A phase II trial of bevacizumab and rucaparib in recurrent carcinoma of the cervix or endometrium.

OBJECTIVE: The aim of this study was to examine the tolerability and efficacy of combination bevacizumab rucaparib therapy in patients with recurrent cervical or endometrial cancer. PATIENTS & METHODS: Thirty-three patients with recurrent cervical or endometrial cancer were enrolled. Patients were required to have tumor progression after first line treatment for metastatic, or recurrent disease. Rucaparib was given at 600 mg BID twice daily for each 21-day cycle. Bevacizumab was given at 15 mg/kg on day 1 of each 21-day cycle. The primary endpoint was efficacy as determined by objective response rate or 6-month progression free survival. RESULTS: Of the 33 patients enrolled, 28 were evaluable. Patients with endometrial cancer had a response rate of 17% while patients with cervical cancer had a response rate of 14%. Median progression free survival was 3.8 months (95% C·I 2.5 to 5.7 months), and median overall survival was 10.1 months (95% C·I 7.0 to 15.1 months). Patients with ARID1A mutations displayed a better response rate (33%) and 6-month progression free survival (PFS6) rate (67%) than the entire study population. Observed toxicity was similar to that of previous studies with bevacizumab and rucaparib. CONCLUSIONS: The combination of bevacizumab with rucaparib did not show significantly increased anti-tumor activity in all patients with recurrent cervical or endometrial cancer. However, patients with ARID1A mutations had a higher response rate and PFS6 suggesting this subgroup may benefit from the combination of bevacizumab and rucaparib. Further study is needed to confirm this observation. No new safety signals were seen.

Patupilone in patients with pretreated metastatic/locally recurrent colorectal cancer: results of the Phase II CINATRA trial.

BACKGROUND: Phase I trials of the microtubule stabilising agent patupilone showed encouraging tumour control and response rates in patients with metastatic colorectal cancer. METHODS: Patients with metastatic or locally recurrent colorectal cancer who had progressed following treatment with oxaliplatin, irinotecan and fluoropyrimidines were treated with patupilone (8 mg/m(2) IV every 3 weeks) in combination with dexamethasone or prednisolone. RESULTS: The trial was closed early after 29 patients had been enrolled due to concerns about toxicity. 20 patients (71.4 %) experienced at least one grade 3-5 toxicity, most commonly diarrhoea (14 patients), dehydration (7 patients) and lethargy (6 patients). The 12 week progression-free survival rate was 16.7 % (95 % CI 6.1 %-36.5 %) in the 24 patients with a 12 week scan available or who had died prior to the 12 week scan. No complete or partial responses were seen by 12 weeks. The median progression-free survival was 2.6 months (95 % CI 2.3-2.9) and median overall survival was 6.1 months (95 % CI 3.7-8.4). CONCLUSION: Patupilone given at a dose of 8 mg/m(2) IV over 20 min every 3 weeks was associated with high levels of toxicity and no significant evidence of efficacy in patients with pre-treated colorectal cancer.

The human pharmacokinetics of oral ingestion of glucosamine and chondroitin sulfate taken separately or in combination.

OBJECTIVE: As part of the National Institutes of Health (NIH)-sponsored Glucosamine/Chondroitin sulfate Arthritis Intervention Trial (GAIT) our objective here was to examine (1) the pharmacokinetics (PK) of glucosamine (GlcN) and chondroitin sulfate (CS) when taken separately or in combination as a single dose in normal individuals (n=29) and (2) the PK of GlcN and CS when taken as a single dose after 3 months daily dosing with GlcN, CS or GlcN+CS, in patients with symptomatic knee pain (n=28). METHODS: The concentration of GlcN in the circulation was determined by established fluorophore-assisted carbohydrate electrophoresis (FACE) methods. The hydrodynamic size and disaccharide composition of CS chains in the circulation and dosage samples was determined by Superose 6 chromatography and FACE. RESULTS: We show that circulating levels of CS in human plasma are about 20 microg/ml. Most significantly, the endogenous concentration and CS disaccharide composition were not detectably altered by ingestion of CS, when the CS was taken alone or in combination with GlcN. On the other hand, the Cmax (single-dose study) and AUC values (multiple-dose study) for ingested GlcN were significantly reduced by combination dosing with CS, relative to GlcN dosing alone. CONCLUSIONS: We conclude that pain relief perceived following ingestion of CS probably does not depend on simultaneous or prior intake of GlcN. Further, such effects on joint pain, if present, probably do not result from ingested CS reaching the joint space but may result from changes in cellular activities in the gut lining or in the liver, where concentrations of ingested CS, or its breakdown products, could be substantially elevated following oral ingestion. Moreover, since combined dosing of GlcN with CS was found to reduce the plasma levels seen with GlcN dosing alone, any improved pain relief by combination dosing cannot be explained by higher circulating concentrations of GlcN.

