Friday, July 4, 2008

Patients Undergoing Photodynamic Therapy for Barrett’s Dysplasia

nexium

Results


Treatment Results: Effect of Gender and Barrett's Segment Length

We have treated 102 consecutive patients with Barrett's HGD or mucosal adenocarcinoma with a median follow-up of 1.6 years (range: 0.5-6.5; Table 1). All patients were treated with a single course of PDT and complete ablation of Barrett's glandular epithelium has been confirmed in a majority of patients (56%; 57 patients). In the remaining patients, any residual Barrett's mucosa was thermo ablated at follow-up endoscopy using an argon beam coagulator. While most of our patients are elderly men, our study included a larger number of women compared with previous studies that typically include around 10% women.[12,13] There appeared to be no significant differences between men and women with regards to age, Barrett's segment length, treatment outcome (complete ablation of glandular epithelium), stricture rate or follow-up time. Mucosal adenocarcinoma patients had lengths of Barrett's glandular epithelium that were significantly shorter than those in patients with HGD. Mucosal adenocarcinoma patients experienced a higher success rate of complete Barrett's ablation (76% vs. 52% for Barrett's HGD patients) but this difference did not reach statistical significance (P = 0.07; Table 2).Barrett's Dysplasia and Carcinoma Detection at Surveillance vs. Index Endoscopy

Only a slight majority of patients (55 patients; 54%) were referred from endoscopy surveillance programmes where these patients had been monitored for Barrett's disease over a median of 5 years. Most of these patients (39 patients; 89%) had symptoms of chronic acid reflux disease. The remaining 47 patients referred for endoscopic ablation therapy had been diagnosed at their index endoscopy with Barrett's dysplasia or carcinoma without a prior diagnosis of Barrett's dysplasia (Table 3). Most of these patients presented with non-reflux-related symptoms including gastrointestinal bleeding, chest pain and dysphagia (Table 4). The length of the Barrett's segment was significantly longer (median 5 cm, range: 1-16) for surveillance patients compared with those diagnosed on index endoscopy (median 3 cm, range: 1-10, P < 0.001). There was no difference in the oesophageal vs. non-oesophageal symptoms between surveillance and index endoscopy patients.Complications Associated With Photodynamic Therapy

Treatment complications are summarized in Figure 1. Oesophageal stricture requiring dilation occurred in 20% of patients who underwent a median of five dilation procedures to restore stable lumen patency. These strictures generally have the endoscopic appearance of blanched, thickened, inelastic mucosa similar to strictures related to external beam radiation. Dilations were performed in the usual manner with Savary or American dilators over a guidewire, with or without the use of fluoroscopic guidance. Tight post-PDT strictures tend to reform rapidly so repeat dilation is performed at short intervals (every 10-14 days) until a stable lumen is established. Photocutaneous toxicity (severe sunburn-like reactions) occurred in 18% of patients related to inadvertent exposure to sunlight especially within the first 2 weeks after treatment when cutaneous porfimer sodium concentrations are highest. All patients responded to medical therapy (typically a short course of oral corticosteroids), none required hospitalization and there have been no long-term sequelae. Cardiovascular complications occurred in two patients. One man with Barrett's HGD developed new onset atrial fibrillation after receiving PDT to a 15 cm Barrett's segment. Cardiac evaluation found no significant underlying coronary artery disease and PDT-associated inflammation and irritation of the left atrium adjacent to the proximal oesophagus was the presumed cause of atrial fibrillation. He was given oral anticoagulant therapy on an out-patient basis and converted spontaneously to normal sinus rhythm. Five years later, he has had no further problems with cardiac dysrythmias. The other patient had significant coronary artery disease and history of heart failure. After PDT delivery to a 12 cm Barrett's segment, she developed recurrent congestive heart failure that required hospitalization and medical treatment. She recovered uneventfully with medical treatment. Oesophageal perforation occurred in one man treated for a 7 cm segment Barrett's HGD who developed severe chest pain within 2 days after PDT. The physical examination was otherwise unchanged and he did not manifest haemodynamic instability or cardiopulmonary symptoms. Contrast oesophageal radiography found no sign of perforation but CT documented free air in the chest and abdomen implicating a transient perforation at the gastro-oesophageal junction probably related to vomiting. Admitted for observation, bowel rest and antibiotics, his symptoms completely resolved during a 1-week hospitalization, without the need for surgery. Overall, complications occurred in 41% of patients.

