Quality of Life Analysis of Patients Treated with Percutaneous Hepatic Perfusion for Uveal Melanoma Liver Metastases.

PURPOSE: Percutaneous hepatic perfusion with melphalan (M-PHP) is a minimally invasive therapy with proven efficacy in patients with uveal melanoma (UM) liver metastases. M-PHP is associated with a short hospital admission time and limited systemic side effects. In this study, we assessed quality of life (QoL) in UM patients treated with M-PHP. MATERIALS AND METHODS: A prospective, single-center study including 24 patients treated with M-PHP for UM metastases to the liver. QoL questionnaires were collected at baseline, on day 2/3 after M-PHP, and on day 7 and day 21 after M-PHP, according to study protocol. The results were scored according to EORTC-QLQ C30 global health status (GHS), functional scales, and symptom scales. The difference in scores at baseline and subsequent time points was analyzed with the Wilcoxon signed-rank test and multiple testing Bonferroni correction. Adverse events (AE) were registered up to 30 days after M-PHP according to CTCAE v5.0. RESULTS: Twenty-four patients (14 males; median age 63.0 years) completed 96 questionnaires. Most scores on all scales declined on day 2/3 after M-PHP. On day 21 after M-PHP, 12 out of 15 scores returned to baseline, including median GHS scores. Three variables were significantly worse on day 21 compared to baseline: fatigue (6-33; p = 0.002), physical functioning (100 vs 86.7; p = 0.003), and role functioning (100 vs 66.7; p = 0.001). Grade 3/4 AEs consisted mainly of hematological complications, such as leukopenia and thrombopenia. CONCLUSION: M-PHP causes fatigue and a decline in physical and role functioning in the 1st weeks after treatment, but GHS returns to baseline levels within 21 days. LEVEL OF EVIDENCE 3: Cohort study.

Combining Melphalan Percutaneous Hepatic Perfusion with Ipilimumab Plus Nivolumab in Advanced Uveal Melanoma: First Safety and Efficacy Data from the Phase Ib Part of the Chopin Trial.

PURPOSE: To define a safe treatment dose of ipilimumab (IPI) and nivolumab (NIVO) when applied in combination with percutaneous hepatic perfusion with melphalan (M-PHP) in metastatic uveal melanoma (mUM) patients (NCT04283890), primary objective was defining a safe treatment dose of IPI/NIVO plus M-PHP. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.03 (CTCAEv4.03). Secondary objective was response rate, PFS and OS. MATERIALS AND METHODS: Patients between 18-75 years with confirmed measurable hepatic mUM according to RECIST 1.1 and WHO performance score 0-1 were included. Intravenous IPI was applied at 1 mg/kg while NIVO dose was increased from 1 mg/kg in cohort 1 to 3 mg/kg in cohort 2. Transarterial melphalan dose for M-PHP was 3 mg/kg (maximum of 220 mg) in both cohorts. Treatment duration was 12 weeks, consisting of four 3-weekly courses IPI/NIVO and two 6-weekly M-PHPs. RESULTS: Seven patients were included with a median age of 63.6 years (range 50-74). Both dose levels were well tolerated without dose-limiting toxicities or deaths. Grade III/IV adverse events (AE) were observed in 2/3 patients in cohort 1 and in 3/4 patients in cohort 2, including Systemic Inflammatory Response Syndrome (SIRS), febrile neutropenia and cholecystitis. Grade I/II immune-related AEs occurred in all patients, including myositis, hypothyroidism, hepatitis and dermatitis. There were no dose-limiting toxicities. The safe IPI/NIVO dose was defined as IPI 1 mg/kg and NIVO 3 mg/kg. There was 1 complete response, 5 partial responses and 1 stable disease (3 ongoing responses with a median FU of 29.1 months). CONCLUSION: Combining M-PHP with IPI/NIVO was safe in this small cohort of patients with mUM at a dose of IPI 1 mg/kg and NIVO 3 mg/kg.

Sublingual Sufentanil versus Standard-of-Care (Patient-Controlled Analgesia with Epidural Ropivacaine/Sufentanil or Intravenous Morphine) for Postoperative Pain Following Pancreatoduodenectomy: A Randomized Trial.

