Lancet

Effect of diagnosis on survival benefit of lung transplantation for end-stage lung disease.

Hosenpud JD. Bennett LE. Keck BM. Edwards EB. Novick RJ.
Joint United Network for Organ Sharing/International Society for Heart and Lung Transplantation Thoracic Registry, Richmond, VA, USA.
BACKGROUND: Although certain forms of end-stage lung disease are debilitating, whether the associated mortality rate exceeds that of transplantation is unclear. We undertook analysis to clarify the survival benefit of lung transplantation for various types of end-stage lung disease. METHODS: We analysed data for all patients listed for transplantation in the USA for emphysema, cystic fibrosis, or interstitial pulmonary fibrosis in the years 1992-94. The numbers of patients entered on the waiting list, post-transplantation, died waiting, and currently waiting were: emphysema group 1274, 843, 143, and 165; cystic fibrosis group 664, 318, 193, and 59; interstitial pulmonary fibrosis group 481, 230, 160, and 48. A time-dependent non-proportional hazard analysis was used to assess the risk of mortality after transplantation relative to that for patients on the waiting list. FINDINGS: The clearest survival benefit from lung transplantation occurred in the cystic fibrosis group. The relative risks of transplantation compared with waiting were 0.87, 0.61, and 0.61 at 1 month, 6 months, and 1 year (p = 0.008), respectively. For interstitial pulmonary fibrosis, the corresponding relative risks were 2.09, 0.71, and 0.67 (p = 0.09). No survival benefit was apparent in the emphysema group. The risks of transplantation relative to waiting were 2.76, 1.12, and 1.10 at 1 month, 6 months, and 1 year, respectively, and the relative risk did not decrease to below 1.0 during 2 years of follow-up. INTERPRETATION: These findings suggest that lung transplantation does not confer a survival benefit in patients with end-stage emphysema by 2 years of follow-up. Other benefits not accounted for in this analysis such as improved quality of life, however, may justify lung transplantation for these patients.

Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. The Swedish Study Group.

Reichard O. Norkrans G. Fryden A. Braconier JH. Sonnerborg A. Weiland O.
Department of Infectious Diseases, Huddinge University Hospital, Stockholm, Sweden.
BACKGROUND: Pilot studies suggested that more patients with chronic hepatitis C virus (HCV) infection had a sustained virological response when treated with the combination of interferon alpha-2b and ribavirin than with interferon alpha-2b alone. We investigated the biochemical and virological responses and safety of treatment with interferon alpha-2b and ribavirin compared with interferon alpha-2b alone. METHODS: In this double-blind trial 100 patients were randomly assigned to treatment with interferon alpha-2b (3 MU three times a week) in combination with ribavirin (1000 or 1200 mg per day) or placebo for 24 weeks and then followed up for a further 24 weeks. A further follow-up was done 1 year after active treatment stopped. The primary endpoint was the sustained virological response, defined as no detectable HCV RNA by PCR at both week 24 and week 48. Retrospectively, the baseline HCV-RNA load was analysed as a predictor of a sustained virological response. Data were analysed by intention to treat. FINDINGS: 18 (36%) of the 50 patients in the interferon alpha-2b and ribavirin group had a sustained virological response compared with nine (18%) of the 50 patients in the interferon alpha-2b and placebo group (p = 0.047). At the 1 year follow-up the proportion of patients with a virological response was greater in the interferon alpha-2b and ribavirin group than the interferon alpha-2b and placebo group (42 vs 20%, p = 0.03), respectively. More patients with baseline HCV-RNA concentrations greater than 3 x 10(6) genome equivalents (Eq) per mL had a sustained response with interferon alpha-2b and ribavirin than with interferon alpha-2b and placebo (12/29 vs 1/26, p = 0.009), whereas the sustained response did not differ between the two treatment groups for HCV-RNA amounts less than 3 x 10(6) Eq per mL (6/21 vs 8/24, p = 0.67), respectively. INTERPRETATION: More patients with chronic hepatitis C have a sustained virological response with interferon alpha-2b and ribavirin than with only interferon alpha-2b treatment. We suggest that patients with high HCV-RNA loads should be treated with interferon alpha-2b and ribavirin.

Randomised trial of laparoscopic exploration of common bile duct versus postoperative endoscopic retrograde cholangiography for common bile duct stones.

