Differentiation of glioblastoma multiforme and single brain metastasis by peak height and percentage of signal intensity recovery derived from dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging.

BACKGROUND AND PURPOSE: Glioblastoma multiforme (GBM) and single brain metastasis (MET) are the 2 most common malignant brain tumors that can appear similar on anatomic imaging but require vastly different treatment strategy. The purpose of our study was to determine whether the peak height and the percentage of signal intensity recovery derived from dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion MR imaging could differentiate GBM and MET. MATERIALS AND METHODS: Forty-three patients with histopathologic diagnosis of GBM (n=27) or MET (n=16) underwent DSC perfusion MR imaging in addition to anatomic MR imaging before surgery. Regions of interest were drawn around the nonenhancing peritumoral T2 lesion (PTL) and the contrast-enhancing lesion (CEL). T2* signal intensity-time curves acquired during the first pass of gadolinium contrast material were converted to the changes in relaxation rate to yield T2* relaxivity (Delta R2*) curve. The peak height of maximal signal intensity drop and the percentage of signal intensity recovery at the end of first pass were measured for each voxel in the PTL and CEL regions of the tumor. RESULTS: The average peak height for the PTL was significantly higher (P=.04) in GBM than in MET. The average percentage of signal intensity recovery was significantly reduced in PTL (78.4% versus 82.8%; P=.02) and in CEL (62.5% versus 80.9%, P<.01) regions of MET compared with those regions in the GBM group. CONCLUSIONS: The findings of our study show that the peak height and the percentage of signal intensity recovery derived from the Delta R2* curve of DSC perfusion MR imaging can differentiate GBM and MET.

Protease pretreatment increases the efficacy of adenovirus-mediated gene therapy for the treatment of an experimental glioblastoma model.

Effective virus-mediated gene therapy for cancer will be facilitated by procedures that enhance the low level of gene transfer mediated by replication-deficient, recombinant viral vectors. We found recently that protease pretreatment of solid tumors is a useful strategy for enhancing virus-mediated gene transduction in vivo. In this study, we examined the potential of protease pretreatment to improve the efficacy of a gene therapy strategy for prodrug activation that depends on infection with a recombinant adenovirus encoding herpes simplex virus thymidine kinase (Ad-HSV-tk). Trypsin or a dissolved mixture of collagenase/dispase was inoculated into xenografts derived from the human glioblastoma multiforme-derived cell lines, U87 or U251. Ad-HSV-tk was administered 24 h after protease pretreatment, and animals were then treated for 10 days with ganciclovir (GCV). We found that protease pretreatment increased the efficacy of adenovirus mediated HSV-tk/GCV gene therapy in these experimental tumor models. Mice receiving Ad-HSV-tk/GCV after protease pretreatment demonstrated a significantly greater regression of tumors compared with those treated with Ad-HSV-tk/GCV alone. No adverse effects of protease pretreatment were observed. No signs of metastasis were seen either by histological inspection of lymph nodes or by a PCR-based analysis of selected mouse tissues to detect human tumor cells. Our findings indicate that protease pretreatment may be a useful strategy to enhance the efficacy of virus-mediated cancer gene therapy.

Apoptosis in the subependyma of young adult rats after single and fractionated doses of X-rays.

