Poor tolerability of thalidomide in end-stage oesophageal cancer.

Oesophageal cancer cachexia is a significant clinical problem, resulting in excessive morbidity and mortality. In a pilot study, 10 patients with cachexia due to advanced cancer of the oesophagus gained weight, including lean tissue, after 14-day treatment with thalidomide. Here, we present randomised placebo controlled trial data over a 6-week period to test the hypothesis that thalidomide is superior to placebo in terms of weight gain in patients with cachexia caused by oesophageal cancer. Thalidomide, 200 mg daily, or an identical placebo was given to patients with advanced oesophageal cancer. Total body weight and lean body mass were assessed in addition to drug tolerability and performance indices. Thirty-four patients were recruited. Of these, six given thalidomide and 16 given placebo completed the protocol; all withdrawals were due to adverse drug reactions or complications of disease. Thalidomide showed no benefit over placebo in participants who completed the protocol. These data suggest that thalidomide is poorly tolerated in patients with advanced cancer of the oesophagus and may not ameliorate the progression of cachexia. In the absence of hard supportive evidence, off-licence treatment with thalidomide should be used with great caution as an adjunct to nutritional support in patients with advanced cancer.

Catecholamines in murine bone marrow derived mast cells.

Cultured murine bone marrow derived mast cells (BMMC) were found to store high levels of dopamine (3753+/-844 pg/10(7) cells) and occasionally produce norepinephrine and epinephrine. The catecholamine synthesis inhibitor, alpha-methyl-para-tyrosine, decreased intracellular catecholamine concentrations, and activation with ionomycin stimulated dopamine release. Neither dopaminergic receptor antagonists nor exogenous dopamine < or =10 microM affected IL-3-induced cell proliferation. High exogenous dopamine (20-100 microM) decreased proliferation and increased apoptosis, and the anti-oxidant ascorbic acid prevented these effects. Increased expression of the anti-apoptotic factor Bcl-2 or loss of pro-apoptotic Bax expression attenuated dopamine-induced apoptosis, suggesting the apoptosis proceeds through a mitochondrial pathway.

Review: the pharmacological control of variceal bleeding.

The haemodynamic effects and clinical uses of drugs used in the management of patients with oesophageal variceal bleeding are reviewed. Vasoconstrictor agents (vasopressin, teripressin) alone or in combination with nitrates continue to be used for acute bleeding episodes, while somatostatin is an alternative. Alpha- and beta-adrenergic blocking drugs and vasodilators which lead to a sustained decrease in portal pressure can be used for the prevention of bleeding episodes, but despite numerous studies the pharmacological treatment of variceal bleeding remains controversial.

Haemodynamic responses to 1.25 and 2 mg of terlipressin intravenously in man.

The systemic and hepatic haemodynamic effects following terlipressin (Glypressin) administration were studied. Bolus intravenous injections of 1.25 and 2 mg significantly decreased wedged hepatic vein pressure gradient by 29% and 31%, respectively. With each dose there was a small increase in mean arterial blood pressure but after 1.25 mg of terlipressin, estimated hepatic blood flow fell by only 11% (not significant) compared to 24% after 2 mg, while the cardiac index fell by 12% compared to 29%. The adverse haemodynamic effects of terlipressin were diminished by a decrease in dosage, without any alteration in the beneficial effect of the drug upon portal pressure. Whether the smaller dose will be effective in arresting variceal haemorrhage remains to be determined.

A pilot study to investigate the use of oxpentifylline (pentoxifylline) and thalidomide in portal hypertension secondary to alcoholic cirrhosis.

BACKGROUND: Tumour necrosis factor-alpha is thought to be important in the pathogenesis of portal hypertension. Oxpentifylline (pentoxifylline) and thalidomide inhibit endotoxin-induced tumour necrosis factor-alpha production in vitro. AIMS: To assess the toxicity of oxpentifylline (pentoxifylline) and thalidomide in cirrhosis and their effect on the hepatic venous pressure gradient and tumour necrosis factor-alpha production. METHODS: In an open-label pilot study, 20 abstinent patients with stable alcoholic cirrhosis and oesophageal varices were recruited; 12 patients completed haemodynamic measurements before and after treatment with oxpentifylline (pentoxifylline) 1800 mg (n=6) or thalidomide 200 mg (n=6) daily for 2 weeks. Tumour necrosis factor-alpha production was assessed in ex vivo monocyte cultures stimulated with endotoxin. RESULTS: Thalidomide reduced the hepatic venous pressure gradient from 19.7 mmHg (9.3-23.5 mmHg) to 12.2 mmHg (4.7-19.5 mmHg) (P=0.03) without reducing the hepatic blood flow or altering systemic haemodynamic parameters. Thalidomide reduced ex vivo tumour necrosis factor-alpha production by approximately 50%. Oxpentifylline (pentoxifylline) had no significant effect on any of the parameters measured. Side-effects led to dose reduction or treatment withdrawal in 40% of patients. CONCLUSION: Thalidomide, but not oxpentifylline (pentoxifylline), reduces the hepatic venous pressure gradient in stable alcoholic cirrhotics, an effect that may be mediated by the inhibition of tumour necrosis factor-alpha production. The role of tumour necrosis factor-alpha inhibitory drugs in the therapy of portal hypertension should be investigated in a randomized controlled trial.