Figure 1. (click image to zoom) Percentage of patients with serious adverse events associated with photodynamic therapy (PDT). Oesophageal strictures requiring dilation occurred in 20% of patients and photosensitivity-requiring intervention occurred in 18%. There were two patients with a cardiac complication (one with new onset atrial fibrillation and one with an exacerbation of congestive heart failure). Finally, there was one oesophageal perforation that resolved without surgical intervention.

Incomplete ablation of Barrett's neoplasia occurred in four patients (4%). Despite our intensive surveillance endoscopy protocol, we have not found residual subsquamous glands in any other patients. In three of these patients, the residual disease was detected within 8 weeks of PDT at follow-up surveillance endoscopy when biopsies taken throughout the segment of previously treated Barrett's segment documented subsquamous glandular HGD or carcinoma. Argon plasma coagulation, therefore, was not utilized in any of these patients. Neither CT nor EUS detected mucosal or para-oesophageal abnormalities. Subsequently, oesophagectomy successfully resected the oesophageal intramucosal disease without evidence of submucosal disease and no sign of lymph node involvement. The fourth patient had previously undergone endoscopic mucosal resection elsewhere documenting intramucosal carcinoma with extensive thermal cautery effect limiting evaluation of deeper tissue layers. However, CT and EUS documented abnormal oesophageal lymphadenopathy 8-12 weeks after PDT. Despite chemoradiation therapy and oesophagectomy, as described below, the patient developed metastatic adenocarcinoma.

Previous PageSection 3 of 4Aliment Pharmacol Ther 20(10):1125-1131, 2004. © 2004 Blackwell Publishing
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Thursday, July 3, 2008

Body Composition, Metabolic Syndrome and Testosterone in Aging Men

finasteride

Abstract and Introduction


Abstract

The ageing process in men is marked by changes in body composition (loss of fat-free mass (FFM) and skeletal muscle, and gain in fat mass (FM)) and is associated with a decline in serum testosterone. Correlations between these aspects of ageing and the acknowledged role of exogenous testosterone in reversing the loss of FFM and gain in FM seen in adult men with congenital or acquired hypoandrogenism have led to the hypothesis that testosterone therapy in ageing men will result in favourable changes in body composition and may improve metabolic status and/or cardiovascular risk. Data from randomized controlled trials of testosterone therapy in ageing men addressing the endpoints of body composition and components of the metabolic syndrome and cardiovascular risk factors are reviewed, and the impact of the increasing prevalence of obesity on these relationships is considered.Introduction

As men age beyond 40 years, they experience a decline in serum testosterone. The rate of fall in testosterone has been well documented in cross-sectional[1, 2] and longitudinal[3, 4] studies and is estimated to be 1–2% per annum, excluding the further impact of other variables such as ill health or concomitant medications,[1, 5] and possibly environmental factors.[6]

The age-related fall in testosterone may impact the physical, sexual and/or psychological domains of a man's health; however, the relationship between ageing, declining sex steroids and symptomatology is complex. In particular, symptoms related to well being are often of a nonspecific nature.[7] As androgens are known to be important determinants of body composition, this provides an objective parameter by which to examine the impact of declining testosterone levels in ageing men.

