Phase I clinical and pharmacologic study of weekly cisplatin and irinotecan combined with amifostine for refractory solid tumors.

PURPOSE: This Phase I study was designed primarily to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of irinotecan and cisplatin with and without amifostine in children with refractory solid tumors. PATIENTS AND METHODS: Cisplatin, at a fixed dose of 30 mg/m(2), and escalating doses of irinotecan (starting dose, 40 mg/m(2)) were administered weekly for four consecutive weeks, every 6 weeks. After the MTD of irinotecan plus cisplatin was determined, additional cohorts of patients were enrolled with amifostine (825 mg/m(2)) support. Leukocyte DNA-platinum adducts and pharmacokinetics of cisplatin and WR-1065 (amifostine-active metabolite) were also determined. RESULTS: Twenty-four patients received 43 courses of therapy. The MTD for irinotecan administered in combination with cisplatin (30 mg/m(2)) was 50 mg/m(2). The DLTs of this combination were neutropenia and thrombocytopenia. With the addition of amifostine, at an irinotecan dose of 65 mg/m(2) and cisplatin dose of 30 mg/m(2), the DLT was hypocalcemia. Although no objective responses were observed, six patients received at least three courses of therapy. The amounts of platinum adducts (mean +/- SD) were 10 +/- 20 molecules/10(6) nucleotides. The maximum plasma concentrations (C(max)) for free cisplatin and WR-1065 were 4.5 +/- 1.6 micro M and approximately 89 +/- 10 micro M, respectively. The half-life (t(1/2)) for free plasma cisplatin was 25.4 +/- 5.4 min. The initial t(1/2) for plasma WR-1065 was approximately 7 min and terminal t(1/2) approximately 24 min. CONCLUSION: The combination of cisplatin and irinotecan administered weekly for 4 weeks in children with refractory cancer is well tolerated. Amifostine offers some myeloprotection, likely permitting >/=30% dose escalation for irinotecan, when administered in a combination regimen with cisplatin. However, effective antiemetics and calcium supplementation are necessary with the use of amifostine. Further escalation of irinotecan dosing, using these precautions for amifostine administration, may be possible.     

Growth of asthmatic children is slower during than before treatment with inhaled glucocorticoids

Reports on the influence of inhaled glucocorticoids on growth have been controversial. We studied the growth of prepubertal asthmatic children prior to and during glucocorticoid therapy. We collected retrospectively the notes of 201 asthmatic children aged 1–11 years receiving inhaled beclomethasone dipropionate or budesonide. We calculated their height and height velocity standard deviation scores (HSDS and HVSDS, respectively) before the treatment and up to 5 years during the treatment and compared those with the growth of healthy peers. The dose of the medication was calculated and the severity of asthma was assessed. The asthmatic children grew similarly to their healthy peers before treatment with inhaled glucocorticoids: the mean HSDS was +0.02 and the mean HVSDS +0.01 for boys and -0.16 and +0.13 for girls, respectively. Growth retardation took place soon after the start of the treatment, the most profound decrease in the growth velocity (the change in the mean HVSDS from +0.05 to -0.88) occurring during the first year of treatment. The growth-retarding effect of inhaled glucocorticoids was not dose dependent. In the covariance analysis the increasing severity of asthma had a significant interaction with repeated measurements, showing more growth retardation along with more severe asthma, especially during long-term treatment. Asthma per se does not impair growth, but inhaled glucocorticoids may do so. Careful monitoring of the growth of all asthmatic children receiving inhaled glucocorticoids is necessary because the growth-retarding effect of the medication is not dose dependent. Individual sensitivity might explain the differences seen in the growth patterns of children receiving inhaled glucocorticoids.     

Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel.

PURPOSE: To retrospectively evaluate the effects of six known allelic variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes on the pharmacokinetics of the anticancer agent paclitaxel (Taxol). EXPERIMENTAL DESIGN: A cohort of 97 Caucasian patients with cancer (median age, 57 years) received paclitaxel as an i.v. infusion (dose range, 80-225 mg/m(2)). Genomic DNA was analyzed using PCR RFLP or using Pyrosequencing. Pharmacokinetic variables for unbound paclitaxel were estimated using nonlinear mixed effect modeling. The effects of genotypes on typical value of clearance were evaluated with the likelihood ratio test within NONMEM. In addition, relations between genotype and individual pharmacokinetic variable estimates were evaluated with one-way ANOVA. RESULTS: The allele frequencies for the CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP3A4*3, CYP3A5*3C, and ABCB1 3435C>T variants were 0.7%, 9.2%, 2.1%, 0.5%, 93.2%, and 47.1%, respectively, and all were in Hardy-Weinberg equilibrium. The population typical value of clearance of unbound paclitaxel was 301 L/h (individual clearance range, 83.7-1055 L/h). The CYP2C8 or CYP3A4/5 genotypes were not statistically significantly associated with unbound clearance of paclitaxel. Likewise, no statistically significant association was observed between the ABCB1 3435C>T variant and any of the studied pharmacokinetic variables. CONCLUSIONS: This study indicates that the presently evaluated variant alleles in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not explain the substantial interindividual variability in paclitaxel pharmacokinetics.     

Transmetatarsal Amputation in the Setting of Antiphospholipid Antibody Syndrome

Antiphospholipid syndrome is a hypercoagulable disease that can present foot and ankle surgeons with a unique challenge in treating patients who present with thrombosis and ischemia despite having normal pedal pulses. Appropriate perioperative management is imperative in these patients, because limb- and life-threatening complications can occur postoperatively, despite aggressive anticoagulation. We present the case of a 46-year-old male who underwent a transmetatarsal amputation and, despite aggressive therapy, developed a myriad of complications postoperatively. At 10 months postoperatively, the patient was doing well in an accommodative orthotic with minimal pain while receiving continued aggressive therapy and follow-up examinations by a number of specialists to treat his antiphospholipid syndrome.     