Rhodes M. Sussman L. Cohen L. Lewis MP.
Department of Surgery, Norfolk and Norwich NHS Trust Hospital, UK.
BACKGROUND: The management of stones in the common bile duct in the laparoscopic era is controversial. The three major options are preoperative endoscopic retrograde cholangiography (ERCP), laparoscopic exploration of the common bile duct (LECBD), or postoperative ERCP. METHODS: Between August, 1995, and August, 1997, 471 laparoscopic cholecystectomies were done in our department. In 427 (91%), satisfactory peroperative cholangiography was obtained. In 80 (17%) of these cases there were stones in the common bile duct, 40 patients were randomised to LECBD and 40 to postoperative ERCP. If LECBD failed, patients had either open exploration of the common bile duct or postoperative ERCP. If one postoperative ERCP failed, the procedure was repeated until the common bile duct was cleared of stones or an endoprosthesis was placed to prevent stone impaction. The primary endpoints were duct-clearance rates, morbidity, operating time, and hospital stay. Analyses were by intention to treat. FINDINGS: Age and sex distribution of patients was similar in the randomised groups. Duct clearance after the first intervention was 75% in both groups. By the end of treatment, duct clearance was 100% in the laparoscopic group compared with 93% in the ERCP group. Duration of treatment was a median of 90 min (range 25-310) in the laparoscopic group (including ERCPs for failed LECBD) compared with 105 min (range 60-255) in the postoperative ERCP group (p = 0.1, 95% CI for difference -5 to 40). Hospital stay was a median of 1 day (range 1-26) in the laparoscopic group compared with 3.5 days (range 1-11) in the ERCP group (p = 0.0001, 95% CI 1-2). INTERPRETATION: LECBD is as effective as ERCP in clearing the common bile duct of stones. There is a non-significant trend to shorter time in the operating theatre and a significantly shorter hospital stay in patients treated by LECBD.

Double-blind randomised controlled trial of effect of metronidazole on pain after day-case haemorrhoidectomy.

Carapeti EA. Kamm MA. McDonald PJ. Phillips RK.
Department of Surgery, St Mark's Hospital, Middlesex, UK.
BACKGROUND: Haemorrhoidectomy is commonly an inpatient procedure because patients and doctors worry about postoperative pain. Day-case haemorrhoidectomy (DCH) is possible if patient anxiety is addressed and postoperative pain and bowel function are managed. Pain sometimes increases a few days after haemorrhoidectomy, possibly because of secondary infection. We studied the effect of metronidazole on pain after DCH. METHODS: We randomly assigned 40 consecutive patients admitted for DCH metronidazole 400 mg (n = 20) or placebo (n = 20) three times daily, both for 7 days. All patients received lactulose from 2 days before surgery for 2 weeks. Diathermy DCH was performed without pedicle ligature or anal-canal dressing, and a diclofenac suppository was administered at the end of the procedure. Patients were discharged on the same day with diclofenac, 0.2% glyceryl-trinitrate ointment, lactulose, a telephone number to call for queries in emergencies, and an outpatient appointment. Patients took paracetamol or Co-dydramol (dihydrocodeine and paracetamol) as required; they completed linear analogue charts every day and completed questionnaires on satisfaction at 1 and 6 weeks. FINDINGS: 34 patients had all three major piles excised, of whom seven had additional division and reconstruction of the posterior skin bridge. Overall, both groups of patients experienced less pain than expected, except on days 3 and 4. Patients in the metronidazole group had significantly less pain than those in the placebo group on days 5, 6, and 7 (p = 0.004, p = 0.02, and p = 0.006). Median time to return to work or normal activity was 15 days (range 12-28) in the metronidazole group and 18 days (7-34) in the placebo group (p = 0.009). The patient satisfaction score was higher in the metronidazole group than in the placebo group at 1 week (p = 0.005). INTERPRETATION: Prophylactic metronidazole in diathermy DCH suppressed secondary pain around days 5-7 and increased patient satisfaction and earlier return to work.

Treatment of HIV-1-associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy.

