Avoiding Prostate Biopsies in Patients at Low Risk for Prostate Cancer: A Prospective Evaluation of a PSA-Density-Based Safety Net.

INTRODUCTION AND OBJECTIVES: Decision-making to perform prostate biopsy should include individual risk assessment. Patients classified as low risk by the Rotterdam Prostate Cancer Risk Calculator are advised to forego biopsy (PBx). There is concern about missing clinically significant prostate cancer (csPCa). A clear pathway for follow-up is needed. MATERIAL AND METHODS: Data for 111 consecutive patients were collected. Patients were encouraged to adhere to a PSA-density-based safety net after PBx was omitted. Cut off values indicating a re-evaluation were PSA density >0.15 ng/mL/ccm in PBx-naïve patients and >0.2 ng/mL/ccm in men with past-PBx. Primary endpoint was whether men had their PSA taken regularly. Secondary endpoint was whether a new multiparametric MRI was performed when PSA-density increased. Tertiary endpoint was whether biopsy was performed when risk stratification revealed an increased risk. RESULTS: Median follow-up was 12 months (IQR 9-15 months). The primary endpoint was reached by 97.2% (n = 106). The secondary endpoint was reached by 30% (n = 3). The tertiary endpoint was reached by 50% (n = 2). Histopathologic analyses revealed csPCa in none of these cases. Risk stratification did not change (p = 0.187) with the majority of patients (89.2%, n = 99). CONCLUSION: The concern of missing csPCa when omitting PBx in the risk-stratified pathway may be negated. Changes in risk stratification during follow-up should lead to subsequent PBx. We suggest implementing a safety net based on PSA density and digital rectal examination (DRE).

Assessment of complications after transperineal and transrectal prostate biopsy using a risk-stratified pathway identifying patients at risk for post-biopsy infections.

INTRODUCTION: Evidence of transperineal (TP) superiority over transrectal (TR) biopsy is growing due to lower infectious complication rates. However, TR biopsy is the most common procedure, and it seems that a cross-over to TP is delayed by logistical challenges such as costs, complexity, and lack of experience. We investigate whether well-selected patients without any risk factors may further undergo TR biopsy if all precautions to avoid infections are warranted. MATERIALS AND METHODS: Data were collected in our academic institution between August 2021 and March 2022 and after clinical implementation of the currently updated European Association of Urology guideline recommendations on the performance of prostate biopsy. Patients underwent either TP or TR biopsy according to a riskstratification based on risk factors of infectious complications. Follow-up asked for post-biopsy complications. Inverse Probability of Treatment Weighting (IPTW) propensity score was used to balance baseline characteristics. Complications were subdivided into infectious and non-infectious complications. RESULTS: In total, 294 patients were included with 161 patients undergoing TR vs. 133 patients undergoing TP biopsy. Complication rates were 2.2% for TP vs. 5.5% for TR biopsy concerning all complications. Infectious complication rates only were 0.7% for TP vs. 1.8% for TR biopsy. After IPTW adjustment, differences were statistically significant different (p = 0.01). CONCLUSION: Our study revealed that even in a well-selected patient cohort with presumably lower risk of infectious complications, TR biopsy leads to more post-biopsy complications than TP biopsy. This conclusion should motivate the urological community to switch to TP biopsy.

Chronic Nodular Prurigo: A European Cross-sectional Study of Patient Perspectives on Therapeutic Goals and Satisfaction.

Chronic nodular prurigo is characterized by recalcitrant itch. Patient perspectives on therapeutic goals, satisfaction with therapy and efficacy of therapeutic regimens for this condition are unknown. This questionnaire study examined these issues in 406 patients with chronic nodular prurigo from 15 European dermatological centres. Improvements in itch, skin lesions and sleep were the most important goals. Emollients, topical corticosteroids and antihistamines were the most frequently used treatments, while a minority of patients were prescribed potent medications, such as systemic immunosuppressants and gabapentinoids. Most patients were not satisfied with their previous therapy (56.8%), while 9.8% did not receive any therapy despite having active disease. A substantial number of respondents (28.7%) considered none of the therapeutic options effective. Although chronic nodular prurigo is a severe disease, most patients were not treated with potent systemic drugs, which may contribute to the high levels of dissatisfaction and disbelief in available therapies. Specific guidelines for chronic nodular prurigo and the development of novel therapies are necessary to improve care.

10 kHz Spinal Cord Stimulation for the Treatment of Failed Back Surgery Syndrome with Predominant Leg Pain: Results from a Prospective Study in Patients from the Dutch Healthcare System.

