Does severe bleeding in HHT patients respond to intravenous bevacizumab? Review of the literature and case series.

BACKGROUND: Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant genetic disorder, with a wide variety of clinical manifestations due to the presence of multiple arteriovenous manifestations. Severe bleeding from the gastrointestinal (GI) tract and/or epistaxis presents a significant problem in a subgroup of patients and systemic bevacizumab, an angiogenesis inhibitor, has been suggested to benefit these patients. OBJECTIVE: To perform a review of the literature concerning the efficacy of systemic bevacizumab in treatment of bleeding from the nose or GI tract in patients with HHT, including patients from our own HHT-center. METHODS: A literature review was performed using the guideline "Preferred Reporting Items for systematic Reviews and MetaAnalysis statement" (PRISMA). RESULTS: After careful selection, we finally analysed the results of eight case series and 33 case reports. Among 195 patients 171 (88%) had reduced bleeding after bevacizumab. CONCLUSIONS: Based on the literature review and data from our own case series, systemic bevacizumab is very promising as treatment for HHT patients with severe epistaxis and/or GI-bleeding. However, care should be taken using bevacizumab, a potent angiogenesis inhibitor; long-term side effects have not been studied in this population. A randomized controlled study is warranted to support the results in HHT patients.

T cells isolated from patients with checkpoint inhibitor-resistant melanoma are functional and can mediate tumor regression.

Background: Almost half of the patients with metastatic melanoma obtain only short-term or no benefit at all from checkpoint inhibitor (CPI) immunotherapy. In this study, we investigated whether the immune system of patients progressing following CPI treatment was able to generate functional tumor-specific immune responses. Materials and methods: Tumor-infiltrating lymphocytes (TILs) were isolated and expanded from metastatic melanoma lesions which progressed during or after anti-programmed cell death protein 1 (PD)-1 and anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) treatment. Tumor-specific immune responses were assessed with co-culture assays of TILs and autologous tumor cells. Results: TILs from 23 metastases of individual patients could be assessed for T cells recognition of autologous tumor cells. All metastases were progressive on or following anti-PD-1 (23/23, 100%), and the majority also after anti-CTLA-4 (17/23, 74%). Functional antitumor immune responses were detected in 19/23 patients (83%). Both CD8+ (in 18/23 patients, 78%) and CD4+ (in 16/23 patients, 70%) TILs were able to recognize autologous tumors. A large fraction of CD8+ TILs (median 23%, range 1.0%-84%) recognized tumor cells. This is similar to the cohorts of unselected patient populations with metastatic melanoma presented in previous studies. The localization of intratumoral immune infiltrates was heterogeneous among samples. In a phase I/II clinical trial, TILs were administered with lymphodepleting chemotherapy, pegIFNα2b and interleukin-2 to 12 patients with CPI-resistant melanoma. Out of 12 patients who previously failed CPI therapy, treatment with TILs resulted in two partial responses, of which one is ongoing. Conclusions: Tumor-reactive T cells appear to heavily infiltrate the tumor microenvironment of patients who failed previous CPI treatment. These patients can still respond to an infusion of unselected autologous TILs. Our results warrant further testing of novel immune re-activation strategies in melanoma patients who failed multiple CPI therapy.

Short sleep duration and large variability in sleep duration are independently associated with dietary risk factors for obesity in Danish school children.

BACKGROUND: Lack of sleep and increased consumption of energy-dense foods and sugar-sweetened beverages (SSBs) have all been suggested as factors contributing to the increased prevalence of overweight and obesity. OBJECTIVE: To evaluate whether objectively measured sleep duration (average and day-to-day variability) as well as parent-reported sleep problems are independently associated with proposed dietary risk factors for overweight and obesity in 8-11-year-old children. DESIGN: In this cross-sectional study, data on sleep duration and day-to-day variability in sleep duration were measured in 676 Danish, apparently healthy children by an objective measure (actigraphy) for 8 nights, and the Children's Sleep Habits Questionnaire (CSHQ) was filled out by the parents. Diet was recorded using a web-based food record for 7 consecutive days. Fasting blood samples were obtained for measurements of plasma leptin and ghrelin levels. RESULTS: Sleep duration (h per night) was negatively associated with energy density (ED) of the diet (ß = -0.32 kJ g(-1)), added sugar (ß = -1.50 E%) and SSBs (ß = -1.07 E%) (all P ≤ 0.003). Furthermore, variability in sleep duration (10-min per night) was positively associated with SSBs (ß = 0.20 E%, P = 0.03), independent of sleep duration, and CSHQ score was positively associated with ED (ß = 0.16 kJ g(-1), P = 0.04). All of these associations were independent of potential confounders (age, sex, pubertal status, height, weight, screen time, moderate-to-vigorous physical activity and parental education and ethnicity). CONCLUSION: Our study suggests that short sleep duration, high sleep duration variability and experiencing sleep problems are all associated with a poor, obesity-promoting diet in children.