Ionizing radiation is commonly used in the treatment of brain tumors but can cause significant damage to surrounding normal brain. The pathogenesis of this damage is uncertain, and understanding the response of potential target cell populations may provide information useful for developing strategies to optimize therapeutic irradiation. In the mammalian forebrain, the subependyma is a mitotically active area that is a source of oligodendrocytes and astrocytes, and it has been hypothesized that depletion of cells from this region could play a role in radiation-induced white matter injury. Using a distinct morphological pattern of nuclear fragmentation and an immunohistochemical method to specifically label the 3'-hydroxyl termini of DNA strand breaks (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling), we quantified apoptosis in the subependyma in the young adult rat brain after single and fractionated doses of X-rays. Significant increases in apoptotic index (percentage of cells showing apoptosis) were detected 3 h after irradiation, and the peak apoptotic index was detected at 6 h. Six h after irradiation, the dose response for apoptosis was characterized by a steep increase in apoptotic index between 0.5 and 2.0 Gy and a plateau from 2-30 Gy. The fraction of cells susceptible to apoptosis was estimated to be about 40%, and treatment of rats with cycloheximide inhibited apoptosis. When daily 1.5-Gy fractions of X-rays were administered, the first three fractions were equally effective at decreasing the cell population via apoptosis. There was no additional apoptosis or decrease in cellularity in spite of one to four additional doses of X-rays. Those data suggested some input of cells into the subependymal population during fractionated treatment, and subsequent studies showed that there was a significant rise in 5-bromo-2' deoxyuridine labeling index 2-3 days after irradiation, indicating increased cellular proliferation. The proliferative response after depletion of cells via apoptosis may represent the recruitment of a relatively quiescent stem cell population. It is possible that the radiation response of subependymal stem cells and not the apoptotic-sensitive population per se are critical elements in the response of the brain to radiation injury.

Genetic subgroups of anaplastic astrocytomas correlate with patient age and survival.

Astrocytomas are brain tumors with variable responses to radiation and chemotherapy. Tumor grade and patient age are important prognostic factors but do not account for the variability in clinical outcome. We hypothesized that genetic subgroups play a role in the outcome of grade III astrocytomas and studied 80 grade III astrocytomas by comparative genomic hybridization. Some chromosomal aberrations (+7p/q, -9p, -10q, -13q, +19q) were related to aberrations that are frequent in grade IV astrocytoma, whereas others (+10p, -11q, +11p, -Xq) were more frequent in grade III astrocytoma. +7p, +19 and -4q were more frequent in tumors from older patients while -11p was more frequent in tumors from younger patients. Finally, gains of 7p and 7q were associated with shorter patient survival, independent of age. Our results indicate that genetic events underlie the well-known effects of age on survival in grade III astrocytoma and demonstrate the importance of molecular classification in astrocytic tumors.

Prognostic factors for radioimmunotherapy in patients with B-lymphocytic malignancies.

The Ann Arbor staging classification has proven less useful in nonHodgkin's lymphoma, because this malignancy is inherently a multifocal disorder. Since 1985, 57 adult patients with advanced B-lymphocytic malignancies that progressed despite standard therapy entered into one of three different therapy trials using radiolabeled Lym-1 antibody. Tumor regression in 31 (54%) of these patients fulfilled conventional requirements for an oncological response to the therapy. To define the role of radioimmunotherapy in B-lymphocytic malignancies better and to find opportunities for improving its therapeutic efficacy, the records of these patients were reviewed to assess the significance of various parameters as prognostic indicators. Twenty-one pretherapy characteristics were evaluated, including age at diagnosis, age at study entry, sex, Karnofsky performance status, prior chemotherapy and radiation therapy, interval since diagnosis, histology, constitutional B symptoms, extranodal malignancy (excluding marrow), bone marrow malignancy, tumor bulk, and circulating malignant cells; blood tests included lymphocyte, granulocyte, platelet, hematocrit, serum lactate dehydrogenase (LDH), interleukin 2 receptor, and human antimouse antibody levels. In the multivariate analysis, LDH and Karnofsky performance status were the parameters that best predicted survival, complete and partial remission, and time to progression; interleukin 2 receptor and LDH best predicted complete remission. These prognostic factors for radioimmunotherapy outcome are consistent with the pretherapy characteristics observed to be significant for chemotherapy.

Analysis of complex relationships between age, p53, epidermal growth factor receptor, and survival in glioblastoma patients.