Performance of a non-fluoroscopically assisted substitute for the Lyon schuss knee radiograph: quality and reproducibility of positioning and sensitivity to joint space narrowing in osteoarthritic knees.

OBJECTIVE: This study evaluated the longitudinal performance of a modified Lyon schuss (LS) knee examination in the detection of radiographic joint space narrowing (JSN) in knees with osteoarthritis (OA). The modified LS exam entails two to four iterative acquisitions with empirically adjusted angulation of the X-ray beam to achieve superimposition of the anterior and posterior margins of the medial tibial plateau (MTP), a marker of parallel radioanatomic alignment that the original LS exam achieves with fluoroscopically guided beam angulation. METHODS: Seventy-four obese women with symptomatic knee OA underwent LS and fixed-flexion (FF, caudal 10 degrees beam angulation) X-ray exams at baseline and 1 year later. For 47 subjects, beam angulation for both LS exams was guided by fluoroscopy. For 27 subjects, the modified LS exam was performed at one or both times. Modified and original LS procedures were evaluated relative to concurrent FF radiographs with respect to the inter-margin distance (IMD) at the MTP midpoint (quality and reproducibility of alignment) and sensitivity to JSN. RESULTS: Compared to FF radiographs, modified LS radiographs afforded a smaller mean IMD at baseline (0.89 vs 2.06 mm, P=0.002), more reproducible IMD (mean change=0.49 vs 0.91 mm, P=0.007) and more rapid JSN (mean=0.25 vs 0.02 mm/yr, P=0.005). These differences paralleled those observed between original LS and FF procedures with respect to baseline alignment (0.96 vs 1.94 mm, P<0.001), reproducibility of alignment (0.49 vs 1.00 mm, P<0.001) and sensitivity to JSN (0.16 vs -0.01 mm/yr, P=0.007). CONCLUSION: In clinical centers where the absence of fluoroscopy equipment precludes use of the original LS protocol, a modified procedure employing iterative, empirical adjustment of the beam angle to achieve parallel radioanatomic alignment with the MTP affords a degree of superiority over the FF protocol with respect to quality and reproducibility of positioning and sensitivity to JSN in OA knees similar to that of the original.

Head-to-head comparison of the Lyon Schuss and fixed flexion radiographic techniques. Long-term reproducibility in normal knees and sensitivity to change in osteoarthritic knees.

OBJECTIVE: The Lyon Schuss (LS) and fixed flexion (FF) views of the knee are superior to a conventional standing anteroposterior view in evaluating joint space narrowing (JSN) in osteoarthritis (OA). Both position the knee identically but only the LS aligns the medial tibial plateau (MTP) with the x-ray beam fluoroscopically. The present study provides the first head-to-head comparison of the LS and FF views. METHODS: At baseline and 12 months, 62 OA and 99 control knees were imaged twice on the same day with LS and FF views. Minimum joint space width (mJSW) was measured by computer and MTP alignment was assessed from the distance between anterior and posterior margins of the MTP (intermargin distance, IMD). Reproducibility of measurements of mJSW and sensitivity to change were evaluated. RESULTS: In normal knees, JSW did not vary over 12 months with either view. In OA knees, 12-month mJSN was 0.22 (0.43) mm with the LS view and -0.01 (0.46) mm with the FF view (p = 0.0002 and p = 0.92, respectively). Mean IMD was only half as large in LS as in FF views (0.9 (0.5) mm vs 1.9 (1.2) mm, p<0.0001). CONCLUSIONS: LS and FF radiographs offer similar reproducibility in JSW measurement. However, presumably due to its superiority in aligning the MTP, the LS view is much more sensitive to JSN in OA knees.

Management of middle ear hemangiomas.

