An open prospective study evaluating efficacy and safety of a new medical device for rectal application of activated carbon in the treatment of chronic, uncomplicated perianal fistulas.

PURPOSE: It has been proposed that biological/chemical substances in the intestine might play a role in the occurrence and deterioration of perianal fistulas. Elimination of such unidentified factors from the lower gastrointestinal tract might offer a new strategy for the management of anal fistulas. The aim of this study was to evaluate the clinical effects on non-Crohn's disease perianal fistula healing, and the safety and tolerability of a new medical device that applies high-purity, high-activity granular activated carbon locally into the rectum twice daily of patients with perianal fistulas without any concomitant medication. METHODS: An open, single-arm, prospective study with active treatment for 8 weeks and an optional follow-up until week 24 ( ClinicalTrial.gov identifier NCT01462747) among patients with chronic, uncomplicated perianal fistulas scheduled for surgery was conducted. RESULTS: Of 28 patients included, 10 patients (35.7%) showed complete fistula healing (closed, no discharge on palpation) after 8 weeks; seven of these patients, corresponding to 25% of the enrolled patients, remained in remission for up to 31 weeks. At week 8, there was a statistically significant reduction in the discharge visual analog scale (p = 0.04), a significant improvement in the patient-perceived quality of life for the category of embarrassment (p = 0.002), and a trend toward improvement in the other assessment categories. CONCLUSIONS: The treatment was well tolerated, and patient acceptance was high. The results support the efficacy and safety of locally administered activated carbon for the treatment of patients with chronic uncomplicated perianal fistulas not receiving any other medication for fistula problems.

Direct and indirect costs for anal fistula in Sweden.

INTRODUCTION: Anal fistula is an abnormal tract with an external and internal opening that cause leakage, discomfort, and occasionally pain. Surgery is standard treatment, but recurrence and anal incontinence is common. The objective of the study was to analyze resource use, costs and sick leave for newly diagnosed patients with anal fistula in Sweden. METHODS: The study was based on register data from linkages between Swedish population-based registers including patients treated for anal fistula in Västra Götaland County, Sweden. Health care resource use, costs and sick leave were estimated. RESULTS: The sample included 362 patients of which 27% had no surgery, 37% had one surgery and 36% had multiple surgeries. Patients with multiple surgeries underwent over four surgeries on average. Approximately 67% of the contacts occurred during the first year after diagnosis. Estimated mean sick leave was 10.4 full-time equivalent days per patient. Total discounted costs were €5,561 per patient where approximately 80% were direct costs. DISCUSSION: To our knowledge this is the first study of resource use, costs and sick leave related to anal fistulas. The study indicates that anal fistula is a condition that is costly for society and that the burden of anal fistula in terms of health care resources and sick leave is especially high for patients experiencing multiple surgeries. CONCLUSION: Anal fistula is a condition that is costly for society and there is an unmet need for the group of patients with multiple surgeries to find appropriate treatment interventions.

Reduction of direct and indirect costs in patients with AS receiving etanercept: results from an open-label 36-week extension of the ASCEND study in four European countries.

OBJECTIVE: To characterize the impact of etanercept (ETN) in AS on cost, work productivity and quality of life (QoL). METHODS: A Phase 4, open-label, multi-centre (UK, Scandinavia) extension study in AS. Eligible subjects (n = 84) were treated for 36-52 weeks with ETN 50 mg s.c. once weekly. Analysis included direct costs (transformed out-patient and in-patient care elements), indirect costs (sick leave and lost working days), efficacy and QoL. RESULTS: Annualized direct and indirect costs decreased (55.5%, P ≤ 0.008) during ETN treatment, as did out-patient and in-patient episodes (physiotherapist/physician visits, P = 0.012). Work productivity and QoL increased. CONCLUSION: ETN therapy significantly reduces direct and indirect health-care costs and increases work ability and QoL in AS. Trial Registration. EUDRACT, https://eudract.ema.europa.eu/, 2006-001061-42.

Cost-effectiveness of treatment with etanercept for psoriasis in Sweden.

OBJECTIVE: To estimate the cost-effectiveness, from a Swedish societal perspective, of intermittent use of etanercept (Enbrel) with interruptions of use after 24 weeks compared to continuous use of adalimumab (Humira) as well as non-systemic standard of care in patients with moderate to severe psoriasis. METHODS: A Markov decision-tree model was constructed from clinical trials results. Patients starting etanercept, adalimumab, or non-systemic therapy moved through the model's 10-years horizon. Model input parameters included clinical response rates. Outcome measures included direct and indirect costs and quality-adjusted life-years (QALYs). RESULTS: The incremental total (direct and indirect) costs per QALY were 1,559,939 kr (165,354) for adalimumab 40 mg every other week, compared with intermittent once-weekly Enbrel 50 mg, and 93,629 kr (9,925) for once-weekly intermittent etanercept 50 mg compared with non-systemic standard of care. CONCLUSIONS: This analysis showed that, with a 470,000 kr (50,000) per QALY willingness-to-pay threshold, once-weekly etanercept 50 mg, used intermittently, is a cost-effective treatment for moderate to severe psoriasis compared with adalimumab and non-systemic standard of care.