Glioblastoma multiforme (GBM) carries a dismal prognosis. However, a range of survival times exists, and parameters that define prognostic groups may help to optimize treatment. To identify such prognostic groups, we analyzed tumor tissue from 110 cases of newly diagnosed GBM from two clinical protocols. Similar to other studies, we found no association of epidermal growth factor receptor (EGFR) overexpression (as assessed by immunohistochemistry), p53 immunopositivity, or p53 mutation with survival in the entire sample. However, EGFR overexpression showed trends toward worse prognosis in patients younger than the median age, but better prognosis in patients older than the median age. This interaction of EGFR with age group was statistically significant and led us to focus our further analyses on the younger patients. In this group, a statistically significant association of EGFR overexpression with worse survival was identified in the p53-negative but not p53-positive tumors. We found a similar result after screening these cases for mutations in p53: EGFR overexpression was negatively associated with survival only in the p53 wild-type cases. To confirm this unexpected result, this finding was reproduced in a validation sample of an additional 42 tumors from younger patients on the same two clinical protocols. This complex relationship between EGFR and p53 in younger patients remained in a multivariate analysis that incorporated additional prognostic variables. The results suggest that analysis of prognostic markers in GBM is complex, and maximal information may require analysis of subgroups based on age and the status of specific markers such as p53. In addition, they suggest a specific group of patients on which to focus promising therapies targeting EGFR.

Yttrium-90 chimeric L6 therapy of human breast cancer in nude mice and apoptosis-related messenger RNA expression.

Radioimmunotherapy (RIT) in breast cancer patients using I-131-chimeric L6 (ChL6) and in human breast cancer xenografts in nude mice using Y-90-1,4,7,10-tetraazacylododecant N,N',N",N"'-tetraacetic acid-peptide ChL6 (Y-90-ChL6) has shown promise. Tumor cell response to low-dose rate (5-25 rads/h) irradiation from Y-90-ChL6 RIT, therefore, was correlated with levels of tumor cell mRNA for selected genes linked to programmed cell death (apoptosis). Three groups of 10-16 mice with 1-2 HBT 3477 xenograft tumors were treated with 100, 150, or 250 microCi Y-90-ChL6. Three tumors were taken before and two tumors each were taken 3, 6, and 24 h after injection of 150 microCi Y-90-ChL6. Tumor expression of mRNA was amplified by PCR for p53, PIC1, c-myc, and transforming growth factor-beta 1; quantitated; and standardized to N-ras. Tumors received radiation doses of 2000, 3000, and 5000 rads, respectively, for the groups of mice that received 100, 150, and 250 microCi Y-90-ChL6, and tumor regression occurred in each group, with mean tumor volumes decreased by 10, 50, and 95% at nadir after Y-90-ChL6 injection. At the highest dose level, 30% of mice had complete remissions, and no treatment deaths occurred, although tumors subsequently recurred. Continuous up-regulation of transforming growth factor-beta 1 and c-myc mRNA expression was observed from 3 to 24 h after treatment. Expression of p53 and PIC1 increased at 3 h and subsequently decreased to the untreated control levels. These observations are consistent with previous observations of early responses of p53 and PIC1 to cellular DNA damage and subsequent G1 cell cycle arrest or apoptosis. Apoptosis-associated gene expression patterns observed in this tumor model provide evidence that changes are initiated in the first 24 h of RIT associated with radiation doses of 100-700 rads. These preliminary data suggest that insight into the molecular basis of RIT-induced tumor regression may be gained by further studies using different radiation doses.

Second cancers following pediatric Hodgkin's disease.

