Depot buprenorphine as an opioid agonist therapy in New South Wales correctional centres: a costing model.

BACKGROUND: In 2019 daily liquid methadone and sublingual buprenorphine-naloxone were primary opioid agonist treatments for correctional centres in New South Wales, Australia. However, both had significant potential for diversion to other patients, and their daily administration was resource intensive. An alternative treatment in the form of subcutaneous depot buprenorphine became a viable option following a safety trial in 2020 - the UNLOC-T study. Depot preparation demonstrated advantages over current treatments as more difficult to divert and requiring fewer administrations. This paper reports the results of economic modelling of staffing costs in medication administration comparing depot buprenorphine, methadone, and sublingual buprenorphine provision in UNLOC-T trial facilities. METHODS: The costing study adopted a micro-costing approach involving the synthesis of cost data from the UNLOC-T clinical trial as well as data collected from Justice Health and Forensic Mental Health Network records. Labour and materials data were collected during site observations and interviews. Costs were calculated from two payer perspectives: a) the New South Wales (state) government which funds custodial and health services; and b) the Australian Commonwealth government, which pays for medications. The analysis compared the monthly-per-patient cost for each of the three medications in trial-site facilities during July 2019. This was followed by simulation of depot buprenorphine implementation across the study population. Costs associated with medical assessment and reviews were excluded. RESULTS: The monthly-per-patient New South Wales government service costs of depot buprenorphine, methadone and sublingual buprenorphine were: $151, $379 and $1,529 respectively while Commonwealth government medication costs were $434, $80 and $525. The implementation simulation found that service costs of depot buprenorphine declined as patients transitioned from weekly to monthly administration. Costs of treatment using the other medications increased as patient numbers decreased alongside fixed costs. At 12 months, monthly-per-patient service costs for depot buprenorphine, methadone and sublingual buprenorphine-which would be completely phased out by month 13-were $92, $530 and $2,162 respectively. CONCLUSIONS: Depot buprenorphine was consistently the least costly of the treatment options. Future modelling could allow for dynamic patient populations and downstream impacts for participants and the state health system. TRIAL REGISTRATION: ACTRN12618000942257 . Registered 4 June 2018.

Alcohol use disorders in Australia.

Alcohol use disorders are common in Australia and are often unrecognised. Alcohol places a significant burden on our healthcare system by increasing the risk of injuries as well as many chronic medical conditions. Diagnosis requires a high index of suspicion and can be aided by the use of specific questionnaires, such as the Alcohol Use Disorder Identification Test-C. The current available laboratory tests are of limited sensitivity and specificity, but can nevertheless aid in the diagnosis in some circumstances. Newer tests, such as ethyl-glucuronide and phosphatidylethanol, are more sensitive and specific but are costly and not widely available. The effective management of alcohol use disorder entails psychosocial or pharmacological treatments or a combination of both. In those who cannot reduce alcohol consumption, harm reduction strategies can be applied to reduce the burden of harm to the drinkers as well as the community at large.

Is Specialized Integrated Treatment for Comorbid Anxiety, Depression and Alcohol Dependence Better than Treatment as Usual in a Public Hospital Setting?

AIM: To assess the effectiveness of a 12 week specialized, integrated intervention for alcohol dependence with comorbid anxiety and/or mood disorder using a randomized design in an outpatient hospital setting. METHODS: Out of 86 patients meeting the inclusion criteria for alcohol dependence with suspicion of comorbid anxiety and/or depressive disorder, 57 completed a 3-week stabilization period (abstinence or significantly reduced consumption). Of these patients, 37 (65%) met a formal diagnostic assessment of an anxiety and/or depressive disorder and were randomized to either (a) integrated intervention (cognitive behavioural therapy) for alcohol, anxiety and/or depression, or (b) usual counselling care for alcohol problems. RESULTS: Intention-to-treat analyses revealed a beneficial treatment effect of integrated treatment relative to usual counselling care for the number of days to relapse (χ(2) = 6.42, P < 0.05) and lapse (χ(2) = 10.73, P < 0.01). In addition, there was a significant interaction effect of treatment and time for percentage days of abstinence (P < 0.05). For heavy drinking days, the treatment effect was mediated by changes in DASS anxiety (P < 0.05). There were no significant treatment interaction effects for DASS depression or anxiety symptoms. CONCLUSIONS: These results provide support for integrated care in improving drinking outcomes for patients with alcohol dependence and comorbid depression/anxiety disorder. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01941693.

