Sorafenib in metastatic thyroid cancer

Although thyroid cancer usually has an excellent prognosis, few therapeutic options are available in the refractory setting. Based on the recent results of phase II studies with tyrosine kinase inhibitors, we designed a retrospective analysis of patients with metastatic thyroid cancer treated with sorafenib in seven Spanish referral centers. Consecutive patients with progressive metastatic thyroid cancer (papillary, follicular, medullary, and anaplastic) not suitable for curative surgery, radioactive-iodine therapy, or radiotherapy were treated with sorafenib 400 mg twice a day. The primary end point was objective response rate (RR). Secondary end points included toxicity, median progression-free survival (mPFS), median overall survival (mOS), and correlation between tumor marker levels (thyroglobulin, calcitonin, and carcinoembryonic antigen) and efficacy. Between June 2006 and January 2010, 34 patients were included in the study. Sixteen patients presented differentiated thyroid carcinomas (DTC) of which seven (21%) were papillary, nine (26%) follicular, 15 (44%) medullary (MTC), and three (9%) were anaplastic (ATC). Eleven (32%) patients achieved partial response and 14 (41%) had stable disease beyond 6 months. Regarding histological subtype, RRs were 47% (seven of 15) for MTC, 19% (three of 16) for DTC, and 33% (one of three) for ATC. With a median follow-up of 11.5 months, mPFS were 13.5, 10.5, and 4.4 months for DTC, MTC, and ATC respectively. Tumor markers were evaluated in 22 patients, and a statistically significant association was observed between RR and decrease in tumor marker levels >50% (P=0.033). In this retrospective trial, sorafenib showed antitumor efficacy in all histological subtypes of thyroid cancer, warranting further development in this setting.     

A randomised,double blind,placebo controlled study of celecoxib,a selective cyclooxygenase 2 inhibitor,on duodenal polyposis in familial adenomatous polyposis

BACKGROUND: Non-selective cyclooxygenase (COX) inhibitors (non-steroidal anti-inflammatory drugs) inhibit large bowel carcinogenesis in patients with familial adenomatous polyposis (FAP). Their role in the duodenum of these patients is less certain. The disease modifying activity of specific COX-2 inhibitors has not been explored in humans. Patients and methods: This was a randomised, double blind, placebo controlled study of celecoxib (100 mg twice daily (n=34) or 400 mg twice daily (n=32)) versus placebo (n=17), given orally twice daily for six months to patients with FAP. Efficacy was assessed qualitatively by blinded review of shuffled endoscopy videotapes comparing the extent of duodenal polyposis at entry and at six months and quantitatively by measurement of the percentage change in duodenal area covered by discrete and plaque-like adenomas from photographs of high and low density polyposis. RESULTS: Shuffled and blinded video review showed a statistically significant effect of 400 mg twice daily celecoxib compared with placebo treatment (p=0.033) with all five independent observers scoring a beneficial effect. Overall, patients taking celecoxib 400 mg twice daily showed a 14.5% reduction in involved areas compared with a 1.4% for placebo (p=0.436). However, patients with clinically significant disease at baseline (greater than 5% covered by polyps) showed a 31% reduction in involved areas with celecoxib 400 mg twice daily compared with 8% on placebo (p=0.049). CONCLUSIONS: A panel of five endoscopists found a significant reduction in duodenal polyposis after six months of treatment with celecoxib 400 mg twice daily. COX-2 inhibition may help this otherwise untreatable condition.     

Brain metastasis from follicular thyroid carcinoma: treatment with sorafenib

Background: Sorafenib has shown promise in the treatment of patients with advanced or metastatic thyroid carcinoma. However, its therapeutic effect has not been assessed in patients with brain metastases from follicular thyroid carcinoma (FTC). Here, we report a patient in whom this treatment was employed with a relatively favorable response. Patient and Methods: A 56-year-old woman had a thyroidectomy 8 years previously for FTC. She subsequently developed lung metastases, for which she received seven courses of radioiodine ((131)I) therapy. She developed right hemiplegia and other symptoms and was found to have a ～5-cm lesion in the left parietal lobe. Radiosurgery with a total dose of 28?Gy (7?Gy/day, for 4 days) to treat her brain metastatic lesion was ineffective, and she was referred to us. We treated her with sorafenib, 200?mg orally, on a twice-daily basis. The effect of this intervention was assessed clinically and radiographically using Response Evaluation Criteria in Solid Tumors (RECIST). Summary: Symptoms and signs improved dramatically and continuously after initiation of sorafenib treatment. Partial response (PR) in the brain metastasis and stable disease (SD) in lung metastatic lesions were verified by consecutive imaging findings for more than one year. Despite alopecia, other treatment-related adverse events did not occur. Conclusions: Targeted therapy such as with sorafenib could be an effective alternative therapeutic strategy in the treatment of progressive brain metastasis from differentiated thyroid carcinoma (DTC) when surgery, external beam radiation, and (131)I are not suitable or give poor outcomes. A paradigm of sustained low dose of sorafenib (200?mg,twice a day) may be well-tolerated without compromising maintenance of the therapeutic effect.     

