Pharmacokinetics of Intramuscularly Administered Thermoresponsive Polymers.

Aqueous solutions of some polymers exhibit a lower critical solution temperature (LCST); that is, they form phase-separated aggregates when heated above a threshold temperature. Such polymers found many promising (bio)medical applications, including in situ thermogelling with controlled drug release, polymer-supported radiotherapy (brachytherapy), immunotherapy, and wound dressing, among others. Yet, despite the extensive research on medicinal applications of thermoresponsive polymers, their biodistribution and fate after administration remained unknown. Thus, herein, they studied the pharmacokinetics of four different thermoresponsive polyacrylamides after intramuscular administration in mice. In vivo, these thermoresponsive polymers formed depots that subsequently dissolved with a two-phase kinetics (depot maturation, slow redissolution) with half-lives 2 weeks to 5 months, as depot vitrification prolonged their half-lives. Additionally, the decrease of TCP of a polymer solution increased the density of the intramuscular depot. Moreover, they detected secondary polymer depots in the kidneys and liver; these secondary depots also followed two-phase kinetics (depot maturation and slow dissolution), with half-lives 8 to 38 days (kidneys) and 15 to 22 days (liver). Overall, these findings may be used to tailor the properties of thermoresponsive polymers to meet the demands of their medicinal applications. Their methods may become a benchmark for future studies of polymer biodistribution.

How much does a Medical and Healthcare Products Regulatory Agency medical device alert for metal-on-metal hip arthroplasty patients really cost?

BACKGROUND: Many worldwide regulatory authorities recommend regular surveillance of metal-on-metal hip arthroplasty patients given high failure rates. However, concerns have been raised about whether such regular surveillance, which includes asymptomatic patients, is evidence-based and cost-effective. We determined: (1) the cost of implementing the 2015 MHRA surveillance in "at-risk" Birmingham Hip Resurfacing (BHR) patients; and (2) how many asymptomatic hips with adverse reactions to metal debris (ARMD) would have been missed without patient recall. METHODS: All BHR patients eligible for the 2015 MHRA recall (all females, and males with head sizes ⩽46 mm, regardless of symptoms) at one centre were invited for review (hips = 707; patients = 593). All patients were investigated (Oxford Hip Score, radiographs, blood metal ions, and targeted cross-sectional imaging) and managed accordingly. Surveillance costs were calculated using finance department data. RESULTS: The surveillance cost £105,921.79 (range £147.76-£257.50/patient). Radiographs (£39,598) and nurse practitioner time/assistance (£23,618) accounted for 60% of overall costs. 31 hips had ARMD on imaging (12 revised; 19 under surveillance). All revisions were symptomatic. 7 hips with ARMD under surveillance were asymptomatic and remain under regular review. The number needed to treat to avoid missing one asymptomatic ARMD case was 101 patients, representing a cost of £18,041 to avoid one asymptomatic case. CONCLUSIONS: Implementing MHRA surveillance for "at-risk" BHR patients was extremely costly. The risk of asymptomatic ARMD was low with the BHR (1%), suggesting recommended follow-up in asymptomatic patients is not cost efficient. This raises concerns about the increasingly intensive surveillance recommended in the 2017 MHRA guidance for metal-on-metal hip patients.

Morbidity and mortality in patients undergoing lower limb arthroplasty surgery during the initial surge of the COVID-19 pandemic in the UK at a single-speciality orthopaedic hospital.

AIMS: The COVID-19 pandemic posed significant challenges to healthcare systems across the globe in 2020. There were concerns surrounding early reports of increased mortality among patients undergoing emergency or non-urgent surgery. We report the morbidity and mortality in patients who underwent arthroplasty procedures during the UK first stage of the pandemic. METHODS: Institutional review board approval was obtained for a review of prospectively collected data on consecutive patients who underwent arthroplasty procedures between March and May 2020 at a specialist orthopaedic centre in the UK. Data included diagnoses, comorbidities, BMI, American Society of Anesthesiologists grade, length of stay, and complications. The primary outcome was 30-day mortality and secondary outcomes were prevalence of SARS-CoV-2 infection, medical and surgical complications, and readmission within 30 days of discharge. The data collated were compared with series from the preceding three months. RESULTS: There were 167 elective procedures performed in the first three weeks of the study period, prior to the first national lockdown, and 57 emergency procedures thereafter. Three patients (1.3%) were readmitted within 30 days of discharge. There was one death (0.45%) due to SARS-CoV-2 infection after an emergency procedure. None of the patients developed complications of SARS-CoV-2 infection after elective arthroplasty. There was no observed spike in complications during in-hospital stay or in the early postoperative period. There was no statistically significant difference in survival between pre-COVID-19 and peri-COVID-19 groups (p = 0.624). We observed a higher number of emergency procedures performed during the pandemic within our institute. CONCLUSION: An international cohort has reported 30-day mortality as 28.8% following orthopaedic procedures during the pandemic. There are currently no reports on clinical outcomes of patients treated with lower limb reconstructive surgery during the same period. While an effective vaccine is developed and widely accepted, it is very likely that SARS-CoV2 infection remains endemic. We believe that this report will help guide future restoration planning here in the UK and abroad. Cite this article: Bone Jt Open 2021;2(5):323-329.

