A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist in development for the treatment of NASH with liver fibrosis. METHODS: We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score. RESULTS: Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group. CONCLUSIONS: Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.).

[Use of specific antidotes in DOAC-associated severe gastrointestinal bleeding - an expert consensus - Antagonozation of direct oral anticoagulants in gastrointestinal hemorrhages]. / Einsatz von spezifischen Antidots bei DOAK-assoziierter schwerer gastrointestinaler Blutung ­ ein Expertenkonsensus.

Gastrointestinal (GI) bleeding is one of the most common complications associated with the use of direct oral anticoagulants (DOAC). Clear algorithms exist for the emergency measures in (suspected) GI bleeding, including assessing the medication history regarding anti-platelet drugs and anticoagulants as well as simple coagulation tests during pre-endoscopic management. Platelet transfusions, fresh frozen plasma (FFP), or prothrombin complex concentrate (4F-PCC) are commonly used for optimizing the coagulation status. For severe bleeding under the thrombin inhibitor dabigatran, idarucizumab is available, and for bleeding under the factor Xa inhibitors rivaroxaban or apixaban, andexanet alfa is available as specific antidotes for DOAC antagonization. These antidotes represent emergency drugs that are typically used only after performing guideline-compliant multimodal measures including emergency endoscopy. Antagonization of oral anticoagulants should be considered for severe gastrointestinal bleeding in the following situations: (1) refractory hemorrhagic shock, (2) endoscopically unstoppable bleeding, or (3) nonavoidable delays until emergency endoscopy for life-threatening bleeding. After successful (endoscopic) hemostasis, anticoagulation (DOACs, vitamin K antagonist, heparin) should be resumed timely (i.e. usually within a week), taking into account individual bleeding and thromboembolic risk.

Long-term results of teduglutide treatment for chronic intestinal failure - Insights from a national, multi-centric patient home-care service program.

BACKGROUND & AIMS: Teduglutide is a Glucagon-like peptide-2 (GLP-2) agonist indicated for the treatment of patients with parenteral support (PS) dependent short bowel syndrome (SBS) with chronic intestinal failure (cIF). Its application is accompanied by a structured nation-wide home-care service program in Germany. We investigated care characteristics and outcome parameters in a clinical real-world observational setting. METHODS: Data generated within a therapy-accompanying home-care service program for adult SBS-cIF patients were analyzed retrospectively for patients treated up to 1 year (data cut: April 2020). RESULTS: In total, 52 teduglutide-treated patients were included by 6 German cIF centers. At teduglutide administration start, 49/52 patients were on PS, 3 of them without macronutrients. The majority of patients received individualized parenteral nutrition (PN) (n = 32/46), while 13/46 were on commercial premixed bags. PS application was done by patients themselves (37%), home-care nurses (19%), relatives (8%) or by a combination of those (16%). In patients with PS dependency at baseline and available follow-up data (n = 40-44), teduglutide treatment resulted in significantly reduced PN days, caloric needs, infusion time, and infusion volume after 6 and 12 months. After 1 year, reduction of infusion time was positively correlated with a reduction of PN calories and volume; 30 patients (68%) were responders (PS-volume reduction ≥20%), and 6 patients (14%) were completely weaned off PS. Sleep disturbances per night were significantly reduced after 3 months of treatment and stool characteristics improved in consistency and significantly in frequency, while meal frequency remained stable. CONCLUSIONS: Teduglutide treatment associated reduction in PS volume and calories was accompanied by reduced infusion days, infusion times, sleep disturbances, stable oral intake surrogates, and improved stool characteristics, all of these potential parameters for improving quality of life. Furthermore, analyzed care characteristics reflect SBS-cIF treatment as a complex, resource-intensive and demanding task for both, healthcare system and patients.

Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study).