Background: The optimal treatment strategy for postoperative pain following pancreatoduodenectomy remains unknown. The aim of this study was to investigate whether sublingual sufentanil tablet (SST) is a non-inferior analgesic compared to our standard-of-care (patient-controlled epidural analgesia [PCEA] or PCA morphine) in the treatment of pain following pancreatoduodenectomy. Methods: This was a pragmatic, strategy, open-label, non-inferiority, parallel group, randomized (1:1) trial. The primary outcome was an overall mean pain score (Numerical Rating Scale: 0-10) on postoperative days 1 to 3 combined. The non-inferiority margin was -1.5 since this difference was considered clinically relevant. Results: Between October 2018 and July 2021, 190 patients were assessed for eligibility and 36 patients were included in the final analysis: 17 patients were randomized to SST and 19 patients to standard-of-care. Early treatment failure in the SST group occurred in 2 patients (12%) due to inability to operate the SST system and in 2 patients (12%) due to severe nausea despite antiemetics. Early treatment failure in the standard-of-care group occurred in 2 patients (11%) due to preoperative PCEA placement failure and in 1 patient (5%) due to hemodynamic instability caused by PCEA. The mean difference in pain score on postoperative day 1 to 3 was -0.10 (95% CI -0.72-0.52), and therefore the non-inferiority of SST compared to standard-of-care was demonstrated. The mean pain score, number of patients reporting unacceptable pain (pain score >4), Overall Benefit of Analgesia Score, and patient satisfaction per postoperative day, perioperative hemodynamics and postoperative outcomes did not differ significantly between groups. Conclusion: This first randomized study investigating the use of SST in 36 patients following pancreatoduodenectomy showed that SST is non-inferior compared to our standard-of-care in the treatment of pain on postoperative days 1 to 3. Future research is needed to confirm that these findings are applicable to other settings.

Acute pain after total hip and knee arthroplasty does not affect chronic pain during the first postoperative year: observational cohort study of 389 patients.

Chronic pain is frequently reported after total hip and knee arthroplasties (THA/TKA) in osteoarthritis (OA) patients. We investigated if severity of acute postoperative pain following THA/TKA in OA patients was associated with pain during the first postoperative year. From an observational study, OA patients scheduled for primary THA/TKA (June 2012-December 2017) were included from two hospitals in the Netherlands. Acute postoperative pain scores were collected within 72 h postoperatively and categorized as no/mild (NRS ≤ 4) or moderate/severe (NRS > 4). Pain was assessed preoperatively, 3, 6 and 12 months postoperatively using the HOOS/KOOS subscale pain. With Multilevel Mixed-effects-analyses, we estimated associations between acute and chronic pain until one year postoperative, adjusted for confounders and including an interaction term (Time*Acute pain). 193 THA and 196 TKA patients were included, 29% of THA and 51% of TKA patients reported moderate/severe pain acutely after surgery. In the THA group, the difference in pain at 3 months between the no/mild and moderate/severe groups, was approximately six points, in favor of the no/mild group (95% CI [-12.4 to 0.9]) this difference became smaller over time. In the TKA group we found similar differences, with approximately four points (95% CI [-9.6 to 1.3]) difference between the no/mild and moderate/severe group at 6 months, this difference attenuated at 12 months. No association between severity of acute postoperative pain and pain during the first postoperative year was found. These findings suggest that measures to limit acute postoperative pain will likely not impact development of chronic pain.

Comparison of neuromuscular block measured by compressomyography at the upper arm and electromyography at the adductor pollicis muscle in obese and non-obese patients: An observational study.

STUDY OBJECTIVE: Quantitative neuromuscular monitoring is traditionally evaluated at the adductor pollicis muscle. By contrast, the TOF-Cuff compressomyograph evaluates neuromuscular block (NMB) at the upper arm. However, compressomyography has not been fully validated against other monitoring entities. This study evaluates the agreement between NMB measured by compressomyography at the upper arm and electromyography at the adductor pollicis muscle during various levels of neuromuscular block in patients with and without obesity. INTERVENTIONS: NMB was measured at the upper arm by compressomyography (TOF-Cuff) and by electromyography (GE-NMT) at the adductor pollicis. DESIGN: Prospective, multicenter, observational study. SETTING: Secondary and tertiary care hospitals' operating theatres. PATIENTS: 200 non-obese and 50 obese patients. MEASUREMENTS: During onset and offset of deep (post-tetanic-count 1-15 twitches), moderate (Train-of-Four-count 1-3 twitches) and shallow (Train-of-Four-ratio 0.01-1.0) depths of NMB were measured in obese and non-obese patients. The bias and limits of agreement of both devices were calculated using a Bland-Altman analysis for repeated measurements. Data obtained during spontaneous recovery (i.e. without the use of reversal agents) were used in the primary analyses. MAIN RESULTS: Data from enrolled patients yielded 942 paired post-tetanic-counts, 1175 paired train-of-four-counts and 1574 paired train-of-four ratios during spontaneous recovery. In non-obese patients, mean bias (95% CI) between the two devices was 3.405 (2.294 to 4.517) during deep NMB; -0.023 (-0.205 to 0.160) during moderate NMB and 0.312 (0.287 to 0.338) during shallow NMB. In obese patients, bias was -0.170 (-2.872 to 2.531); 0.178 (-0.202 to 0.558); 0.384 (0.299 to 0.469) for deep, moderate and shallow NMB respectively. CONCLUSIONS: There is variable disagreement between the level of NMB measured at the upper arm by compressomyography and at the adductor pollicis muscle measured by electromyography, throughout the various stages of NMB in obese and non-obese patients. Recovery of NMB on compressomyography preceded recovery on electromyography, which may have consequences for reversal and extubation decisions in clinical practice.