Has the threshold for revision surgery for adverse reactions to metal debris changed in metal-on-metal hip arthroplasty patients? A cohort study of 239 patients using an adapted risk-stratification algorithm.

Background and purpose - A risk-stratification algorithm for metal-on-metal hip arthroplasty (MoMHA) patients was devised by US experts to help clinicians make management decisions. However, the proposed algorithm did not cover all potential patient or surgical abnormalities. Therefore we adapted the US risk-stratification algorithm in MoMHA patients revised for adverse reactions to metal debris (ARMD) to determine the variability in the revision threshold, and also whether high-risk patients had inferior outcomes following revision.Patients and methods - We analysed 239 MoMHA revisions for ARMD between 2001 and 2016 from 2 centres with pre-revision blood metal ions and imaging. Patients were stratified (low risk, moderate risk, high risk) using pre-revision factors (implant, radiographic, blood metal ions, cross-sectional imaging) by adapting a published algorithm. The risk categories for each factor were assessed against revision year, revision centre, and post-revision outcomes (re-revision surgery, and any poor outcome).Results - Compared with hips revised before 2012, hips revised from 2012 onwards included more high-risk implants (44% vs. 17% pre-2012), high-risk radiographic features (85% vs. 69% pre-2012), and low-risk metal ions (41% vs. 19% pre-2012). 1 centre more frequently revised patients with high-risk implants (48% vs. 14%) and low-risk blood metal ions (45% vs. 15%) compared with the other. All these comparisons were statistically significant (p < 0.05). With the limited sample size available, implant, radiographic, blood metal ion, and cross-sectional imaging risk groups did not statistically significantly affect the rates of re-revision surgery or frequency of poor outcomes post-revision.Interpretation - When applying the adapted risk-stratification algorithm the threshold for ARMD revision changed over time, presumably due to increasing evidence, patient surveillance, and investigation since 2012. Lower blood metal ion thresholds were used from 2012 for ARMD revisions; however, there was evidence that centres attached different importance to metal ions when managing patients. High-risk patients did not have inferior outcomes following ARMD revision.

No Threshold Exists for Recommending Revision Surgery in Metal-on-Metal Hip Arthroplasty Patients With Adverse Reactions to Metal Debris: A Retrospective Cohort Study of 346 Revisions.

BACKGROUND: Surgeons currently have difficulty when managing metal-on-metal hip arthroplasty (MoMHA) patients with adverse reactions to metal debris (ARMD). This stems from a lack of evidence, which is emphasized by the variability in the recommendations proposed by different worldwide regulatory authorities for considering MoMHA revision surgery. We investigated predictors of poor outcomes following MoMHA revision surgery performed for ARMD to help inform the revision threshold and type of reconstruction. METHODS: We retrospectively studied 346 MoMHA revisions for ARMD performed at 2 European centers. Preoperative (metal ions/imaging) and intraoperative (findings, components removed/implanted) factors were used to predict poor outcomes. Poor outcomes were postoperative complications (including re-revision), 90-day mortality, and poor Oxford Hip Score. RESULTS: Poor outcomes occurred in 38.5%. Shorter time (under 4 years) to revision surgery was the only preoperative predictor of poor outcomes (odds ratio [OR] = 2.12, confidence interval [CI] = 1.00-4.46). Prerevision metal ions and imaging did not influence outcomes. Single-component revisions (vs all-component revisions) increased the risk of poor outcomes (OR = 2.99, CI = 1.50-5.97). Intraoperative modifiable factors reducing the risk of poor outcomes included the posterior approach (OR = 0.22, CI = 0.10-0.49), revision head sizes ≥36 mm (vs <36 mm: OR = 0.37, CI = 0.18-0.77), ceramic-on-polyethylene revision bearings (OR vs ceramic-on-ceramic = 0.30, CI = 0.14-0.66), and metal-on-polyethylene revision bearings (OR vs ceramic-on-ceramic = 0.37, CI = 0.17-0.83). CONCLUSION: No threshold exists for recommending revision in MoMHA patients with ARMD. However postrevision outcomes were surgeon modifiable. Optimal outcomes may be achieved if surgeons use the posterior approach, revise all MoMHA components, and use ≥36 mm ceramic-on-polyethylene or metal-on-polyethylene articulations.

Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: Results from a British Thoracic Oncology Group randomised phase III trial.

BACKGROUND: Platinum-based combination chemotherapy is standard treatment for the majority of patients with advanced non-small-cell lung cancer (NSCLC). The trial investigates the importance of the choice of platinum agent and dose of cisplatin in relation to patient outcomes. METHODS: The three-arm randomised phase III trial assigned patients with chemo-naïve stage IIIB/IV NSCLC in a 1:1:1 ratio to receive gemcitabine 1250 mg/m2 on days 1 and 8 of a 3-week cycle with cisplatin 80 mg/m2 (GC80) or cisplatin 50 mg/m2 (GC50) or carboplatin AUC6 (GCb6) for a maximum of four cycles. Primary outcome measure was survival time, aiming to test for a difference between treatment arms and also assess non-inferiority with pre-defined margin selected as hazard ratio (HR) of 1.2. Secondary outcome measures included response rate, adverse events and quality of life (QoL). FINDINGS: The trial recruited 1363 patients. Survival time differed significantly across the three treatment arms (p = 0.046) with GC50 worst with median 8.2 months compared to 9.5 for GC80 and 10.0 for GCb6. HRs (adjusted) for GC50 compared to GC80 was 1.13 (95% confidence interval [CI] 0.99-1.29) and for GC50 compared to GCb6 was 1.23 (95% CI: 1.08-1.41). GCb6 was significantly non-inferior to GC80 (HR = 0.93, upper limit of one-sided 95% CI 1.04). Adjusting for QoL did not change the findings. Best objective response rates were 29% (GC80), 20% (GC50) and 27% (GCb6), p < 0.007. There were more dose reductions and treatment delays in the GCb6 arm and more adverse events (60% with at least one grade 3-4 compared to 43% GC80 and 30% GC50). INTERPRETATION: In combination with gemcitabine, carboplatin at AUC6 is not inferior to cisplatin at 80 mg/m2 in terms of survival. Carboplatin was associated with more adverse events and not with better quality of life. Cisplatin at the lower dose of 50 mg/m2 has worse survival which is not compensated by better quality of life. CLINICALTRIALS. GOV IDENTIFIER: NCT00112710. EUDRACT NUMBER: 2004-003868-30. CANCER RESEARCH UK TRIAL IDENTIFIER: CRUK/04/009.

The Effectiveness of Blood Metal Ions in Identifying Patients with Unilateral Birmingham Hip Resurfacing and Corail-Pinnacle Metal-on-Metal Hip Implants at Risk of Adverse Reactions to Metal Debris.