BACKGROUND & AIMS: Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on-chronic liver failure (ACLF). Herein, we aimed to evaluate the safety and efficacy of G-CSF in patients with ACLF. METHODS: In this multicenter, prospective, controlled, open-label phase II study, 176 patients with ACLF (EASL-CLIF criteria) were randomized to receive G-CSF (5 µg/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n = 88) or SMT alone. The primary efficacy endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. The key secondary endpoints were overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores during the entire observation period. RESULTS: Patients treated with G-CSF had a 90-day transplant-free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio [HR] 1.05; 95% CI 0.711-1.551; p = 0.805). Transplant-free and overall survival at 360 days did not differ between the 2 arms (HR 0.998; 95% CI 0.697-1.430; p = 0.992 and HR 1.058; 95% CI 0.727-1.548; p = 0.768, respectively). G-CSF did not improve liver function scores, the occurrence of infections, or survival in subgroups of patients without infections, with alcohol-related ACLF, or with ACLF defined by the APASL criteria. Sixty-one serious adverse events were reported in the G-CSF+SMT group and 57 were reported in the SMT group. In total, 7 drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation. CONCLUSIONS: In contrast to previous findings, G-CSF had no significant beneficial effect on patients with ACLF in this multicenter controlled trial, which suggests that it should not be used as a standard treatment for ACLF. CLINICALTRIALS. GOV NUMBER: NCT02669680 LAY SUMMARY: Granulocyte-colony stimulating factor was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled phase II trial, which showed that G-CSF did not improve survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies.

Questions and answers on iron deficiency treatment selection and the use of intravenous iron in routine clinical practice.

Iron deficiency is a common cause of morbidity and can arise as a consequence or complication from many diseases. The use of intravenous iron has increased significantly in the last decade, but concerns remain about indications and administration. Modern intravenous iron preparations can facilitate rapid iron repletion in one or two doses, both for absolute iron deficiency and, in the presence of inflammation, functional iron deficiency, where oral iron therapy is ineffective or has not worked. A multidisciplinary team of experts experienced in iron deficiency undertook a consensus review to support healthcare professionals with practical advice on managing iron deficiency in gastrointestinal, renal and cardiac disease, as well as; pregnancy, heavy menstrual bleeding, and surgery. We explain how intravenous iron may work where oral iron has not. We provide context on how and when intravenous iron should be administered, and informed opinion on potential benefits balanced with potential side-effects. We propose how intravenous iron side-effects can be anticipated in terms of what they may be and when they may occur. The aim of this consensus is to provide a practical basis for educating and preparing staff and patients on when and how iron infusions can be administered safely and efficiently. Key messages Iron deficiency treatment selection is driven by several factors, including the presence of inflammation, the time available for iron replenishment, and the anticipated risk of side-effects or intolerance. Intravenous iron preparations are indicated for the treatment of iron deficiency when oral preparations are ineffective or cannot be used, and therefore have applicability in a wide range of clinical contexts, including chronic inflammatory conditions, perioperative settings, and disorders associated with chronic blood loss. Adverse events occurring with intravenous iron can be anticipated according to when they typically occur, which provides a basis for educating and preparing staff and patients on how iron infusions can be administered safely and efficiently.

A Pooled Analysis of Serum Phosphate Measurements and Potential Hypophosphataemia Events in 45 Interventional Trials with Ferric Carboxymaltose.

Ferric carboxymaltose (FCM) has been shown to achieve rapid replenishment of iron stores and correction of anaemia in various populations with iron deficiency. A decrease in serum phosphate (PO43-) levels, which in most cases is asymptomatic, has been reported with IV iron preparations. Hypophosphataemia (HP) is a known adverse drug reaction with FCM. This post hoc pooled analysis investigates the frequency, duration, risk factors, and clinical signs of HP as reported in interventional clinical trials with FCM. Pooled data from subjects enrolled across 45 clinical trials in different therapy areas were included. A three-step adjudication process was utilised to identify adverse events of HP. Stratified analyses by therapy group and stepwise logistic regression analysis were used to identify predictors of HP. This pooled analysis confirms that FCM is associated with increased rates of serum PO43- lowering, but mean serum PO43- values were seen to recover at Week 4 and further recover at Week 8. Among all subjects receiving FCM therapy (n = 6879), 41.4% (n = 2847) reached a PO43- nadir value <2.5 mg/dL at any point on study and 0.7% (n = 49) reached a nadir <1 mg/dL. Although gastroenterology and women's health subjects were identified to be at higher risk, occurrence of severe HP (<1 mg/dL [0.3 mmol/L]) following FCM administration was not observed to be common among subjects in these studies. Furthermore, there was no correlation between laboratory serum PO43- values and the occurrence of reported adverse events related to low PO43- levels.

Efficacy and safety of prolonged release budesonide granules in mesalazine-refractory ulcerative colitis: A multi-centre Phase IIa study (TOPICAL-1).

