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Topical capsaicin is a well-established model of experimental hyperalgesia. Its application to the study of animals has been limited to few species. The effect of topical capsaicin on hyperalgesia in porcine skin was evaluated as part of a study of inflammatory pain in the pig. Two experiments were carried out on pigs of 27 ± 5 kg (n = 8) and 57 ± 3 kg (n = 16). Thermal and mechanical noxious stimuli were provided (CO2 laser and Pressure Application Measurement device) to assess avoidance behaviours. Capsaicin induced significant thermal hyperalgesia in the smaller pigs (P < 0.05), while no mechanical hyperalgesia was observed in either animal group. The present model of topical capsaicin application may be useful to investigate the mechanisms of primary hyperalgesia in this species, although some experimental conditions, such as the administration route and cutaneous morphology, need to be evaluated. [ABSTRACT FROM AUTHOR]

Objective: To assess the diagnostic accuracy of laser Doppler flowmetry (LDF) with mercury-in-silastic strain gauge plethysmography (SGP) as a reference test for measuring the toe and ankle pressures in patients with known or suspected peripheral arterial disease (PAD). Methods: This was a prospective, randomized, blinded diagnostic accuracy study. Toe and ankle pressures were measured using both methods in 200 consecutive patients, who were recruited at our vascular laboratory over a period of 30 working days. Classification of PAD and critical limb ischemia (CLI) was made in accordance with TASC-II criteria. Results: The LDF method demonstrated 5.8 mm Hg higher mean toe pressures than the SGP method for the right limb and 7.0 mm Hg for the left limb (both P < .001). There were no significant differences in the mean ankle pressures (both P > .129). The limits of agreement for the differences (SGP − LDF) were −31.7 to 20.2 mm Hg for right toe pressures, −28.0 to 14.0 mm Hg for left toe pressures, −25.5 to 22.8 mm Hg for right ankle pressures, and −26.9 to 24.6 mm Hg for left ankle pressures. A correlation analysis of the absolute pressures using the two methods showed an intraclass correlation coefficient of 0.902 (95% confidence interval [CI], 0.835-0.938) for right toe pressures, 0.919 (95% CI, 0.782-0.960) for the left toe pressures, 0.953 (95% CI, 0.937-0.965) for right ankle pressures, and 0.952 (95% CI, 0.936-0.964) for left ankle pressures. Cohen's Kappa showed an agreement in the diagnostic classification of κ = 0.775 (95% CI, 0.631-0.919) for PAD and κ = 0.780 (95% CI, 0.624-0.936) for CLI. Conclusions: LDF showed a good correlation with SGP over a wide range of toe and ankle pressures, as well as substantial agreement for the diagnostic classification of PAD including CLI. [Copyright &y& Elsevier]

Background: Peripheral arterial disease (PAD) can be diagnosed noninvasively by segmental blood pressure measurement and calculating an ankle-brachial index (ABI) or toe-brachial index (TBI). The ABI is known to be unreliable in patients with vascular stiffness and fails to detect the early phase of arteriosclerotic development. The toe vessels are less susceptible to vessel stiffness, which makes the TBI useful. However, the diagnostic limits used in guidelines, clinical settings, and experimental studies vary substantially. This review provides an overview of the evidence supporting the clinical use of the TBI. Methods: A review of the literature identified studies reporting the use of the TBI regarding guideline recommendations, normal populations, correlations to angiographic findings, and prognostic implications. Results: Eight studies conducted in a normal population were identified, of which only one study used imaging techniques to rule out arterial stenosis. A reference value of 0.71 was estimated as the lowest limit of normal based on the weighted average in studies with preheating of the limbs. A further seven studies showed correlations of the TBI with angiographic findings. The TBI had a sensitivity of 90% to 100% and a specificity of 65% to 100% for the detection of vessel stenosis. Few studies investigated the value of the TBI as a prognostic marker for cardiovascular mortality and morbidity, and no firm conclusions could be made. Studies have, however, shown correlation between the TBI and comorbidities such as kidney disease, diabetes, and microvasculature disease. Conclusions: In contrast to the well-defined and evidence-based limits of the ABI, the diagnostic criteria for a pathologic TBI remain ambiguous. Although several guidelines and reviews of PAD diagnostics recommend a TBI <0.70 as cutoff, it is not strictly evidence-based. The current literature is not sufficient to conclude a specific cutoff as diagnostic for PAD. The current studies in normal populations and the correlation with angiography are sparse, and additional trials are needed to further validate the limits. Large-scale trials are needed to establish the risk of morbidity and mortality for the various diagnostic limits of the TBI. [ABSTRACT FROM AUTHOR]