BACKGROUND: We investigated whether blood metal ions could effectively identify patients with metal-on-metal hip implants with two common designs (Birmingham Hip Resurfacing [BHR] and Corail-Pinnacle) who were at risk of adverse reactions to metal debris. METHODS: This single-center, prospective study involved 598 patients with unilateral hip implants (309 patients with the BHR implant and 289 patients with the Corail-Pinnacle implant) undergoing whole blood metal ion sampling at a mean time of 6.9 years. Patients were classified into two groups, one that had adverse reactions to metal debris (those who had to undergo revision for adverse reactions to metal debris or those with adverse reactions to metal debris on imaging; n = 46) and one that did not (n = 552). Three metal ion parameters (cobalt, chromium, and cobalt-chromium ratio) were compared between groups. Optimal metal ion thresholds for identifying patients with adverse reactions to metal debris were determined using receiver operating characteristic analysis. RESULTS: All ion parameters were significantly higher (p < 0.0001) in the patients who had adverse reactions to metal debris compared with those who did not. Cobalt maximized the area under the curve for patients with the BHR implant (90.5%) and those with the Corail-Pinnacle implant (79.6%). For patients with the BHR implant, the area under the curve for cobalt was significantly greater than that for the cobalt-chromium ratio (p = 0.0005), but it was not significantly greater than that for chromium (p = 0.8483). For the patients with the Corail-Pinnacle implant, the area under the curve for cobalt was significantly greater than that for chromium (p = 0.0004), but it was similar to that for the cobalt-chromium ratio (p = 0.8139). Optimal blood metal ion thresholds for identifying adverse reactions to metal debris varied between the two different implants. When using cobalt, the optimal threshold for identifying adverse reactions to metal debris was 2.15 µg/L for the BHR group and 3.57 µg/L for the Corail-Pinnacle group. These thresholds had good sensitivities (88.5% for the BHR group and 80.0% for the Corail-Pinnacle group) and specificities (84.5% for the BHR group and 76.2% for the Corail-Pinnacle group), high negative predictive values (98.8% for the BHR group and 98.1% for the Corail-Pinnacle group), and low positive predictive values (34.3% for the BHR group and 20.0% for the Corail-Pinnacle group). The authority thresholds proposed by the United States (3 µg/L and 10 µg/L) and the United Kingdom (7 µg/L) missed more patients with adverse reactions to metal debris at 2.0% to 4.7% (twelve to twenty-eight patients) compared with our implant-specific thresholds at 1.2% (seven patients missed). CONCLUSIONS: Patients who underwent metal-on-metal hip arthroplasty performed with unilateral BHR or Corail-Pinnacle implants and who had blood metal ions below our implant-specific thresholds were at low risk of adverse reactions to metal debris. These thresholds could be used to rationalize follow-up resources in asymptomatic patients. Analysis of cobalt alone is acceptable. Implant-specific thresholds were more effective than currently recommended fixed authority thresholds for identifying patients at risk of adverse reactions to metal debris requiring further investigation. LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Metal-on-Metal Total Hip Arthroplasty Associated with Adverse Local Tissue Reaction and Pseudoaneurysm of the Superior Gluteal Artery: A Case Report and Literature Review.

Adverse local tissue reaction (ALTR) and pseudoaneurysm formation are rare but known complications following metal-on-metal hip total hip arthroplasty (THA). We report the first known case in the English literature of a concurrent unilateral ALTR and pseudoaneurysm of the superior gluteal artery in the same patient. Following minimal rise in serum metal ions, an ultrasound of the right hip demonstrated an avascular solid/cystic lesion anterolaterally in keeping with an ALTR. More posterolaterally, a second discrete thick-walled cystic lesion was identified. Doppler interrogation demonstrated a "yin yang" pattern suggestive of a pseudoaneurysm. Magnetic resonance imaging confirmed the presence of an anterolateral periarticular lesion with a second discrete lesion within the gluteus medius. Subsequent computed tomography angiography confirmed the presence of arterial contrast blush within the posterior gluteal lesion adjacent to the superior gluteal artery. The patient remains asymptomatic and is being managed conservatively. We review the imaging characteristics of ALTR and pseudoaneurysm occurring post-THA. When a complex solid/cystic lesion is encountered in a patient with a THA, radiologists must ensure that the lesion is interrogated with color Doppler to confidently distinguish a pseudotumor from a pseudoaneurysm. This information is vital to the surgeon to avoid unexpected hemorrhage if revision joint replacement surgery is being contemplated.

Predicting high blood metal ion concentrations following hip resurfacing.

PURPOSE: To determine whether gender, femoral head size, acetabular inclination, and time since surgery predicted high blood metal ion concentrations following Birmingham Hip Resurfacing (BHR). METHODS: BHR patients with unilateral bearings at one specialist centre with blood cobalt and chromium concentrations measured up to May 2013 were included. This comprised a mixed (at-risk) group including symptomatic patients and asymptomatic individuals with specific clinical and/or radiological findings. Blood sampling was at a mean of 7.5 years (range 1-15.4 years) postoperatively. RESULTS: Of 319 patients (mean age 49.3 years; 53% male), blood metal ions greater than 7 µg/l were observed in 9% (n = 28). Blood metal ions were significantly higher in females (p<0.001), femoral head sizes ≤48 mm (p<0.01), and cup inclinations >55° (p<0.001). Linear regression demonstrated femoral head size was responsible for the highest proportion of variance in blood metal ions (cobalt p<0.001, R2 = 8%; chromium p<0.001, R2 = 11%). Analysis of femoral head size and inclination together demonstrated 36% of BHRs with head sizes of 38-44 mm and inclination >55° had blood metal ions >7 µg/l. BHR 10-year survival for this at-risk group was 91% (95% confidence intervals 86.0%-95.0%) with 30 hips revised. CONCLUSIONS: If blood metal ions are used to screen hip resurfacing patients for adverse reactions to metal debris it is recommended those with small femoral head sizes (38-44 mm) and high acetabular inclinations (>55°) are targeted. These findings require validation in other cohorts as they may not be applicable to all hip resurfacing devices given the differences in radial clearance, coverage arc, and metallurgy.