INTRODUCTION: Persistent back/and or leg pain is a common outcome after spinal surgery (otherwise known as failed back surgery syndrome [FBSS]). Studies have shown that spinal cord stimulation (SCS) at 10 kHz provides effective analgesia in FBSS patients with both back and leg pain symptoms and in those with predominant back pain. This study is the first to evaluate the therapy in FBSS patients with predominant leg pain. METHODS: The safety and efficacy of 10 kHz SCS was evaluated in an uncontrolled, open-label, prospective study of FBSS patients with predominant leg pain in the Netherlands. Follow-ups were performed at 1, 3, 6, and 12 months post implantation. RESULTS: Sixty out of 68 patients (88%) experienced sufficient pain relief during a stimulation trial. Of these, 58 proceeded to permanent implantation of a 10 kHz SCS system. After 12 months of treatment, 80% of patients experienced ≥ 50% reduction in baseline leg pain, and a similar proportion (76%) experienced ≥ 50% reduction in baseline back pain. At least two-thirds of patients were also leg pain and back pain remitters (visual analog scale [VAS] ≤ 2.5 cm). The therapy was also associated with a general improvement in patients' quality of life, as measured by secondary outcomes including disability, perception of health improvement, mental well-being, and satisfaction. A positive impact on opioid consumption was also observed. CONCLUSIONS: Consistent with previous findings, 10 kHz SCS for the treatment of FBSS patients with predominant radicular symptoms is safe and effective and is associated with improved quality of life.

Antihyperalgesic activity of nucleoside transport inhibitors in models of inflammatory pain in guinea pigs.

BACKGROUND AND METHODS: The role of the endogenous purine nucleoside, adenosine, in nociception is well established. Inhibition of the equilibrative nucleoside transporter (ENT1) prevents adenosine uptake into cells, and could therefore enhance the antinociceptive properties of adenosine. The effects of ENT1 inhibition were studied in two animal models of inflammatory pain. Analgesic activity was assessed in a complete Freund's adjuvant (CFA)-induced and carrageenan-induced mechanical and thermal hyperalgesia model in the guinea pig. RESULTS: Draflazine, dipyridamole, dilazep, lidoflazine, soluflazine, and KF24345 showed efficacy in the CFA thermal hyperalgesia model. Draflazine, the most potent compound in this test, was further characterized in the CFA model of mechanical hyperalgesia and the carrageenan inflammation model of thermal and mechanical hyperalgesia, where it completely reversed the hypersensitivity. The antihyperalgesic effects of draflazine (10 mg/kg, administered subcutaneously) were attenuated by the A1 receptor antagonist, cyclopentyltheophylline (5-40 mg/kg, administered intraperitoneally), by the nonselective adenosine antagonist, caffeine (10-40 mg/kg intraperitoneally), and by the A2 antagonist, DMPX (10 mg/kg administered intraperitoneally). CONCLUSION: ENT1 inhibition is an effective way of reversing mechanical and thermal inflammatory hyperalgesia in the guinea pig, and these effects are mediated by enhancement of endogenous adenosine levels. Both A1 and A2 adenosine receptor subtypes are likely to be involved.

Increased cold allodynia following intrathecal N-methyl-D-aspartate in rats with a mononeuropathy.

NMDA receptors are involved in the modulation of neuropathic pain behavior and central sensitization. In vivo, this is mostly demonstrated by the use of specific antagonists such as MK801. Because studies evaluating the direct impact of spinal NMDA in neuropathic pain models are lacking, we performed a series of experiments to study the role of spinal NMDA injection on existing cold allodynia, as a measurement of neuropathic pain behavior in rodents. Intrathecal injection of NMDA resulted in an enhanced neuropathic pain behavior in CCI rats on a cold plate. The activity was present from a dose of 5 ng/rat onward and could selectively be reversed by intraperitoneal injections of doses of > or = 0.01 mg/kg MK801. These results support the regulatory role of NMDA receptors in the hypersensitivity to cold observed in neuropathic pain behavior in rodents.

Exogenous interleukin-6 increases cold allodynia in rats with a mononeuropathy.

Interleukin-6 (IL-6) is a pleiotropic cytokine, signaling intracellularly via its unique membrane-bound receptor IL-6R and gp130. In peripheral nerve injury models, IL-6 and IL-6R are increased at the injured nerve and the respective dorsal root ganglion. IL-6 is increased at the ipsilateral dorsal and ventral horn of the spinal cord. IL-6 is known to affect neuronal survival, differentiation and regeneration. It is involved in synaptic plasticity and hyperexitability and induces the synthesis or release of other substances with known neuroprotective or neuromodulatory effects. In this study, intrathecal administration of recombinant rat IL-6 to rats with a chronic constriction injury of the sciatic nerve, induced a logarithmic dose-dependent increase in cold allodynia with a threshold of 10 pg IL-6 and a maximal effect at 100 ng IL-6. Intrathecal administration of saline or denaturated IL-6 was without effect. In rats with a chronic constriction injury, systemic administered IL-6 did not induce a hyperalgesic effect, illustrating that IL-6 acts at the level of the dorsal root ganglion or the spinal cord. Intraplantar injection of 100 ng IL-6 in the operated hind paw resulted in an increased cold allodynia. This study demonstrates that the sensitivity to exogenous intrathecal or peripheral IL-6 increases in rats with a mononeuropathy.