Abstract: Bone-seeking radionuclides, such as Sr-89, Sm-153, and Re-186, have been shown to have an effect on pain from bone metastasis in prostate cancer. The effect on bone pain in other cancer types, including breast cancer, remains unclear. The purpose of the study was to perform a systematic review of the use of radioisotopes for pain relief in metastatic breast cancer. A literature search was performed in PubMed, EMBASE, and Web of Science (1970 to September 2009) for clinical studies with a primary outcome of pain, performance status, or quality of life. Eligibility criteria were the following: (1) the trial must include at least 10 breast cancer patients with painful bone metastasis, (2) the radionuclide has been approved by regulatory authorities in Europe or the United States and is commercially available (Sr-89, Sm-153, and Re-186), (3) the dose of radionuclides must be clinically effective, (4) the primary endpoint must be pain, performance status or quality of life, and (5) separate reporting of efficacy should be available for breast cancer patients provided the trial included patients with various types of cancer. The literature search identified 189 individual studies of which 19 trials fulfilled the eligibility criteria. There were three randomized controlled trials of which two trials compared two different radionuclides, and one trial compared two doses of Sm-153. In addition, there were 16 uncontrolled trials. Reporting of trial research methodology in the randomized as well as the uncontrolled trials was low (median Jadad score of 1, range 1–2). Key trial details, such as patient recruitment, description of prior palliative therapies, baseline characteristics, follow up, and reporting of outcome was insufficient in a large proportion of the trials. According to Center of Evidence-based Medicine criteria, there is level 4 documentation for the effect of radionuclides in painful bone metastasis in breast cancer. It has been concluded that there is limited clinical evidence supporting the clinical effect of radionuclides in relieving pain from bone metastasis in breast cancer. Large, randomized controlled trials are needed to establish the utility of bone-seeking radionuclides in the palliative care of breast cancer patients. [Copyright &y& Elsevier]

Abstract: Cancer patients in general have a high risk of venous thromboembolic events (VTE) driven not only by patient-related risk factors, but also risk factors related to the disease and anti-cancer therapies. Cancer patients with documented VTE have a notably worse outcome than non-cancer VTE patients. Since VTE is a highly preventable condition, it is striking that large surveys have shown significant underuse of VTE prophylaxis in surgical cancer patients and in medical cancer patients in particular. Recently, guidelines have been issued from European and American medical oncology societies and organizations for identification of cancer patients at risk, and the guidelines give recommendations for treatment of individual groups of cancer patients. This review summarizes the recommendations for VTE prophylaxis and treatment from the recent guidelines and reviews some outstanding issues in VTE prophylaxis and treatment of cancer patients. [Copyright &y& Elsevier]