Oesophageal cancer and cachexia: the effect of short-term treatment with thalidomide on weight loss and lean body mass.

BACKGROUND: Cachexia is common in patients with advanced cancer and has a direct impact on well-being and mortality. AIM: To test the hypothesis that thalidomide can promote weight gain and lean body mass in patients with advanced oesophageal cancer. METHODS: In an open-label study, 11 patients with non-obstructing and inoperable oesophageal cancer were established on an isocaloric diet for 2 weeks, followed by 2 weeks on thalidomide, 200 mg daily. The primary end-points were weight change and lean body mass. Secondary end-points were quality of life and changes in resting energy expenditure. RESULTS: Ten patients completed the study protocol. The average caloric intake remained the same throughout the study period in all patients. Nine of 10 patients (95% confidence interval, 0.60, 0.98) lost weight on diet alone. The mean weight gain on thalidomide in the following 2 weeks was 1.29 kg (median, 1.25 kg). A similar trend was shown in the lean body mass. Eight of nine patients (95% confidence interval, 0.57, 0.98) initially lost lean body mass on diet alone (missing data in one patient). The mean gain in lean body mass on thalidomide in the following 2 weeks was 1.75 kg (median, 1.33 kg). CONCLUSIONS: Thalidomide treatment appeared to reverse the loss of weight and lean body mass over the 2-week trial period.

Serial use of aprotinin and incidence of allergic reactions.

Allergic reactions to aprotinin, a polypeptide, have been reported on several occasions. A survey of 136 courses of aprotinin, given to patients with gastric cancer as a protease inhibitor, has shown an incidence of less than 1% of acute anaphylaxis and a similar incidence of minor allergic responses. Two cases of acute allergic responses are described. Fifteen patients received repeated courses of aprotinin at 6-weekly intervals and no allergic phenomena were detected. Provided patients are challenged intra-dermally or with eye drops before each course, it is considered that aprotinin is safe to use in repeated fashion.

Local effects of colorectal cancer are well palliated by endoscopic laser therapy.

We review the results of treating the local effects of 26 cases of inoperable colorectal cancer with Nd:YAG laser. There were 16 men and 10 women of mean age 75, with 17 (65%) rectal, eight (31%) sigmoid and one (4%) ascending colon cancer. They presented with symptoms primarily of obstruction in 12 patients (46%), bleeding in 10 (39%) and diarrhoea in four (15%). Initial therapy to relieve symptoms required a mean of 1.5 (1-3) laser treatments over a mean of 1.5 (1-2) weeks. Twelve patients (46%) had total relief and 12 (46%) had partial relief. Sixteen patients received follow-up maintenance therapy, with laser treatments performed over a mean interval of 7.3 (1-20) weeks. One died at first follow-up treatment; all but two of the others were well maintained by laser treatment alone. Three patients (12%) suffered complications, with two deaths (8%), one due to cardiac failure and the other due to stercoral perforation of the colon. Four patients remained alive after a mean follow-up period of 51 (9-84) months. The mean survival of the others was 5 (0-23) months. Laser palliation for colorectal cancer is efficacious and relatively safe, allows improved quality of survival in 92% of patients after initial treatment, and, alone, can satisfactorily keep patients relatively free of local symptoms in 88% of patients surviving into the follow-up period.

Ampullary somatostatinoma associated with von Recklinghausen's neurofibromatosis presenting as obstructive jaundice.

A case of von Recklinghausen's disease associated with a somatostatinoma of the pancreas causing obstructive jaundice is described. Discussion on the association of von Recklinghausen's disease with somatostatinoma is presented.

Characterization of treatment dose delivered by albumin dialysis in the treatment of acute renal failure associated with severe hepatic dysfunction.