Neoadjuvant therapy with celecoxib to women with early stage breast cancer

Cyclooxygenase-2 (COX-2) is preferentially expressed in breast cancer cells compared to normal breast tissue. COX-2 inhibitors are, therefore, potential therapeutic options for patients with breast cancer. Women newly diagnosed with non metastatic breast cancer were enrolled into the study after undergoing a diagnostic core needle biopsy. Patients received celecoxib treatment at 400 mg orally twice a day for 14 days, and then underwent surgical excision of their tumor. Core biopsies obtained at the time of initial diagnostic procedure and surgical excision specimens were stained for Ki-67, as well as COX-2 and cleaved poly (ADP-ribose) polymerase (PARP) expression (as an apoptosis marker). Appropriate negative and positive controls were included. We assessed the difference in Ki-67, COX-2 and cleaved PARP expression levels, before and after treatment using the Wilcoxon's matched-pair ranks test and the McNemar's test with continuity correction. Sixteen patients were enrolled. The median age was 54 years. ER and/or PR expression was present in 81% of tumors; Her-2 neu overexpression was present in 25%. No significant change in COX-2 or cleaved PARP expression was noticed in the post intervention specimen compared to the core biopsies. Surprisingly, there was a significant increase in the Ki-67 expression (p < 0.009). This short term prospective study was conducted to assess the effects of celecoxib, on the proliferative and apoptotic indexes in patients with early stage breast cancer. We have found an increase in the Ki-67 activity, with no significant down regulation of COX-2 or increase in cleaved PARP expression with 14 days of therapy. This could be partly due to the small sample size.     

Clinical outcomes following empiric radioiodine therapy in patients with structurally identifiable metastatic follicular cell-derived thyroid carcinoma with negative diagnostic but positive post-therapy (131)i whole-body scans

Background: While radioiodine (RAI) therapy remains the most effective treatment modality for RAI-avid distant metastatic follicular cell-derived thyroid cancer, the therapeutic utility of empiric RAI therapy in patients with structurally identifiable distant metastases that demonstrate RAI avidity only on the post-therapy scan (negative diagnostic whole-body scan [DxWBS]) remains uncertain. Methods: We report a retrospective assessment of the structural response to RAI therapy in 27 patients (median age 54 years, 59% male) with metastatic thyroid cancer (45% classical papillary thyroid cancer, 21% poorly differentiated, 15% tall-cell variant, 15% follicular variant, and 4% Hurthle cell carcinoma) with structurally identifiable distant metastases (86% pulmonary metastases) in whom a properly conducted DxWBS was negative, and the post-therapy scan showed RAI-avid metastatic lesions at the time of RAI remnant ablation. Results: In response to the initial RAI ablation, none of the selected patients demonstrated structural disease regression, and no patient was rendered free of disease. However, 12 patients (44%) demonstrated stable lesions on serial structural imaging after an RAI ablation. Structural disease progression was seen in the remaining 56% (15/27), a median of 6 months after ablation. Unfortunately, additional RAI therapies given to 12/15 patients with progressive disease and 5/12 patients with stable lesions failed to cause structural disease regression, cure, or conversion from progressive to stable disease in any patient. All of the disease-specific deaths (7/27) were in patients who had structural disease progression (n=15) in response to RAI ablation. None of the patients with persistent but stable lesions on structural imaging (n=12) have died of thyroid cancer over a median follow-up period of 3.7 years. Conclusions: While 44% of patients with the DxWBS-negative/post-therapy scan-positive macroscopic distant metastasis will have stable cross-sectional imaging after RAI remnant ablation, the other 56% will demonstrate structural disease progression that cannot be effectively treated with repeated empiric RAI activities. Furthermore, the high disease-specific mortality rate seen within the first few years of remnant ablation in this small subset of patients with persistent progressive disease despite a positive post-therapy RAI scan argues that treatments other than repeated empiric RAI dosing be strongly considered.     

