The WECS affected the neutrophil to lymphocyte ratio and mean corpuscular hemoglobin concentration. The main diet effect on plasma metabolites was recorded for plasma NEFA, with higher values in WECS diets compared with the CON. The metabolic cage housing affected both hematological (red blood cell count, hemoglobin, hematocrit) and metabolic (protein and its fractions) items, which can be markers of hemodilution. These results indicate the possibility to use this feed in the diet of heavy pigs without negative effects on physiology. The absolute values from metabolic profile of pigs in metabolic cages must be considered with caution for possible comparisons with values obtained on-field in group pens, particularly because a different hemodilution may affect the results.

Efficacy and tolerability of ketoprofen 200 mg controlled-release cps vs indomethacin 50 mg cps in patients with symptomatic hip osteoarthritis. A multicentre study.

BACKGROUND: An open-label, randomised, multicentre study was carried out to compare the efficacy and tolerability of indomethacin capsules and ketoprofen controlled-release capsules in the symptomatic treatment of coxarthrosis. MATERIALS AND METHODS: 113 out-patients were enrolled: 57 were assigned to receive indomethacin 50 mg twice daily and 56 ketoprofen 200 mg once daily for 4 weeks. RESULTS: Indomethacin and ketoprofen proved equally effective in relieving osteoarticular pain and stiffness and in improving the quality of life of patients. There was essentially no difference as to gastrointestinal adverse events which occurred in 25% of patients on indomethacin and in 27% of those on ketoprofen. Indomethacin caused more non-gastrointestinal untoward effects, especially CNS effects (headache and dizziness: 11%) which were not observed with ketoprofen. Indomethacin was discontinued because of adverse events in a larger proportion of patients (20%) than ketoprofen (11%).

An arranged marriage for precision medicine: hypoxia and genomic assays in localized prostate cancer radiotherapy.

Prostate cancer (CaP) is the most commonly diagnosed malignancy in males in the Western world with one in six males diagnosed in their lifetime. Current clinical prognostication groupings use pathologic Gleason score, pre-treatment prostatic-specific antigen and Union for International Cancer Control-TNM staging to place patients with localized CaP into low-, intermediate- and high-risk categories. These categories represent an increasing risk of biochemical failure and CaP-specific mortality rates, they also reflect the need for increasing treatment intensity and justification for increased side effects. In this article, we point out that 30-50% of patients will still fail image-guided radiotherapy or surgery despite the judicious use of clinical risk categories owing to interpatient heterogeneity in treatment response. To improve treatment individualization, better predictors of prognosis and radiotherapy treatment response are needed to triage patients to bespoke and intensified CaP treatment protocols. These should include the use of pre-treatment genomic tests based on DNA or RNA indices and/or assays that reflect cancer metabolism, such as hypoxia assays, to define patient-specific CaP progression and aggression. More importantly, it is argued that these novel prognostic assays could be even more useful if combined together to drive forward precision cancer medicine for localized CaP.

Locally advanced prostate cancer: current controversies and optimisation opportunities.

Prostate cancer is the most common malignancy in men worldwide. The rate of patients presenting with locally advanced prostate cancer has declined in recent decades, mainly due to prostate-specific antigen screening, but the management of these patients still remains controversial. Current literature suggests that the standard of care for these patients is a combination approach with radiation therapy and androgen deprivation therapy. However, there remain many unresolved issues, including the role of dose-escalated radiation therapy, the additional benefit of surgery and the role of systemic therapy, both standard chemotherapeutic agents and novel agents. Furthermore, in the era of personalised medicine, additional research is needed to evaluate the role of biomarkers to better predict the risk of local and systemic relapse in this population.

Combining radiation therapy and androgen deprivation for localized prostate cancer-a critical review.

Interest has been increasing in the use of androgen deprivation therapy (ADT) combined with radiation therapy (RT) in the management of localized prostate cancer. Preclinical studies have provided some rationale for the use of this combination. In patients with high-risk disease, the benefit of a combined approach, with the addition of adjuvant hormonal therapy, is supported by results of randomized trials. In contrast, for patients with low-risk disease, there is no obvious therapeutic advantage except for cytoreduction. The usefulness of short-term hormonal therapy in association with rt for intermediate-risk patients is still debatable, particularly in the context of doseescalated RT. The optimal timing and duration of ADT, in the neoadjuvant and adjuvant settings alike, are still under investigation. In view of the potential side effects with ADT, further studies are being performed to better identify subsets of patients who will definitely benefit from this therapy in combination with rt.

Searching for optimal dose-volume constraints to reduce rectal toxicity after hypofractionated radiotherapy for prostate cancer.