Combining Hepatic Percutaneous Perfusion with Ipilimumab plus Nivolumab in advanced uveal melanoma (CHOPIN): study protocol for a phase Ib/randomized phase II trial.

BACKGROUND: While immune checkpoint inhibition (ICI) has revolutionized the treatment of metastatic cutaneous melanoma, no standard treatments are available for patients with metastatic uveal melanoma (UM). Several locoregional therapies are effective in the treatment of liver metastases, such as percutaneous hepatic perfusion with melphalan (M-PHP). The available literature suggests that treatment with ICI following locoregional treatment of liver UM metastases can result in clinical response. We hypothesize that combining M-PHP with ICI will lead to enhanced antigen presentation and increased immunomodulatory effect, improving control of both hepatic and extrahepatic disease. METHODS: Open-label, single-center, phase Ib/randomized phase II trial, evaluating the safety and efficacy of the combination of M-PHP with ipilimumab (anti-CTLA-4 antibody) and nivolumab (anti-PD-1 antibody) in patients with unresectable hepatic metastases of UM in first-line treatment, with or without the limited extrahepatic disease. The primary objective is to determine the safety, toxicity, and efficacy of the combination regimen, defined by maximum tolerated dose (MTD) and progression-free survival (PFS) at 1 year. Secondary objectives include overall survival (OS) and overall response rate (ORR). A maximum of 88 patients will be treated in phase I and phase II combined. Baseline characteristics will be described with descriptive statistics (t-test, chi-square test). To study the association between risk factors and toxicity, a logistic regression model will be applied. PFS and OS will be summarized using Kaplan-Meier curves. DISCUSSION: This is the first trial to evaluate this treatment combination by establishing the maximum tolerated dose and evaluating the efficacy of the combination treatment. M-PHP has shown to be a safe and effective treatment for UM patients with liver metastases and became the standard treatment option in our center. The combination of ICI with M-PHP is investigated in the currently described trial which might lead to a better treatment response both in and outside the liver. TRIAL REGISTRATION: This trial was registered in the US National Library of Medicine with identifier NCT04283890 . Registered as per February 2020 - Retrospectively registered. EudraCT registration number: 2018-004248-49. Local MREC registration number: NL60508.058.19.

Meta-analysis of epidural analgesia in patients undergoing pancreatoduodenectomy.

Background: The optimal analgesic technique after pancreatoduodenectomy remains under debate. This study aimed to see whether epidural analgesia (EA) has superior clinical outcomes compared with non-epidural alternatives (N-EA) in patients undergoing pancreatoduodenectomy. Methods: A systematic review with meta-analysis was performed according to PRISMA guidelines. On 28 August 2018, relevant literature databases were searched. Primary outcomes were pain scores. Secondary outcomes were treatment failure of initial analgesia, complications, duration of hospital stay and mortality. Results: Three RCTs and eight cohort studies (25 089 patients) were included. N-EA treatments studied were: intravenous morphine, continuous wound infiltration, bilateral paravertebral thoracic catheters and intrathecal morphine. Patients receiving EA had a marginally lower pain score on days 0-3 after surgery than those receiving intravenous morphine (mean difference (MD) -0·50, 95 per cent c.i. -0·80 to -0·21; P < 0·001) and similar pain scores to patients who had continuous wound infiltration. Treatment failure occurred in 28·5 per cent of patients receiving EA, mainly for haemodynamic instability or inadequate pain control. EA was associated with fewer complications (odds ratio (OR) 0·69, 95 per cent c.i. 0·06 to 0·79; P < 0·001), shorter duration of hospital stay (MD -2·69 (95 per cent c.i. -2·76 to -2·62) days; P < 0·001) and lower mortality (OR 0·69, 0·51 to 0 93; P = 0·02) compared with intravenous morphine. Conclusion: EA provides marginally lower pain scores in the first postoperative days than intravenous morphine, and appears to be associated with fewer complications, shorter duration of hospital stay and less mortality.