Effect of treatment willingness on specialist assessment and treatment uptake for hepatitis C virus infection among people who use drugs: the ETHOS study.

Among people who inject drugs (PWID) with chronic HCV, the association between HCV treatment willingness and intent, and HCV specialist assessment and treatment were evaluated. The Enhancing Treatment for Hepatitis C in Opioid Substitution Settings (ETHOS) is a prospective observational cohort. Recruitment was through six opioid substitution treatment clinics, two community health centres and one Aboriginal community controlled health organisation in Australia. Analyses were performed using logistic regression. Among 415 participants (mean age 41 years, 71% male), 67% were 'definitely willing' to receive HCV treatment and 70% reported plans to initiate therapy 12 months postenrolment. Those definitely willing to receive HCV treatment were more likely to undergo specialist assessment (64% vs 32%, P < 0.001) and initiate therapy (36% vs 9%, P < 0.001), compared to those with lower treatment willingness. Those with early HCV treatment plans were more likely to undergo specialist assessment (65% vs 27%, P < 0.001) and initiate therapy (36% vs 5%, P < 0.001), compared to those without early plans. In adjusted analyses, HCV treatment willingness independently predicted specialist assessment (aOR 3.06, 95% CI 1.90, 4.94) and treatment uptake (aOR 4.33, 95% CI 2.14, 8.76). In adjusted analysis, having early HCV treatment plans independently predicted specialist assessment (aOR 4.38, 95% CI 2.63, 7.29) and treatment uptake (aOR 9.79, 95% CI 3.70, 25.93). HCV treatment willingness was high and predicted specialist assessment and treatment. Strategies for enhanced HCV care should be developed with an initial focus on people willing to receive treatment and to increase treatment willingness among those less willing.

Effect of multiple binge alcohol on diet-induced liver injury in a mouse model of obesity.

BACKGROUND: Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are highly prevalent liver diseases that may coexist and contribute significantly to liver disease-related mortality. Obesity is a common underlying risk factor for both disorders. There has been little research investigating the combined effects of high fat diet (HFD) and alcohol. Current mouse models of alcohol- or fat-rich diet alone do not lead to severe liver injury. There is a need to develop animal models recapitulating human settings of drinking and diet to study the mechanisms of liver injury progression. METHODS: C57BL6 male mice were fed either chow or HFD ad libitum for 12 weeks. A sub-set of mice from each group were also given alcohol (2 g kg(-)(1) body weight) twice a week via intra-gastric lavage. Animals were monitored progressively for weight gain and blood and livers were harvested at termination. The extent of liver injury was examined by histopathology as well as by liver and serum biochemistry. The expression of lipid metabolism, inflammation and fibrogenesis-related molecules was examined by quantitative reverse transcription PCR (Q-PCR) and immunofluorescence staining. RESULTS: HFD significantly increased total body weight, triglyceride and cholesterol, whereas alcohol increased liver weight. Alcohol+HFD in combination produced maximum hepatic steatosis, increased micro- and macro-vesicular lipid droplets, increased de novo lipogenesis (steroid response-element binding protein 1 (SREBP-1) and stearoyl-CoA desaturase-1 (SCD-1)) and proliferation peroxisome activated receptor alpha (PPARα), and decreased fatty acid ß-oxidation (Acyl-CoA oxidase 1 (ACOX1)). Alcohol+HFD treatment also increased the inflammation (CD45+, CD68+, F4/80+ cells; tumour necrosis factor-alpha (TNF-α), F4/80 mRNAs) and fibrogenesis (vimentin+ activated stellate cells, collagen 1 (Col1) production, transforming growth factor-beta (TGF-ß) and Col-1 mRNAs) in mice livers. CONCLUSIONS: We report a novel mouse model with more severe liver injury than either alcohol or HFD alone recapitulating the human setting of intermittent alcohol drinking and HFD.