Hemangioma rarely presents as an isolated middle ear lesion. Because congenital hemangiomas usually regress spontaneously, surgical excision is not always necessary. However, a hemangioma in the middle ear can be complicated by infection and hearing impairment. We present 2 cases to show contrasting management strategies, both with successful outcomes. Two children who presented with unilateral otitis media were found to have concomitant mesotympanic hemangiomas on examination. The first child was asymptomatic and subsequently had an incisional biopsy, confirming the suspected diagnosis. The residual tumor then involuted over the following year. The second child, however, developed chronic otitis media refractory to medical therapy and required surgical removal of the entire hemangioma. Once a tissue diagnosis is made, middle ear hemangiomas can be managed expectantly (ie, wait for spontaneous resolution) or surgically. If growth of a middle ear hemangioma appears to be causing complications refractory to conservative therapy, then early surgical excision may be indicated.

Potential for areawide integrated management of Mediterranean fruit fly (Diptera: Tephritidae) with a braconid parasitoid and a novel bait spray.

The braconid wasp, Fopius arisanus (Sonan), a biological control agent for Mediterranean fruit fly, Ceratitis capitata (Wiedemann), was studied in coffee, Coffea arabica L. Fopius arisanus, comprised 79.3% of the total parasitoids (7,014) recovered from fruits collected at three small coffee farms. Data from seasonal host/parasitoid studies at a large coffee plantation also suggested that the most effective natural enemy of C. capitata in coffee may now reside in Hawaii. The original parasitoids introduced into Hawaii for C. capitata control (Diachasmimorpha tryoni (Cameron), Tetrastichus giffardianus Silvestri, and Dirhinus giffardii Silvestri) are now rare. Abundance of F. arisanus with respect to other parasitoids collected was influenced by elevation (274, 457, 610 m). Fopius arisanus was the dominant parasitoid at all three elevations, Diachasmimorpha longicaudata (Ashmead) occurred consistently, and T. giffardianus was abundant only at low elevation. The impacts on C. capitata and F. arisanus populations of bait sprays containing malathion, spinosad, or phloxine B applied to coffee were also evaluated. All three bait sprays suppressed C. capitata populations. Spinosad and phloxine B bait sprays appeared less harmful to the wasp than malathion. Fopius arisanus offers the potential for areawide management of C. capitata that includes biological control and integration with more environmentally safe chemical controls such as spinosad and phloxine B bait sprays.

Glomus tympanicum and glomus jugulare tumors.

The ideal management of most paragangliomas is complete surgical excision. Because of technical advances, issues of resectability have given way to issues of functional outcome and postsurgical quality of life. This article reviews the surgical strategy for craniocervical paragangliomas. Intracranial extension, defect reconstruction, and cranial nerve rehabilitation are addressed.

Lateral skull base surgery for glomus tumors: long-term control.

OBJECTIVE: The age of modern microsurgery has made resection of glomus tumors with extensive skull base involvement possible. Resection of extensive lesions is not without risk of major complication or new cranial nerve deficit. Because glomus tumors are rare and slow growing, data reflecting recurrence risk after resection using modern skull base techniques are lacking. These factors complicate the accurate definition of efficacy of surgical resection and its functional cost. The object of this review is to determine the current incidence of major complications, the surgical cranial nerve deficit, the long-term control rate, and the recurrence risk in patients undergoing surgical resection of glomus jugulare tumors. STUDY DESIGN: Retrospective case review. SETTING: Private practice tertiary referral center. PATIENTS AND INTERVENTIONS: One hundred seventy-six patients with glomus tumors underwent 182 lateral skull base resections between 1972 and 1998. MAIN OUTCOME MEASURES: Major complications, tumor recurrence, postoperative functional capacity, and factors affecting the incidence of each were assessed. RESULTS: Complete surgical control was achieved in 85% of cases. There were nine cases of recurrence, for a recurrent rate of 5.5% (9/164). Cerebrospinal fluid leakage occurred in 4.5% of cases with intracranial extension. New deficits for cranial nerves IX, X, XI, and XII occurred in 39%, 25%, 26%, and 21% of cases, respectively. Satisfactory functional recovery was achieved in an overwhelming majority of cases. The mortality rate was 2.7% (5/182). CONCLUSIONS: Surgical resection of glomus tumors is established as an effective technique with good functional outcomes and long-term control.

Long-term control of surgically treated glomus tympanicum tumors.