A randomized, double-blinded, placebo-controlled, parallel trial of vitamin D3 supplementation in adult patients with migraine.

BACKGROUND: Vitamin D levels have been linked to certain pain states, including migraine. This study investigated whether vitamin D supplementation would be beneficial for adult patients with migraine (ClinicalTrials.gov Identifier: NCT01695460). METHODS: A randomized, double-blinded, placebo-controlled parallel trial was conducted in migraine patients (36 women and 12 men, 18-65 years of age). A 4-week baseline period was conducted before randomization to 24 weeks of treatment. Participants were assigned to receive D3-Vitamin (n = 24, 18 women and 6 men, 100 µg/day D3-Vitamin) or placebo (n = 24, 18 women and 6 men). Migraine attacks and related symptoms were assessed by self-reported diaries. The response rate (i.e. experiencing a 50% or greater reduction in migraine frequency from baseline to week 24), change in migraine severity, and number of migraine days were recorded. Changes in migraine-related symptoms, HIT-6TM scores, and pain sensitivity tests (pressure pain threshold and temporal summation) were also evaluated. Serum levels of both 25 (OH)D and 1,25 (OH)2D were assessed from baseline to week 24. RESULTS: The number of headache days changed from 6.14 ± 3.60 in the treatment group and 5.72 ± 4.52 in the placebo group at baseline to 3.28 ± 3.24 and 4.93 ± 3.24 by the end of the trial, respectively. Migraine patients on D3-Vitamin demonstrated a significant decrease (p < .001) in migraine frequency from baseline to week 24 compared with placebo. However, migraine severity, pressure pain thresholds, or temporal summation did not show a significant change. 25(OH)D levels increased significantly for the D3-Vitamin group during the first 12 weeks of treatment. There was no significant change in 1,25(OH)2D. No side-effects were reported or noted. CONCLUSIONS: D3-Vitamin was superior to placebo in reducing migraine days in migraine patients. Larger studies are required to confirm that vitamin D3 might be one of the prophylactic options for adult patients with migraine.

The intestinal tissue homeostasis - the role of extracellular matrix remodeling in inflammatory bowel disease.

Introduction: Extracellular matrix (ECM) remodeling of the intestinal tissue is important in inflammatory bowel disease (IBD) due to the extensive mucosal remodeling. There are still gaps in our knowledge as to how ECM remodeling is related to intestinal epithelium homeostasis and healing of the intestinal mucosa.Areas covered: The aim of this review is to highlight the importance of the ECM in relation to the pathogenesis of IBD, while addressing basement membrane and interstitial matrix remodeling, and the processes of wound healing of the intestinal tissue in IBD.Expert opinion: In IBD, basement membrane remodeling may reflect the integrity of the intestinal epithelial-cell homeostasis. The interstitial matrix remodeling is associated with deep inflammation such as the transmural inflammation as seen in fistulas and intestinal fibrosis leading to fibrostenotic strictures, in patients with CD. The interplay between wound healing processes and ECM remodeling also affects the tissue homeostasis in IBD. The interstitial matrix, produced by fibroblasts, holds a very different biology as compared to the epithelial basement membrane in IBD. In combination with integration of wound healing, quantifying the interplay between damage and repair to these sub compartments may provide essential information in IBD patient profiling, mucosal healing and disease management.

Poor Outcomes of Complicated Pouch-Related Fistulas after Ileal Pouch-Anal Anastomosis Surgery.