Effect of the cyclooxygenase-2 inhibitor celecoxib on bronchial responsiveness and cough reflex sensitivity in asthmatics

Cyclooxygenase (COX), an essential enzyme in the pathway of prostaglandin formation from arachidonic acid, exists in two isoforms. Cyclooxygenase-1 (COX-1) is expressed under normal physiologic conditions, whereas COX-2, the inducible isoform, is associated with inflammation. Recent studies have linked COX-2 induction to the asthmatic inflammatory response, but potentially beneficial results, such as enhanced production of antiinflammatory and bronchoprotective substances, may also occur. The aim of the present study was to investigate the effect of selective COX-2 inhibition on bronchial responsiveness and cough reflex sensitivity. Eight adult subjects with stable asthma underwent spirometry, bronchoprovocation challenge with methacholine, and cough challenge testing with capsaicin, before and after a 7 day course of the COX-2 inhibitor celecoxib (200 mg orally, twice daily) and placebo, in a randomized, double-blind, crossover fashion. No significant changes in pulmonary function, bronchial responsiveness, or cough reflex sensitivity were induced by celecoxib. It appears, therefore, that 1 week of therapy with celecoxib does not significantly affect basal airway tone, nor the afferent airway receptors controlling bronchoconstriction and cough. However, the results of this trial cannot be extrapolated to subjects with severe asthma, or those suffering an asthmatic exacerbation. In such conditions of enhanced inflammatory response, the role of selective COX-2 inhibition remains to be elucidated. Copyright Academic Press.     

Lithium as adjuvant to radioiodine therapy in differentiated thyroid carcinoma: clinical and in vitro studies

OBJECTIVE: Lithium has been reported to increase radioactive iodine (RaI) doses in benign thyroid disease and in differentiated thyroid carcinoma (DTC). It is not known whether lithium influences the outcome of RaI therapy in DTC. We therefore studied the clinical effects of RaI without and with lithium carbonate in patients with proven metastatic DTC. Controversy also exists on the mechanism by which lithium increases RaI dose in DTC. We performed an in vitro study specifically aimed at examining the effects of lithium on the sodium iodide symporter (NIS). DESIGN: In a clinical study, 12 patients were selected with metastases of DTC who had received previous RaI therapy without lithium (control) that had not influenced tumour progression, despite RaI accumulation in metastases. The patients received 1200 mg lithium carbonate/day followed by 6000 MBq RaI. Outcome parameters were RaI uptake, serum thyroglobulin (Tg) levels and radiological dimensions of metastases compared between RaI with lithium and control. In an in vitro study, iodide uptake was studied in the benign rat thyroid cell line FRTL-5, in the polarized non-thyroid MDCK cell line, stably transfected with human sodium iodide symporter (hNIS) to study the effects of lithium on NIS in a non-thyroid background, and the human follicular thyroid carcinoma cell line FTC133-hNIS to study lithium effects in a background of DTC. Lithium chloride (LiCl) was added in concentrations up to 2 mM for 0-48 h. Both steady-state iodide uptake (30 min) and initial rate (2 min) were studied using a specific activity of 100 mCi/mmol I, the latter experiment to determine lithium effects on substrate dependency. Iodide efflux studies were performed as well. RESULTS: Despite an increased uptake of RaI in seven patients, no beneficial effect of RaI with lithium was observed on the clinical course as assessed by serum Tg measurements and radiographically. In the in vitro studies, no effects of LiCl on iodide uptake or efflux were observed. CONCLUSIONS: The addition of lithium to RaI did not have any beneficial effects on the clinical course in 12 patients with metastatic DTC. No beneficial effects of lithium on iodide uptake were observed in vitro. Therefore, the clinical value of lithium in DTC remains subject to debate.     

