Validation of a Metastatic Assay using biopsies to improve risk stratification in patients with prostate cancer treated with radical radiation therapy.

Background: Radiotherapy is an effective treatment of intermediate/high-risk locally advanced prostate cancer, however, >30% of patients relapse within 5 years. Clinicopathological parameters currently fail to identify patients prone to systemic relapse and those whom treatment intensification may be beneficial. The purpose of this study was to independently validate the performance of a 70-gene Metastatic Assay in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Patients and methods: A bridging cohort of prostate cancer diagnostic biopsy specimens was profiled to enable optimization of the Metastatic Assay threshold before further independent clinical validation in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Multivariable Cox proportional hazard regression analysis was used to assess assay performance in predicting biochemical failure-free survival (BFFS) and metastasis-free survival (MFS). Results: Gene expression analysis was carried out in 248 patients from the independent validation cohort and the Metastatic Assay applied. Ten-year MFS was 72% for Metastatic Assay positive patients and 94% for Metastatic Assay negative patients [HR = 3.21 (1.35-7.67); P = 0.003]. On multivariable analysis the Metastatic Assay remained predictive for development of distant metastases [HR = 2.71 (1.11-6.63); P = 0.030]. The assay retained independent prognostic performance for MFS when assessed with the Cancer of the Prostate Assessment Score (CAPRA) [HR = 3.23 (1.22-8.59); P = 0.019] whilst CAPRA itself was not significant [HR = 1.88, (0.52-6.77); P = 0.332]. A high concordance [100% (61.5-100)] for the assay result was noted between two separate foci taken from 11 tumours, whilst Gleason score had low concordance. Conclusions: The Metastatic Assay demonstrated significant prognostic performance in patients treated with radical radiotherapy both alone and independent of standard clinical and pathological variables. The Metastatic Assay could have clinical utility when deciding upon treatment intensification in high-risk patients. Genomic and clinical data are available as a public resource.

Conditioned pain modulation identifies altered sensitivity in extremely preterm young adult males and females.

BACKGROUND: Conditioned pain modulation is a potential biomarker for risk of persistent pain. As early-life experience can alter subsequent somatosensory processing and pain response, we evaluated conditioned pain modulation after extremely preterm birth. METHODS: This observational study recruited extremely preterm (<26 weeks gestation; n=98) and term-born control (n=48) young adults (19-20 yr) from the longitudinal EPICure cohort. Pressure pain threshold (PPT; variable test stimulus lower leg) was measured before, during, and after a conditioning stimulus (contralateral hand immersion; 5°C water; 30 s). Questionnaires assessed current pain, medication use, anxiety, and pain catastrophising. RESULTS: For participants tolerating conditioning, there were significant main effects of extremely preterm status, sex, and time on PPT during and after hand immersion. Inhibitory modulation was evoked in 64/98 extremely preterm (3, no change) and 38/48 term-born control (3, facilitation) subjects. The conditioned pain modulation effect (percentage change in PPT) did not differ between the extremely preterm and term-born control groups {53% [95% confidence interval (CI): 41-65] vs 57% [95% CI: 42-71]}. Reduced cold tolerance (<20 s) hampered conditioned pain modulation quantification in a higher proportion of extremely preterm participants [extremely preterm vs term-born control: 31/98 (32%) vs 7/48 (15%); P=0.03]. One-third of extremely preterm females withdrew the hand before parallel PPT (<15 s), and had lower baseline PPT than term-born control females [4.9 (95% CI: 4.8-5.1) vs 5.3 (95% CI: 5.1-5.5) ln kPa; P=0.02]. Higher anxiety, pain catastrophising, and medication use correlated with pain intensity, but not conditioned pain modulation effect. CONCLUSIONS: Cold conditioning evoked inhibitory modulation in the majority of young adults and identified a subgroup of extremely preterm females with increased baseline sensitivity. Early-life experience and sex/gender should be considered when evaluating persistent pain risk with conditioned pain modulation.

Opioid analgesia and the somatosensory memory of neonatal surgical injury in the adult rat.