Baclofen for the Treatment of Alcohol Dependence and Possible Role of Comorbid Anxiety.

AIM: To conduct a double-blind, placebo-controlled randomized clinical trial of baclofen in the treatment of alcohol dependence. METHODS: Out of 69 participants consecutively screened, 42 alcohol-dependent patients were randomized to receive placebo, baclofen 30 mg/day or baclofen 60 mg/day for 12 weeks. All subjects were offered BRENDA, a structured psychosocial therapy for alcohol dependence that seeks to improve motivation for change, enhance strategies to prevent relapse and encourage compliance with treatment. RESULTS: Intention-to-treat analyses revealed that alcohol consumption (heavy drinking days, drinks per drinking day) significantly reduced across all three groups during the treatment period. There were no statistically significant advantages to treatment on time to first heavy drinking day (relapse) (P = 0.08), nor time to first drink (lapse) (P = 0.18). A post hoc analysis stratifying according to whether there had been a comorbid anxiety disorder, revealed a beneficial effect of baclofen 30 mg/day versus placebo on time to lapse and relapse (P < 0.05). There was also a beneficial effect for baclofen 60 mg/day relative to placebo on time to relapse in this comorbid group (P < 0.05). Both doses of baclofen were well tolerated. There were no serious adverse events. CONCLUSIONS: In spite of the small sample for a 3-arm clinical trial, this study suggests a specific role of baclofen in alcohol-dependent individuals with comorbid anxiety. Replication in larger, fully-powered studies is required.

Twenty-year trends in benzodiazepine dispensing in the Australian population.

AIM: Considerable concern has been expressed about overprescribing of benzodiazepines and related harms. Past analyses have relied on World Health Organization-defined daily doses (DDD) which are sometimes out of keeping with clinical usage. This study examines 20-year (1992-2011) trends of benzodiazepine dispensing in Australia using both DDD and Ashton equivalent dose. METHODS: Data from the Drug Utilisation Sub-Committee and the Pharmaceutical Benefits Scheme (PBS) website were analysed. Trends in number of prescriptions, DDD/1000 people/day and DDD/prescription were examined over time, and between states/territories. RESULTS: In the 20-year period, 174 080 904 scripts were recorded, with temazepam the most dispensed benzodiazepine (35% of scripts), followed by diazepam (23%). Overall recorded utilisation fell from 27.7 DDD/1000 people/day in 1992 to 20.8 in 2011 (24.9% decrease). There were striking changes in use of individual benzodiazepines over time, with reductions in oxazepam and flunitrazepam and dramatic increases in alprazolam. Since 1998, there has been a steady increase, albeit modest, in per script DDD. The DDD/1000 people/day for items dispensed through PBS/Repatriaton-PBS was highest in Tasmania and lowest in Northern Territory. CONCLUSION: Despite a modest overall decline in the amount of benzodiazepine dispensed, the level of use is still likely to reflect relative over-prescribing given the paucity of accepted indications for long-term use. Since 1998, there was a polynomial increase in quantity dispensed per script. The WHO-defined DDD for clonazepam seems inappropriate and could impede monitoring of its abuse. Other problems include lack of national data for medications not subsidised on PBS/Repatriation PBS. A broad policy approach is required, not one which targets only one particular benzodiazepine.

The efficacy and biobehavioural basis of baclofen in the treatment of alcoholic liver disease (BacALD): study protocol for a randomised controlled trial.