Objective: To prospectively determine the prognostic value of the bone scan index (BSI) for time to development of castration-resistant prostate cancer (CRPC) in consecutive, hormone-naïve patients with newly diagnosed prostate cancer.Patients and Methods: Eligible patients participated in a prospective, observational, multicenter study of the value of bone scintigraphy (BS) at staging. BSI was determined using the EXINI BoneBSI software in 208 consecutive patients undergoing androgen deprivation therapy. The presence or absence of bone metastases at staging was classified by BS with or without supplementary imaging. Follow-up was performed >5 years after including the last patient.Results: During follow-up, 149 of the 208 patients (72%) were diagnosed with CRPC. Median time to CRPC was 20 months. Median follow-up time was 4.4 years in patients without CRPC. In univariate analyses, presence of bone metastases (M1) (hazard ratio [HR] 3.00, 95% confidence interval [CI] 2.10-4.30), Gleason grade (HR 1.53, 95% CI 1.31-1.79), and BSI (HR 1.17, 95% CI 1.12-1.23) but not PSA significantly predicted time to CRPC (all, P < .001). The predictive values of M1 (HR 2.06), Gleason grade (HR 1.47), and BSI (HR 1.10) were confirmed in multivariate analyses. Log-rank test for equality of time to CRPC showed the significant predictive value of BSI (BSI = 0 vs 0 < BSI ≤ 1 vs BSI > 1, P < .001). In addition to routine assessment of M1 vs M0 status, BSI contributed to the predictive power.Conclusions: BSI is an independent risk factor for the time from initiation of androgen deprivation therapy to CRPC in hormone-naïve patients. The significant prognostic factors, in rank order, were M1 status, Gleason grade, and BSI. [ABSTRACT FROM AUTHOR]

Several local ablative modalities have been introduced for the treatment of locally advanced pancreatic cancer (LAPC). However, there is no consensus on how to evaluate the imaging response after treatment. A systematic review was performed regarding the use of imaging for response assessment in LAPC. A systematic literature search was conducted in PubMed. Studies reporting imaging outcomes were included in the review. Studies were excluded if the imaging outcomes could not be differentiated between different disease stages, tumor histology or surgical approaches. Thirty-four studies were included in the analysis. Fourteen studies used standardized response criteria, while six studies did not report the response evaluation method. The rest used self-determined criteria, absolute size comparisons or similar methods. One study found a correlation between early systemic progression (<6 months) and overall survival. There was notable variation in the use of imaging for response assessment in LAPC. This significantly hinders cross-comparison of results among studies. There is currently only sparse evidence of an association between imaging responses and overall survival. The field calls for standardized recommendations regarding the choice of response assessment method, timing of scans, target definition and reporting of outcomes. [ABSTRACT FROM AUTHOR]

Oligometastatic disease represents a clinical and anatomical manifestation between localised and polymetastatic disease. In prostate cancer, as with other cancers, recognition of oligometastatic disease enables focal, metastasis-directed therapies. These therapies potentially shorten or postpone the use of systemic treatment and can delay further metastatic progression, thus increasing overall survival. Metastasis-directed therapies require imaging methods that definitively recognise oligometastatic disease to validate their efficacy and reliably monitor response, particularly so that morbidity associated with inappropriately treating disease subsequently recognised as polymetastatic can be avoided. In this Review, we assess imaging methods used to identify metastatic prostate cancer at first diagnosis, at biochemical recurrence, or at the castration-resistant stage. Standard imaging methods recommended by guidelines have insufficient diagnostic accuracy for reliably diagnosing oligometastatic disease. Modern imaging methods that use PET-CT with tumour-specific radiotracers (choline or prostate-specific membrane antigen ligand), and increasingly whole-body MRI with diffusion-weighted imaging, allow earlier and more precise identification of metastases. The European Organisation for Research and Treatment of Cancer (EORTC) Imaging Group suggests clinical algorithms to integrate modern imaging methods into the care pathway at the various stages of prostate cancer to identify oligometastatic disease. The EORTC proposes clinical trials that use modern imaging methods to evaluate the benefits of metastasis-directed therapies. [ABSTRACT FROM AUTHOR]