Revision of metal-on-metal hip replacements and resurfacings for adverse reaction to metal debris: a systematic review of outcomes.

PURPOSE: This systematic review assessed evidence on outcomes following revision of MoM hip resurfacings (HRs) and total hip replacements (THRs) for adverse reaction to metal debris (ARMD). METHODS: Four electronic databases were searched between January 2009 and July 2013 to identify studies reporting clinical outcomes following revision of MoM HRs and THRs for ARMD. Only studies reporting cohorts with more than 10 metal-on-metal (MoM) hips revised for ARMD were included. Outcomes of interest following ARMD revision were: (1) complication rates; (2) re-revision rates; (3) surgical intervention other than re-revision; (4) functional outcome. RESULTS: Of 148 unique studies identified, six studies were eligible for inclusion containing 216 MoM hips (197 HRs and 19 THRs) revised for ARMD. Mean follow-up time from ARMD revision ranged between 21-61 months. Complication rates were 4%-50% for HR and 68% for THR. Re-revision rates were 3%-38% for HR and 21% for THR. Dislocation (n = 14), ARMD recurrence (n = 11), and acetabular loosening (n = 9) were the three commonest complications and indications for re-revision. All six studies reported between one and three cases of ARMD recurrence during follow-up. One study specifically reported on performing procedures other than re-revision with 26% requiring closed reductions for dislocated THRs. Functional outcomes following ARMD revision were good or satisfactory in all but two studies. CONCLUSIONS: Limited evidence exists regarding outcomes following revision of MoM hips for ARMD, especially for THRs. This should be addressed in future studies and may be important when counselling asymptomatic individuals in whom revision is considered for raised blood metal ions.

Clinical outcome following surgical intervention for periprosthetic hip fractures at a tertiary referral centre.

Complications following surgical intervention for periprosthetic hip fractures are not uncommon. We report the clinical outcome following definitive surgical intervention for this indication at a single tertiary referral centre. All patients admitted between 2003 and 2009 undergoing such treatment were included. Patient demographics, all surgical interventions, complications following definitive fracture treatment, and postoperative mortality were recorded. Radiographs were reviewed to determine the Vancouver classification for each fracture. There were 67 patients (mean age at revision 76.7 years; 61% female). Fractures occurred around primary total hip arthroplasties (43%), revision arthroplasties (34%), and hip hemiarthroplasties (23%). Mean time to fracture from the most recent arthroplasty performed was 7.0 years. Most fractures were Vancouver type B2 (49%). The majority of patients underwent revision total hip arthroplasty (96%), using long-stemmed prostheses or proximal femoral endoprostheses, with cables for fracture fixation. Wound infection and systemic complications were seen in 16% and 13% respectively. One or more further surgical interventions were performed in 12%. There were no deaths in-hospital or at 30-days, with 10 fatalities (15%) at a mean 2-year follow-up. Lower rates of re-intervention and mortality were observed when surgery for acute periprosthetic hip fractures was performed at a tertiary centre. Revision hip arthroplasty with or without fracture fixation proved an effective and safe treatment of periprosthetic hip fractures in a high-risk patient population.

The effect of bexarotene on atorvastatin pharmacokinetics: results from a phase I trial of bexarotene plus chemotherapy in patients with advanced non-small cell lung cancer.