Carr A. Marriott D. Field A. Vasak E. Cooper DA.
HIV Medicine Unit and Centre for Immunology, St Vincent's Hospital, Sydney, Australia. acarr@stvincents.com.au
BACKGROUND: Enterocytozoon bieneusi and Cryptosporidium parvum cause chronic antimicrobial-resistant gastrointestinal infections in HIV-1-infected individuals. HIV-1 reverse transcriptase inhibitors delay the onset of opportunistic infections, but are not known to reverse established infections. HIV-1 protease inhibitors are more effective across a broader range of HIV-1-infected immune cells. Combination antiretroviral therapy that includes a protease inhibitor could improve immunity to E bieneusi and C parvum. METHODS: HIV-1 infected patients with chronic microsporidiosis (five), cryptosporidiosis (three), or dual infection (one), were treated with combination therapy that included at least one HIV-1 protease inhibitor. Outcome measures were symptoms, weight, use of antidiarrhoeal and antimicrobial drugs, T-lymphocyte subsets, HIV-1 viraemia, stool microscopy, and biopsy by endoscopy. FINDINGS: All patients had complete clinical responses, gained a median 15 kg in weight, and ceased all antidiarrhoeal and antimicrobial therapies. Biliary cryptosporidiosis responded in both affected patients. Neither pathogen was detected in follow-up stool microscopy (eight of eight patients) or in biopsy samples by endoscopy (five of five). Intestinal architecture returned to normal in three patients. There was a dense CD8 lymphocyte and macrophage infiltrate and staining of intraepithelial E bieneusi with interferon-gamma before and after treatment, but little staining for CD4 or B lymphocytes, interleukin 10, or HIV-1 gp41. Five patients remained symptom-free after a median 13 months follow-up. Four patients had recurrent diarrhoea at 7-13 months (one with positive stool microscopy), associated with declining CD4 counts. INTERPRETATION: Combination antiretroviral therapy that includes a protease inhibitor can restore immunity to E bieneusi or C parvum in HIV-1 infected individuals, and result in complete clinical, microbiological, and histological responses. The persistent CD8 cell and macrophage infiltrate, and the rapid time to relapse in patients with declining CD4 lymphocyte counts, suggest that neither infection was eradicated.

De-novo autoimmune hepatitis after liver transplantation.

Kerkar N. Hadzic N. Davies ET. Portmann B. Donaldson PT. Rela M. Heaton ND. Vergani D. Mieli-Vergani G.
Department of Child Health, King's College Hospital, London, UK.
BACKGROUND: Late graft dysfunction that does not result from recognised causes, such as rejection, infection, or vascular or biliary complications, can occur after liver transplantation. We investigated a particular type of unexplained graft dysfunction that is associated with autoimmune features in children who underwent transplantation at our unit between 1991 and 1996. METHODS: Seven (4%) of 180 liver-transplant recipients developed an unexplained but characteristic form of graft dysfunction (five boys, two girls; median age at presentation 10.3 years, range 2.0-19.4). The median period after surgery was 24 months (6-45). The indications for transplantation had been extrahepatic biliary atresia (four patients), Alagille's syndrome (one), drug-induced acute liver failure (one), and alpha1-antitrypsin deficiency (one). Four patients were on triple immunosuppression with cyclosporin, azathioprine, and prednisolone; and three were on tacrolimus. Immunoglobulin measurements, autoantibody studies, serological studies, and HLA typing were undertaken. Liver-biopsy samples were taken. FINDINGS: Infectious and surgical complications were excluded. Liver-biopsy samples showed the histological changes of chronic hepatitis, including portal and periportal hepatitis with lymphocytes and plasma cells, bridging collapse, and perivenular-cell necrosis without changes typical of acute or chronic rejection. All patients had high concentrations of IgG (median 22 g/L [range 17.2-34.4]) and high titres of autoantibodies. All but one patient responded to prednisolone 2 mg/kg daily and an increase in or addition of azathioprine (1.5 mg/kg daily) within a median of 32 days (7-316). One responder relapsed owing to poor compliance but went into remission after treatment was restored. All six respondents remain in remission on a reduced dose of prednisolone (5-10 mg/day) and 1.5 mg/kg daily azathioprine at a median of 283 days (range 108-730) follow-up. INTERPRETATION: Our data show that symptoms of autoimmune hepatitis, which are responsive to the classical treatment for this condition, can appear in liver-transplant patients while they are on anti-rejection immunosuppression. Whether the liver damage in these patients is a form of rejection or the consequence of autoimmune attack has yet to be established.

Primary symptomless colonisation by Clostridium difficile and decreased risk of subsequent diarrhoea.