Multicentre phase II trial of capecitabine and oxaliplatin in combination with radiotherapy for unresectable colorectal cancer: the CORGI-L Study.

AIMS: This study assessed radiotherapy combined with capecitabine and oxaliplatin in patients with primary, inextirpable colorectal adenocarcinoma. PATIENTS AND METHODS: Forty-nine patients entered the trial. Two cycles of XELOX (capecitabine 1000 mg/m(2) bid d1-14+oxaliplatin 130 mg/m(2) d1, q3w) were followed by radiotherapy (50.4 Gy), combined with capecitabine 825 mg/m(2) bid every radiotherapy day and oxaliplatin 60 mg/m(2) once weekly. The primary end-point was objective response. RESULTS: Forty-seven patients were evaluable. Twenty-nine (62% [95% CI: 46-75%]) achieved complete or partial response. Thirty-eight (81%) went through surgery of whom 37 (97%) had an R0 resection and five (13%) had a pathological complete response. Seventy-eight percent were alive and estimated local progression rate was 11% at 2 years. The most common grade 3+ toxicity during chemoradiotherapy was diarrhoea (24%). CONCLUSIONS: XELOX-RT was feasible and showed promising efficacy when treating patients with primary inextirpable colorectal cancer, establishing high local control rate.

Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27.

Chronic exposure of pancreatic islets to elevated plasma lipids (lipotoxicity) can lead to beta-cell dysfunction, with overtime becoming irreversible. We examined, by confocal microscopy and biochemistry, whether the expression of islet inducible nitric oxide synthase (iNOS) and the concomitant inhibition of glucose-stimulated insulin release seen after lipid infusion in rats was modulated by the islet neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP)27. Lipid infusion for 8 days induced a strong expression of islet iNOS, which was mainly confined to beta-cells and was still evident after incubating islets at 8.3 mmol/l glucose. This was accompanied by a high iNOS-derived NO generation, a decreased insulin release, and increased cyclic GMP accumulation. No iNOS expression was found in control islets. Addition of PACAP27 to incubated islets from lipid-infused rats resulted in loss of iNOS protein expression, increased cyclic AMP, decreased cyclic GMP, and suppression of the activities of neuronal constitutive (nc)NOS and iNOS and increased glucose-stimulated insulin response. These effects were reversed by the PKA inhibitor H-89. The suppression of islet iNOS expression induced by PACAP27 was not affected by the proteasome inhibitor MG-132, which by itself induced the loss of iNOS protein, making a direct proteasomal involvement less likely. Our results suggest that PACAP27 through its cyclic AMP- and PKA-stimulating capacity strongly suppresses not only ncNOS but, importantly, also the lipid-induced stimulation of iNOS expression, possibly by a nonproteasomal mechanism. Thus PACAP27 restores the impairment of glucose-stimulated insulin release and additionally might induce cytoprotection against deleterious actions of iNOS-derived NO in beta-cells.

Working capacity and well-being after radical cystectomy with continent cutaneous diversion.

OBJECTIVES: The primary aim was to compare the working capacity in patients with continent urinary diversion with a control group. Secondary aims were to assess the changes in electrolyte and acid-base homeostasis and the functional status during strenuous physical activity, and finally, the well-being in the two groups. METHODS: Eleven patients who had undergone radical cystectomy and continent cutaneous diversion using an ileocolonic segment participated. The control group consisted of 12 men, matched for age and activity level. Working capacity was assessed by ergospirometry on an exercise bicycle. Venous blood samples were taken before the test, when the expiratory exchange ratio (RER) was about 1.0 and immediately after completion of the test. SF-36 was used to evaluate the subject's functional status and well-being. RESULTS: The median working capacity in the patient group was 155 (85-190) W and 155 (125-215) W in the control group (n.s.) corresponding to 72 (43-97) % and 80 (59-97) % respectively of predicted values. Peak oxygen uptake was somewhat low in both groups when compared to P-O Astrands norms. Blood tests revealed that patients developed a slight metabolic hyperchloremic acidosis, not seen in the control group. There were no differences between the groups as assessed with SF-36. CONCLUSION: Patients with a continent urinary diversion have a working capacity equal to a control group despite a slight metabolic hyperchloremic acidosis. Quality of life was similar in the two groups and corresponded well with the norms for the general Swedish population aged 65 to 74.