AIMS: Late rectal toxicity is a major concern for prostate cancer patients treated with radiotherapy. Rectal dose-volume constraints, set as guidelines to reduce its incidence, vary among institutions. From a group of patients uniformly treated with hypofractionated radiotherapy, we correlated the incidence of late rectal toxicity with rectal dose-volume rectal constraints as described in three randomised trials for prostate cancer. MATERIALS AND METHODS: Favourable-risk prostate cancer patients received a dose of 66 Gy in 22 fractions without hormonal therapy. Toxicity was prospectively assessed using Common Toxicity Criteria v3. The whole or part of the rectum and rectal wall were contoured as an organ at risk for all patients. The rectal constraints of the RTOG 0126, RTOG 0415 and the PROFIT trials were used to correlate with late rectal toxicity. RESULTS: The median follow-up time was 58 months. Late rectal toxicity was 62, 20 and 18% for grades 0, 1 and 2/3, respectively. No statistically significant correlation was found between late rectal toxicity and the rectal constraints used in the three trials. The number of patients violating the recommended constraints was similar for the group with grade 2/3 toxicity and the group without any toxicity. Analysis derived from the actual dose-volume histogram dose parameters of this group of patients did not show a relationship between dose to volume of the rectum and late rectal toxicity that could generate a guideline of dose constraints. CONCLUSION: For this group of patients, despite the use of recognised dose-volume constraint guidelines of three trials, we were unable to establish a relationship between these constraints and the late rectal toxicity registered. Further studies on the correlation of dosimetric parameters with rectal toxicity, particularly for hypofractionated regimens, are required. Non-dosimetric factors may also be involved in the risk of late rectal toxicity.

X-ray study on homo-oligopeptides t-Boc(L-Nva)6OMe and HCl.H(L-Nva)6OMe.

Observations of extended peptide chains, whose direction is perpendicular to the fiber axis (cross-beta-structure) have hitherto been confined to fibrous proteins and to some synthetic polydisperse polypeptides of rather low molecular weight. This structure has now been found in some monodisperse linear homo-oligopeptides with aliphatic hydrocarbon side chains. X-ray fiber diagrams of t-Boc(L-Nva)6OMe and HCl.H(L-Nva)6OMe show the characteristic reflections of this form. In addition, the good orientation of suitably prepared specimens has enabled a fairly complete determination of the hexapeptides unit cell to be made. Both molecules are packed in a pseudomonoclinic lattice whose dimensions are: a = 4.80, b = 59.0, c = 14.86 A, beta = 85 degrees and a = 4.80, b = 58.50, c = 14.84 and beta = 86 degrees for t-Boc(L-Nva)6-OMe and HCl.H(L-Nva)6OMe respectively. It has not been possible from the available experimental data to establish whether the arrangement of the chains within the sheets is parallel or antiparallel.

A PC-based workstation for processing and analysis of MRI data.

The present work demonstrates that a low cost, flexible and user-friendly workstation for the MRI laboratory can be implemented by using a personal computer and public-domain software. The workstation is based on a Pentium personal computer, operating under the Linux operative system, and uses the software Khoros (Khoral Research, Albuquerque, NM). This software is a general purpose package for handling signals and we here report its suitability for MR images analysis. Khoros allows to create workspaces where different procedures (also written by the users) can be combined for implementing more complex procedures. We created workspaces for obtaining 2D and 3D images from time domain data which also allow for apodization and zero-filling. The time required for a 3D-FFT (matrix size 128x128x128) is about 12 min with the presently used microprocessor. We have also created workspaces for calculating apparent diffusion coefficient maps and for segmentation of MR images. Our results demonstrate that a personal computer equipped with public-domain software can represent a powerful tool to fulfil the MRI laboratory common needs.

Conformational studies on sequential polypeptides. Part VII. Structural investigations on (Pro-Phe-Gly)n and (Phe-Pro-Gly)n.

The conformational properties of (Pro-Phe-Gly)n and (Phe-Pro-Gly)n were investigated both in the solid state and in solution. In solid state X-ray diffraction patterns seem to indicate that (Pro-Phe-Gly)n assumes a single chain triple helical structure. In solution, by circular dichroism studies, it was possible to show the existence of beta-bends in the presence of ethylene glycol. Similar studies carried out on (Phe-Pro-Gly)n showed no collagen or polyproline II-like structure in the solid state. In solution the beta-bend formation was apparent in all the solvent systems studied.

Conformational studies on sequential polypeptides Part VI. Structural investigations on (Pro-Leu-Gly)10, (Pro-Leu-Gly)n and (Leu-Pro-Gly)n.

The conformational properties of (Pro-Leu-Gly)10, (Pro-Leu-Gly)n and (Leu-Pro-Gly)n were investigated both in solution and in solid state. By circular dichroism studies it was possible to demonstrate the formation of an ordered collagen-like structure for (Pro-Leu-Gly)n in hexafluroisopropanol-water mixtures and in ethylene glycol; (Leu-Pro-Gly)n assumes an ordered conformation only in ethylene glycol; (Pro-Leu-Gly)10 is unordered under all the conditions studied. X-ray diffraction patterns indicated that (Pro-Leu-Gly)n and (Leu-Pro-Gly)n assume a triple helical structure in solid state. In addition, the investigation of (Pro-Leu-Gly)n strongly suggests that this type of structure is a single chain triple helix. The X-ray patterns of (Pro-Leu-Gly)10 do not allow us to ascertain a collagen or polyproline II-like structure for this decatripeptide.

[Floppy eyelid syndrome. 5 cases]. / Syndrome de la paupière "Floppy". Cinq cas.

First described in 1981, the floppy eyelid syndrome is characterized by loose upper lids that evert spontaneously and chronic papillary conjunctivitis. We present five patients with this syndrome and illustrate the distinctive clinical findings.