Sphygmomanometry-Evoked Allodynia in Chronic Pain Patients With and Without Fibromyalgia

BACKGROUND:: Fibromyalgia is a chronic pain syndrome that affects about 2% of the U.S. general population, with greater prevalence among women (3.5%) than men (0.5%). Previous research results suggest that the experience of pain (allodynia) upon sphygmomanometry may indicate the presence of fibromyalgia. OBJECTIVE:: The aim of this study was to confirm these findings in patients with fibromyalgia and other chronic pain conditions and evaluate the use of sphygmomanometry as a potential screening tool for the identification of patients with fibromyalgia. METHODS:: A total of 150 people participated in this multicenter, cross-sectional observational study. The study included a physician-conducted evaluation to determine if the participant met the American College of Rheumatology (ACR) 1990 diagnostic criteria for fibromyalgia. The presence of sphygmomanometry-evoked allodynia was assessed during a seated cuff pressure inflation that was repeated three times on each arm. Each site was provided a sphygmomanometer to ensure standardization, and the pressure of the cuff at the moment of pain initiation was recorded. If the patient did not indicate pain prior to 180 mmHg, then the inflation was stopped, a notation of no pain was made, and a cuff pressure of 180 mmHg was recorded. The mean of the six cuff pressure measurements was used for the analyses. Logistic regression was performed to analyze the relationship between sphygmomanometry-evoked allodynia and fibromyalgia. RESULTS:: The evaluable sample was 148 (one participant had too large an arm circumference for the sphygmomanometer and another did not receive the clinician evaluation of ACR-determined fibromyalgia diagnosis). Over half of the participants were determined to have an ACR diagnosis of fibromyalgia. Of these, 71 (91%) were women and had an average age of 54 years. Of the 70 participants with no fibromyalgia diagnosis, 42 (60%) were women and also had an average age of 54 years. Sixty-one (78%) of the fibromyalgia participants, compared with 25 (36%) of those with no fibromyalgia diagnosis, reported sphygmomanometry-evoked allodynia. The participants with fibromyalgia reported pain ata lower cuff pressure compared with those without fibromyalgia (132 mmHg vs. 166 mmHg, p < .01). The logistic regression showed that sphygmomanometry-evoked allodynia predicted an ACR-determined FM diagnosis (χ = 19.4, p < .01). DISCUSSION:: These findings support previous research suggesting that patients who report pain upon sphygmomanometry may warrant further evaluation for the presence of fibromyalgia.     

Design and validation of a virtual reality trainer for ultrasound-guided regional anaesthesia

Virtual reality is a form of high-fidelity simulation that may be used to enhance the quality of medical education. We created a bespoke virtual reality trainer software using high resolution motion capture and ultrasound imagery to teach cognitive-motor needling skills necessary for the performance of ultrasound-guided regional anaesthesia. The primary objective of this study was to determine the construct validity between novice and experienced regional anaesthetists. Secondary objectives were: to create learning curves for needling performance; compare the virtual environment immersion with other high-fidelity virtual reality software; and compare cognitive task loads imposed by the virtual trainer compared with real-life medical procedures. We recruited 21 novice and 15 experienced participants, each of whom performed 40 needling attempts on four different virtual nerve targets. Performance scores for each attempt were calculated based on measured metrics (needle angulation, withdrawals, time taken) and compared between the groups. The degree of virtual reality immersion was measured using the Presence Questionnaire, and cognitive burden was measured using the NASA-Task Load Index. Scores by experienced participants were significantly higher than novices (p = 0.002) and for each nerve target (84% vs. 77%, p = 0.002; 86% vs. 79%, p = 0.003; 87% vs. 81%, p = 0.002; 87% vs. 80%, p = 0.003). Log–log transformed learning curves demonstrated individual variability in performance over time. The virtual reality trainer was rated as being comparably immersive to other high-fidelity virtual reality software in the realism, possibility to act and quality of interface subscales (all p > 0.06) but not in the possibility to examine and self-performance subscales (all p < 0.009). The virtual reality trainer created workloads similar to those reported in real-life procedural medicine (p = 0.53). This study achieved initial validation of our new virtual reality trainer and allows progression to a planned definitive trial that will compare the effectiveness of virtual reality training on real-life regional anaesthesia performance.     

Safety profile of sural nerve in posterolateral approach to the ankle joint: MRI study

The posterolateral approach to ankle joint is well suited for ORIF of posterior malleolar fractures. There are no major neurovascular structures endangering this approach other than the sural nerve. The sural nerve is often used as an autologous peripheral nerve graft and provides sensation to the lateral aspect of the foot. The aim of this paper is to measure the precise distance of the sural nerve from surrounding soft tissue structures so as to enable safe placement of skin incision in posterolateral approach. This is a retrospective image review study involving 64 MRI scans. All measurements were made from Axial T1 slices. The key findings of the paper is the safety window for the sural nerve from the lateral border of tendoachilles (TA) is 7 mm, 1.3 cm and 2 cm at 3 cm above ankle joint, at the ankle joint and at the distal tip of fibula respectively. Our study demonstrates the close relationship of the nerve in relation to TA and fibula in terms of exact measurements. The safety margins established in this study should enable the surgeon in preventing endangerment of the sural nerve encountered in this approach.