BACKGROUND: Nociceptive input during early development can produce somatosensory memory that influences future pain response. Hind-paw incision during the 1st postnatal week in the rat enhances re-incision hyperalgesia in adulthood. We now evaluate its modulation by neonatal analgesia. METHODS: Neonatal rats [Postnatal Day 3 (P3)] received saline, intrathecal morphine 0.1 mg kg-1 (IT), subcutaneous morphine 1 mg kg-1 (SC), or sciatic levobupivacaine block (LA) before and after plantar hind-paw incision (three×2 hourly injections). Six weeks later, behavioural thresholds and electromyography (EMG) measures of re-incision hyperalgesia were compared with an age-matched adult-only incision (IN) group. Morphine effects on spontaneous (conditioned place preference) and evoked (EMG sensitivity) pain after adult incision were compared with prior neonatal incision and saline or morphine groups. The acute neonatal effects of incision and analgesia on behavioural hyperalgesia at P3 were also evaluated. RESULTS: Adult re-incision hyperalgesia was not prevented by neonatal peri-incision morphine (saline, IT, and SC groups > IN; P<0.05-0.01). Neonatal sciatic block, but not morphine, prevented the enhanced re-incision reflex sensitivity in adulthood (LA < saline and morphine groups, P<0.01; LA vs IN, not significant). Morphine efficacy in adulthood was altered after morphine alone in the neonatal period, but not when administered with neonatal incision. Morphine prevented the acute incision-induced hyperalgesia in neonatal rats, but only sciatic block had a preventive analgesic effect at 24 h. CONCLUSIONS: Long-term effects after neonatal injury highlight the need for preventive strategies. Despite effective analgesia at the time of neonatal incision, morphine as a sole analgesic did not alter the somatosensory memory of early-life surgical injury.

Somatosensory function and pain in extremely preterm young adults from the UK EPICure cohort: sex-dependent differences and impact of neonatal surgery.

BACKGROUND: Surgery or multiple procedural interventions in extremely preterm neonates influence neurodevelopmental outcome and may be associated with long-term changes in somatosensory function or pain response. METHODS: This observational study recruited extremely preterm (EP, <26 weeks' gestation; n=102, 60% female) and term-born controls (TC; n=48) aged 18-20 yr from the UK EPICure cohort. Thirty EP but no TC participants had neonatal surgery. Evaluation included: quantitative sensory testing (thenar eminence, chest wall); clinical pain history; questionnaires (intelligence quotient; pain catastrophising; anxiety); and structural brain imaging. RESULTS: Reduced thermal threshold sensitivity in EP vs TC participants persisted at age 18-20 yr. Sex-dependent effects varied with stimulus intensity and were enhanced by neonatal surgery, with reduced threshold sensitivity in EP surgery males but increased sensitivity to prolonged noxious cold in EP surgery females (P<0.01). Sex-dependent differences in thermal sensitivity correlated with smaller amygdala volume (P<0.05) but not current intelligence quotient. While generalised decreased sensitivity encompassed mechanical and thermal modalities in EP surgery males, a mixed pattern of sensory loss and sensory gain persisted adjacent to neonatal scars in males and females. More EP participants reported moderate-severe recurrent pain (22/101 vs 4/48; χ2=0.04) and increased pain intensity correlated with higher anxiety and pain catastrophising. CONCLUSIONS: After preterm birth and neonatal surgery, different patterns of generalised and local scar-related alterations in somatosensory function persist into early adulthood. Sex-dependent changes in generalised sensitivity may reflect central modulation by affective circuits. Early life experience and sex/gender should be considered when evaluating somatosensory function, pain experience, or future chronic pain risk.

Financial toxicity: a potential side effect of prostate cancer treatment among Australian men.