PURPOSE: Bexarotene (Targretin(®) capsules) is a retinoid-X-receptor agonist and an inducer of CYP3A4-mediated metabolism. This phase I trial evaluated the pharmacokinetic (PK) and drug-drug interactions of bexarotene with chemotherapy and a lipid-lowering agent (atorvastatin or fenofibrate). This trial was run in parallel with phase III trials of the combinations to determine whether repeated doses of bexarotene capsules affect the pharmacokinetics (PK) of the chemotherapeutic or the lipid-lowering agents. METHODS: Patients (n = 48) with advanced non-small cell lung cancer were treated with repetitive cycles of either paclitaxel/carboplatin or cisplatin/vinorelbine chemotherapy, bexarotene (400 mg/m(2)/day) administered continuously starting on day 4 of chemotherapy, and a lipid-lowering drug, either atorvastatin or fenofibrate, starting at least 5 days before chemotherapy due to hypertriglyceridemia induced by bexarotene. Extensive plasma sampling to characterize the PK profiles of the lipid-lowering drugs, relevant chemotherapy agents was performed on day 1 (without bexarotene) and during chemotherapy cycles 2 or 3 (with bexarotene). RESULTS: Here, we report the drug-drug interactions between the lipid-lowering agents and bexarotene. Mean atorvastatin clearance and dose-corrected AUC values were reduced by nearly 50% with the addition of concomitant bexarotene. As fenofibrate was less effective at controlling hypertriglyceridemia, too few patients received this agent to make any meaningful conclusions about drug-drug interactions. CONCLUSIONS: A drug-drug interaction was seen in this trial with bexarotene co-administration leading to a significant reduction in the AUC of atorvastatin. The likely mechanism for this interaction is through induction of CYP3A4 by bexarotene given the role of this enzyme in the metabolism of atorvastatin. Knowledge of this interaction is important for optimizing lipid management with atorvastatin for patients receiving bexarotene.

A phase I pharmacokinetic study of bexarotene with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer (NSCLC).

PURPOSE: This is a phase I study of the retinoid X receptor agonist bexarotene (Targretin(®)) in combination with the chemotherapeutic drugs cisplatin and vinorelbine and lipid-lowering therapy. This study looked for pharmacokinetic (PK) interactions between the agents in parallel with a phase III study of the combination. METHODS: Patients (n = 26) with advanced-stage non-small-cell lung cancer received intravenous cisplatin 100 mg/m(2) on day 1 and at 4-week intervals plus intravenous vinorelbine 25 mg/m(2) weekly. Continuous oral bexarotene therapy (400 mg/m(2)/day) was initiated at day 4. Lipid-lowering therapy was initiated in all patients due to hypertriglyceridemia associated with bexarotene use. PK profiles of the chemotherapeutic agents were obtained on day 1 (without bexarotene) and during cycles 2-4 (with bexarotene). Vinorelbine (n = 18) and free cisplatin (n = 17) PK parameters in evaluable patients were determined using non-compartmental methods. RESULTS: Mean vinorelbine and free cisplatin clearance and dose-corrected AUC values with bexarotene were within 20% of respective values without concomitant bexarotene. Bexarotene levels did not vary with or without co-administration of the chemotherapeutic agents. There was no evidence of increased toxicity when bexarotene was co-administered with the chemotherapeutic agents. CONCLUSIONS: Bexarotene does not substantially affect vinorelbine or cisplatin PK, and the combination is well tolerated. The results are consistent with the mechanisms of elimination of vinorelbine (high metabolic clearance) and cisplatin (non-enzymatic and renal elimination).

Overcoming CYP1A1/1A2 mediated induction of metabolism by escalating erlotinib dose in current smokers.

PURPOSE: Cigarette smoking induces CYP1A1/1A2 and is hypothesized to alter erlotinib pharmacokinetics. This study aimed to determine the maximum tolerated dose (MTD) of erlotinib in advanced non-small-cell lung cancer (NSCLC) patients who smoke and compare the pharmacokinetics of erlotinib at the MTD in current smokers with 150 mg. PATIENTS AND METHODS: Cohorts of NSCLC patients currently smoking > or = 10 cigarettes per day for > or = 1 year received escalating doses of erlotinib for 14 days until dose-limiting toxicity (DLT). A separate cohort of patients was then randomly assigned to erlotinib at either MTD or 150 mg daily with pharmacokinetics assessed at day 14. Erlotinib was continued until progression or intolerable toxicity. RESULTS: Four dose levels were evaluated in 22 patients: 200, 250, 300, and 350 mg. DLT was observed in one of six patients at 300 mg (rash) and two of five patients at 350 mg (acneiform dermatitis and fatigue/decreased Eastern Cooperative Oncology Group performance status). Thirty-five patients were randomly assigned to 150 mg or 300 mg. Common adverse events (all grades) were: skin toxicity (150 mg, 29%; 300 mg, 67%), diarrhea (150 mg, 18%; 300 mg, 50%), and fatigue (150 mg, 12%; 300 mg, 17%). Erlotinib exposure was dose-proportional within dose range tested. Median steady-state trough erlotinib plasma concentrations were 0.375 and 1.22 microg/mL for 150 mg and 300 mg, respectively. CONCLUSION: The MTD of erlotinib in NSCLC patients who smoke was 300 mg. Steady-state trough plasma concentrations and incidence of rash and diarrhea in smokers at 300 mg were similar to those in former or never smokers receiving 150 mg in previous studies. The potential benefit of higher erlotinib doses in current smokers warrants further evaluation.