BACKGROUND AND AIMS: Development of a pouch-related fistula tract is an uncommon but highly morbid complication to restorative proctocolectomy with ileal pouch-anal anastomosis. Pouch failure with permanent ileostomy is reported in 21%-30% of patients, yet the factors contributing to pouch excision remain poorly defined. The aim of this study was to determine the incidence and treatment results of complicated pouch-related fistula, as well as to evaluate factors involved in excision after pouch failure. MATERIAL AND METHODS: The study was conducted as a retrospective study. All patients with diagnosed pouch-related fistulas were registered with information related to fistula classification, treatments, and outcome. RESULTS AND CONCLUSION: The final analysis included 48 (10.7%) of the 447 total ileal pouch-anal anastomosis patients with complicated pouch-related fistulas. Pouch-vaginal fistulas, pouch-perianal fistulas, and other pouch-related fistulas were observed in 19 (63%), 29 (60%), and 10 (21%) patients, respectively, corresponding to an accumulated risk of 8%, 6%, and 2%, respectively. Time from ileal pouch-anal anastomosis surgery to fistula presentation was 24 (0.2-212) months. Overall pouch failure, defined as pouch excision or a diverting stoma, was seen in 34 (71%) patients, while pouch excision was seen in 23 (48%) of the patients. Patients who developed Crohn's disease had a significantly higher risk of pouch excision, as did patients with an early onset of the fistula after ileal pouch-anal anastomosis (P = 0.006 and P = 0.007, respectively). In conclusion, the present study demonstrated a high risk of pouch failure in patients with complicated pouch-related fistulas. Furthermore, it showed that Crohn's disease and the development of early onset fistulas are associated with pouch excision.

Blockade of leukotriene production by a single oral dose of MK-0591 in active ulcerative colitis.

BACKGROUND: 5-Lipoxygenase products of arachidonic acid metabolism are thought to play a central role in the secondary amplification of the inflammatory response in a number of human inflammatory diseases, such as ulcerative colitis. MK-0591 (3-(1((4-chlorophenyl)methyl)-3((1,1-dimethyl-ethyl)thio)-5(quinolin+ ++-2ylmethyl-oxy)-1H-indol-2yl)-2,2-dimethyl-propanoate) exerts its effect by binding to the 5-lipoxygenase activating protein, thereby inhibiting the translocation and activation of 5-lipoxygenase. METHODS: Concentrations of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) in rectal dialysis fluid, ex vivo biosynthesis of LTB4 in whole blood, and urinary excretion of leukotriene E4 (LTE4) from 16 patients with mild to moderately active distally located ulcerative colitis were measured by use of radioimmunoassays in a double-blind, placebo-controlled parallel-design study before and after oral administration of a 250 mg dose of MK-0591 or placebo. RESULTS: The mean LTB4 concentration in rectal dialysis fluid was lowered after MK-0591 by > 90% (p < 0.05) from 4 to 8 hours, with a maximum inhibition of 97.5% +/- 3.4% (mean +/- SD) at 20 to 24 hours after dosing, whereas PGE2 was unchanged. In whole blood, MK-0591 decreased ex vivo biosynthesis of LTB4 (p < 0.01), with a maximum inhibition of 96.4% +/- 2.1% at 4 hours after dosing. Urinary excretion of LTE4 was reduced by more than 85% (p < 0.001) from 4 to 48 hours. No adverse events were observed. CONCLUSION: These findings show that a single oral 250 mg dose of MK-0591 results in nearly complete blockade of systemic leukotriene production and LTB4 formation in the target tissue of inflammation (the rectum). Controlled multiple-dose trials to assess the clinical efficacy of this novel 5-lipoxygenase-activating protein inhibitor seem to be worthwhile.

[Defense mechanisms of the gastroduodenal mucosa: the role of mucus and bicarbonate in the development of peptic ulcer]. / Gastroduodenalmucosa'ens forsvarsmekanismer: mucus' og bikarbonats betyndning for udviklingen af peptisk ulcus.