BACKGROUND: In patients with mesalazine-refractory ulcerative colitis, systemic corticosteroids are the treatment of choice. OBJECTIVE: To evaluate the efficacy and safety of prolonged release budesonide granules for the induction of remission in patients with mesalazine-refractory ulcerative colitis. METHODS: Patients with mesalazine-refractory ulcerative colitis discontinued mesalazine at baseline and received 9 mg prolonged release budesonide granules daily for 8 weeks in this open-label, phase IIa study, followed by a 2-week follow-up phase wherein patients continued treatment on alternate days (EudraCT number 2014-005635-14; ClinicalTrials.gov identifier NCT02550418). The primary endpoint was clinical remission (Clinical Activity Index ≤4; stool frequency <18 per week; absence of rectal bleeding) at Week 8. Secondary endpoints included clinical, endoscopic and histological measures of disease at Week 8. A post hoc analysis assessed histo-endoscopic mucosal healing. Treatment-emergent adverse events and morning cortisol levels were assessed throughout the treatment and follow-up phases. RESULTS: A total of 61 patients were included in the intention-to-treat population; 50 were included in the follow-up analysis set. Clinical remission was achieved in 29 patients (47.5%; 95% confidence interval: 34.6-60.7%) by Week 8. Mean stool and bloody stool frequency decreased significantly from 32.5 to 22.9 per week (p<0.0001) and from 17.6 to 8.1 per week (p<0.0001), respectively. Rates of mucosal healing, endoscopic remission and histological remission were 58.0%, 54.0% and 36.0%, respectively. Histo-endoscopic mucosal healing was achieved by 34.0% of patients. Twenty-four patients (39.3%) experienced treatment-emergent adverse events, of which gastrointestinal disorders (16.4%) were the most common. Mean morning cortisol levels were not significantly suppressed by Week 8. CONCLUSIONS: Treatment with prolonged release budesonide granules for 8 weeks was associated with clinical, endoscopic and histological remission and demonstrated a favourable safety profile in patients with mesalazine-refractory ulcerative colitis. These results warrant further investigation into the potential of prolonged release budesonide granules as an alternative treatment for this patient population.

Early Health Technology Assessment during Nonalcoholic Steatohepatitis Drug Development: A Two-Round, Cross-Country, Multicriteria Decision Analysis.

Background. The assessment of value along the clinical development of new biopharmaceutical compounds is a challenging task. Complex and uncertain evidence has to be analyzed, considering a multitude of value preferences from different stakeholders. Objective. To investigate the use of multicriteria decision analysis (MCDA) to support decision making during drug development while considering payer and health technology assessment (HTA) value concerns, by applying the Advance Value Framework in nonalcoholic steatohepatitis (NASH) and testing for the consistency of the results. Design. A multiattribute value theory methodology was applied and 2 rounds of decision conferences (DCs) were organized in 3 countries (England, France, and Germany), with the participation of national key experts and stakeholders using the MACBETH questioning protocol and algorithm. A total of 51 health care professionals, patient advocates, and methodologists, including (ex-) committee members or assessors from national HTA bodies, participated in 6 DCs in the study countries. Target Population. NASH patients in fibrosis stages F2 to 3 were considered. Interventions. The value of a hypothetical product profile was assessed against 3 compounds under development using their phase 2 results. Outcome Measures. DC participants' value preferences were elicited involving criteria selection, options scoring, and criteria weighting. Results. Highly consistent valuation rankings were observed in all DCs, always favoring the same compound. Highly consistent rankings of criteria clusters were observed, favoring therapeutic benefit criteria, followed by safety profile and innovation level criteria. Limitations. There was a lack of comparative treatment effects, early evidence on surrogate endpoints was used, and stakeholder representativeness was limited in some DCs. Conclusions. The use of MCDA is promising in supporting early HTA, illustrating high consistency in results across countries and between study rounds.

Unmet needs in clinical nutrition in oncology: a multinational analysis of real-world evidence.