Antecedentes: La técnica analgésica óptima tras una duodenopancreatectomía permanece en debate. El objetivo de este estudio fue analizar si la analgesia epidural (epidural analgesia, EA) presenta resultados clínicos superiores en comparación con las alternativas no epidurales (non­epidural alternatives, N­EA) en pacientes que se someten a una duodenopancreatectomía. Métodos: Se realizó una revisión sistemática con metaanálisis de acuerdo con las recomendaciones PRISMA. El 28 de agosto de 2018, se realizó una búsqueda en las bases de datos relevantes de la literatura. El objetivo primario fueron las puntuaciones de dolor. Los objetivos secundarios fueron el fracaso del tratamiento de la analgesia inicial, las complicaciones, la duración de la estancia hospitalaria y la mortalidad. Resultados: Se incluyeron tres ensayos aleatorizados y controlados y ocho estudios de cohortes (25.089 pacientes). Las N­EA estudiadas fueron: morfina intravenosa (iv), infiltración continua de la herida, catéteres torácicos paravertebrales bilaterales y morfina intratecal. Los pacientes con EA tuvieron una puntuación de dolor marginalmente más baja en los días postoperatorios 0 a 3 en comparación con la morfina iv (diferencia de medias (MD) = ­ 0,50, i.c. del 95% ­0,80 a ­0,21; P < 0,001) y puntuaciones de dolor similares en comparación con la infiltración continua de la herida. El fallo del tratamiento ocurrió en el 28,5% de los pacientes con EA, principalmente por inestabilidad hemodinámica o control inadecuado del dolor. La EA se asoció con menos complicaciones (razón de oportunidades, odds ratio, OR = 0,69, i.c. del 95% 0,061 a 0,79; P < 0,001), menor duración de la estancia hospitalaria (MD = ­2,69 días, i.c. del 95% ­2,76 a ­2,62; P < 0,001) y menor mortalidad en comparación con la morfina iv (OR = 0,69, i.c. del 95% 0,51 a 0,93; P = 0,01). Conclusión: La EA proporciona puntuaciones de dolor ligeramente más bajas en los primeros días postoperatorios en comparación con la morfina iv y parece asociarse con menos complicaciones, menor duración de la estancia hospitalaria y menor mortalidad.

Safety of sugammadex for reversal of neuromuscular block.

Introduction: Sugammadex is a modified cyclodextrin that is able to reverse neuromuscular block induced by aminosteroidal neuromuscular blocking drugs. Compared to reversal with neostigmine, it reverses neuromuscular block quicker and more predictable and without cholinergic side effects. However, there have been concerns about sugammadex ability to bind other drugs and its effects on QT interval and clotting times. In addition, sugammadex might induce hypersensitivity reactions more frequently than initially anticipated. This review summarizes current evidence with regard to these and other safety aspects of sugammadex. Areas covered: This review provides an overview of the efficacy of sugammadex in various patient populations, evaluates potential interactions with other drugs and discusses adverse effects and reactions that have been reported in the literature. Expert opinion: Sugammadex quickly reverses aminosteroid neuromuscular block with less side effects compared to neostigmine. As such, it has the potential to significantly reduce the incidence of residual neuromuscular block and to improve postoperative pulmonary outcome. Current safety concerns mainly focus on hypersensitivity reactions and cardiac arrhythmias. Although the absolute risk for these events is low, ongoing vigilance and research in this area are needed.

Deep neuromuscular blockade improves surgical conditions during low-pressure pneumoperitoneum laparoscopic donor nephrectomy.