Effect of celecoxib on cyclooxygenase-2 expression and possible variants in a patient with Barrett''s esophagus

Cyclooxygenase-2 (COX-2) expression is increased in metaplastic and dysplastic Barrett's esophageal epithelium and it is thought that selective COX-2 inhibitors could offer hope as chemoprevention therapy. The aim of the study was to investigate the in vivo effect of celecoxib on COX-2 expression in patients with Barrett's esophagus and no recent history of non-steroidal anti-inflammatory drug use. Endoscopic mucosal biopsy specimens were collected at baseline and after 28 days of therapy in a patient treated with celecoxib 200 mg twice daily. Samples were analyzed for COX-2 expression by immunoblot analysis with chemiluminescence detection. COX-2 expression was found to decline 20% and 44% at two different biopsy sites compared to the baseline sample. Longer exposures revealed a number of previously unidentified proteins above and below the 67 kDa COX-2 protein including 38 kDa and 45 kDa proteins which were present only at study completion consistent with up-regulation after celecoxib therapy. Further investigations of the 38 kDa and 45 kDa proteins were undertaken using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) with immunoblot and MALDI-TOF (matrix assisted laser desorption ionization - time of flight) analysis but no matches were found and results were inconclusive. Unmatched masses from MALDI-TOF peptide mass fingerprinting were compared with human COX-2 (67 kDa) and COX-2b (39 kDa) using unspecific cleavage. Peptide sequence homology with COX-2 and COX-2b was found for a length of 19 amino acids. Based on immunodetection, molecular weight and equivical MALDI-TOF results, one of these up-regulated proteins may be COX-2b.     

Treatment of gastrointestinal stromal tumor with imatinib mesylate: a retrospective single-center experience in Heidelberg

BACKGROUND: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. Surgery has been the only effective therapy. However, many patients still eventually die of disease recurrence. Chemotherapy and radiation therapy have been of limited value. Imatinib mesylate (Glivec) is an orally administered competitive inhibitor of tyrosine kinases associated with the KIT, ABL protein, licensed for the treatment of metastatic GIST since 2002 in Germany. METHODS: We summarized the data of 16 patients with advanced or metastatic GIST treated with imatinib mesylate in palliative and neoadjuvant settings. RESULTS: Overall response was 81%, with no evidence of disease (NED) in 3/16 (19%), partial response (PR) in 9/16 (56%) and stable disease (SD) in 1/16 (6%), whereas 3/16 patients (19%) suffered from progressive disease (PD). Mean follow-up was 18.6 months [range: 4-30]. Mean progression-free survival (PFS) was 17.6 months [range: 0-30], mean overall survival (OS) from initial diagnosis was 32.3 months [range: 5-122]. Most common side effects were periorbital edema and skin rash. CONCLUSION: Imatinib mesylate is well tolerated in a dose of up to 800 mg/day and has significant activity during long- term treatment of patients with advanced or metastatic GIST.     

Radioiodine treatment of metastatic differentiated thyroid cancer in patients on L-thyroxine, using recombinant human TSH

OBJECTIVE: This study tested the hypothesis that administration of human recombinant thyroid-stimulating hormone (rhTSH: Thyrogen, thyrotropin alpha) could promote iodine-131 ((131)I) uptake in the therapy for metastatic or locally invasive differentiated thyroid cancer (DTC), obviating L-thyroxine suppressive therapy (L-T4) withdrawal and hypothyroidism in patients with advanced disease. METHODS: Twelve totally (or almost completely) thyroidectomized adults, nine of whom had received earlier therapy after L-T4 withdrawal, underwent (131)I treatment while euthyroid on L-T4, after rhTSH administration. Nine underwent diagnostic whole-body scanning (WBS) after two consecutive daily i.m. injections (0.9 mg) of rhTSH. They then received an identical second course of rhTSH to promote therapeutic (131)I uptake. Post-therapy WBS was performed one week later. Three patients received only rhTSH (131)I therapy. RESULTS: Administration of rhTSH promoted (131)I uptake in all patients, as demonstrated by post-therapy WBS. Administration of rhTSH also promoted a significant increase in serum thyroglobulin (Tg) concentrations. According to the most recent measurements, 3-12 months after therapy, serum Tg levels fell in four, and stabilized in two out of eleven patients. Upon additional rhTSH-WBS 8 months post-study, a reduction in one metastatic site was noted in one patient. The rhTSH was well tolerated, with mild, transient fever and/or nausea occurring in only a minority of patients. Individuals with bone metastases experienced degrees of peritumoral pain and swelling that were similar (though more short-lived) to those seen in the same or other patients after L-T4 withdrawal. CONCLUSIONS: Administration of rhTSH is a safe, successful tool for inducing (131)I uptake in local and metastatic DTC lesions, and avoids L-T4 withdrawal, preserving metabolic homeostasis and preventing the debilitating effects of hypothyroidism.     