BACKGROUND: Effective treatments for alcohol use disorders in those with significant liver disease are critically lacking. The primary aim of the current study is to explore the effectiveness and biobehavioural basis of low and high dose baclofen in improving treatment outcomes for alcohol dependence in people with alcoholic liver disease (The BacALD study). METHODS: This double-blind, placebo-controlled study will randomize 180 participants to a 12-week regime of either baclofen (30 mg/day baclofen, 75 mg/day baclofen) or placebo. Participants must meet the ICD-10 criteria for alcohol dependence in addition to alcoholic liver disease (ALD) defined as the presence of symptoms and/or signs referable to liver disease or its complications with or without cirrhosis. Primary outcome measures will include total abstinence duration, and time to lapse and relapse. Furthermore, 60 of the ALD patients enrolled in the trial will also participate in a pharmacokinetic and cue-reactivity component, along with an additional 30 healthy volunteers matched for age and gender randomised to a 1 week regime of either 30 mg/day baclofen or 75 mg/day baclofen. At week 1, plasma levels of baclofen and ß-p-chlorophenol-γ-hydroxybutric acid will be measured at 0, 1 and 4 h following baclofen administration and psychophysiological responses to alcohol-associated stimuli will be assessed in a cue reactivity paradigm. Recruitment commenced in late March 2013. CONCLUSIONS: This trial will demonstrate the efficacy and safety of two doses of baclofen in patients with alcoholic liver disease and will explore the biobehavioural mechanisms of the treatment effect.

Examination of opioid prescribing in Australia from 1992 to 2007.

BACKGROUND: Opioid prescribing is controversial with evidence of both significant under-utilization and over-utilization. There is some evidence to support efficacy for chronic non-malignant pain, but community and individual harms are increasingly reported. AIMS: To review availability of opioid preparations and prescription patterns of opioids through the subsidized Pharmaceutical Benefits Scheme in Australia from 1992 to 2007. METHODS: Interrogation of the Health Insurance Commission database from 1992 to 2007. Item numbers for all available opioid preparations were identified, and frequency of dispensing was collected and collated. RESULTS: The number of opioids on the Pharmaceutical Benefits Scheme (PBS) increased from 11 preparations of four medications to 70 preparations of eight medications during this period. The total number of PBS opioid prescriptions increased from 2 397 006 in 1992 to 6 998 556 in 2007. We identified a dramatic and continuing increase in prescription of oxycodone in all dose ranges. Fentanyl prescribing is increasing to a lesser degree. Morphine and tramadol prescribing appears to have plateaued. CONCLUSION: Opioid use is increasing. There is a pressing need for co-ordinated assessment of efficacy and harms to facilitate quality usage of opioids.

Nurse-provided screening and brief intervention for risky alcohol consumption by sexual health clinic patients.

OBJECTIVES: Brief intervention for excessive alcohol consumption is effective yet not implemented widely. Alcohol misuse is implicated in unsafe sex and sexually transmitted infections and is common in clients of sexual health services. Our aims were to assess feasibility, acceptability and effectiveness of screening and brief intervention for risky alcohol consumption by a nurse in a sexual health clinic. METHODS: Patients completed the AUDIT questionnaire on handheld computers. Those scoring >or=8 on AUDIT were asked to participate in the study and the 3 months' follow-up and were randomised to intervention or control groups. The Drink-less package (based on WHO validated methods) was used to implement the brief intervention by a trained registered nurse. RESULTS: Of 519 (87%) who completed screening, 204 (39%) scored >or=8 on AUDIT (eligible), 184 agreed to follow-up and 133 completed it. At follow-up, both groups showed significant reductions in AUDIT scores. Mean scores decreased from 13.7 to 11.5 (control group) and 14.0 to 10.7 (intervention group); most (94%) recalled the intervention and 62% reported reducing drinking compared with 47% of controls (p<0.001). The nurse screening and intervention process was reported acceptable by 74% of patients at follow-up and a majority (71%) of staff. CONCLUSIONS: Screening and brief intervention in a sexual health clinic for risky alcohol consumption is feasible, acceptable and effective in producing significant reductions in drinking as measured by AUDIT. Both intervention and control groups decreased consumption, suggesting that screening alone is sufficient to influence behaviour. Further study of brief intervention in this setting is appropriate.

Acute hepatitis C virus infection in an Australian prison inmate: tattooing as a possible transmission route.