Long-term infusion of nutrients (total parenteral nutrition) suppresses circulating ghrelin in food-deprived rats.

BACKGROUND: Ghrelin derives from endocrine cells (A-like cells) in the stomach (mainly the oxyntic mucosa). Its concentration in the circulation increases during fasting and decreases upon re-feeding. This has fostered the notion that the absence of food in the upper gastrointestinal (GI) tract stimulates the secretion of ghrelin. The purpose of the present study was to determine the concentration of ghrelin in serum and oxyntic mucosa after replacing food with intravenous (iv) infusion of nutrients for 8 days using the technique known as total parenteral nutrition (TPN) MATERIALS AND METHODS: Male Sprague-Dawley rats (200-250 g) were given nutrients (lipids, glucose, amino acids, minerals and vitamins) by iv infusion for 8 days during which time they were deprived of food and water; another group was deprived of food for 24-48 h (fasted controls), while fed controls had free access to food and water. Serum ghrelin, gastrin and pancreastatin concentrations were measured together with the ghrelin content of the oxyntic mucosa. Plasma insulin and glucose as well as serum lipid concentrations were also determined. RESULTS: Fasted rats had higher serum ghrelin than TPN rats and fed controls. The oxyntic mucosal ghrelin concentration (and content) was lower in TPN rats than in fasted rats or fed controls. The serum gastrin and pancreastatin concentrations were lower in TPN rats and fasted rats than in fed controls. The plasma insulin concentration was 87 pmol/l+/-8 (SEM) in TPN rats compared to 101+/-16 pmol/l in fed controls; it was 26+/-14 pmol/l in fasted rats. The basal plasma glucose level was 11+/-0.6 mmol/l in TPN rats and 12+/-0.8 mmol/l in fed controls; it was 7+/-0.3 mmol/l in fasted rats. In TPN rats, the serum concentrations of free fatty acids, triglycerides and cholesterol were increased by 100%, 50% and 25%, respectively, compared to fed controls. Fasted rats had higher circulating concentrations of free fatty acids (20%) and lower concentrations of triglycerides (-40%) than fed controls; fasted rats did not differ from fed controls with respect to serum cholesterol. CONCLUSION: The circulating ghrelin concentration is high in situations of nutritional deficiency (starvation) and low in situations of nutritional plenty (free access to food or TPN). The actual presence or absence of food in the GI tract seems irrelevant. Circulating insulin and glucose concentrations did not differ much between TPN rats and fed controls; serum lipids, however, were elevated in the TPN rats. We suggest that elevated blood lipid levels contribute to the suppression of circulating ghrelin in rats subjected to TPN for 8 days.

Ghrelin activates neuronal constitutive nitric oxide synthase in pancreatic islet cells while inhibiting insulin release and stimulating glucagon release.

In view of our previous data, showing that ghrelin and nitric oxide (NO) display apparently parallel effects on insulin secretion (inhibitory) and glucagon secretion (stimulatory), we have now investigated the effect of ghrelin on islet hormone secretion in relation to its effect on NO synthase (NOS) isoenzymes in isolated rat pancreatic islets. Dose-response studies revealed that ghrelin at concentrations of 0.01-1 micromol l-1 inhibited insulin secretion stimulated by 8.3 mmol l-1 glucose, while ghrelin at concentrations lower than the physiological range (0.01 pmol l-1 to 1 nmol l-1) were without effect. In contrast, glucagon secretion was stimulated by 1.0 nmol l-1 to 1 micromol l-1 ghrelin. These effects of ghrelin on insulin and glucagon secretion were accompanied by increased NO production through activation of neuronal constitutive NOS (ncNOS). Ghrelin had no appreciable effect on the activity of inducible NOS (iNOS) in the islets. Addition of an NO scavenger (cPTIO) or the NOS inhibitor L-NAME to the incubation medium prevented the effects of ghrelin on hormone secretion from isolated islets. The present results confirm our previous data showing that ghrelin inhibits insulin and stimulates glucagon secretion from pancreatic islets of the mouse and we now show similar effects in rat islets. The effects of ghrelin were accompanied by an increased rate of NO production. Conceivably, ncNOS activation partly accounts for to the inhibitory effect of ghrelin on insulin secretion and the stimulatory effect of ghrelin on glucagon secretion.

Defective insulin secretion during total parenteral nutrition in rat and its normalization by pituitary adenylate cyclase-activating polypeptide 27.