BACKGROUND: Acute liver cell failure (ALCF) commonly results in death and when complicated by acute renal failure (ARF), the mortality approaches 90%. Albumin dialysis allows partial replacement of some of the liver's excretory functions. The molecular absorbents recirculating system (MARS) has been recently introduced to provide this therapy. Thus allowing bridging to transplantation or hepatic regeneration. We have attempted to define the degree of "uremic" dialysis that this system can deliver as well as characterizing the dose of "hepatic" treatment, using a similar approach to solute remove as applied to assessing hemodialysis adequacy. As a secondary issue we also report on the clinical outcomes of this group of patients. METHOD: We treated 7 patients with ALCF and acute renal failure (6 of the patients having a formal diagnosis of hepatorenal syndrome), aiming to deliver a 5 treatment consecutive course consisting of 8 hours of albumin dialysis using the MARS monitor, combined with hemodialysis. Clinical and biochemical outcomes were assessed, and dialysis adequacy measured using urea reduction ratios, calculated Kt/V and measured Kt/V (using ionic dialysance). Treatment dose, with respect to the highly protein bound and lipophilic toxins that accumulate in hepatic failure, was assessed by calculating the bilirubin reduction ratio and percentage reduction in plasma ammonia and total bile acids. RESULTS: All of the patients had a degree of biochemical improvement with albumin dialysis. Urine output increased and the degree of encephalopathy improved. Mean bilirubin fell from 612 +/- 105.5 micromol/l (range 165.6 - 1,024 micromol/l) to 370.4 +/- 49.7 micromol/l (range 190.4 - 569.2 micromol/l), ALT reduced from 3,280 +/- 2,266 IU/l (range 40 - 18,876) to 639 +/- 230 IU/l (range 33 - 1677). Hepatic synthetic function improved with INR falling from 4.1 +/- 0.5 (range 2.1 - 6.4) to 2.8 +/- 0.6 (range 1.4 - 5.5). Plasma ammonia was reduced, falling from 162.4 +/- 15.4 (range 131.1 - 191.9 micromol/l) to 73.1 +/- 15 micromol/l (range 45.6 - 106.4 micromol/l). Bile acid levels fell from 132 +/- 10.2 micromol/l (range 110.7 - 155.8 micromol/l) to 36.9 +/- 6.1 micromol/l (range 24.6 49.6 micromol/l). The mean urea reduction ratio (URR) was 58.4 +/- 3.2% (range 39 - 76%). Mean Kt/V as assessed by ionic dialysance was 1.7 +/- 0.01 (range 0.8-2.4). Mean bilirubin reduction ratio (BRR) was 28.6 +/- 1.4% (range 12.5 - 39%). BRR was proportional to both URR and Kt/V. BRR was also proportional to the percentage reduction of ammonia and bile acid levels. Three of the 7 patients survived to be discharged from hospital and 4 died. CONCLUSION: Albumin dialysis appears capable of improving the outcome in patients with ALCF and hepatorenal syndrome. Eight-hour intermittent treatments with the MARS system in combination with hemodialysis deliver an adequate dose of dialysis with respect to urea. BRR may be an appropriate tool to allow further quantitative and comparative study of this technique.

Plasmapheresis in acute liver failure.

A series of 9 patients with acute hepatic failure and Grade IV hepatic coma received daily plasmapheresis until they recovered or death ensued. Of the nine, seven (77%) showed an improvement in coma grade and five (55%) survived to leave hospital. Plasmapheresis significantly decreased serum bilirubin, aspartate aminotransferase and plasma ammonia concentrations. Survival following plasmapheresis appeared substantially better than in a non randomized group of similar patients not plasmapheresed. The simplicity of the procedure, biochemical improvements observed and apparent efficacy, suggest that further evaluation of the technique as a means of providing temporary hepatic support is indicated.

Laser therapy combined with brachytherapy for the palliation of malignant dysphagia.

BACKGROUND/AIM OF STUDY: Laser therapy is effective in relieving malignant dysphagia, but repeated treatments at 4 to 6 week intervals are usually required. This prospective randomised trial is designed to determine if addition of brachytherapy offers any advantages over laser therapy alone. METHODS: Patients with inoperable carcinoma of the oesophagus were randomised to receive either endoscopic Nd:YAG laser therapy alone, or laser followed by brachytherapy. Patients who developed worsening dysphagia during follow-up were offered further treatment as appropriate. RESULTS: Fourteen patients were randomised to receive laser only, and 12 to receive laser followed by brachytherapy. Of these 12, one was lost to follow-up and four did not receive brachytherapy because they were unfit, had extension into the cardia or had mainly extrinsic compression. These 4 are included on an 'intention-to-treat' basis. The mean therapeutic interval for the brachytherapy group was significantly longer, 83 days compared to 36 days for the laser group (p = 0.026). There were no differences in the degree of dysphagia relief, number of endoscopic procedures or survival times. CONCLUSION: The preliminary results of this trial suggest that brachytherapy in addition to laser therapy prolongs the first therapeutic interval. However, no long-term advantages have been shown.

Cholestasis and biliary dilatation associated with chronic ketamine abuse: a case series.