Use of recombinant human thyrotropin before radioiodine therapy in patients with advanced differentiated thyroid carcinoma

The use of 131I for radioablative therapy in patients with differentiated thyroid cancer (DTC) requires a sufficient serum concentration of TSH for efficient thyroid tissue uptake of iodine. We describe the use of recombinant human TSH (rhTSH) in conjunction with ablative radioiodine therapy (RIT) in 11 patients (16 total treatments) with advanced and/or recurrent DTC (5 papillary, 6 follicular) for whom withdrawal of thyroid hormone suppression therapy (THST), the standard method to increase serum TSH, was not an option. Indications for rhTSH use in these patients included inability to tolerate withdrawal of thyroid hormones due to very poor physical condition or inability to achieve sufficient serum TSH levels after THST withdrawal. Ten patients had undergone thyroidectomy, and most (9 of 11) had received prior ablative RIT after THST withdrawal. Baseline thyroglobulin levels ranged from 25 to nearly 30,000 ng/mL, reflecting the heterogeneity of the patient population. In 7 cases (5 patients), posttherapy thyroglobulin levels assessed at a mean of 4.3 months (range, 2-10 months) after 131I therapy were decreased by at least 30% compared to pretherapy levels. In follow-up visits, an additional 3 patients showed marked clinical improvement or decreased or stabilized tumor burden in whole body scans compared to pretherapy scans. Three patients died of progressive disease within 2 months of therapy before follow-up assessments occurred. No adverse events were reported among the 8 surviving patients. The results suggest that rhTSH offers a promising alternative to THST withdrawal to allow ablative RIT after effective TSH stimulation in patients with advanced recurrent DTC who would not otherwise be able to receive this treatment. This therapeutic indication extends the clinical potential of this new agent, already demonstrated to be effective for use with 131I for diagnostic purposes.     

Reduced incidence of gastroduodenal ulcers with celecoxib, a novel cyclooxygenase-2 inhibitor, compared to naproxen in patients with arthritis

OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandin production by inhibiting cyclooxygenase (COX); they are believed to cause gastroduodenal damage by inhibiting the COX-1 isoform and to have analgesic and anti-inflammatory effects by inhibiting the COX-2 isoform. As compared to conventional NSAIDs, celecoxib, a COX-2 specific inhibitor, has been shown in previous single posttreatment endoscopy studies to be associated with lower gastroduodenal ulcer rates. In response to concerns that such studies may under-represent ulceration rates, the present serial endoscopy study was designed to compare cumulative gastroduodenal ulcer rates associated with the use of celecoxib to those of naproxen, a conventional NSAID. METHODS: In this double-blind, parallel-group, multicenter study, 537 patients with osteoarthritis (OA) or rheumatoid arthritis (RA) were randomized to treatment with celecoxib 200 mg b.i.d. (n = 270) or naproxen 500 mg b.i.d. (n = 267) for 12 wk. Gastroduodenal damage was determined from esophagogastroduodenoscopy after 4, 8, and 12 wk of therapy. Arthritis efficacy was evaluated with Patient's and Physician's Global Assessments. RESULTS: Gastroduodenal ulcer rates after celecoxib and naproxen treatment were 4% versus 19% in the 0-4 wk interval (p < 0.001), 2% versus 14% in the 4-8 wk interval (p < 0.001), and 2% versus 10% in the 8-12 wk interval (p < 0.001), respectively. After 12 wk of treatment, the cumulative incidence of gastroduodenal ulcers was 9% with celecoxib and 41% with naproxen. In the celecoxib group, gastroduodenal ulcers were significantly associated with Helicobacter pylori status (p < 0.05), concurrent aspirin usage (p = 0.001), and a history of ulcer (p = 0.010), but not with disease type (OA/RA), age, gender, other relevant medical histories, or concurrent corticosteroid or disease-modifying antirheumatic drugs usage (p > 0.05). Celecoxib produced a significantly lower incidence rate of both gastric (p < 0.001) and duodenal (p < 0.030) ulcers. The two agents produced similar improvements in Patient's and Physician's Global Assessments of arthritis efficacy. The incidence of adverse events and withdrawal rates did not differ significantly between treatments. CONCLUSIONS: As compared to naproxen (500 mg b.i.d.), use of celecoxib (200 mg b.i.d.), a COX-2 specific agent, at the recommended RA dose and twice the most frequently prescribed OA dose, was associated with lower rates of gastric, duodenal, and gastroduodenal ulcers but had comparable efficacy, in patients with OA and RA.     