Effects of NMDA receptor antagonists on opioid-induced respiratory depression and acute antinociception in rats.

Although exogenous opioids alter the responses of animals to tissue-damaging stimuli and therefore are the cornerstone in the treatment of acute antinociception, they have profound side effects on ventilation. To diminish ventilatory effects, combination therapies have been advocated. Recent studies reported the effectiveness of the addition of N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine to morphine in the treatment of acute pain. However, NMDA receptors, together with non-NMDA receptors are known to be involved in the neurotransmission of inspiratory drive to phrenic motoneurons. Co-administration of NMDA and non-NMDA receptor antagonists has been shown to be deleterious to respiratory function. The present study investigated the hypothesis that the association of opioids and NMDA receptor antagonists may add to the impairment of respiratory parameters. In male Wistar rats, combinations of opioids (fentanyl or morphine) at antinociceptive doses and NMDA receptor antagonists (ketamine, 40 mg/kg, or dextromethorphan, 10 mg/kg) at subanesthetic doses were administered intraperitoneally. Antinociception was tested with the tail-withdrawal reaction (TWR) test, while the effect on respiratory parameters was investigated with blood-gas analysis. We found that, in rats, co-administration of NMDA receptor antagonists and opioids may result in an increased respiratory depression as compared to the opioids alone. The effect of the NMDA receptor antagonists on opioid-induced antinociception was limited.

Epidural ketamine potentiates epidural morphine but not fentanyl in acute nociception in rats.

Epidural opioids have been reported to provide superior analgesia in acute pain management. Despite the fact that the required doses are low, major side effects such as respiratory depression may still occur. In an effort to maximize analgesia and to minimize the rate of side effects, epidural NMDA receptor antagonists, especially ketamine, may be co-administered with opioids. This study investigated whether ketamine had beneficial effects on fentanyl- or morphine-induced antinociception in an acute pain model in rats. In male Wistar rats, an epidural catheter was placed under general anaesthesia. After 1 week the animals were subjected to the tail withdrawal reaction (TWR) test. After determination of the basal reaction latencies, fentanyl, morphine, ketamine or combinations of an opioid with ketamine were administered epidurally. TWR latencies were measured for up to 2h after treatment. Both opioids showed a dose related antinociceptive effect. Fentanyl had a fast onset and a short duration of action whereas the reverse was true for morphine. Ketamine exhibited only limited antinociceptive properties. In the combinations, ketamine improved morphine-induced antinociception both in terms of maximal possible effect (MPE) as well as in duration of action. The combination of fentanyl with ketamine did not result in any improvement, neither in terms of MPE nor in duration of action. Moreover, increasing doses of ketamine tended to decrease the MPE of various doses of fentanyl. These data confirm that ketamine, contrary to opioids, does not possess important antinociceptive properties in an acute test such as the TWR test. Furthermore, these data indicate that additive drugs such as ketamine may have different effects on different opioids.

Dextromethorphan and ketamine potentiate the antinociceptive effects of mu- but not delta- or kappa-opioid agonists in a mouse model of acute pain.

Animal and clinical studies have reported potentiation of opioid antinociception by NMDA receptor antagonists such as ketamine and dextromethorphan. The aim of this study was to compare these clinically available NMDA antagonists in combination with classical morphine, mu-selective fentanyl-like opioids, the delta-opioid agonist SNC80 and the kappa-opioid agonist U50,488H. Using a mouse hot-plate test, dose-response relationships were first determined for all compounds individually and then for opioids co-administered with fixed doses of ketamine or dextromethorphan. All compounds were administered intraperitoneally ED(50) values were calculated from the proportion of animals failing to exhibit any response within a fixed cut-off criterion of 30 s. To varying degrees, all compounds produced increases in response latencies over time. Dextromethorphan produced lower ED(50) values for morphine, fentanyl and sufentanil but exerted no effect on the potency of SNC80 or U50,488H. Similarly, ketamine potentiated the antinociceptive potency of morphine, fentanyl and sufentanil but not SNC80 or U50,488H. In summary, these results support the use of mu-opioid agonists in combination with NMDA antagonists, but suggest that there may be no advantage in combining dextromethorphan or ketamine with delta- or kappa-opioids in the management of acute pain.