The purpose of this study was to understand the extent, nature and variability of the current economic burden of prostate cancer among Australian men. An online cross-sectional survey was developed that combined pre-existing economic measures and new questions. With few exceptions, the online survey was viable and acceptable to participants. The main outcomes were self-reported out-of-pocket costs of prostate cancer diagnosis and treatment, changes in employment status and household finances. Men were recruited from prostate cancer support groups throughout Australia. Descriptive statistical analyses were undertaken. A total of 289 men responded to the survey during April and June 2013. Our study found that men recently diagnosed (within 16 months of the survey) (n = 65) reported spending a median AU$8000 (interquartile range AU$14 000) for their cancer treatment while 75% of men spent up to AU$17 000 (2012). Twenty per cent of all men found the cost of treating their prostate cancer caused them 'a great deal' of distress. The findings suggest a large variability in medical costs for prostate cancer treatment with 5% of men spending $250 or less in out-of-pocket expenses and some men facing very high costs. On average, respondents in paid employment at diagnosis stated that they had retired 4-5 years earlier than planned.

Cancer treatment-related neuropathic pain: proof of concept study with menthol--a TRPM8 agonist.

PURPOSE: Effective treatment of neuropathic pain without unacceptable side effects is challenging. Cancer sufferers increasingly live with long-term treatment-related neuropathic pain, resulting from chemotherapy-induced peripheral neuropathy (CIPN) or surgical scars. This proof-of-concept study aimed to determine whether preclinical evidence for TRPM8 ion channels in sensory neurons as a novel analgesic target could be translated to clinical benefit in patients with neuropathic pain, using the TRPM8 activator menthol. PATIENTS AND METHODS: Patients with problematic treatment-related neuropathic pain underwent a baseline assessment using validated questionnaires, psychophysical testing, and objective functional measures. The painful area was treated with topical 1 % menthol cream twice daily. Assessments were repeated at 4-6 weeks. The primary outcome was the change in Brief Pain Inventory total scores at 4-6 weeks. Secondary outcomes included changes in function, mood and skin sensation. RESULTS: Fifty-one patients (female/male, 32/19) were recruited with a median age of 61 (ranging from 20 to 89). The commonest aetiology was CIPN (35/51), followed by scar pain (10/51). Thirty-eight were evaluable on the primary outcome. Eighty-two per cent (31/38) had an improvement in total Brief Pain Inventory scores (median, 47 (interquartile range, 30 to 64) to 34 (6 to 59), P < 0.001). Improvements in mood (P = 0.0004), catastrophising (P = 0.001), walking ability (P = 0.008) and sensation (P < 0.01) were also observed. CONCLUSION: This proof-of-concept study indicates that topical menthol has potential as a novel analgesic therapy for cancer treatment-related neuropathic pain. Improvements in patient-rated measures are supported by changes in objective measures of physical function and sensation. Further systematic evaluation of efficacy is required.

Morphology and surface topography of the schistosome Bivitellobilharzia nairi from the Asian elephant (Elephas maximus maximus) in Sri Lanka.

Bivitellobilharzia nairi was first recorded from an Indian elephant (Elephas maximus) in Berlin. Infections with this parasite have become increasingly important in E. maximus maximus populations in Sri Lanka. The present work is the first morphological description of this schistosome from Sri Lanka. A number of adult worms were recovered from a dead Asian elephant near the elephant orphanage, Pinnawala, in Sri Lanka. The observed clinical features of the infected elephant included emaciation, subventral oedema and anaemia. Post-mortem results indicated that the liver was enlarged and adult schistosomes were found in the blood vessels of the liver parenchyma. The total number of worms recovered from a portion of the liver was 129,870, which is an average of 22 worms per 100 g of liver. The present study uses both light microscopic and scanning electron microscope (SEM) techniques for the morphological and topographical characterization of this parasite and to permit comparison with other species of schistosomes. Morphologically, these worms correspond very well to the description of B. nairi by Dutt & Srivastava (1955). Moreover, it is clear that B. nairi is a distinctive species easily differentiated from other schistosomes. The SEM study of the tegument of male worms shows that the surface of B. nairi is smoother than in other schistosomes.

Immunotherapy for allergic rhinitis.