The role of PACAP27, PACAP38 and VIP in the regulation of insulin release from pancreatic islets isolated from rats previously subjected to total parenteral nutrition (TPN) for 10 days was studied. Glucose-stimulated insulin secretion from islets of TPN rats was attenuated in parallel with cyclic AMP production. Immunocytochemistry showed an increased number of VIP-immunoreactive nerve fibers in the pancreatic islets of TPN rats. PACAP27, PACAP38 and VIP dose dependently and to the same magnitude potentiated insulin secretion from the islets of freely fed controls in the presence of a substimulatory glucose concentration (8.3 mmol/l). The secretory response of islets from TPN-treated rats to these neuropeptides was, however, markedly exaggerated compared to the controls. The insulin response of islets from TPN-treated rats to PACAP27 and PACAP38 was much greater than to VIP. With respect to insulin secretion, TPN treatment shifted the PACAP27 and PACAP38 dose-response curve to the left by two orders of magnitude. In the presence of 8.3 mmol/l glucose, cAMP accumulation was slightly higher in islets from TPN rats and the PACAP27, PACAP38 and VIP-stimulated increase in the cAMP production was markedly greater compared to the controls. Additional complementary in vivo experiments showed that PACAP27 normalized the defective glucose-stimulated insulin secretory response of TPN-treated rats. The data suggest that the defective nutrient-stimulated insulin secretion seen after long-term TPN treatment could be normalized by agents stimulating cAMP production possibly through cAMP/PK A-pathway.

Cytogenetic aberrations and heterogeneity of mutations in repeat-containing genes in a colon carcinoma from a patient with hereditary nonpolyposis colorectal cancer.

The majority of tumors from patients affected by hereditary nonpolyposis colorectal cancer (HNPCC) exhibit a mutator phenotype characterized by widespread microsatellite instability (MSI) and somatic mutations in repeated sequences in several cancer-associated genes. An inverse relationship between MSI and chromosomal instability (CIN) has been demonstrated and HNPCC-associated tumors are generally characterized by diploid or near-diploid cells with few or no chromosomal rearrangements. We have studied MSI, somatic mutations in repeat-containing genes, DNA-ploidy, and cytogenetic aberrations in a colon carcinoma from a patient with a germline MLH1 mutation. Mutations in coding repeats were assessed in 10 macroscopically separate areas of the primary tumor and in two lymph nodes. Some of the genes studied (E2F4, MSH3, MSH6, TCF4, and TGFBRII) showed a consistent lack of mutations, whereas others (BAX, Caspase-5 and IGFIIR) displayed alterations in some tumor regions but not in others. The tumor had DNA-index 1.1-1.2 and a stable, aberrant karyotype with extra copies of chromosomes 7 and 12 and the structural aberrations i(1q), der(20)t(8;20), and der(22)t(1;22). The finding of CIN, MSI, and somatic mutations in coding repeats in this tumor suggests that these phenomena may act together in HNPCC tumorigenesis. Furthermore, the observed intratumoral heterogeneity of mutations in coding repeats implies these changes occur late in tumorigenesis and, thus, probably play a role in tumor progression rather than initiation.

Management of appendiceal masses.

OBJECTIVE: To evaluate the outcome of patients treated for appendiceal abscess, and managed either conservatively or surgically, and to describe the short and long-term outcome as well as incidence of interval appendicectomy in those treated conservatively. DESIGN: Retrospective study. SETTING: University hospital, Sweden. PATIENTS: Ninety-three patients with the diagnosis of appendiceal abscess, 50 treated conservatively and 43 who were operated on, with a mean age of 46 (14-93) years. Mean (range) follow-up for patients operated on was 65 (11-135) and for those treated conservatively 66 (6-136) months. MAIN OUTCOME MEASURES: Course of acute disease, recorded complications, recurrence of appendicitis and incidence of interval appendicectomy during follow-up. RESULTS: The duration of pain before admission was 4 (0.5-82) days for those operated on and 7 (2-60) days for those treated conservatively. A palpable mass was more common in the conservatively managed group. Complications were common among patients who were operated on. No interval appendicectomies were done during the second half of the study period. 4 of the patients treated conservatively (8%) had an underlying tumour diagnosed at follow-up. CONCLUSIONS: Operative management of patients with appendiceal masses seems to be associated with a high risk of postoperative complications and the risk of a more extensive surgical procedure. If possible, a conservative approach should be advocated. Because of inaccurate radiological imaging during the acute phase and the risk of an underlying malignancy, routine follow-up is necessary. Routine interval appendicectomy cannot be recommended.