Objective: To determine the relationship between bone pain and bone metastases in newly diagnosed prostate cancer.Patients and Methods: This prospective study of bone scintigraphy enrolled 567 consecutive patients with newly diagnosed prostate cancer. The presence of all-cause bone pain, known benign bone disease, and unexplained bone pain (ie, not related to known benign bone disease) was derived from a patient questionnaire. Univariate logistic regression models (LRMs) were used to assess the relationship between individual clinical variables (all-cause bone pain, unexplained bone pain, prostate-specific antigen, Gleason grade, T stage, and age) and bone metastases. A multivariate LRM was used to assess the relationship between bone metastases and all factors in combination. Agreement between the LRMs and bone metastases was estimated by accuracy and by Cohen's κ.Results: All-cause bone pain predicted bone metastasis in univariate but not multivariate analysis. Unexplained bone pain remained an independent predictor of bone metastases in multivariate analysis (odds ratio: 4.5; P < .001). Prostate-specific antigen was the single most important predictor of bone metastases (P < .001).Conclusion: Unexplained bone pain was a strong independent risk factor for bone metastasis. Guidelines should recommend staging bone scintigraphy in patients with unexplained bone pain, regardless of other risk factors. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of habituation and isolation on mechanical nociceptive thresholds in pigs at the pelvic limbs and at the tail. Study design Prospective randomized multifactorial study. Animals Thirty-two healthy castrated male (experiment 1), and 12 castrated male and 12 female (experiment 2) Danish Landrace × Yorkshire pigs, weighing 63.5 ± 0.8 kg and 55.4 ± 0.6 kg (the mean ± SD, experiment 1 and 2, respectively). Methods Mechanical nociceptive thresholds were quantified with a von Frey anesthesiometer applied to two distinct anatomical regions (tail and pelvic limbs). Pigs receiving the mechanical challenge in the pelvic limbs were tested inside a cage, whereas pigs exposed to stimuli at the tail region were tested in an open arena. For both experiments, the effect of familiarity to the procedure was evaluated by comparing thresholds of nociception in habituated versus naïve pigs. The presence of a companion animal was also evaluated in pigs receiving stimuli at the pelvic limbs. Results Pigs tested inside the cage were affected by the habituation to the procedure as indicated by the increase in willingness and time spent by the animals in the test cage. This effect was reflected in the lower mechanical nociceptive thresholds (medians with 25-75 percentiles) recorded for familiar pigs compared with naïve animals [495 g (302-675) versus 745 g (479-1000), respectively; p = 0.026]. Mechanical nociceptive thresholds measured at the tail of the pigs in the open arena were not affected by the familiarity of the animals with the experimental procedure. Conclusions and clinical relevance The current results reiterate the value of habituation in research involving animal behaviour. Further characterization of the methodology is needed to allow its application in the evaluation of clinical conditions in pigs. [ABSTRACT FROM AUTHOR]

Summary Upon activation nociceptors release neuropeptides in the skin provoking vasodilation and plasma protein extravasation in rodents, but only vasodilation in humans. Pivotal peptides in the induction of neurogenic inflammation comprise calcitonin gene-related peptide and substance P, the latter being suggested to act partly via degranulation of mast cells. In this study substance P and calcitonin gene-related peptide-induced vasodilation, protein extravasation, histamine release, and sensory effects were investigated simultaneously in human skin by dermal microdialysis. The vasodilatory prostaglandin E2 and the mast cell activator codeine served as positive controls. Substance P and calcitonin gene-related peptide applied intradermally via large cut-off plasmapheresis capillaries induced dose-dependent local vasodilation, but only SP provoked protein extravasation in concentrations greater than 10-9 M. Substance P-induced (10-8-10-6 M) protein extravasation was not accompanied by histamine release and was unaffected by cetirizine (histamine H1 blocker, 200 μg per ml). Only the highest concentration of substance P (10-5 M) induced significant histamine release. Neither neuropeptide caused any axon reflex erythema or any itch or pain sensation, whereas mast cell degranulation by codeine dose dependently provoked itch, flare, protein extravasation, and histamine release. In human skin calcitonin gene-related peptide and substance P induce vasodilation by a mechanism not involving histamine. No evidence for neuropeptide-induced activation of nociceptors was obtained. Our results suggest that endogenous calcitonin gene-related peptide and substance P have no acute sensory function in human skin. The lack of neurogenic protein extravasation in humans can most probably be attributed to low local concentrations of this neuropeptide still sufficient to exert trophic and immunomodulatory effects (10-11 M), but too low to induce protein extravasation (10-8 M) or even mast cell degranulation (10-5 M). J Invest Dermatol 115:1015–1020 2000. [ABSTRACT FROM AUTHOR]