Combination therapy with gefitinib and rofecoxib in patients with platinum-pretreated relapsed non small-cell lung cancer.

PURPOSE: In non-small-cell lung cancer (NSCLC), the epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) play major roles in tumorigenesis. This phase I/II study evaluated combined therapy with the EGFR tyrosine kinase inhibitor (TKI) gefitinib and the COX-2 inhibitor rofecoxib in platinum-pretreated, relapsed, metastatic NSCLC (n = 45). PATIENTS AND METHODS: Gefitinib 250 mg/d was combined with rofecoxib (dose escalated from 12.5 to 25 to 50 mg/d through three cohorts, each n = 6). Because the rofecoxib maximum-tolerated dose was not reached, the 50 mg/d cohort was expanded for efficacy evaluation (n = 33). RESULTS: Among the 42 assessable patients, there was one complete response (CR) and two partial responses (PRs) and 12 patients with stable disease (SD); disease control rate was 35.7% (95% CI, 21.6% to 52.0%). Median time to tumor progression was 55 days (95% CI, 47 to 70 days), and median survival was 144 days (95% CI, 103 to 190 days). In a pilot study, matrix-assisted laser desorption/ionization (MALDI) proteomics analysis of baseline serum samples could distinguish patients with an objective response from those with SD or progressive disease (PD), and those with disease control (CR, PR, and SD) from those with PD. The regimen was generally well tolerated, with predictable toxicities including skin rash and diarrhea. CONCLUSION: Gefitinib combined with rofecoxib provided disease control equivalent to that expected with single-agent gefitinib and was generally well tolerated. Baseline serum proteomics may help identify those patients most likely to benefit from EGFR TKIs.

DHA-paclitaxel (Taxoprexin) as first-line treatment in patients with stage IIIB or IV non-small cell lung cancer: report of a phase II open-label multicenter trial.

INTRODUCTION: This prospective, open-label, non-randomized, multi-institutional phase II study was undertaken to assess the antitumor activity and safety of docosahexaenoic acid-paclitaxel (Taxoprexin) as first-line treatment of patients with advanced non-small cell lung cancer. PATIENTS AND METHODS: Chemotherapy-naive patients were eligible if they had measurable stage IIIB or IV non-small cell lung cancer. Forty-four patients received docosahexaenoic acid-paclitaxel by intravenous infusion every 21 days. Two doses were evaluated: 1100 mg/m and 900 mg/m. Patients were monitored for toxicity and tumor response. RESULTS: Patients received between one and seven (median, two) cycles of treatment. Twenty-eight courses were administered in the cohort starting at 1100 mg/m and 109 courses at 900 mg/m. The starting dose was reduced to 900 mg/m because of toxicity in the first 13 patients. Subsequently, the most severe toxicity was neutropenia (grade III/IV in 68% of patients treated with 900 mg/m). Forty patients were eligible for assessment of tumor response. Two partial responses (4.5%) were documented, and a further 16 patients (36.4%) had stable disease based on an intent-to-treat analysis. The median duration of survival for all patients was 243 days (range, 154-359) and the 1-year survival rate was 35%. CONCLUSION: As a single-agent, docosahexaenoic acid-paclitaxel has little activity in patients with advanced non-small cell lung cancer, with 18 patients (40.1%) achieving either stable disease or a partial response after treatment. Despite the low objective response rate, treatment was associated with survival comparable to that seen with standard platinum-based combination chemotherapy. The dose-limiting toxicity was myelosuppression.

Regulation of serine racemase activity by amino acids.

The effects of various amino acids on the activity of serine racemase, purified from mouse brain, were examined. Those acting as inhibitors included compounds with electron withdrawing groups on the beta-carbon of alanine (beta-halo-alanines and L-serine-O-sulfate), which can act as enzyme-activated inhibitors, and compounds containing beta-SH groups (cysteine and homocysteine) which react with enzyme-bound pyridoxal phosphate to form thiazolidine derivatives. Glycine and a series of metabolites related to L-aspartic acid (L-aspartic acid, L-asparagine, and oxaloacetic acid) were also found to be competitive inhibitors of the racemase. The Ki values for glycine and aspartic acid inhibition were 0.15 and 1.9 mM, respectively, indicating that alterations in the concentrations of these amino acids might play a role in the regulation of D-serine synthesis.