OBJECTIVE: The glomus tumor is an enigmatic middle ear neoplasm commonly delayed in diagnosis. Frequently grouped with its skull base counterpart, surgery and radiation are often recommended as therapy. The objective of this report is to highlight the diagnosis and surgical treatment of this neoplasm in a large series. Tumor control in the long term is defined. STUDY DESIGN: Retrospective case review. SETTING: Private practice-tertiary referral center. PATIENTS: All patients surgically treated for glomus tympanicum tumors from May 25, 1972 to July 3, 1998 (N = 80). INTERVENTIONS: Surgical excision of glomus tympanicum tumors. MAIN OUTCOME MEASURE: Total tumor control in the long term. RESULTS: Surgical treatment resulted in long-term tumor control for the vast majority of the patients studied. CONCLUSIONS: Surgery provides excellent control of glomus tympanicum tumors. It is safe and well tolerated, with minimal morbidity.

Methods for marking insects: current techniques and future prospects.

Tracking the movement of insects in their natural habitat is essential for understanding their basic biology, demography, and ethology. A wide variety of markers have been used to assess insect population dynamics, dispersal, territoriality, feeding behavior, trophic-level interactions, and other ecological interactions. The ideal marker should persist without inhibiting the insect's "normal" biology. Furthermore, the marker should be environmentally safe, cost-effective, and easy to use. In this article, we review the current state of knowledge regarding insect marking, document the advantages and limitations of each marking technique, and discuss advances made in marking insects over the past decade.

Immunomodulating drugs in the management of psoriatic arthritis.

Psoriatic arthritis is a chronic inflammatory arthropathy which can be distinguished from rheumatoid arthritis on the basis of differing patient demographics, genetic predisposition, histopathologic change, radiographic appearance, and clinical course. The cause of psoriatic arthritis remains unknown but appears to be autoimmune in nature as its pathogenesis is characterized by persistent synovial inflammation resulting in damage to the articular cartilage and osteolysis. Compared with rheumatoid arthritis, distinct lymphocyte subpopulations and pro-inflammatory cytokine levels appear to be present within the joint but the importance and therapeutic implications of these differences is uncertain. The clinical presentation of psoriatic arthritis is variable and overlapping patterns of joint involvement affecting both the appendicular and axial skeleton are seen. For patients with mild synovial disease and a favorable prognosis, the use of a nonsteroidal anti-inflammatory drug for symptomatic relief is often sufficient. However, the destructive potential of psoriatic arthritis is increasingly recognized and patients with more synovial disease and radiographic change at presentation appear to be at risk for greater morbidity and increased mortality. Immunomodulating therapy has the potential to suppress joint inflammation and preserve functional capacity but true disease modification has yet to be shown. The toxicity associated with presently available immunomodulatory agents makes careful patient selection and conscientious monitoring essential. The efficacy of methotrexate and sulfasalazine in patients with psoriatic arthritis is well defined while more anecdotal reports of benefit exist for other agents including the antimalarials, azathioprine, colchicine, cyclosporine, and the retinoids. For all treatment regimens, the magnitude of clinical improvement demonstrated to date has been rather small and quite subjective in character with few controlled studies of adequate size and duration having been reported. Emerging biologic therapies, such as those which target tumor necrosis factor, will hopefully provide future treatment options with greater efficacy and improved safety for patients with psoriatic arthritis.

Therapeutic potential of COX-2 inhibitors in arthritis.

Arthritis and related musculoskeletal conditions occur with great frequency in the population world wide, causing significant morbidity and, in some instances, increased mortality. Affecting both the young and the old, 15% of the population in the US was estimated in 1995 to have some form of arthritis with an increase to 18% projected by the year 2020 [1]. The economic impact of arthritis and related disorders in the US alone was estimated to be 194.4 billion US dollars in 1992 and future costs are virtually certain to increase given the chronic nature of these diseases, their expanding prevalence and the considerable expense associated with newer therapies [2]. With no cure presently available, the aim of current treatment is to reduce inflammation, ameliorate symptoms and improve functional capacity. Non-steroidal anti-inflammatory drugs (NSAIDs), which suppress the formation of pro-inflammatory prostaglandins by antagonising the action of cyclooxygenase (COX), have been the mainstay of arthritis treatment for hundreds, if not, thousands of years. The clinical use of NSAIDs, however, has long been associated with significant toxicity. The recognition of two COX isoforms, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), both suppressed by traditional NSAIDs, has led to an expanded hypothesis of NSAID action which consists of two postulates, namely, the efficacy of NSAIDs in the treatment of arthritis is due to the suppression of COX-2, while much of the toxicity associated with non-selective NSAIDs is the consequence of COX-1 suppression. The emergence of agents which selectively inhibit COX-2 has made it possible to clinically evaluate the validity of each of these postulates. In this report, the published experience with selective COX-2 inhibitors in the treatment of mechanical and inflammatory arthropathies is reviewed to examine the premise that isolated COX-2 suppression is comparable in efficacy to the dual COX-1/COX-2 suppression produced by non-selective NSAIDs.