BACKGROUND: Knowledge about cancer-related malnutrition and the use of clinical nutrition (CN) in the real-world setting are lacking. We investigated diagnosis and treatment frequency of malnutrition in a multinational survey to identify unmet needs in cancer patients' care. METHODS: Retrospective analyses were conducted on data from three administrative healthcare datasets from France (n = 570,727), Germany (n = 4642) and Italy (n = 58,468). Data from France described frequency and timing of malnutrition diagnosis in hospitalized gastrointestinal cancer patients. The German data detailed home parenteral nutrition (HPN) use in cancer patients with stage III/IV cancers. The Italian data analysed three cohorts: metastatic with CN, metastatic without CN, and patients without metastatic disease. RESULTS: In France, malnutrition diagnosis at first hospitalization occurred in 10% of patients, 13% were subsequently diagnosed, and 77% had no malnutrition diagnosis. In Germany, 16% of patients received HPN. Patients started HPN around 3 months before death. In Italy, 8.4% of metastatic cancer patients received CN; average time between metastasis diagnosis and first CN prescription was 6.6 months. Average time between first CN prescription and death was 3.5 months. CONCLUSIONS: These data indicate that in the real-world clinical practice, cancer-related malnutrition is under-recognized and undertreated. CN often appears to be prescribed as an end-of-life intervention or is not prescribed at all.Appropriate CN use remains challenging, and current practice may not allow optimal oncologic outcomes for patients at nutritional risk. Improving awareness of malnutrition and generating further evidence on clinical and economic benefits of CN are critical priorities in oncology.

RNA Interference Therapy With ARC-520 Results in Prolonged Hepatitis B Surface Antigen Response in Patients With Chronic Hepatitis B Infection.

BACKGROUND AND AIMS: ARC-520, the first an RNA interference (RNAi) therapeutic, was designed to reduce all RNA transcripts derived from covalently closed circular DNA, leading to a reduction in viral antigens and hepatitis B virus (HBV) DNA. APPROACH AND RESULTS: We aimed to evaluate the depth of hepatitis B surface antigen (HBsAg) decline in response to multiple doses of ARC-520 compared to placebo (PBO) in two randomized, multicenter studies in nucleoside/nucleotide analogue reverse-transcriptase inhibitor (NUC)-experienced patients with hepatitis B early antigen (HBeAg)-negative (E-neg) or HBeAg-positive (E-pos) disease. A total of 58 E-neg and 32 E-pos patients were enrolled and received four monthly doses of PBO (n = 20 E-neg, 11 E-pos), 1 mg/kg ARC-520 (n = 17 E-neg, 10 E-pos), or 2 mg/kg ARC-520 (n = 21 E-neg, 11 E-pos) concomitantly with NUC. HBsAg change from baseline to 30 days after the last ARC-520 dose were compared to PBO. Both E-neg and E-pos high-dose groups significantly reduced HBsAg compared to PBO, with mean reductions of 0.38 and 0.54 log IU/mL, respectively. HBsAg reductions persisted for approximately 85 days and >85 days after the last dose in E-neg and E-pos patients, respectively. The low-dose groups did not reach statistical significance in either study. E-pos patients showed a dose-dependent reduction in HBeAg from baseline. Mean maximum reduction was 0.23 and 0.69 log Paul Ehrlich IUs/mL in the low-dose and high dose ARC-520 groups respectively. ARC-520 was well tolerated, with only two serious adverse events of pyrexia possibly related to study drug observed. CONCLUSIONS: ARC-520 was active in both E-neg and E-pos, NUC-experienced HBV patients; but absolute HBsAg reductions were moderate, possibly due to expression of HBsAg from integrated HBV DNA, indicating the need for RNAi therapeutics that can target viral transcripts regardless of origin.

Willing to go the extra mile: Prospective evaluation of an intensified non-surgical treatment for patients with morbid obesity.

BACKGROUND & AIMS: Bariatric surgery has been well established and considered the treatment of choice in morbid obesity. However, some patients refuse surgery because long-term effects have not been fully elucidated, quality of life might change and lifelong supplementation with vitamins and trace elements may be required. Our aim was to exhaust non-surgical treatment modalities and to evaluate such an intensified treatment alternative. METHODS: A total of 206 patients (mean age = 46 years; BMI = 49 kg/m2) enrolled since 2013 into a non-surgical multimodality obesity treatment program covered by major health insurances were prospectively evaluated over a three year period. The 12-month treatment course comprised 57 h cognitive-behavioral therapy, 53.5 h physical exercise training, and 43.5 h nutritional therapy offered in small groups. Weight loss was induced by a formula-based, very low-calorie diet for 12 weeks in combination with a gastric balloon. The primary outcome was relative weight loss (RWL). Secondary outcome measures were waist-to-hip ratio, blood pressure, antihypertensive drug treatment, anti-diabetic medication, HbA1c, and quality of life. RESULTS: 166 Patients (81%) completed treatment. Mean (±SD) weight loss after 12 months for women and men were 28.8 kg (±14.7) and 33.7 kg (±19.5), respectively, among completers. RWL was 21.9% (±10.0) and excess weight loss (EWL) was 46.9% (±22.2), whereas intention-to-treat analysis revealed a RWL of 20.0% (±10.4) and an EWL of 42.9% (±22.9). Weight loss was accompanied by improved quality of life, lowered HbA1c values, and a significantly reduced need of antihypertensive and diabetes medications over the study period. Three year follow-up data from the first 78 patients (76% follow-up rate) revealed a RWL of 13% (±13.1) and an EWL of 27.2% (±28.8). The majority of patients (51%) maintained a RWL of 10% or more, and 44% had an EWL > 30%. CONCLUSIONS: In patients with morbid obesity, an intensified non-surgical multimodality treatment program may achieve significant and sustained weight loss accompanied by improvement of disease markers as well as quality of life for at least three years.