Clinically apparent hepatitis C virus (HCV) infection developed in a prison inmate after two tattooing episodes within the recognised incubation period for HCV infection. Seroconversion and HCV viraemia with subsequent resolution of hepatitis and loss of plasma viraemia were documented. Introducing licensed tattooists, and thereby improving infection control practices, may reduce the risk of hepatitis C virus infection in prisons.

Activation of pancreatic stellate cells in human and experimental pancreatic fibrosis.

The mechanisms of pancreatic fibrosis are poorly understood. In the liver, stellate cells play an important role in fibrogenesis. Similar cells have recently been isolated from the pancreas and are termed pancreatic stellate cells. The aim of this study was to determine whether pancreatic stellate cell activation occurs during experimental and human pancreatic fibrosis. Pancreatic fibrosis was induced in rats (n = 24) by infusion of trinitrobenzene sulfonic acid (TNBS) into the pancreatic duct. Surgical specimens were obtained from patients with chronic pancreatitis (n = 6). Pancreatic fibrosis was assessed using the Sirius Red stain and immunohistochemistry for collagen type I. Pancreatic stellate cell activation was assessed by staining for alpha-smooth muscle actin (alphaSMA), desmin, and platelet-derived growth factor receptor type beta (PDGFRbeta). The relationship of fibrosis to stellate cell activation was studied by staining of serial sections for alphaSMA, desmin, PDGFRbeta, and collagen, and by dual-staining for alphaSMA plus either Sirius Red or in situ hybridization for procollagen alpha(1) (I) mRNA. The cellular source of TGFbeta was examined by immunohistochemistry. The histological appearances in the TNBS model resembled those found in human chronic pancreatitis. Areas of pancreatic fibrosis stained positively for Sirius Red and collagen type I. Sirius Red staining was associated with alphaSMA-positive cells. alphaSMA staining colocalized with procollagen alpha(1) (I) mRNA expression. In the rat model, desmin staining was associated with PDGFRbeta in areas of fibrosis. TGFbeta was maximal in acinar cells adjacent to areas of fibrosis and spindle cells within fibrotic bands. Pancreatic stellate cell activation is associated with fibrosis in both human pancreas and in an animal model. These cells appear to play an important role in pancreatic fibrogenesis.

Transmission of hepatitis C within Australian prisons.

Transmission of hepatitis C virus (HCV) within prisons has long been suspected but has not been satisfactorily documented. We present four cases of HCV infection occurring during periods of continuous imprisonment. Each subject was HCV seronegative on entering prison and on repeat testing after 4-52 months in prison, but subsequently became seropositive. Two subjects gave a history of injecting drug use, and the most likely means of infection in the other two subjects were lacerations from barbers shears and lacerations arising from physical assault. There is an urgent need for detailed study of the incidence of HCV infection and the modes of transmission in prisons.

Alcoholic pancreatitis and polymorphisms of the variable length polythymidine tract in the cystic fibrosis gene.

BACKGROUND: The observation that only a minority of alcoholics develops clinical pancreatic disease has led to a search for a predisposing factor to the disease. One possible predisposing factor is mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene as cystic fibrosis leads to pancreatic injury. We have recently demonstrated that 15 common CFTR mutations are not found in patients with alcoholic pancreatitis. Another common polymorphism of the CFTR gene has recently been implicated in the pathogenesis of idiopathic chronic pancreatitis, the 5T variant of the variable length polythymidine tract in intron 8 (the normal genotypes are 7T and 9T). The 5T variant inhibits transcription of exon 9 resulting in a CFTR protein lacking chloride channel activity. The aim of this study was to determine whether the 5T variant is associated with alcoholic pancreatitis. METHODS: Fifty-two patients with alcoholic pancreatitis were identified using standardized diagnostic criteria. Fifty alcoholics without pancreatitis were also studied as controls. Genomic DNA was extracted from peripheral blood leukocytes and the polythymidine tract of intron 8 was amplified by nested polymerase chain reaction using established primers. The polymerase chain reaction products were digested with MseI, separated by electrophoresis on 15% polyacrylamide gels and genotypes assigned by comparison with known positive controls. RESULTS: The 5T allele we found in only two patients with alcoholic pancreatitis (3.9% of th index group; 95% confidence intervals 0-10%) and in seven alco holic controls. Allele frequencies for 5T, 7T, and 9T in patients with alcoholic pancreatitis were 1.9%, 85.6%, and 12.5%, respectively These did not differ from the allele frequencies in alcoholic controls (7%, 79%, and 14% for 5T, 7T, and 9T, respectively). CONCLUSION: The 5T allele was not associated with alcoholic pancreatitis. Individual susceptibility to this disease remains unexplained.

Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis.

BACKGROUND: The pathogenesis of pancreatic fibrosis is unknown. In the liver, stellate cells play a major role in fibrogenesis by synthesising increased amounts of collagen and other extracellular matrix (ECM) proteins when activated by profibrogenic mediators such as cytokines and oxidant stress. AIMS: To determine whether cultured rat pancreatic stellate cells produce collagen and other ECM proteins, and exhibit signs of activation when exposed to the cytokines platelet derived growth factor (PDGF) or transforming growth factor beta (TGF-beta). METHODS: Cultured pancreatic stellate cells were immunostained for the ECM proteins procollagen III, collagen I, laminin, and fibronectin using specific polyclonal antibodies. For cytokine studies, triplicate wells of cells were incubated with increasing concentrations of PDGF or TGF-beta. RESULTS: Cultured pancreatic stellate cells stained strongly positive for all ECM proteins tested. Incubation of cells with 1, 5, and 10 ng/ml PDGF led to a significant dose related increase in cell counts as well as in the incorporation of 3H-thymidine into DNA. Stellate cells exposed to 0.25, 0.5, and 1 ng/ml TGF-beta showed a dose dependent increase in alpha smooth muscle actin expression and increased collagen synthesis. In addition, TGF-beta increased the expression of PDGF receptors on stellate cells. CONCLUSIONS: Pancreatic stellate cells produce collagen and other extracellular matrix proteins, and respond to the cytokines PDGF and TGF-beta by increased proliferation and increased collagen synthesis. These results suggest an important role for stellate cells in pancreatic fibrogenesis.

Metabolism of ethanol by rat pancreatic acinar cells.

It has been postulated that ethanol-induced pancreatic injury may be mediated by the oxidation of ethanol within the pancreas with secondary toxic metabolic changes, but there is little evidence of pancreatic ethanol oxidation. The aims of this study were to determine whether pancreatic acinar cells metabolize significant amounts of ethanol and, if so, to compare their rate of ethanol oxidation to that of hepatocytes. Cultured rat pancreatic acinar cells and hepatocytes were incubated with 5 to 50 mmol/L carbon 14-labeled ethanol (25 dpm/nmol). Ethanol oxidation was calculated from the production of 14C-labeled acetate that was isolated by Dowex ion-exchange chromatography. Ethanol oxidation by pancreatic acinar cells was demonstrable at all ethanol concentrations tested. At an intoxicating ethanol concentration (50 mmol/L), 14C-labeled acetate production (227+/-20 nmol/10(6) cells/h) approached that of hepatocytes (337+/-61 nmol/10(6) cells/h). Phenanthroline (an inhibitor of classes I through III isoenzymes of alcohol dehydrogenase (ADH)) inhibited pancreatic ethanol oxidation by 90%, but 4-methylpyrazole (a class I and II ADH inhibitor), carbon monoxide (a cytochrome P450 inhibitor), and sodium azide (a catalase inhibitor) had no effect. This study has shown that pancreatic acinar cells oxidize significant amounts of ethanol. At intoxicating concentrations of ethanol, pancreatic acinar cell ethanol oxidation may have the potential to contribute to pancreatic cellular injury. The mechanism appears to involve the class III isoenzyme of ADH.

Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture.