BACKGROUND: Evidence indicates that low-pressure pneumoperitoneum (PNP) reduces postoperative pain and analgesic consumption. A lower insufflation pressure may hamper visibility and working space. The aim of the study is to investigate whether deep neuromuscular blockade (NMB) improves surgical conditions during low-pressure PNP. METHODS: This study was a blinded randomized controlled multicenter trial. 34 kidney donors scheduled for laparoscopic donor nephrectomy randomly received low-pressure PNP (6 mmHg) with either deep (PTC 1-5) or moderate NMB (TOF 0-1). In case of insufficient surgical conditions, the insufflation pressure was increased stepwise. Surgical conditions were rated by the Leiden-Surgical Rating Scale (L-SRS) ranging from 1 (extremely poor) to 5 (optimal). RESULTS: Mean surgical conditions were significantly better for patients allocated to a deep NMB (SRS 4.5 versus 4.0; p < 0.01). The final insufflation pressure was 7.7 mmHg in patients with deep NMB as compared to 9.1 mmHg with moderate NMB (p = 0.19). The cumulative opiate consumption during the first 48 h was significantly lower in patients receiving deep NMB, while postoperative pain scores were similar. In four patients allocated to a moderate NMB, a significant intraoperative complication occurred, and in two of these patients a conversion to an open procedure was required. CONCLUSIONS: Our data show that deep NMB facilitates the use of low-pressure PNP during laparoscopic donor nephrectomy by improving the quality of the surgical field. The relatively high incidence of intraoperative complications indicates that the use of low pressure with moderate NMB may compromise safety during LDN. Clinicaltrials.gov identifier: NCT 02602964.

Effect of subanaesthetic ketamine on plasma and saliva cortisol secretion.

BACKGROUND: The commonality between chronic conditions that are treated with low-dose ketamine, such as specific chronic pain conditions, depression, and post-traumatic stress disorder, can be found in relation to the stress system, particularly the hypothalamus-pituitary-adrenal axis. In this study we assess the effect of ketamine on the stress system by measuring plasma and saliva cortisol production during and following exposure to low-dose ketamine. METHODS: In a double-blind, randomized, placebo-controlled study, the influence of subanaesthetic ketamine (0.29 mg kg(-1) h(-1) for 1 h, followed by 0.57 mg kg(-1) h(-1) for another hour) was studied with repeated plasma and saliva cortisol samples in 12 healthy male volunteers. A pharmacokinetic-pharmacodynamic model was used to describe the circadian rhythm-dependent ketamine-induced production of cortisol. RESULTS: The endogenous mean baseline cortisol production was 7.9 (SE 1.5) nM min(-1). Consistent with the circadian rhythm, cortisol production decayed by 1.25 nM min(-1) h(-1). Ketamine doubled the cortisol production at a concentration of 165 (SE 35) ng ml(-1). The salivary cortisol concentration closely mirrored the plasma concentration and was exponentially related to the plasma concentration with, at 100 ng ml(-1) ketamine, a saliva:plasma ratio of 0.036 (se 0.006). CONCLUSIONS: Ketamine has an appreciable effect on cortisol production. This may impact on critical physiological and psychological functions. CLINICAL TRIAL REGISTRATION: This study was registered in the Dutch Trial Register under number NTR2717 at www.trialregister.nl.

A randomized controlled trial and novel mathematical analysis of the analgesic effect of oxycodone versus paracetamol orodispersible tablets.

BACKGROUND: For effective treatment of acute pain, a rapid onset of action is important. Here we quantify the antinociceptive profile of an orodispersible oxycodone tablet (OOT) in a randomized, double-blind, active comparator (paracetamol orodispersible tablet, POT), crossover study design in a population of healthy volunteers. METHODS: Twelve female volunteers were randomized to receive 20 mg OOT and 500 mg POT sublingually on two occasions. The electrical pain threshold (EPTh), electrical pain tolerance (EPTol) and pressure pain threshold (PPT) were obtained at regular intervals for 5 h. Time-response data were analysed with a longitudinal pharmacodynamic model characterized by rate constants for analgesia onset (kON ), offset (kOFF ), potency parameter (EFF) and validated with a bootstrap analysis. Values are the median (95% CI) as derived from the bootstrap analysis. RESULTS: OOT produced a rapid increase in response values. For electrical pain analgesia onset, t½kON , 44 (25-67) versus analgesia offset, t½kOFF , 156 (63-552) min, p < 0.01. For pressure pain, t½kON equalled t½kOFF : 30 (16-48) min. OOT was most potent on EPTol: EFF 0.95 (0.39-1.71), p < 0.01, with similar potencies on EPTh, 0.43 (0.19-0.87) and PPT, 0.40 (0.21-0.67). Paracetamol displayed 14% of the analgesic efficacy of oxycodone. CONCLUSIONS: The analgesic effect of orodispersible oxycodone was successfully quantified using a mathematical model of analgesia evolution. This method allows quantification of a variety of responses times from sparse data sets. Response times as defined by a 30% increase in response thresholds varied significantly among end points: EPTol 15 min, PPTh 18 min and EPTh 41 min.