Ketamine is a dissociative anaesthetic agent that is still widely used in veterinary and human medicine. It is increasingly being used as a recreational hallucinogenic drug. Chronic ketamine abuse is known to account for lower urinary tract symptoms and urinary bladder dysfunction. There is now emerging evidence that ketamine misuse is also associated with abnormal liver function tests and biliary tract abnormality. We report three cases of chronic ketamine misuse in three young men who all presented with obstructive jaundice and biliary tract abnormality. We also describe the clinical features, radiological findings and potential underlying mechanisms for this new entity.

Autoimmune pancreatitis presenting as a pancreatic mass mimicking malignancy.

Autoimmune pancreatitis is a rare cause of chronic pancreatitis and pancreatic mass. We describe a case of focal autoimmune pancreatitis in a 51-year-old man presenting with obstructive jaundice and pancreatic mass, mimicking malignancy. The immunological test was suggestive of autoimmune pancreatitis, and the patient responded well to a course of steroids, with complete resolution of the pancreatic mass. Autoimmune pancreatitis, therefore, must be kept in mind as a differential diagnosis of pancreatic mass. Recognition of this disease by its typical radiological and serological findings may help to avoid unnecessary surgical resection.

Throat spray for upper gastrointestinal endoscopy is quite acceptable to patients.

BACKGROUND AND STUDY AIMS: The use of sedation in upper gastrointestinal endoscopy is widespread, mainly because of the belief that patients are likely to tolerate the procedure better. The aim of the present study was to assess patients' response to the policy of actively persuading them to accept a throat spray for upper gastrointestinal endoscopy. PATIENTS AND METHODS: Three hundred patients who had recently undergone endoscopy were sent a questionnaire; 244 of them responded (81%). Data on age, sex, procedure tolerance, anxiety levels, and future choice of sedation or throat spray for repeat procedures were sought. The results were analysed using the chi-squared test. RESULTS: One hundred and ninety-two (79%) chose, or were persuaded to have, throat spray, and only nine (5%) had to be transferred to sedation. Thirty-two percent of patients who had throat spray tolerated endoscopy well, compared to 70% of those who chose sedation. One hundred and nineteen throat spray patients (62%) showed a low level of reluctance to undergo repeat endoscopy, compared to 37 (71%) sedated patients (not significant). One hundred and forty-four throat spray patients (76%) expressed satisfaction with the throat spray, but if given a choice, only 124 (66%) would choose throat spray again. Male patients, those with lower anxiety levels, and those over 50 years old, tolerated endoscopy with throat spray better, showed less reluctance to undergo repeat endoscopy, and were more likely to choose throat spray again. Those who had any previous experience of endoscopy under sedation were less likely to choose throat spray again. CONCLUSION: The present study shows that the use of throat spray for diagnostic endoscopy is quite acceptable to patients. For safety reasons, we should be encouraging greater use of throat spray in routine diagnostic upper gastrointestinal endoscopy.

The antemortem diagnosis of pyogenic liver abscess due to perforation of the gut by a foreign body.

Perforation of the gastrointestinal tract by ingested foreign bodies is rare; the diagnosis of pyogenic liver abscess resulting from such perforations is usually made at post-mortem. We present a case of perforation of the gut, due to an ingested dental plate, with a resultant pyogenic liver abscess, which presented as a pyrexia of unknown origin.

Sulphasalazine and spermatogenesis.

The semen of 11 patients with inflammatory bowel disease treated with sulphasalazine (Salazopyrin) was analysed and compared with that of 6 men with similar disease not treated with the drug. The treated group had significantly reduced sperm population density and motility compared with the untreated group. Both groups had high numbers of abnormal spermatozoa compared with the standard for our laboratory, but there was no significant difference between the two groups for this parameter. Sulphasalazine has a deleterious effect on spermatogenesis.

Crohn's disease in the city of Derby, 1951-85.

An epidemiological survey of Crohn's disease in the city of Derby showed that the incidence of the condition increased from 0.7/10(5) per year between 1951 and 1955 to 6.67/10(5) per year between 1981 and 1985 but seemed to reach a plateau between 1976 and 1985. Large bowel Crohn's disease was more common in patients presenting aged 60-79 years than in those aged 20-39 years. The increase in incidence was not solely due to the detection of milder disease. There was no evidence that the Asian (Indian subcontinent) population of Derby was resistant to the development of Crohn's disease.

Placebo-controlled trial of terlipressin (glypressin) in the management of acute variceal bleeding.

In a double-blind trial 60% of acute variceal bleeding episodes were controlled with terlipressin (glypressin) compared with 37% in patients given placebo (NS). Rebleeding was more common in the placebo group so that at 5 days bleeding remained under control in 54% of patients treated with terlipressin compared with only 19% after placebo therapy (p less than 0.025). Blood transfusion requirements were similar in the two groups. Terlipressin appeared to be the most effective in those patients with severe hepatic dysfunction.