Year 1998
Shim JK. Johnson S. Samore MH. Bliss DZ. Gerding DN.
Department of Medicine, Veterans Affairs Chicago Healthcare System, Northwestern University Medical School, Chicago, Illinois 60611, USA.
BACKGROUND: Little is known about whether patients who develop Clostridium-difficile-associated diarrhoea (CDAD) are culture-positive or culture-negative before illness. The most important risk factor is antibiotic exposure. We aimed to find out whether patients identified as primary symptom-free C difficile carriers are at higher risk of developing CDAD than patients who are culture-negative. METHOD: We reviewed four longitudinal studies in which 810 patients admitted to hospital were followed up by prospective rectal-swab culture. At least two consecutive weekly cultures were obtained. We calculated the difference in risk of CDAD between colonised and non-colonised patients in each study and combined the results of the four studies in a random-effects model. FINDINGS: Of 618 non-colonised patients (mean follow-up 1.7 weeks [SD 1.3]), 22 (3.6%) developed CDAD, whereas only two (1.0%) of 192 primary symptom-free carriers (1.5 [1.5]) developed CDAD (pooled risk difference -2.3% [95% CI 0.3-4.3], p=0.021). Of patients who received antibiotics, the risk difference was increased: 22 (4.5%) of 491 non-colonised patients compared with two (1.1%) of 176 colonised patients developed CDAD (-3.2% [0.4-6.0], p=0.024). Of the primary symptom-free C difficile carriers, 95 were colonised with toxigenic strains, 76 with non-toxigenic strains, 12 with both toxigenic and non-toxigenic strains (non-concurrently), and nine with strains of undetermined toxigenicity. Nine of the 12 toxogenic strains of C difficile isolates that cause CDAD were also recovered from stools of symptom-free patients. INTERPRETATION: Primary symptomless C difficile colonisation is associated with a decreased risk of CDAD. Although the mechanism is unknown, risk reduction is found in colonisation with non-toxigenic and toxigenic strains.

Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children.

Year 1998
Wakefield AJ. Murch SH. Anthony A. Linnell J. Casson DM. Malik M. Berelowitz M. Dhillon AP. Thomson MA. Harvey P. Valentine A. Davies SE. Walker-Smith JA.
Inflammatory Bowel Disease Study Group, University Department of Medicine, Royal Free Hospital and School of Medicine, London, UK.
BACKGROUND: We investigated a consecutive series of children with chronic enterocolitis and regressive developmental disorder. METHODS: 12 children (mean age 6 years [range 3-10], 11 boys) were referred to a paediatric gastroenterology unit with a history of normal development followed by loss of acquired skills, including language, together with diarrhoea and abdominal pain. Children underwent gastroenterological, neurological, and developmental assessment and review of developmental records. Ileocolonoscopy and biopsy sampling, magnetic-resonance imaging (MRI), electroencephalography (EEG), and lumbar puncture were done under sedation. Barium follow-through radiography was done where possible. Biochemical, haematological, and immunological profiles were examined. FINDINGS: Onset of behavioural symptoms was associated, by the parents, with measles, mumps, and rubella vaccination in eight of the 12 children, with measles infection in one child, and otitis media in another. All 12 children had intestinal abnormalities, ranging from lymphoid nodular hyperplasia to aphthoid ulceration. Histology showed patchy chronic inflammation in the colon in 11 children and reactive ileal lymphoid hyperplasia in seven, but no granulomas. Behavioural disorders included autism (nine), disintegrative psychosis (one), and possible postviral or vaccinal encephalitis (two). There were no focal neurological abnormalities and MRI and EEG tests were normal. Abnormal laboratory results were significantly raised urinary methylmalonic acid compared with age-matched controls (p=0.003), low haemoglobin in four children, and a low serum IgA in four children. INTERPRETATION: We identified associated gastrointestinal disease and developmental regression in a group of previously normal children, which was generally associated in time with possible environmental triggers.

Cerebral oedema and increased intracranial pressure in chronic liver disease.

Year 1998
Donovan JP. Schafer DF. Shaw BW Jr. Sorrell MF.
Department of Internal Medicine, University of Nebraska Medical Center, Omaha 68198-3285, USA.
BACKGROUND: Cerebral oedema is a cause of morbidity and mortality in fulminant hepatic failure but has not been well documented as a complication of chronic liver diseases. We report here the development of cerebral oedema and increased intracranial pressure in 12 patients with chronic liver disease. METHODS: Between July 1, 1987, and Dec 31, 1993, we studied 12 patients aged 29-67 years with end-stage chronic liver disease. All the patients had cirrhosis, portal hypertension, hypoprothrombinaemia, hepatic encephalopathy, and decreased serum concentrations of albumin (

Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists Collaborative Group.