Combined treatment of oxaliplatin and capecitabine in patients with metastatic esophageal squamous cell cancer

AIM： To investigate the efficacy and side effects of the combined therapy of oxaliplatin and capecitabine in patients with metastatic esophageal squamous cell cancer （ESCC） and the survival of the patients. METHODS： Sixty-four patients （median age of 63 years） with histological or cytological confirmation of ESCC received oxaliplatin 120 mg/m^2 intravenously on day 1 and capecitabine 1000 mg/m^2 orally twice daily on days 1 to 14 in a 21-d treatment cycle as palliative chemotherapy. Each patient received at least two cycles of treatment. The efficacy, side effects and patient survival were evaluated. RESULTS： The partial response （PR） rate was 43.8% （28/64）. Stable disease （SD） rate was 47.9% （26/64）, and disease progression rate was 15.6% （10/64）. The clinical benefit rate （PR ＋ SD） was 84.4%. The main toxicities were leukopenia （50.0%）, nausea and vomiting （51.6%）, diarrhea （50.0%）, stomatitis （39.1%）, polyneuropathy （37.5%） and hand-foot syndrome （37.5%）. No grade 4 event in the entire cohort was found. The median progression-free survival was 4 mo, median overall survival was 10 mo （95% CI： 8.3-11.7 mo）, and the 1- and 2-year survival rates were 38.1% and 8.2%, respectively. High Karnofsky index, single metastatic lesion and response to the regimen indicated respectively good prognosis. CONCLUSION： Oxaliplatin plus capecitabine regimen is effective and tolerable in metastatic ESCC patients. The regimen has improved the survival moderately and merits further studies.     

Gemcitabine treatment in patients with inoperable locally advanced/metastatic pancreatic cancer and prognostic factors

OBJECTIVE: Most patients with pancreatic cancer show an inoperable locally advanced/ metastatic tumour at the time of diagnosis. The present study was aimed at determining the prognostic factors in patients with advanced pancreatic carcinoma treated with gemcitabine. MATERIAL AND METHODS: Sixty-seven unresectable or metastatic pancreatic cancer patients treated with gemcitabine were included in the study and a total of 258 cycles of treatment were applied. RESULTS: The overall response rate was 5%. Thirty-one percent of the patients had stable disease, whereas progressive disease was seen in 49%. Clinical benefit response rate was 15%. The median duration of response was 7.3 months. Median progression-free survival was 3 months, while median overall survival was 9 months. Univariate analysis revealed that worse results were found in patients with performance status (PS) = 2, and in patients with primary tumour location in the body or tail of the pancreas (p<0.05). Multivariate analysis of data revealed that the most important factor was PS of the patient, as the patients with PS = 2 had worse results than the patients with PS = 0-1 (p<0.05). CONCLUSIONS: Low PS is a negative predictive factor for the survival of patients with advanced pancreatic carcinoma treated with gemcitabine.     

A comparison of the efficacy and safety of celecoxib 200 mg and celecoxib 400 mg once daily in treating the signs and symptoms of psoriatic arthritis

OBJECTIVE: To evaluate the efficacy of the cyclooxygenase-2 selective inhibitor celecoxib in treating patients with psoriatic arthritis (PsA) in flare. METHODS: This 12-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study compared the efficacy and safety of celecoxib 400 mg (n=201) or celecoxib 200 mg (n=213) once daily (qd) with placebo (n=194) in treating the signs and symptoms of PsA in flare. The primary efficacy measure was the number of patients responding to treatment according to the American College of Rheumatology Responders Index 20% (ACR-20) at week 12. Efficacy and safety were assessed for all randomized patients who received at least 1 dose of study medication. RESULTS: At the week-12 primary endpoint, approximately 50% of patients in each treatment group were responders according to the ACR-20 criteria, and no statistically significant treatment differences between treatment groups were observed. However, at week 2, the ACR-20 response rates for the celecoxib 400 mg (49%) and 200 mg (39%) groups were significantly higher than for the placebo group (28%) (P<0.001 and P=0.016, respectively). Within the celecoxib 400 mg group, ACR-20 response rates were similar at weeks 2, 6 (46%), and 12 (49%). In contrast, in the celecoxib 200 mg and placebo treatment groups, ACR-20 response rates increased 7 and 16%, respectively, from week 2 to week 6, and remained relatively unchanged from week 6 to week 12. There were no statistically significant differences in ACR-20 response rates between the celecoxib 400 mg and 200 mg groups at any time point. Treatment with celecoxib 200 and 400 mg qd was statistically superior to placebo treatment at weeks 2 and 6 for Patient's Assessment of Arthritis Pain. Both doses of celecoxib were well tolerated. CONCLUSIONS: Celecoxib 400 mg and 200 mg qd were efficacious and well tolerated in treating the signs and symptoms of PsA in flare after 2 weeks of treatment. However, although the clinical effects of celecoxib 400 mg and 200 mg qd were observed for 12 weeks, there was a high placebo response at these time points, and there were no differences relative to placebo treatment at week 12.     