Serum testosterone levels correlate positively with fat-free mass (FFM) and negatively with fat mass (FM),[8] and hypoandrogenism in young men is associated with a decline in FFM and skeletal muscle.[9] Testosterone replacement therapy increases FFM and decreases FM in men with acquired hypogonadism and hypoandrogenism due to ageing.[10, 11] Furthermore, muscle mass has been shown to correlate with strength (as measured by dynamometry) in healthy older men,[12] and in turn strength has been shown to positively correlate with bioavailable testosterone.[13] This has led to interest in the hypothesis that testosterone supplementation may attenuate or even reverse age-associated sarcopaenia and enhance the physical strength and well being of older males. Also, because of the integral nature of the relationship between body composition, and visceral fat in particular, and metabolic health, change in FM is an important outcome measure when considering the role of testosterone therapy in this cohort. In this context, there is growing recognition of the need to define the role played by testosterone in the metabolic status of men as they age.  Printer- Friendly Email This

Int J Impot Res.  2007;19(5):448-457.  ©2007 Nature Publishing Group
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Healing of NSAID-Associated Gastric Ulcers in Patients Continuing NSAIDs

esomeprazole

Results


Patients and Disposition

The study was conducted from February 2001 to April 2003. In all, 440 patients were randomized at 75 study sites as follows: Bulgaria, 89 patients from nine sites; Indonesia, 51 patients from two sites; Romania, 45 patients from seven sites; the Ukraine, eight patients from three sites, and the US, 247 from 54 sites. Patient disposition in the study is shown in Figure 1. Of the 440 patients randomized, 30 were not included in the primary efficacy analysis because of no study drug use, the lack of a documented baseline GU, or a GCP violation at a single site identified after the site was audited. Of 410 patients included in the primary efficacy analyses, 88 (21%) were in Bulgaria, 51 (12%) were in Indonesia, 45 (11%) were in Romania, 8 (2%) were in the Ukraine and 218 (53%) were in the United States.

Figure 1.  (click image to zoom)

Patient disposition. GCP, good clinical practice; NSAID, non-steroidal anti-inflammatory drug; GU, gastric ulcer. * Some patients had more than one type of protocol deviation.      

Baseline demographics and characteristics for patients included in the efficacy analysis are summarized in Table 1 . The study population included more women than men, and most patients were white. The proportion of patients with positive H. pylori status, as determined by histology, was similar among the three groups and included 13.8% (30 of 218) of patients in the United States and 40.1% (77 of 192) of patients in the non-US countries. The most common chronic condition for which patients were taking NSAIDs was osteoarthritis (51% of the patients). Across the three treatment groups, most patients (88%) used non-selective NSAIDs; the most commonly used non-selective NSAIDs were aspirin, diclofenac, ibuprofen, and naproxen. Of these patients, approximately 14% (51/362) used only low-dose aspirin (80 to 325 mg per day). Baseline OGD findings showed that the mean maximum GU size was approximately 8.2 mm, and 129 patients (31%) had GUs > /=10 mm ( Table 2 ). Also, four patients (< 1%) had baseline GUs of maximum size < 5 mm. The GU healing results for these four patients were included in the mITT analysis for completeness. Excluding the healing results for these patients would not have changed the results of the analysis. Only 34 patients included in the efficacy population had concurrent baseline DUs ( Table 2 ).

Overall, for patients in the efficacy analysis, compliance with study medication was 97% (396 of 410 patients) and was similar among the three treatment groups. NSAID compliance was also generally similar among the treatment groups with an overall compliance rate of 88% (361 of 410) of the patients.Efficacy

Table 3 reports the GU healing rates at 4 and 8 weeks. Although the observed GU healing rates at week 8 were numerically higher with the esomeprazole treatments than with ranitidine, these results were not statistically significant. In contrast, at week 4, the observed GU healing rates were significantly higher for patients treated with esomeprazole 40 and 20 mg than for patients treated with ranitidine ( Table 3 ). The observed GU healing rates in the esomeprazole groups compared with the ranitidine group are shown for subgroups evaluated according to age group (Figure 2), baseline H. pylori status determined by histology (Figure 3), and non-selective vs. selective baseline NSAID used (Figure 4).

Figure 2.  (click image to zoom)

Gastric ulcer (GU) healing rates by age. E40, esomeprazole 40 mg once daily; E20, esomeprazole 20 mg once daily; R150, ranitidine 150 mg twice daily (mITT population).      

Figure 3.  (click image to zoom)

Gastric ulcer (GU) healing rates by baseline Helicobacter pylori status determined by histology. E40, esomeprazole 40 mg once daily; E20, esomeprazole 20 mg once daily; R150, ranitidine 150 mg twice daily. †Baseline H. pylori status was missing for one patient in the esomeprazole 40-mg group (mITT population).      