Allergic rhinitis (AR) affects more than 20% of the population in the United Kingdom and western Europe and represents a major cause of morbidity that includes interference with usual daily activities and impairment of sleep quality. This guidance prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI) is for the management of AR in patients that have failed to achieve adequate relief of symptoms despite treatment with intranasal corticosteroids and/or antihistamines. The guideline is based on evidence and is for use by both adult physicians and paediatricians practising allergy. During the development of these guidelines, all BSACI members were included in the consultation process using a web-based system. Their comments and suggestions were carefully considered by the SOCC. Where evidence was lacking, consensus was reached by the experts on the committee. Included in this guideline are indications and contraindications for immunotherapy, criteria for patient selection, the evidence for short- and long-term efficacy of subcutaneous and sublingual immunotherapy, and discussion on safety and the different modes of immunotherapy including, pre-seasonal and co-seasonal treatments. There are sections on children, allergen standardization, vaccines used in the United Kingdom, oral allergy syndrome, cost effectiveness of immunotherapy and practical considerations of undertaking immunotherapy including recommendations on who should undertake immunotherapy and dosing schedules. Finally, there is discussion on potential biomarkers of response to immunotherapy, the use of component-resolved diagnostics, novel approaches, alternative routes and potential areas for future research.

Population dynamics of the liver fluke, Fasciola hepatica: the effect of time and spatial separation on the genetic diversity of fluke populations in the Netherlands.

An evaluation of the genetic diversity within Fasciola hepatica (liver fluke) may provide an insight into its potential to respond to environmental changes, such as anthelmintic use or climate change. In this study, we determined the mitochondrial DNA haplotypes of > 400 flukes from 29 individual cattle, from 2 farms in the Netherlands, as an exemplar of fasciolosis in a European context. Analysis of this dataset has provided us with a measure of the genetic variation within infrapopulations (individual hosts) and the diversity between infrapopulations within a herd of cattle. Temporal sampling from one farm allowed for the measurement of the stability of genetic variation at a single location, whilst the comparison between the two farms provided information on the variation in relation to distance and previous anthelmintic regimes. We showed that the liver fluke population in this region is predominantly linked to 2 distinct clades. Individual infrapopulations contain a leptokurtic distribution of genetically diverse flukes. The haplotypes present on a farm have been shown to change significantly over a relatively short time-period.

In vitro tolerance induction of primed, IgD-negative murine spleen cells.

The above observations demonstrated induction of immunological tolerance in vitro in primed IgD-, IgG+ B cells. In these studies, addition of trinitrophenylated (TNP) turkey gammaglobulin (TGG) or TNP ovalbumin conjugates suppressed the secondary in vitro response in mice primed with TNP keyhole limpet hemocyanin (TNP-KLH). Suppression was not a reflection of a shift in kinetics of the antibody response, was not dependent on suppressor T cells, and could only be eliciate when conjugate was added within 4 h of addition of TNP-KLH moreover, preincubation of the primed spleen cells with TNP-TGG for 20 h at 37 degrees C, followed by extensive washing, was as effective in inhibiting the response to TNP-KLH as when TNP-TGG was present throughout the 5 d of culture, reflecting induction of a tolerant state. Amounts of conjugate in the concentration range that have been shown by others to tolerize immature or neonatal B cells or mature B cells that have been stripped of surface IgD were sufficient to induce tolerance. The target cells being tolerized did not bear IgD, as determined by B cell depletion and blocking procedures with anti IgD. Whether the lack of surface IgD on the primed cells contributed to the relative ease of tolerance induction was not established by these studies, but the advantages of using primed B cells to examine further the role of surface IgD in tolerance susceptibility was discussed.

Enrichment of antigen-specific B lymphocytes by the direct removal of B cells not bearing specificity for the antigen.

Antigen-specific B cells (ASC) were purified from other B cells by prior incubation with specific antigen followed by rosetting with erythrocytes conjugated with anti-mouse Ig and sedimenting on Ficoll-Isopaque. This procedure allowed the removal of most of the B cells, while those speicifc for the antigen used in incubation were retained. Relative to the B-cell content, ASC were enriched 64- to 132-fold. The method is highly specific in that B cells primed to two different antigens, turkey gamma globulin and sheep erythrocytes, could be separated from each other. The advantages of this indirect purification procedure over purification procedures which obtain ASC directly are the simplicity of obtaining the ASC and the ability of the ASC of respond to antigen without the addition of other cells.