Year 1998

No information.
BACKGROUND: There have been many randomised trials of adjuvant tamoxifen among women with early breast cancer, and an updated overview of their results is presented. METHODS: In 1995, information was sought on each woman in any randomised trial that began before 1990 of adjuvant tamoxifen versus no tamoxifen before recurrence. Information was obtained and analysed centrally on each of 37000 women in 55 such trials, comprising about 87% of the worldwide evidence. Compared with the previous such overview, this approximately doubles the amount of evidence from trials of about 5 years of tamoxifen and, taking all trials together, on events occurring more than 5 years after randomisation. FINDINGS: Nearly 8000 of the women had a low, or zero, level of the oestrogen-receptor protein (ER) measured in their primary tumour. Among them, the overall effects of tamoxifen appeared to be small, and subsequent analyses of recurrence and total mortality are restricted to the remaining women (18000 with ER-positive tumours, plus nearly 12000 more with untested tumours, of which an estimated 8000 would have been ER-positive). For trials of 1 year, 2 years, and about 5 years of adjuvant tamoxifen, the proportional recurrence reductions produced among these 30000 women during about 10 years of follow-up were 21% (SD 3), 29% (SD 2), and 47% (SD 3), respectively, with a highly significant trend towards greater effect with longer treatment (chi2(1)=52.0, 2p

Detection of retroviral antibodies in primary biliary cirrhosis and other idiopathic biliary disorders.

Year 1998
Mason AL. Xu L. Guo L. Munoz S. Jaspan JB. Bryer-Ash M. Cao Y. Sander DM. Shoenfeld Y. Ahmed A. Van de Water J. Gershwin ME. Garry RF.
Section of Gastroenterology and Hepatology, Alton Ochsner Medical Foundation, New Orleans, Louisiana 70121, USA. amason@ochsner.org
BACKGROUND: Retroviruses have been implicated in the aetiology of various autoimmune diseases. We used immunoblots as a surrogate test to find out whether retroviruses play a part in the development of primary biliary cirrhosis. METHODS: We did western blot tests for HIV-1 and the human intracisternal A-type particle (HIAP), on serum samples from 77 patients with primary biliary cirrhosis, 126 patients with chronic liver disease, 48 patients with systemic lupus erythematosus, and 25 healthy volunteers. FINDINGS: HIV-1 p24 gag seroreactivity was found in 27 (35%) of 77 patients with primary biliary cirrhosis, 14 (29%) of 48 patients with systemic lupus erythematosus, 14 (50%) of 28 patients with chronic viral hepatitis, and nine (39%) of 23 patients with either primary sclerosing cholangitis or biliary atresia, compared with only one (4%) of 24 patients with alcohol-related liver disease or alpha1-antitrypsin-deficiency liver disease, and only one (4%) of 25 healthy volunteers (p=0.003). Western blot reactivity to more than two HIAP proteins was found in 37 (51%) of patients with primary biliary cirrhosis, in 28 (58%) of patients with systemic lupus erythematosus, in 15 (20%) of patients with chronic viral hepatitis, and in four (17%) of those with other biliary diseases. None of the 23 patients with either alcohol-related liver disease or alpha1-antitrypsin deficiency, and only one of the healthy controls showed the same reactivity to HIAP proteins (p

Irregular regeneration of hepatocytes and risk of hepatocellular carcinoma in chronic hepatitis and cirrhosis with hepatitis-C-virus infection.

Year 1998
Shibata M. Morizane T. Uchida T. Yamagami T. Onozuka Y. Nakano M. Mitamura K. Ueno Y.
Department of Medicine, Kawasaki Chuo Hospital, Kanagawa, Japan.
BACKGROUND: Hepatocellular carcinoma (HCC) commonly develops in patients with chronic hepatitis or cirrhosis of the liver caused by hepatitis-C-virus (HCV) infection. We prospectively studied whether irregular regeneration of hepatocytes is a risk factor for HCC in these patients. METHODS: 242 patients were enrolled after liver biopsy and followed up by ultrasonographic scanning every 3 months. We examined age, sex, platelet count, the diagnosis of cirrhosis or chronic hepatitis, liver-cell dysplasia, and irregular regeneration. We classified irregular regeneration as slight or severe, based on histological expression of pleiomorphism, anisocytosis, bulging, and map-like distribution of hepatocytes. FINDINGS: 37 of 63 patients with cirrhosis and 26 of 179 with chronic hepatitis were judged to have severe irregular regeneration. HCC was diagnosed in 33 of 63 patients with cirrhosis (29 had severe irregular regeneration) and 12 of 179 patients with chronic hepatitis (11 had severe irregular regeneration) during mean follow-up of 5.5 years (SD 4.1; range 1-16). Multivariate analysis with a proportional-hazards model showed severe irregular regeneration (relative risk 15.1 [95% CI 5.6-40.7], p