Figure 4.  (click image to zoom)

Gastric ulcer (GU) healing rates by baseline non-steroidal anti-inflammatory drug (NSAID) type. The non-selective NSAID group includes patients who were taking a cyclooxygenase (COX) 2-selective NSAID if they were also taking a non-selective NSAID (including low-dose aspirin). E40, esomeprazole 40 mg once daily; E20, esomeprazole 20 mg once daily; R150, ranitidine 150 mg twice daily. †One patient in the ranitidine 150-mg group was not taking an NSAID before or during the study (mITT population).      

The observed GU healing rates were reanalysed including the 15 patients (five in each treatment group) that were excluded from the mITT population because of GCP violations. The results of this reanalysis provided healing rates that were almost identical to those seen in Table 3 . Therefore, removing these patients from the mITT analysis did not affect the findings of this study.

As a secondary analysis of GU healing, the estimated GU healing rates through the final visit (based on Kaplan-Meier estimation) were 92.1% (95% CI, 87.4%-96.8%), 94.6% (95% CI, 90.7%-98.5%) and 89.2% (95% CI, 83.7%-94.7%) in the esomeprazole 40-mg, esomeprazole 20-mg and ranitidine groups, respectively. Estimated GU healing rates through week 4 (based on Kaplan-Meier estimation) were 71.6% (95% CI, 63.9%-79.4%), 75.2% (95%CI, 67.8%-82.5%), and 58.4% (95% CI, 49.9%-66.8%) for the esomeprazole 40-mg, esomeprazole 20-mg, and ranitidine groups, respectively. Comparisons of the time-to-event curves showed that the time to first healing of GUs was significantly different for esomeprazole 40 mg and esomeprazole 20 mg compared with ranitidine, (P = 0.047 and P = 0.002, respectively).

For the 34 patients in the efficacy analysis who had concurrent DUs at baseline, the DU healing rates at week 8 were 90% (nine of 10 patients) with esomeprazole 40 mg, 68.8% (11 of 16 patients) with esomeprazole 20 mg, and 87.5% (seven of eight patients) with ranitidine.Safety

The safety population included 432 patients: 140 patients in the esomeprazole 40-mg group, 145 patients in the esomeprazole 20-mg group, and 147 patients in the ranitidine 150-mg group. The overall percentage of patients with AEs in this study was 56% (79/140) with esomeprazole 40 mg, 58% (84/145) with esomeprazole 20 mg and 58% (85/147) with ranitidine 150 mg. The number of patients with AEs considered by the site investigator to be related to study drug was also similar among the three treatment groups: 12 (9%) for esomeprazole 40 mg, 13 (9%) for esomeprazole 20 mg and 10 (7%) for ranitidine 150 mg. The most commonly reported AEs for esomeprazole 40 mg, esomeprazole 20 mg and ranitidine 150 mg were gastrointestinal and included gastritis [22 (16%), 25 (17%) and 25 (17%) patients, respectively], flatulence [18 (13%), 27 (19%) and 20 (14%), patients respectively], new onset or worsening of existing dyspepsia [14 (10%), 19 (13%) and 18 (12%) patients, respectively], and new onset or worsening of existing nausea [17 (12%), 11 (8%) and 17 (12%) patients, respectively].

Fourteen of the 440 randomized patients had 16 serious AEs (four patients in the esomeprazole 40-mg group, six in the esomeprazole 20-mg group and four in the ranitidine group), but none was the same and none was considered related to treatment. There was one death that occurred due to an unknown cause on the third day of treatment with esomeprazole 20 mg; the investigator did not consider the death to be related to study medication. Of 440 patients, 17 (3.9%) discontinued the study due to AEs; the number in each treatment group was similar. There were no clinically relevant trends in the results of laboratory tests, physical examinations or vital signs.  Printer- Friendly Email This

Aliment Pharmacol Ther.  2007;26(8):1101-1111.  ©2007 Blackwell Publishing
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