Evaluation of surgical conditions during laparoscopic surgery in patients with moderate vs deep neuromuscular block.

BACKGROUND: The routine use of neuromuscular blocking agents reduces the occurrence of unacceptable surgical conditions. In some surgeries, such as retroperitoneal laparoscopies, deep neuromuscular block (NMB) may further improve surgical conditions compared with moderate NMB. In this study, the effect of deep NMB on surgical conditions was assessed. METHODS: Twenty-four patients undergoing elective laparoscopic surgery for prostatectomy or nephrectomy were randomized to receive moderate NMB (train-of-four 1-2) using the combination of atracurium/mivacurium, or deep NMB (post-tetanic count 1-2) using high-dose rocuronium. After surgery, NMB was antagonized with neostigmine (moderate NMB), or sugammadex (deep NMB). During all surgeries, one surgeon scored the quality of surgical conditions using a five-point surgical rating scale (SRS) ranging from 1 (extremely poor conditions) to 5 (optimal conditions). Video images were obtained and 12 anaesthetists rated a random selection of images. RESULTS: Mean (standard deviation) SRS was 4.0 (0.4) during moderate and 4.7 (0.4) during deep NMB (P<0.001). Moderate block resulted in 18% of scores at the low end of the scale (Scores 1-3); deep block resulted in 99% of scores at the high end of the scale (Scores 4 and 5). Cardiorespiratory conditions were similar during and after surgery in both groups. Between anaesthetists and surgeon, there was poor agreement between scores of individual images (average κ statistic 0.05). CONCLUSIONS: Application of the five-point SRS showed that deep NMB results in an improved quality of surgical conditions compared with moderate block in retroperitoneal laparoscopies, without compromise to the patients' peri- and postoperative cardiorespiratory conditions. Trial registration The study was registered at clinicaltrials.gov under number NCT01361149.

A novel approach to identify responder subgroups and predictors of response to low- and high-dose capsaicin patches in postherpetic neuralgia.

BACKGROUND: Treatment of chronic pain conditions is commonly assessed at specific endpoints at preset times during or after treatment by analysis of the total study population. An alternative approach is the identification of specific patient subgroups characterized by differential response patterns in their analgesic response and to determine the presence of significant predictors of effect. METHODS: Data from four double-blind, randomized controlled trials on the efficacy of topical capsaicin 8% (Qutenza) versus an active control (capsaicin 0.04%) in patients with postherpetic neuropathic pain were combined. Longitudinal pharmacodynamic, mixture and covariate analyses were performed on the pooled dataset. RESULTS: Data from 1248 patients treated with Qutenza (n = 722) or topical low-dose capsaicin 0.04% (n = 526) were successfully analysed. Five distinct response subgroups were detected with different treatment efficacies, including a group of non-responders, a group showing partial analgesic effect and a group showing full analgesic effect. Active control and Qutenza had similar response profiles, but the proportional distribution of patients among the five response groups was in favour of Qutenza, with 40% less non-responders and 25% more patients showing a full analgesic response. For Qutenza, important predictors of efficacy were efficacy of lidocaine pretreatment and greater pretreatment pain score variability. CONCLUSIONS: The analyses indicate the existence of different response groups to treatment with Qutenza and an active control patch that may possibly be related to different pain mechanisms among these groups, despite a presumed common underlying disease process, and that require different treatment approaches among subgroups.

The effect of genetic variants in the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI-antigen levels, clot lysis time and the risk of venous thrombosis.

Thrombin activatable fibrinolysis inhibitor (TAFI) is an important inhibitor of fibrinolysis. High TAFI antigen levels are associated with an increased risk of deep venous thrombosis (DVT). Because TAFI levels are partly determined genetically, we assessed the association between three TAFI gene polymorphisms (-438 G/A, 505 A/G and 1040 C/T), TAFI antigen levels and clot lysis times and the risk of DVT. Carriers of the 505G allele, which is associated with lower TAFI antigen levels than the 505A allele, showed an increased risk of DVT. This indicates that the relationship between TAFI and venous thrombosis is more complex than previously suggested.