PURPOSE: To define the magnitude of second cancer risk among pediatric Hodgkin's disease survivors and to determine which factors influence this risk. PATIENTS AND METHODS: At Stanford,694 children and teenagers were monitored for 1 to 31.6 years (mean, 13.1) after treatment for Hodgkin's disease. Relative risks (RRs), actuarial risks, and absolute excess risks for second malignancies were calculated. The influences of sex, age, stage, splenectomy, treatment and relapse were assessed by multivariate analysis. RESULTS: Fifty-six patients developed 59 secondary malignancies: 48 solid tumors, eight leukemias, and three non-Hodgkin's lymphomas. The RR of developing a second cancer was 15.4 (95% confidence interval [CI], 10.6 to 21.5) for females and 10.6 (95% CI, 6.6 to 16.0) for males. Breast cancer (n = 16) and sarcoma (n = 13) were the most common solid tumors. The actuarial risk at 20 years follow-up evaluation was 9.7% for males, 16.8% for females, and 9.2% for breast cancer. The median interval to diagnosis of a second malignancy was shortest for leukemia, 4.3 years, and longest for lung cancer, 18.4 years. Relapse of Hodgkin's disease increased the risk of second malignancy (hazards ratio [HR] = 2.6, P < .001). Hodgkin's disease stage, patient age, splenectomy, and treatment modality did not appear to alter overall risk, although chemotherapy was associated with subsequent leukemia. CONCLUSION: Aggressive Hodgkin's disease therapy is successful, but patients have a significant risk of second malignancy. Newer treatment programs focus on obtaining a relapse-free cure of Hodgkin's disease with judicious use of radiation and alkylating agent chemotherapy. Survivors of pediatric Hodgkin's disease require lifelong evaluation and cancer screening.

Maximum-tolerated dose, toxicity, and efficacy of (131)I-Lym-1 antibody for fractionated radioimmunotherapy of non-Hodgkin's lymphoma.

PURPOSE: Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced remissions in patients with non-Hodgkin's lymphoma (NHL) when labeled with iodine 131 ((131)I). Based on the strategy of fractionating the total dose, this study was designed to define the maximum-tolerated dose (MTD) and efficacy of the first two, of a maximum of four, doses of (131)I-Lym-1 given 4 weeks apart. Additionally, toxicity and radiation dosimetry were assessed. MATERIALS AND METHODS: Twenty patients with advanced NHL entered the study a total of 21 times. Thirteen (62%) of the 21 entries had diffuse large-cell histologies. All patients had disease resistant to standard therapy and had received a mean of four chemotherapy regimens. (131)I-Lym-1 was given after Lym-1 and (131)I was escalated in cohorts of patients from 40 to 100 mCi (1.5 to 3.7 GBq)/m2 body surface area. RESULTS: Mean radiation dose to the bone marrow from body and blood (131)I was 0.34 (range, 0. 1 6 to 0.63) rad/mCi (0.09 mGy/MBq; range, 0.04 to 0.17 mGy/ MBq). Dose-limiting toxicity was grade 3 to 4 thrombocytopenia with an MTD of 100 mCi/m2 (3.7 GBq/m2) for each of the first two doses of (131)I-Lym-1 given 4 weeks apart. Nonhematologic toxicities did not exceed grade 2 except for one instance of grade 3 hypotension. Ten (71 %) of 14 entries who received at least two doses of (131)I-Lym-1 therapy and 11 (52%) of 21 total entries responded. Seven of the responses were complete, with a mean duration of 14 months. All three entries in the 100 mCi/m2 (3.7 MBq/m2) cohort had complete remissions (CRs). All responders had at least a partial remission (PR) after the first therapy dose of (131)I-Lym-1. CONCLUSION: (131)I-Lym-1 induced durable remissions in patients with NHL resistant to chemotherapy and was associated with acceptable toxicity. The nonmyeloablative MTD for each of the first two doses of (131)I-Lym-1 was 100 mCi/m2 (total, 200 mCi/m2) (3.7 GBq/m2; total, 7.4 GBq/m2).

A multiple-dose, controlled study of phenelzine in depression-anxiety states.

In a double-blind, controlled experiment, 62 outpatients with symptoms of depression with anxiety were selected for treatment with phenelzine sulfate, 60 mg daily, phenelzine sulfate, 30 mg daily, or placebo for six weeks. Forty-nine patients (79%) completed the experiment. Phenelzine sulfate, 60 mg daily, was significantly more effective than placebo in relieving symptoms of both depression and anxiety. Phenelzine sulfate, 30 mg daily, did not differ from the placebo. Only phenelzine sulfate, 60 mg daily, resulted in a median inhibition of platelet monoamine oxidase that exceded 80%. The results confirm a previous study that found phenelzine to be effective in the treatment of outpatients with depressive-anxiety states. Drug dosage is an important variable influencing clinical outcome in this patient group.