Defective efficacy of retinoic Acid treatment in patients with metastatic thyroid carcinoma.

Radioiodine (I-131) therapy is of proven efficacy for differentiated thyroid carcinoma. However, its efficacy relies on specific uptake mechanisms, which may be lost during the evolution of the disease. Attempts to increase the iodine uptake of such tumors have been made using retinoic acid because it exerts redifferentiating effects on thyrocytes. This study aims to assess the capability of the retinoic acid (RA) treatment to reinforce iodine 131-irradiation efficacy for metastatic and progressive multi-irradiated thyroid cancer. In this clinical prospective study, 11 patients (mean age +/- 1 SD = 61 +/- 12 years, sex ratio M/F = 5/6) with a progressive disease despite iterative surgery and iodine irradiations were treated with 13-cis-retinoic acid (1.5 mg/kg day) over 8 weeks prior to I-131 irradiation. The redifferentiating effect of RA was evaluated by serum thyroglobulin (Tg) monitoring during RA treatment and qualitative analysis of iodine uptake on the post-therapeutic whole body scan. The clinical usefulness of RA treatment was assessed by clinical follow-up, Tg monitoring, and tumor size. No serious event that could possibly be related to the treatment was reported. The mean follow up time was 24.2 +/- 12 months (range 3-46 months). Iodine uptake was only slightly improved in two patients. Nevertheless, the clinical benefits of RA seem to be very poor. Five patients died of a metastatic disease. Five others presented new clinical evidences of a progressive disease. In conclusion, this prospective study demonstrates the absence of efficacy of I-131 irradiation combined with RA for the treatment of patients with aggressive, rapidly growing metastatic thyroid cancer. Thus, patients with highly aggressive disease, rapidly growing in a short period from 2 to 6 months, should not be considered for RA therapy.     

A phase II study of gefitinib in patients with advanced thyroid cancer.

OBJECTIVE: To determine the efficacy of gefitinib in patients with advanced thyroid cancer. DESIGN: In this open-label phase II trial, 27 patients with radioiodine-refractory, locally advanced, or metastatic thyroid cancer were treated with 250 mg of daily gefitinib. Histologic subtypes included papillary (41%), follicular (22%), anaplastic (19%), medullary (15%), and Hürthle cell carcinomas (4%). The primary endpoint was overall response rate. Secondary endpoints were toxicity, progression-free survival (PFS), and overall survival (OS). MAIN OUTCOMES: There were no objective responses among the 25 patients evaluated. After 3, 6, and 12 months of treatment, 48%, 24%, and 12% of patients had stable disease (SD), respectively. Median PFS and OS were 3.7 and 17.5 months, respectively. Five patients with SD had a decrease in thyroglobulin (Tg) to <90% of baseline that was maintained for at least 3 months. CONCLUSIONS: Although gefitinib therapy did not result in any tumor responses, 32% of patients had reductions in tumor volume that did not meet criteria for partial response rate. Along with falling Tg levels and prolonged SD in a subset of patients, this may indicate biologic activity.     

Gastrointestinal safety of amtolmetin guacyl in comparison with celecoxib in patients with rheumatoid arthritis