Factor-XIII activity in patients with mild to moderate ulcerative colitis and active bleeding: a prospective observational study.

OBJECTIVE: Coagulation factor XIII plays a key role in fibrin clot stabilization and epithelial healing. Under chronic inflammatory conditions involving bleeding and an activation of the coagulation cascade, the FXIIIa inversely correlate with disease activity. We assumed that FXIIIa could be a predictor of severity in patients with ulcerative colitis (UC). Here, we evaluated the course of plasma activity of FXIIIa in 49 patients with mild to moderate UC and active rectal bleeding. Patients with a partial Mayo bleeding subscore > 2 were eligible to participate in our prospective observational study in an outpatient setting. FXIIIa was investigated during acute flare conditions, after bleeding had stopped and later on in quiescent UC. RESULTS: Plasma activity of FXIIIa did not show any significant differences during the UC course. FXIIIa was measured below normal range < 70% in only 8 patients during the flare and increased to normal values during follow-up in 7 of these patients. Low FXIIIa during the flare was not associated with an increased bleeding activity. In patients with a mild to moderate UC flare and prolonged bleeding, FXIIIa activity is neither predictive of UC severity nor of any bleeding activity in an outpatient setting. Trial registration This non interventional, non pharmacological prospective study was not obligated to receive a unique identifying number. This trial is registered with the Ethics Committee of the State Medical Chamber of Saxony, Dresden, Germany (Clinical Trials Registry number EK-BR-03/14-1).

Usage characteristics and adverse event rates ​of the direct puncture and pull techniques for percutaneous endoscopic gastrostomy in patients with malignant tumors of the upper aerodigestive tract.

BACKGROUND AND STUDY AIMS: Patients with malignant tumors of the upper gastrointestinal tract are at risk of weight loss. Early supportive nutrition therapy is therefore recommended and usually requires placement of a percutaneous endoscopic gastrostomy (PEG). The aim of this study was to compare adverse events and usage characteristics of the direct puncture technique with those of the traditional pull technique when used in patients with endoscopically passable tumors. The primary endpoint was the rate of inflammatory adverse events (AEs) at the gastrostomy fistula. The secondary endpoint was the long-term rate of puncture-site metastases. PATIENTS AND METHODS: One hundred twenty patients (median age 56; IQR 36, 86 years) were randomized and treated per protocol in this prospective open randomized single-center study. Follow-ups were conducted on the third and seventh post-interventional days, after 1, 3 and 6 months and the last follow-up 5 years after intervention. RESULTS: Within the short-term follow-up period of 6 months after PEG placement, AEs were noted in 47 patients (39.2 %). These included 22 inflammations and 16 device dislocations and were mainly found in the puncture group (33 vs. 14 in the pull group) with a significantly increased incidence in the first month after PEG insertion ( P  = 0.001). Evaluation of the 5-year data did not reveal any significant differences. The gastrostomy tube was used in 101 patients (84.2 %) (range 18 days to 5 years). CONCLUSIONS: Our results favor the pull technique for patients with endoscopically passable tumors of the upper gastrointestinal tract due to less short-term adverse events. Both systems contributed equally to secure long-term use.

Topic infliximab injection for refractory rectal stenosis in Crohn's disease: long-term follow-up in two patients.