Treatment-related parameters predicting efficacy of Lym-1 radioimmunotherapy in patients with B-lymphocytic malignancies.

This study was designed to evaluate dosimetric, pharmacokinetic, and other treatment-related parameters as predictors of outcome in patients with advanced B-lymphocytic malignancies. Fifty-seven patients were treated with radiolabeled Lym-1 antibody in early phase trials between 1985 and 1994. Logistic regression and proportional hazards models were used to evaluate treatment parameters for their ability to predict outcome, taking into account patient risk group based on Karnofsky performance status and serum lactic dehydrogenase. The occurrence of a partial or complete response (31 of 57 patients) and development of human antimouse antibody (HAMA) predicted improved survival using a time-dependent proportional hazards model. The final multivariate model for survival with parameters significant at P

67Copper-2-iminothiolane-6-[p-(bromoacetamido)benzyl-TETA-Lym-1 for radioimmunotherapy of non-Hodgkin's lymphoma.

Copper-67 (67Cu) has ideal properties for radioimmunotherapy. The 62-h half-life is similar to the residence time of antibodies in tumor, and the therapeutic beta emission of 67Cu is comparable to that of 131I. 67Cu, however, has gamma emissions similar to 99mtechnetium that are favorable for imaging. The macrocyclic chelating agent 1,4,7,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA) binds 67Cu tightly and selectively, facilitating linkage to Lym-1, a mouse monoclonal antibody that preferentially targets malignant lymphocytes. The safety, efficacy, and practicality of 67Cu-2-iminothiolane (2IT)-6-[p-(bromoacetamido)benzyl]-TETA (BAT)-Lym-1 was assessed in this Phase I/II clinical trial for patients with non-Hodgkin's lymphoma (NHL) who had failed standard therapy. Up to four doses of 67Cu-2IT-BAT-Lym-1, 25 or 50-60 mCi/m2/dose (0.93 or 1.85-2.22 GBq/m2/dose, respectively) were administered; the lower dosage was used when NHL was detected in the bone marrow. 67Cu-2IT-BAT-Lym-1 provided good imaging of NHL, had favorable radiation dosimetry, and had a response rate of 58% (7 of 12). Hematological toxicity was dose-limiting, but no significant nonhematological toxicity was observed. The ability to image and treat NHL patients with a single radiopharmaceutical with useful physical properties makes 67Cu-labeled monoclonal antibody an option for future clinical trials, as this study showed that 67Cu-2IT-BAT-Lym-1 was safe, effective, and practical.

Comparison of 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-peptide-ChL6, a novel immunoconjugate with catabolizable linker, to 2-iminothiolane-2-[p-(bromoacetamido)benzyl]-DOTA-ChL6 in breast cancer xenografts.

Radioimmunotherapy using 131I-ChL6 antibody has shown promise in patients with breast cancer. To enhance this potential, a novel ChL6 immunoconjugate that is catabolizable and tightly binds 90Y and (111)In was developed. The immunoconjugate, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-peptide-ChL6, consists of the macrocyclic chelator DOTA linked to ChL6 by a peptide that is preferentially catabolized in the liver. The pharmacokinetic and dosimetric properties of the radioimmunoconjugates (RICs) (111)In- and 90Y-DOTA-peptide-ChL6 and (111)In- and 90Y-2-iminothiolane (2-IT)-2-[p-(bromoacetamido)benzyl]-DOTA-ChL6 were compared in athymic mice bearing HBT3477 human breast cancer xenografts. Each of the RICs was stable in vivo and concentrated well in the xenografts. Liver concentration, cumulative radioactivity (activity over time), and radiation dose of the DOTA-peptide-ChL6 RICs were one-third to one-half of those of the corresponding 2-IT-2-[p(bromoacetamido)benzyl]-DOTA-ChL6 RICs. Indium-111 RICs were imperfect tracers for corresponding 90Y RICs, although their pharmacokinetics and radiation dosimetries were similar. The results of this study were consistent with previously published in vitro data, which indicated that the peptide linker of DOTA-peptide-ChL6 was catabolized by cathepsin B. The cumulative activities and radiation doses to the liver of DOTA-peptide-ChL6 RICs were one-half of those of corresponding RICs with the 2-IT linker. Preliminary data from pilot studies in patients with breast cancer are in accord with these observations. These novel DOTA-peptide RICs seem to have excellent clinical potential for radioimmunotherapy associated with marrow transplantation, for which liver radiation is likely to be dose limiting for 90Y.