The existing knowledge of the mucus and bicarbonate production of the gastroduodenal mucosa is reviewed. Mucus and bicarbonate are produced in the surface epithelium of both duodenum and ventricle. The production is regulated by neural stimuli, gastrointestinal hormones and local synthesis of prostaglandins. Several of the factors suspected of being of importance to the development of peptic ulcers also have a negative influence on the production of mucus and bicarbonate. This indicates that mucus and bicarbonate are important in the pathogenesis of peptic ulcer. Two newly registered so-called mucosaprotective anti-ulcer drugs (De-Nol, Succralfat) both exert positive influences on the production of mucus and bicarbonate.

[Legionella infection with rhabdomyolysis]. / Legionella-infektion med rabdomyolyse.

Rhabdomyolysis complicating infection with Legionella pneumophila has previously been reported and may in some cases have led to acute tubular interstitial necrosis. We report a case of severe Legionnaires' disease complicated with rhabdomyolysis, myoglobinuria and neurological symptoms. Treatment with erythromycin and rifampicin was initiated early in the course of disease. The myoglobinuria was treated with forced diuresis and alkanization and renal failure did not develop. The frequency of rhabdomyolysis as a complication to Legionnaires' disease is not known. In addition, the pathogenesis and possible risk factors have not yet been determined. Considering the seriousness of this complication and until further investigations have been performed we recommend that routine determinations of creatine phosphokinase are performed in the evaluation of these patients.

[Defence mechanisms of the gastroduodenal mucosa. The significance of epithelial and subepithelial factors for the development of acute and chronic ulceration]. / Gastroduodenalmukosaens forsvarsmekanismer. Betydningen af epiteliale og subepiteliale faktorer for udviklingen af akutte og kroniske ulcerationer.

Extra-epithelial, epithelial and sub-epithelial defence mechanisms protect the gastroduodenal mucosa against acid and pepsin. The epithelial mechanisms include epidermal growth factor, surface active phospholipids on the luminal membrane of the epithelial cells, sulfhydryl compounds and rapid epithelial restitution after damage. The sub-epithelial mechanisms include mucosal blood flow supplying the mucosa with bicarbonate needed for neutralization of the acid which penetrates the epithelium and the protective effect of the process of acid secretion. Prostaglandins, which partially protect the gastroduodenal mucosa against damaging agents, stimulate several of the abovementioned defensive factors but the precise mechanism of the action of prostaglandins is still unknown. The results of several experiments support the idea of the defensive factors being of importance in the development of acute and chronic gastroduodenal ulceration. At present, the therapeutic possibilities seem to be restricted and nothing indicates that stimulation of the defensive factors, only, is more effective in the treatment of peptic ulcer than inhibition of aggressive factors as acid and pepsin.

[Cyclosporine treatment of patients with active ulcerative colitis refractory to high-dose glucocorticoid]. / Ciclosporinbehandling af patienter med aktiv colitis ulcerosa refraktaere over for højdosis-glukokortikoid.

In around 30-40% of patients with acute severe ulcerative colitis the disease is refractory to treatment with high-dose glucocorticoids. Adding intravenous cyclosporine to the therapy in these patients has shown encouraging short-term results. Case notes of twenty-three acutely ill patients, who received intravenous cyclosporine during the period 1992 to 1998 due to failure of high-dose glucocorticoid (n = 20) or due to medical complications (n = 3) which made surgery difficult, were reviewed. Eight patients had their first episode of ulcerative colitis whereas 15 had relapse or chronic active disease. Cyclosporine (4 mg/kg/dag) was added to glucocorticoid treatment after a median of 11 days. Clinical remission was achieved in 13 patients (57%) after a median of nine days, of these five subsequently underwent surgery. Ten did not obtain remission and went to surgery. Approximately a third of acutely ill ulcerative colitis patients refractory to standard treatment with high-dose glucocorticoids will benefit from intravenous cyclosporine in the longer term.

[Cesarean section. Changes in frequency and indications in the county of South Jutland during a 10-year period]. / Kejsersnit. Aendringer i frekvens og indikationer i Sønderjyllands Amt i en 10 års periode.

During recent years, the frequency of Caesarean section has changed everywhere. Changes during a ten-year period in the Department of Gynaecology in Sønderborg Hospital were registered and involve mainly the groups of imminant foetal death, previous Caesarean section, foeto-pelvic disproportion and placental insufficiency. Alterations in the obstetric services in the County of South Jutland and improved neonatal service have played an important part in development of the frequency of Caesarean section of Sønderborg Hospital.