Comparison of postoperative headache after retrosigmoid approach: vestibular nerve section versus vestibular schwannoma resection.

OBJECTIVE: To evaluate intradural drilling as a mechanism for the development of postoperative headache after retrosigmoid craniectomy. STUDY DESIGN: A retrospective review of charts was performed on 565 retrosigmoid approaches to the cerebellopontine angle performed between January 1980 and January 1998. Patients treated with retrosigmoid vestibular nerve section without intradural drilling were compared with patients who underwent retrosigmoid removal of vestibular schwannomas in which intradural drilling was performed for exposure of the internal auditory canal. SETTING: Private practice tertiary referral center. PATIENTS: Consecutive patients undergoing retrosigmoid approach between January 1980 and January 1998 were reviewed. MAIN OUTCOME MEASURES: The presence of headache, duration of headache, and severity of headache were noted. RESULTS: In this large series, 54% of patients experienced headaches after vestibular schwannoma removal, and 5% of patients experienced headaches after vestibular nerve section (p < 0.01, chi-square). CONCLUSIONS: Postoperative headache is not a characteristic of retrosigmoid craniectomy in the absence of intradural drilling. Intradural drilling is a probable cause of headache after the retrosigmoid approach. Cranioplasty is not necessary to prevent a high incidence of postoperative headache after retrosigmoid approach.

Small for gestational age: a new insight?

Acidosis reduces the ability of nitric oxide synthase to generate nitric oxide (NO) from L-arginine (L-arg), even if dietary intake or circulating plasma levels of L-arg are normal. During systemic acidemia, therefore, vascular perfusion in one or more organs may be compromised. Arginine is also a powerful anabolic amino acid. If dietary sources of L-arg are lower than normal, or if the production of NO is reduced even without frank acidemia, then vascular perfusion, and growth, and tissue repair are likely to be compromised. Two conditions in which acidemia is reported to occur, namely slow fetal growth in utero (acidemia is severe) and loss of bone and muscle in microgravity (acidemia is modest), are compared with respect to the accompanying alteration in the balance between acidemia and NO production.

Short-arm (1.9 m) +2.2 Gz acceleration: isotonic exercise load-O2 uptake relationship.

BACKGROUND: The deconditioning syndrome from prolonged bed rest (BR) or spaceflight includes decreases in maximal oxygen uptake (VO2max), muscular strength and endurance, and orthostatic tolerance. In addition to exercise training as a countermeasure, +Gz (head-to-foot) acceleration training on 1.8-2.0 m centrifuges can ameliorate the orthostatic and acceleration intolerances induced by BR and immersion deconditioning. PURPOSE: Study A was designed to determine the magnitude and linearity of the heart rate (HR) response to human-powered centrifuge (HPC) acceleration with supine exercise vs. passive (no exercise) acceleration. Study B was designed to test the hypothesis that moderate +Gz acceleration during exercise will not affect the respective normal linear relationships between exercise load and VO2max, HR, and pulmonary ventilation (VEBTPS). Study C: To determine if these physiological responses from the HPC runs (exercise + on-platform acceleration) will be similar to those from the exercise + off-platform acceleration responses. METHODS: In Study A, four men and two women (31-62 yr) were tested supine during exercise + acceleration and only passive acceleration at 100% [maximal acceleration (rpm) = Amax] and at 25%, 50%, and 75% of Amax. In Studies B and C, seven men (33+/-SD 7 yr) exercised supine on the HPC that has two opposing on-platform exercise stations. A VO2max test and submaximal exercise runs occurred under three conditions: (EX) exercise (on-platform cycle at 42%, 61%, 89% and 100% VO2max) with no acceleration; (HPC) exercise + acceleration via the chain drive at 25%,50%, and 100% Gzmax (35%, 72% and 100% VO2max); and (EXA) exercise (on-platform cycle at 42%, 61%, 89%, and 100% VO2max) with acceleration performed via the off-platform cycle operator at +2.2+/-0.2 Gz [50% of max (rpm) G]. RESULTS: Study A: Mean (+/-SE) Amax was 43.7+/-1.3 rpm (mean = +3.9+/-0.2, range = 3.3 to 4.9 Gz). Amax run time for exercise +acceleration was 50-70 s, and 40-70 s for passive acceleration. Regression of X HR on Gz levels indicated explained variances (r2) of 0.88 (exercise) and 0.96 (passive). The mean exercise HR of 107+/-4 (25%), to 189+/-13 (100%) bpm were 43-50 bpm higher (p < 0.05) than comparable passive HR of 64+/-2 to 142+/-22 bpm, respectively. Study B: There were no significant differences in VO2, HR or VEBTPS at the submaximal or maximal levels between the EX and EXA runs. Mean (+/-SE) VO2max for EX was 2.86+/-0.12 L x min(-1)(35+/-2 ml x min(-1) x kg(-1)) and for EXA was 3.09+/-0.14 L x min(-1) (37+/-2 ml-min(-1) x kg(-1)). Study C: There were no significant differences in the essentially linear relationships between the HPC and EXA data for VO2 (p = 0.45), HR (p < 0.08), VEBTPS (p = 0.28), or the RE (p = 0.15) when the exercise load was % VO2max. CONCLUSION: Addition of + 2.2 Gz acceleration does not significantly influence levels of oxygen uptake, heart rate, or pulmonary ventilation during submaximal or maximal cycle ergometer leg exercise on a short-arm centrifuge.