Regulation of the immune response. I. The potentiation of in vivo and in vitro immune responses by Fc fragments.

Fc fragments derived from human and murine Ig were found to be potent adjuvants when administered with antigen. Both the in vivo and in vitro anti- sheep erythrocytes (SRBC) responses were significantly enhanced by Fc fragments. The adjuvant effect was shown to be extremely dependent upon the dose of antigen used, with the greatest enhancement occurring when suboptimal doses of antigen are employed. The anti-genicity of the Fc molecule was not related to its adjuvanticity because homologous Fc was as potent an adjuvant as heterologous Fc. Moreover, human Fc fragments enhanced anti-SRBC responses in mice which were tolerant to human gamma globulin.

Accuracy of external cause-of-injury coding in hospital records.

OBJECTIVE: To appraise the published evidence regarding the accuracy of external cause-of-injury codes in hospital records. DESIGN: Systematic review. DATA SOURCES: Electronic databases searched included PubMed, PubMed Central, Medline, CINAHL, Academic Search Elite, Proquest Health and Medical Complete, and Google Scholar. Snowballing strategies were used by searching the bibliographies of retrieved references to identify relevant associated articles. SELECTION CRITERIA: Studies were included in the review if they assessed the accuracy of external cause-of-injury coding in hospital records via a recoding methodology. METHODS: The papers identified through the search were independently screened by two authors for inclusion. Because of heterogeneity between studies, meta-analysis was not performed. RESULTS: Very limited research on the accuracy of external cause coding for injury-related hospitalisation using medical record review and recoding methodologies has been conducted, with only five studies matching the selection criteria. The accuracy of external cause coding using ICD-9-CM ranged from approximately 64% when exact code agreement was examined to approximately 85% when agreement for broader groups of codes was examined. CONCLUSIONS: Although broad external cause groupings coded in ICD-9-CM can be used with some confidence, researchers should exercise caution for very specific codes until further research is conducted to validate these data. As all previous studies have been conducted using ICD-9-CM, research is needed to quantify the accuracy of coding using ICD-10-AM, and validate the use of these data for injury surveillance purposes.

Causes of injuries resulting in hospitalisation in Australia: assessing coder agreement on external causes.

OBJECTIVE: To assess extent of coder agreement for external causes of injury using ICD-10-AM for injury-related hospitalisations in Australian public hospitals. METHODS: A random sample of 4850 discharges from 2002 to 2004 was obtained from a stratified random sample of 50 hospitals across four states in Australia. On-site medical record reviews were conducted and external cause codes were assigned blinded to the original coded data. Code agreement levels were grouped into the following agreement categories: block level, 3-character level, 4-character level, 5th-character level, and complete code level. RESULTS: At a broad block level, code agreement was found in over 90% of cases for most mechanisms (eg, transport, fall). Percentage disagreement was 26.0% at the 3-character level; agreement for the complete external cause code was 67.6%. For activity codes, the percentage of disagreement at the 3-character level was 7.3% and agreement for the complete activity code was 68.0%. For place of occurrence codes, the percentage of disagreement at the 4-character level was 22.0%; agreement for the complete place code was 75.4%. CONCLUSIONS: With 68% agreement for complete codes and 74% agreement for 3-character codes, as well as variability in agreement levels across different code blocks, place and activity codes, researchers need to be aware of the reliability of their specific data of interest when they wish to undertake trend analyses or case selection for specific causes of interest.

Peripheral demyelination and neuropathic pain behavior in periaxin-deficient mice.