Environmental factors in a population-based inception cohort of inflammatory bowel disease patients in Europe--an ECCO-EpiCom study.

BACKGROUND AND AIMS: The incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe possibly due to changes in environmental factors towards a more "westernised" standard of living. The aim of this study was to investigate differences in exposure to environmental factors prior to diagnosis in Eastern and Western European IBD patients. METHODS: The EpiCom cohort is a population-based, prospective inception cohort of 1560 unselected IBD patients from 31 European countries covering a background population of 10.1 million. At the time of diagnosis patients were asked to complete an 87-item questionnaire concerning environmental factors. RESULTS: A total of 1182 patients (76%) answered the questionnaire, 444 (38%) had Crohn's disease (CD), 627 (53%) ulcerative colitis (UC), and 111 (9%) IBD unclassified. No geographic differences regarding smoking status, caffeine intake, use of oral contraceptives, or number of first-degree relatives with IBD were found. Sugar intake was higher in CD and UC patients from Eastern Europe than in Western Europe while fibre intake was lower (p<0.01). Daily consumption of fast food as well as appendectomy before the age of 20 was more frequent in Eastern European than in Western European UC patients (p<0.01). Eastern European CD and UC patients had received more vaccinations and experienced fewer childhood infections than Western European patients (p<0.01). CONCLUSIONS: In this European population-based inception cohort of unselected IBD patients, Eastern and Western European patients differed in environmental factors prior to diagnosis. Eastern European patients exhibited higher occurrences of suspected risk factors for IBD included in the Western lifestyle.

Health care and patients' education in a European inflammatory bowel disease inception cohort: an ECCO-EpiCom study.

BACKGROUND AND AIMS: The EpiCom study and inception cohort was initiated in 2010 in 31 centers from 14 Western and 8 Eastern European countries, covering a 10.1million person background population. Our aim was to investigate whether there is a difference between Eastern and Western Europe in health care and education of patients with inflammatory bowel disease (IBD). METHODS: A quality of care (QoC) questionnaire was developed in the EpiCom group consisting of 16 questions covering 5 items: time interval between the onset of symptoms and diagnosis, information, education, empathy and access to health care providers. RESULTS: Of 1,515 patients, 947 (217 east/730 west) answered the QoC questionnaire. Only 23% of all patients had knowledge about IBD before diagnosis. In Eastern Europe, significantly more patients searched out information about IBD themselves (77% vs. 68%, p<0.05), the main source was the Internet (92% vs. 88% p=0.23). In Western Europe, significantly more patients were educated by nurses (19% vs. 1%, p<0.05), while in Eastern Europe, gastroenterologists were easier to contact (80% vs. 68%, p<0.05). CONCLUSION: Health care differed significantly between Eastern and Western Europe in all items, but satisfaction rates were high in both geographic regions. Because of the low awareness and the rising incidence of IBD, general information should be the focus of patient organizations and medical societies. In Western Europe IBD nurses play a very important role in reducing the burden of patient management.

Health-related quality of life improves during one year of medical and surgical treatment in a European population-based inception cohort of patients with inflammatory bowel disease--an ECCO-EpiCom study.

BACKGROUND & AIMS: Health-related quality of life (HRQoL) is impaired in patients with Inflammatory Bowel Disease (IBD). The aim was prospectively to assess and validate the pattern of HRQoL in an unselected, population-based inception cohort of IBD patients from Eastern and Western Europe. METHODS: The EpiCom inception cohort consists of 1560 IBD patients from 31 European centres covering a background population of approximately 10.1 million. Patients answered the disease specific Short Inflammatory Bowel Disease Questionnaire (SIBDQ) and generic Short Form 12 (SF-12) questionnaire at diagnosis and after one year of follow-up. RESULTS: In total, 1079 patients were included in this study. Crohn's disease (CD) patients mean SIBDQ scores improved from 45.3 to 55.3 in Eastern Europe and from 44.9 to 53.6 in Western Europe. SIBDQ scores for ulcerative colitis (UC) patients improved from 44.9 to 57.4 and from 48.8 to 55.7, respectively. UC patients needing surgery or biologicals had lower SIBDQ scores before and after compared to the rest, while biological therapy improved SIBDQ scores in CD. CD and UC patients in both regions improved all SF-12 scores. Only Eastern European UC patients achieved SF-12 summary scores equal to or above the normal population. CONCLUSION: Medical and surgical treatment improved HRQoL during the first year of disease. The majority of IBD patients in both Eastern and Western Europe reported a positive perception of disease-specific but not generic HRQoL. Biological therapy improved HRQoL in CD patients, while UC patients in need of surgery or biological therapy experienced lower perceptions of HRQoL than the rest.