PURPOSE: TNF blockers are approved for intravenous or subcutaneous systemic therapy of many chronic inflammatory diseases. As it is not possible to achieve a sufficient local clinical improvement through systemic therapy in every patient, diverse approaches of topical therapy using TNF blockers have been investigated in recent years. METHODS: In this paper, we report on long-term clinical results of originator infliximab (IFX) injections into symptomatic combined scarring and inflammatory stenoses of the rectum in two patients with Crohn's disease. Aiming at high tissue IFX levels, 25 mg of IFX was injected into each quadrant of the stenosis after endoscopic balloon dilatation. This off-label treatment was repeated as necessary, depending on the clinical success. RESULTS: Topic IFX injection after balloon dilation reduced imperative stool pressure, isolated episodes of incontinence and incomplete emptying. Improvement lasted between 4 and 14 weeks in one patient and the treatment was repeated 13 times in the following 6.6 years. In the other patient, the technique was necessary only twice with no symptom recurrence in the subsequent 5.3 years. CONCLUSION: Our experience suggests that topic application of a systemically approved anti-TNF substance may be a successful individualized therapy for refractory stenosis of the rectum in patients with Crohn's disease.

Advances toward fully automated in vivo assessment of oral epithelial dysplasia by nuclear endomicroscopy-A pilot study.

BACKGROUND: Uncertainties in detection of oral epithelial dysplasia (OED) frequently result from sampling error especially in inflammatory oral lesions. Endomicroscopy allows non-invasive, "en face" imaging of upper oral epithelium, but parameters of OED are unknown. METHODS: Mucosal nuclei were imaged in 34 toluidine blue-stained oral lesions with a commercial endomicroscopy. Histopathological diagnosis showed four biopsies in "dys-/neoplastic," 23 in "inflammatory," and seven in "others" disease groups. Strength of different assessment strategies of nuclear scoring, nuclear count, and automated nuclear analysis were measured by area under ROC curve (AUC) to identify histopathological "dys-/neoplastic" group. Nuclear objects from automated image analysis were visually corrected. RESULTS: Best-performing parameters of nuclear-to-image ratios were the count of large nuclei (AUC=0.986) and 6-nearest neighborhood relation (AUC=0.896), and best parameters of nuclear polymorphism were the count of atypical nuclei (AUC=0.996) and compactness of nuclei (AUC=0.922). Excluding low-grade OED, nuclear scoring and count reached 100% sensitivity and 98% specificity for detection of dys-/neoplastic lesions. In automated analysis, combination of parameters enhanced diagnostic strength. Sensitivity of 100% and specificity of 87% were seen for distances of 6-nearest neighbors and aspect ratios even in uncorrected objects. Correction improved measures of nuclear polymorphism only. The hue of background color was stronger than nuclear density (AUC=0.779 vs 0.687) to detect dys-/neoplastic group indicating that macroscopic aspect is biased. CONCLUSIONS: Nuclear-to-image ratios are applicable for automated optical in vivo diagnostics for oral potentially malignant disorders. Nuclear endomicroscopy may promote non-invasive, early detection of dys-/neoplastic lesions by reducing sampling error.

Interferon-free treatment of chronic hepatitis C virus infection in patients with inherited bleeding disorders.

Chronic hepatitis C virus (HCV) infection causes significant mortality in patients with inherited bleeding disorders, however, data of interferon-free antiviral regimes are scarce in this population. PATIENTS, METHODS: Real-life data of interferon-free therapies of 18 patients with inherited bleeding disorders and chronic HCV genotype 1 infection (94% male, liver cirrhosis Child A/B n = 4/1). RESULTS: Treatment naïve patients were treated for eight weeks with sofosbuvir (SOF)/ledipasvir (n = 3) or for 12 weeks with SOF/ledipasvir (n = 4), SOF/ledipasvir/ribavirin (n = 1), or paritaprevir/r, ombitasvir, dasabuvir (n = 1). Treatment experienced patients without cirrhosis received SOF/ledipasvir (n = 3) or paritaprevir/r, ombitasvir, dasabuvir ± ribavirin (n = 2) for 12 weeks. Re-treated cirrhotic individuals were treated for 24 weeks with SOF/ledipasvir (n = 2) and SOF/daclatasvir (n = 1), or for 12 weeks SOF/simeprevir/1200 mg/d ribavirin (n = 1). Sustained virologic response (SVR-12) was achieved by 17/18 individuals without severe on-treatment side effects. CONCLUSIONS: In real-life, HCV-infected patients with inherited bleeding disorders can be effectively and safely treated with interferon-free therapies.