A hypoxia-regulated adeno-associated virus vector for cancer-specific gene therapy.

The presence of hypoxic cells in human brain tumors is an important factor leading to resistance to radiation therapy. However, this physiological difference between normal tissues and tumors also provides the potential for designing cancer-specific gene therapy. We compared the increase of gene expression under anoxia (<0.01% oxygen) produced by 3, 6, and 9 copies of hypoxia-responsive elements (HRE) from the erythropoietin gene (Epo), which are activated through the transcriptional complex hypoxia-inducible factor 1 (HIF-1). Under anoxic conditions, nine copies of HRE (9XHRE) yielded 27- to 37-fold of increased gene expression in U-251 MG and U-87 MG human brain tumor cell lines. Under the less hypoxic conditions of 0.3% and 1% oxygen, gene activation by 9XHRE increased expression 11- to 18-fold in these cell lines. To generate a recombinant adeno-associated virus (rAAV) in which the transgene can be regulated by hypoxia, we inserted the DNA fragment containing 9XHRE and the LacZ reporter gene into an AAV vector. Under anoxic conditions, this vector produced 79- to 110-fold increase in gene expression. We believe this hypoxia-regulated rAAV vector will provide a useful delivery vehicle for cancer-specific gene therapy.

Killing of brain tumor cells by hypoxia-responsive element mediated expression of BAX.

The presence of radioresistant hypoxic cells in human brain tumors limits the overall effectiveness of conventional fractionated radiation therapy. Tumor-specific therapies that target hypoxic cells are clearly needed. We have investigated the expression of suicide genes under hypoxia by a hypoxia-responsive element (HRE), which can be activated through hypoxia-inducible factor-1 (HIF-1). We transfected plasmids containing multiple copies of HRE into U-87 MG and U-251 MG-NCI human brain tumor cells and tested their ability to induce LacZ gene expression under anoxia. Gene expression under anoxia versus oxia was increased about 12-fold for U-87 MG cells and about fourfold for U-251 MG-NCI cells. At intermediate hypoxic conditions, increased LacZ gene expression in U-87 MG cells was induced by the plasmid that contained three HREs, but not by the plasmid with two HREs. Lastly, when we placed a suicide gene BAX under the control of HREs, cells transfected with the BAX plasmids were preferentially killed through apoptosis under anoxia. Our studies demonstrate that HRE-regulated gene expression is active in brain tumor cells, and that the amount of increased gene expression obtained is dependent on the cell line, the HRE copy number, and the degree of hypoxia.

Transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas: initial outcome and long-term results.