Pre-operative use of anti-TNF-α agents and the risk of post-operative complications in patients with Crohn's disease--a nationwide cohort study.

BACKGROUND: A possible negative role of pre-operative use of antitumour necrosis factor-alpha (anti-TNF-α) agents on post-operative outcomes in Crohn's disease (CD) patients is still debated. AIM: To examine the impact of pre-operative anti-TNF-α agents on post-operative outcomes 30 and 60 days after CD surgery in a nationwide Danish cohort. Outcomes were death, reoperation, anastomosis leakage, intra-abdominal abscess and bacteraemia. METHODS: We identified all patients having surgical procedures from 1 January 2000 to 31 December 2010 (n = 2293). Patients were classified according to use of anti-TNF-α agents within 12 weeks before surgery (exposed) or not (unexposed). Outcomes were obtained from nationwide registries and a bacteraemia registry. Sub-analyses were performed for bacteraemia and for impact of pre-operative timing of anti-TNF-α agents. RESULTS: Among surgical procedures for CD, 214 were exposed and 2079 were not. We found no increased relative risks of death or abscess drainage 30 or 60 days after follow-up. Among exposed, 7.5% had a reoperation within 30 days vs. 8.6% among unexposed, adjusted odds ratio (OR) = 0.92, 95% confidence interval (CI): 0.52-1.63. Among exposed, 3.8% had an anastomosis leakage within 30 days after surgery vs. 2.8% among unexposed, adjusted OR = 1.33, 95% CI: 0.59-3.02. No further cases of anastomosis leakages appeared within 60 days. Sub-analyses indicated no increased risk of bacteraemia after 30 days and no increased risks when anti-TNF-α agents were given ≤14 days before surgery. CONCLUSION: We found no significantly increased relative risks of post-operative complications after use of anti-TNF-α agents either 12 weeks or ≤14 days before surgery for Crohn's disease.

Pre-operative use of anti-TNF-α agents and the risk of post-operative complications in patients with ulcerative colitis - a nationwide cohort study.

BACKGROUND: It is still controversial whether pre-operative anti-tumour necrosis factor-alpha (anti-TNF-α) agents increase post-operative complications in patients with ulcerative colitis (UC). AIM: In a nationwide Danish cohort of patients with UC, we aimed to examine the impact of pre-operative use of anti-TNF-α agents on post-operative adverse outcomes after colectomy for UC. Outcomes (within 30 and 60 days after surgery) were reoperation, anastomosis leakage, intra-abdominal abscess, bacteremia and death. METHODS: Based on the Danish National Patient Registry we identified all UC patients, aged ≥15 years, having their first surgery for UC in the period of 1 January 2003-31 December 2010 (n = 1226). Patients were classified according to use of anti-TNF-α agents within 12 weeks before surgery or not. Outcome data were obtained from Danish registries. Logistic regression analyses were used to estimate adjusted risks [with 95% confidence intervals (CI)] of post-operative outcomes among patients treated with anti-TNF-α agents, relative to those not treated. RESULTS: A total of 199 UC patients were exposed to anti-TNF-α agents within 12 weeks before colectomy, and 1027 were not. Among exposed, the adjusted odds ratio of reoperation and anastomosis leakage within 30 days after colectomy was 1.07 (95% CI: 0.71-1.59) and 0.52 (95% CI: 0.06-4.11) respectively. No deaths, cases of abscess drainage or bacteremia occurred among exposed within 30 days. Furthermore, no increased relative risks were found within 60 days after colectomy. CONCLUSIONS: Based on nationwide data on UC patients having colectomies, pre-operative use of anti-TNF-α agents did not increase the risk of post-operative complications.