The Prx gene in Schwann cells encodes L- and S-periaxin, two abundant PDZ domain proteins thought to have a role in the stabilization of myelin in the peripheral nervous system (PNS). Mice lacking a functional Prx gene assemble compact PNS myelin. However, the sheath is unstable, leading to demyelination and reflex behaviors that are associated with the painful conditions caused by peripheral nerve damage. Older Prx-/- animals display extensive peripheral demyelination and a severe clinical phenotype with mechanical allodynia and thermal hyperalgesia, which can be reversed by intrathecal administration of a selective NMDA receptor antagonist We conclude that the periaxins play an essential role in stabilizing the Schwann cell-axon unit and that the periaxin-deficient mouse will be an important model for studying neuropathic pain in late onset demyelinating disease.

Cold comfort pharm.

Cooling of the skin has long been thought to be beneficial in pain states but intense cold is clearly noxious. Does cooling lead to pain or gain? Rapid progress in this controversy has been made since the discovery of specific ion channels of the transient receptor potential (TRP) family that are activated by cooling of sensory nerve cells to below body temperature. This review focuses on the role of one of these, TRPM8, which has been implicated in cool sensation and cold pain by recent knockout mouse studies, but remarkably also appears capable of eliciting a novel analgesic gating control over noxious inputs in chronic pain states. We discuss hypothetical mechanisms that could bring about this composite profile. It is clear that new and highly selective agents will need to be developed to further evaluate the potential therapeutic opportunities offered by low temperature sensitive TRP channels.

BSACI guidelines for the management of allergic and non-allergic rhinitis.

This guidance for the management of patients with allergic and non-allergic rhinitis has been prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI). The guideline is based on evidence as well as on expert opinion and is for use by both adult physicians and paediatricians practicing in allergy. The recommendations are evidence graded. During the development of these guidelines, all BSACI members were included in the consultation process using a web-based system. Their comments and suggestions were carefully considered by the SOCC. Where evidence was lacking, consensus was reached by the experts on the committee. Included in this guideline are clinical classification of rhinitis, aetiology, diagnosis, investigations and management including subcutaneous and sublingual immunotherapy. There are also special sections for children, co-morbid associations and pregnancy. Finally, we have made recommendations for potential areas of future research.

The distribution of Fasciola hepatica and Fasciola gigantica within southern Tanzania--constraints associated with the intermediate host.

In East Africa, Fasciola gigantica is generally the causative agent of fasciolosis but there have been reports of F. hepatica in cattle from highland regions of Kenya, Ethiopia, Uganda and Zaire. The topography of the Southern Highlands of Tanzania provides an environment where the climatic conditions exist for the sustenance of lymnaeid species capable of supporting both Fasciola hepatica and F. gigantica. Theoretically this would allow interaction between fasciolid species and the possible creation of hybrids. In this report we present molecular data confirming the existence of the snail, Lymnaea truncatula, at high altitude on the Kitulo Plateau of the Southern Highlands, Tanzania, along with morphometric and molecular data confirming the presence of F. hepatica in the corresponding area. At lower altitudes, where climatic conditions were unfavourable for the existence of L. truncatula, the presence of its sister species L. natalensis was confirmed by molecular data along with its preferred fasciolid parasite, F. gigantica. Analysis based on a 618 bp sequence of the 28S rRNA gene did not reveal the presence of hybrid fasciolids in our fluke samples.

Pain in children: recent advances and ongoing challenges.

Significant advances in the assessment and management of acute pain in children have been made, and are supported by an increase in the availability and accessibility of evidence-based data. However, methodological and practical issues in the design and performance of clinical paediatric trials limit the quantity, and may influence the quality, of current data, which lags behind that available for adult practice. Collaborations within research networks, which incorporate both preclinical and clinical studies, may increase the feasibility and specificity of future trials. In early life, the developing nervous system responds differently to pain, analgesia, and injury, resulting in effects not seen in later life and which may have long-term consequences. Translational laboratory studies further our understanding of developmental changes in nociceptor pathway structure and function, analgesic pharmacodynamics, and the impact of different forms of injury. Chronic pain in children has a negative impact on quality of life, resulting in social and emotional consequences for both the child and the family. Despite age-related differences in many chronic pain conditions, such as neuropathic pain, management in children is often empirically based on data from studies in adults. There is a major need for further clinical research, training of health-care providers, and increased resources, to improve management and outcomes for children with chronic pain.