Basic therapy for rheumatoid arthritis: nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are often the initial treatment for rheumatoid arthritis. NSAID-induced inhibition of cyclooxygenase-2 (COX2) and cyclooxygenase-1 appears to correlate with clinical efficacy and toxicity, respectively. Newer NSAIDs with greater COX2 selectivity offer the promise of less toxic therapy.

The facial nerve. Current trends in diagnosis, treatment, and rehabilitation.

Facial paralysis is a potentially devastating disorder with numerous implications. Multiple entities must be considered in its etiology, and recent advances in microbiology, radiographic imaging, electrodiagnostic testing, and microsurgery have provided great insight into the pathophysiology, diagnosis, treatment, and rehabilitation of the facial nerve. Recent DNA PCR testing has shed new insight into the potential cause for Bell's palsy. This article focuses on the evaluation, differential diagnosis, medical treatment, and rehabilitation of facial nerve pathology with primary emphasis on facial paralysis. Surgical management is also discussed, including reanimation of the paralyzed face.

Malignant glomus tumors.

OBJECTIVES/HYPOTHESIS: To ascertain the incidence of malignancy in a large glomus and skull base series and to compare the clinical course of such patients with those who do not have malignant skull base lesions. STUDY DESIGN: Retrospective review of all skull base surgery cases treated at the Otology Group between 1970 and 1995. RESULTS: In a series of 175 jugulotympanic glomus tumors, 9 cases (5.1%) were identified. The surgery required for their extirpation is more extensive than nonmalignant glomus tumors. Attendant deficits and mortality from these procedures are accordingly greater. Five-year survival in this limited population was 72%. Prolonged periods of survival are possible with distant metastases. CONCLUSIONS: This rate of malignancy should advocate against a watchful, waiting approach. Radiation therapy is not advocated as a primary modality for this type of tumor, as it may lead to recurrence/persistence with either subsequent malignant degeneration and metastases or local recurrence.

A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate.

BACKGROUND: Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease. This study was undertaken to determine whether the addition of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein (TNFR:Fc), to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate. METHODS: In a 24-week, double-blind trial, we randomly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week (or as low as 10 mg per week for patients unable to tolerate higher doses) to receive either etanercept (25 mg) or placebo subcutaneously twice weekly while continuing to receive methotrexate. The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity (ACR 20) at 24 weeks. RESULTS: The addition of etanercept to methotrexate therapy resulted in rapid and sustained improvement. At 24 weeks, 71 percent of the patients receiving etanercept plus methotrexate and 27 percent of those receiving placebo plus methotrexate met the ACR 20 criteria (P<0.001); 39 percent of the patients receiving etanercept plus methotrexate and 3 percent of those receiving placebo plus methotrexate met the ACR 50 criteria (for a 50 percent improvement) (P<0.001). Patients receiving etanercept plus methotrexate had significantly better outcomes according to all measures of disease activity. The only adverse events associated with etanercept were mild injection-site reactions, and no patient withdrew from the study because of adverse events associated with etanercept. CONCLUSIONS: In patients with persistently active rheumatoid arthritis, the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than methotrexate alone.