OBJECTIVE: Selective inhibitors of cyclo-oxygenase-2 (COX-2) appear to be safer than conventional NSAIDs on the gastrointestinal (GI) tract. Amtolmetin guacyl (AMG), a NSAID that inhibits both COX-1 and COX-2, has an anti-inflammatory effect comparable to that of traditional NSAIDs, with a better GI safety profile. The primary end-point of this study was to evaluate the gastrointestinal safety of amtolmetin guacyl in comparison with celecoxib in patients affected with rheumatoid arthritis. The assessment of efficacy was the secondary end-point. METHODS: This study was a 24-week, randomized, parallel group, double-blind, double dummy, multicentre trial; 235 patients were enrolled and 180 patients (85 in the AMG group and 95 in the celecoxib group) completed the study. Each patient received twice daily amtolmetin guacyl 600 mg or celecoxib 200 mg. Assessment of safety was performed by upper GI endoscopy, gastrointestinal symptoms evaluation, electrocardiography, blood and urine laboratory tests, adverse events recording. Assessment of efficacy was performed by using the American College of Rheumatology (ACR-20) responder index. RESULTS: Neither amtolmetin guacyl nor celecoxib determined a worsening of baseline gastro-duodenal endoscopy findings. The percentage of patients with normal findings did not significantly change after treatment with both drugs, being virtually identical with AMG (i.e. 75.29%) and increasing from 75.79% to 77.66% with celecoxib. Moreover an evaluation of the other safety parameters did not reveal any difference between the two treatment groups. Therapeutic efficacy was equivalent in both groups, with no statistical difference between the two drugs at all time intervals. CONCLUSIONS: In patients affected with rheumatoid arthritis, AMG and celecoxib proved to be equivalent, showing comparable gastrointestinal safety and therapeutic efficacy of treatment.     

Prognostic factors and follow-up of patients with differentiated thyroid carcinoma with false negative or nondiagnostic FNAC before surgery. Comparison with a control group

Since the clinical implementation of fine needle aspiration cytology (FNAC) to diagnose thyroid carcinoma, few patients remain misdiagnosed and little is known about their clinical outcomes. An observational retrospective study was carried out to analyse prognostic factors and follow-up of patients with differentiated thyroid carcinoma (DTC) not disclosed by FNAC before surgery, compared to a control group. From October 2003 to July 2010, 308 patients underwent surgery as treatment for nodular goitre and 53 had DTC. Cases were 12 subjects with DTC and benign (n?=?7) or nondiagnostic (n?=?5) FNAC. Controls were 39 subjects with DTC and suspicious (n?=?19) or malignant (n?=?20) FNAC. Prognostic factors, recurrence and survival rates were compared. Cases had longer time from FNAC to surgery than the control group (86.8?±?74.1 vs. 16.4?±?23.8?weeks; P?相似文献   

Immunohistochemical analysis of sodium iodide symporter expression in metastatic differentiated thyroid cancer: correlation with radioiodine uptake.

The ability of thyroid cancers to concentrate radioiodine (RAI) is dependent, in part, upon the expression and functional integrity of the sodium iodide symporter (NIS). However, some differentiated thyroid carcinomas (DTCs) and most undifferentiated thyroid carcinomas lack the ability to concentrate iodide and are thereby insensitive to 131I therapy. Variation of NIS protein expression may be an important factor in this behavior. We wished to determine whether NIS protein expression in primary DTC tumors correlated with the subsequent RAI uptake by metastatic lesions in the same patients. We obtained paraffin-embedded tissue specimens from 60 patients with metastatic thyroid cancer who had undergone total or near-total thyroidectomy at the Mayo Clinic for DTC and had known presence or absence of RAI uptake in their tumor deposits determined by total body scanning after thyroid hormone withdrawal. Tissue sections from the primary intrathyroidal tumors were subjected to immunostaining (IS) using a monoclonal antibody against human NIS. Slides were subsequently examined for specific IS by two independent reviewers. For each patient, whole body scan (WBS) uptake was recorded, and correlation between results of IS and WBS was analyzed. Of 43 patients with a positive WBS, 37 also had positive IS of their tumors. In six patients with negative IS, a positive WBS was documented, and in three of these cases TSH at the time of surgery was less than 0.3 mIU/liter. Of the 17 patients with negative WBS, 10 were also negative on IS. Positive IS accurately predicted a positive scan in our study in 84% of cases; the ability of the IS to detect all cases with a positive scan was 86%, and it increased to 90% when patients who were receiving thyroid hormone therapy at the time of surgery were excluded from the analysis. Overall, the results of our retrospective study suggest that NIS IS of the thyroidal primary tumor in patients with papillary and follicular thyroid cancers has substantial ability to predict the behavior of subsequent deposits of metastatic and recurrent cancer with respect to iodine trapping and concentration. Our findings require confirmation in prospective studies to more accurately determine the predictive ability of the test and its role in the postoperative management of patients with DTC. If confirmed, NIS IS of DTC primary lesions may prove useful in the management of patients with known or suspected metastatic thyroid cancer.