Patient satisfaction and functional status after aseptic versus septic revision total knee arthroplasty using the PROSTALAC articulating spacer.

This study compared the functional results of an articulating antibiotic spacer for 2-stage revision knee arthroplasty for infection, to the functional results of aseptic revision. One hundred twenty-five patients who underwent revision of total knee arthroplasty for infection and aseptic loosening were identified. All of the patients with infection were treated with the PROSTALAC system (DePuy). At a minimum 2-year follow-up, WOMAC, Oxford-12, SF-12, patient satisfaction data, Harris Hip Score knee scores, and range of motion were assessed. The 2 cohorts (4 deaths in total, leaving 54 septic, 57 aseptic) were equivalent for age, gender, and comorbidity scores. At a mean of 41 months, none of the outcomes were significantly worse for the septic group, which had 2 recurrences of infection (4%). The satisfactory functional results of the PROSTALAC system may be related to the design features.

Can a new design of pneumatic compression device reduce variations in delivered therapy for the mechanical prophylaxis of thromboembolic disease after total hip arthroplasty?

BACKGROUND: Compression devices have been shown to prevent thromboembolic disease. However, the pressures generated may not be the same as the ones recommended by the manufacturer. The purpose of this study is to investigate a new sequential compression device with feedback to maintain optimal therapy, and to determine whether therapy is improved with this new device. PATIENTS AND METHOD: A series of 50 patients undergoing elective total hip arthroplasty at a major tertiary-care hospital with a special interest in joint replacement were enrolled prospectively. In addition to pharmacological prophylaxis for thromboembolic disease, all patients received compression from a modified device. Maximum pressures generated and the rate of pressure rise in each of the 3 compartments within the device sleeves were measured and the results compared with data from historical controls. RESULTS: We considered therapy to be ideal when in a particular compression cycle all chambers of both right and left sleeves reach within 10% of their target pressures at within 10% of their target pressure rise rates. The average patient received this ideal therapy 88% of the time that the new trial sequential compression device was operating. This represents a dramatic improvement over previous devices. CONCLUSIONS: The new device allows dramatically improved pressures within the device because of a feedback loop that allows dynamic control of each chamber's pressure. Improved consistency of delivery should make it easier to accurately assess the true benefits of mechanical prophylaxis with a sequential compression device.

A cost-effectiveness analysis of docetaxel in the second-line treatment of non-small cell lung cancer.

BACKGROUND: Whilst lung cancer is the most common form of cancer in England and Wales (annual incidence rate of 50 per 100,000) it does not always receive the policy attention accorded to other types of cancer, such as breast and colorectal. Nevertheless, the burden of lung cancer is significant and the UK NHS Plan for cancer has set out the government's commitment to improving all cancer services. The question faced by the NHS is which interventions are most cost effective in implementing this plan. OBJECTIVE: To develop a model to assess the economics of second-line treatment of non-small cell lung cancer (NSCLC) from the perspective of the UK NHS, based on the resources and outcomes from the pivotal clinical study comparing docetaxel 75 mg/m(2) with best supportive care (BSC). METHODS: The area under the survival curve for each treatment was analysed and the difference in mean survival between the docetaxel group and the BSC group was calculated as 3.82 months. Measurable incremental costs for the docetaxel group were largely driven by drug acquisition and administration. These cost drivers, as well as toxicity treatment costs and cost offsets, were varied in the sensitivity analysis. Although the overall timeframe for the model was 2 years, discounting was not applied as the resources and benefits of docetaxel use in this setting are realised relatively immediately. RESULTS: The base case cost-effectiveness analysis (mean values) reported a cost per life-year gained of 13,863 pounds sterling for docetaxel 75 mg/m(2) (year 2000/2001 values). Sensitivity analysis showed that the number of treatment cycles per patient, which affected total treatment cost, had most influence on the cost per life-year gained in the base case scenario. Using the 95% confidence intervals around the mean number of treatment cycles, the base case cost per life-year gained varied from 10,985 pounds sterling to 16,738 pounds sterling. Using the 95% confidence intervals around the mean difference in survival, to represent best and worst case scenarios, the cost per life-year saved ranged from 10,020 pounds sterling to 32,781 pounds sterling . CONCLUSION: This model suggests, with its underlying assumptions and data, docetaxel 75 mg/m(2) in 3-weekly cycles is a cost-effective second-line treatment, from the perspective of the NHS, for pretreated NSCLC in terms of survival gains made for a reasonable increase in costs.