BACKGROUND: The pathogenesis of pancreatic fibrosis is unknown. In the liver, stellate cells (vitamin A storing cells) play a significant role in the development of fibrosis. AIMS: To determine whether cells resembling hepatic stellate cells are present in rat pancreas, and if so, to compare their number with the number of stellate cells in the liver, and isolate and culture these cells from rat pancreas. METHODS: Liver and pancreatic sections from chow fed rats were immunostained for desmin, glial fibrillary acidic protein (GFAP), and alpha smooth muscle actin (alpha-SMA). Pancreatic stellate shaped cells were isolated using a Nycodenz gradient, cultured on plastic, and examined by phase contrast and fluorescence microscopy, and by immunostaining for desmin, GFAP, and alpha-SMA. RESULTS: In both liver and pancreatic sections, stellate shaped cells were observed; these were positive for desmin and GFAP and negative for alpha-SMA. Pancreatic stellate shaped cells had a periacinar distribution. They comprised 3.99% of all pancreatic cells; hepatic stellate cells comprised 7.94% of all hepatic cells. The stellate shaped cells from rat pancreas grew readily in culture. Cells cultured for 24 hours had an angular appearance, contained lipid droplets manifesting positive vitamin A autofluorescence, and stained positively for desmin but negatively for alpha-SMA. At 48 hours, cells were positive for alpha-SMA. CONCLUSIONS: Cells resembling hepatic stellate cells are present in rat pancreas in a number comparable with that of stellate cells in the liver. These stellate shaped pancreatic cells can be isolated and cultured in vitro.

Prognostic significance of MYCN oncogene expression in childhood neuroblastoma.

PURPOSE: To assess the significance of MYCN gene expression as a prognostic factor in patients with neuroblastoma of various ages, and to determine whether it can predict for outcome independently of MYCN gene amplification. PATIENTS AND METHODS: The level of MYCN gene expression in 60 specimens of primary untreated neuroblastoma was determined by reverse-transcriptase polymerase chain reaction (RT-PCR) analysis. RESULTS: High levels of MYCN gene expression were associated with advanced tumor stage (P=.0005), with the presence of MYCN gene amplification (P < .0001), but not with older age at diagnosis. Among patients who lacked MYCN gene amplification, the levels of MYCN gene expression were significantly greater in the tumors of infants compared with those of older children (P < .0005). High MYCN expression was strongly associated with reduced survival and event-free survival in the overall study population (P < .005), and also in the subset of patients aged older than 1 year at diagnosis (P < .001). In contrast, MYCN expression did not appear to be predictive of outcome in infants. After adjustment for the effect of MYCN amplification, high levels of MYCN expression retained significant prognostic value for poor survival (relative hazards, 30.3; P=.003) in children aged older than 12 months at diagnosis. CONCLUSION: High MYCN gene expression is strongly predictive of poor outcome in older children with neuroblastoma, but not in infants. The findings help explain the controversy in the literature about the prognostic value of MYCN gene expression and highlight the different biology of neuroblastoma that presents in infants and older children.

Cystic fibrosis genotypes and alcoholic pancreatitis.

Pancreatitis and pancreatic insufficiency are associated with both cystic fibrosis and alcoholism. The pathogenesis of alcoholic pancreatitis is unknown, but only a minority of alcoholics develop pancreatitis, and it has been suggested that a genetic predisposition may play a role in this disease. Two observations led to the hypothesis that this genetic predisposition could result from mutations in the cystic fibrosis gene. First, the prevalence of cystic fibrosis mutations in the Caucasian population (approximately 5%) is similar to the prevalence of pancreatitis among heavy drinkers. Second, in both diseases, pancreatic duct damage is a prominent feature and has been postulated to be the initial site of injury. Therefore, the aim of this study was to determine whether an increased frequency of mutations in the cystic fibrosis gene occurs in alcoholic pancreatitis. The 15 most common cystic fibrosis mutations in a Caucasian community were sought in 24 subjects with alcoholic pancreatitis. None were homozygous or heterozygous for these mutations. These findings suggest that cystic fibrosis mutations are not a major genetic factor predisposing to pancreatic injury in alcoholics.