Treatment of acromegaly has long been recognized as necessary to relieve symptoms, halt progression of deformities, and decompress the sella turcica. More recently, treatment strategies have focused on decreasing GH levels to a point at which mortality rates normalize, thereby redefining previous concepts of a cure. No surgical series to date has investigated the long-term effect of treatment on mortality rates. We retrospectively reviewed 254 consecutive patients with acromegaly who underwent transsphenoidal microsurgery of GH-secreting adenomas between 1974-1992. Seventy-six percent of these patients had basal GH levels <5 ng/mL within 30 days of surgery, and 24% had persistent disease. Multivariate analysis revealed that higher stage, grade, and preoperative GH levels were all predictive of persistence (P < 0.01). Long-term follow-up was obtained on 129 of the patients in initial remission. Of these, 9 (7%) had disease recurrence and 120 remained in remission. The incidence of major postoperative complications was 8% (2% permanent diabetes insipidus, 2% cerebrospinal fluid leaks requiring surgery, 2% meningitis, and 2% hypopituitarism), with no mortality. In contrast to the 2.4- to 4.8-fold increased mortality among untreated acromegalics, the mortality rate among patients with posttherapy GH levels <5 ng/mL was equivalent to that of age- and sex-matched controls. Aggressive therapy to normalize GH levels should therefore be instituted at diagnosis.

Safety of flurbiprofen in the treatment of ankylosing spondylitis, osteoarthritis, and rheumatoid arthritis. A summary of liver and kidney assay data.

The safety of flurbiprofen (Ansaid, Upjohn) was assessed after pooling data on kidney and liver function collected from nine separate phase III clinical trials involving 1,677 patients (941 receiving flurbiprofen and 736 receiving comparison drugs) with ankylosing spondylitis, osteoarthritis, or rheumatoid arthritis. Multiple categories were created to discern the effects of treatment, disease, age (under 60 and 60 years or older), and duration of exposure to flurbiprofen. No clinically significant trends in kidney or liver function were detected in any category following the administration of flurbiprofen.

Treatment of acute shoulder syndrome with flurbiprofen.

A multi-dose, double-blind, randomized, placebo-controlled, multicenter study was conducted to evaluate 68 patients with acute bursitis or tendinitis following treatment with flurbiprofen (Ansaid, Upjohn) or placebo. Flurbiprofen was administered in a total daily dosage of 200 to 300 mg four times daily. Based on efficacy rating scales, flurbiprofen-treated patients had the greatest proportion of improvement at almost all time periods. They also showed statistically significant improvement compared with placebo-treated patients, according to investigators' overall assessments at all time periods. Most patients showed improvement within three to four days of treatment. Flurbiprofen was both well tolerated and effective for the relief of pain caused by bursitis or tendinitis of the shoulder.

Flurbiprofen for the treatment of bone pain in patients with metastatic breast cancer.

Two investigators enrolled 26 women with metastatic breast carcinoma in a six-week, double-blind, placebo-controlled, crossover study of flurbiprofen (Ansaid, Upjohn) and placebo. The study was designed to determine the efficacy of flurbiprofen in reducing bone pain due to metastatic breast cancer. Pain score, overall performance, and concomitant use of narcotics were evaluated. The overall mean differences in pain scores between flurbiprofen and placebo showed better control of pain during treatment with flurbiprofen. None of these differences approached statistical significance. Evaluation of overall performance status reached statistical significance in one investigator's group. Three out of four patients reported decreased consumption of acetaminophen/aspirin plus codeine combinations while receiving flurbiprofen.

Flurbiprofen in the treatment of ankylosing spondylitis. A comparison with phenylbutazone.

Flurbiprofen (Ansaid, Upjohn), a potent new analgesic and anti-inflammatory agent, was compared with phenylbutazone in 90 patients with ankylosing spondylitis. In this double-blind, randomized, 26-week study, a total daily dose of 200 mg of flurbiprofen, administered three times daily, was as effective as 300 mg of phenylbutazone in controlling the pain and other symptoms of ankylosing spondylitis. In some patients, symptoms were adequately controlled by 150 mg of flurbiprofen per day, administered twice daily. There were no statistically significant differences between flurbiprofen and phenylbutazone in the investigators' and patients' assessments of improvement at all key follow-up periods. In addition, there were no consistently significant differences between drugs in the efficacy pain scales and quantitative measurements studied. Flurbiprofen was well tolerated in doses of up to 300 mg per day, and no clinically significant laboratory abnormalities were detected. Flurbiprofen appears to be an excellent alternative to phenylbutazone in the management of patients with ankylosing spondylitis.