Summary Background Complex perianal fistulas in Crohn's disease are challenging to treat. Allogeneic, expanded, adipose-derived stem cells (Cx601) are a promising new therapeutic approach. We aimed ...to assess the safety and efficacy of Cx601 for treatment-refractory complex perianal fistulas in patients with Crohn's disease. Methods We did this randomised, double-blind, parallel-group, placebo-controlled study at 49 hospitals in seven European countries and Israel from July 6, 2012, to July 27, 2015. Adult patients (≥18 years) with Crohn's disease and treatment-refractory, draining complex perianal fistulas were randomly assigned (1:1) using a pre-established randomisation list to a single intralesional injection of 120 million Cx601 cells or 24 mL saline solution (placebo), with stratification according to concomitant baseline treatment. Treatment was administered by an unmasked surgeon, with a masked gastroenterologist and radiologist assessing the therapeutic effect. The primary endpoint was combined remission at week 24 (ie, clinical assessment of closure of all treated external openings that were draining at baseline, and absence of collections >2 cm of the treated perianal fistulas confirmed by masked central MRI). Efficacy was assessed in the intention-to-treat (ITT) and modified ITT populations; safety was assessed in the safety population. This study is registered with ClinicalTrials.gov , number NCT01541579. Findings 212 patients were randomly assigned: 107 to Cx601 and 105 to placebo. A significantly greater proportion of patients treated with Cx601 versus placebo achieved combined remission in the ITT (53 of 107 50% vs 36 of 105 34%; difference 15·2%, 97·5% CI 0·2–30·3; p=0·024) and modified ITT populations (53 of 103 51% vs 36 of 101 36%; 15·8%, 0·5–31·2; p=0·021). 18 (17%) of 103 patients in the Cx601 group versus 30 (29%) of 103 in the placebo group experienced treatment-related adverse events, the most common of which were anal abscess (six in the Cx601 group vs nine in the placebo group) and proctalgia (five vs nine). Interpretation Cx601 is an effective and safe treatment for complex perianal fistulas in patients with Crohn's disease who did not respond to conventional or biological treatments, or both. Funding TiGenix.
Background
Dominant stricture (DS) is a main cause of complication among patients with Primary Sclerosing Cholangitis (PSC). Endoscopic treatment options include dilation and plastic stenting, each ...with its own benefits and drawbacks.
Aims
The aim of the current study is to assess the safety and efficacy of fully-covered metal stent (FCMS) in these patients.
Methods
A retrospective study of PSC patients with refractory DS, defined as strictures resistance to conventional therapy (balloon dilatation, plastic biliary stent insertion or both) and who underwent FCMS insertion for 3 months were included. The primary outcome was defined as clinical and laboratory improvement, while secondary outcomes were DS resolution upon stent removal and cholangiographic DS recurrence at 12-months after FCMS extraction.
Results
Twenty patients were enrolled from January 2016 through January 2020. Improvement in weakness and pruritus were seen in 80% and 35%, 75% and 65%, 75% and 35% of patients at 1–3 and 6 months following FCMS removal, respectively. Similarly, consistent improvement in all liver enzymes and total bilirubin were seen in up to 6 month following stent removal. Only one patient (5%) needed premature FCMS removal due to cholangitis 1 week after stent placement and 2 cases (10%) of stent related pancreatitis were encountered. At 3-months all remaining stents were softly removed. Cholangiographic DS resolution was demonstrated in 13 patients (65%) after stent removal at 3-months, and DS recurred in 4 patients (4/13 = 30.7%) at 12-months following stent removal. Notably, only proximal biliary DS location showed a trend for DS recurrence (OR 28.6,
P
= 0.06).
Conclusion
Temporary 3 months duration FCMS was feasible, safe and effective treatment option among patients with PSC related refractory DS.
Novel predictors of prognosis in cirrhotic patients have been emerging in recent years and studies show that the lactate/albumin ratio can serve as an early prognostic marker in different patient ...groups. We aimed to uncover the clinical significance of the lactate/albumin ratio in hospitalized patients with acutely decompensated cirrhosis.
A retrospective single-center cohort study was conducted in a tertiary medical center. Subjects included had an established diagnosis of liver cirrhosis and were admitted to the ICU or the Internal Medicine department with a clinical picture of acute-on-chronic liver failure between the years 2010 and 2021. The primary outcome was to assess the utility of the lactate/albumin ratio as a prognostic marker to predict mortality in hospitalized cirrhotic patients with acute-on-chronic hepatic failure.
Two hundred seventy-nine patients were included in this study. Univariate analysis revealed that mean WBC count, platelet/creatinine ratio, aspartate transaminase (AST), lactate, and MELD score were all significantly associated with the primary outcome. Multivariate analysis showed that the lactate/albumin ratio was the strongest statistically significant (p < 0.001) predictor of death during hospitalization - OR 13.196 (95% CI 3.6–48.3), followed by mean WBC count, MELD score, and serum lactate levels. A ROC curve was constructed, which resulted in an area under the curve (AUC) equal to 0.77. Crosstabs from the ROC showed a sensitivity of 66.7% and a specificity of 76.2% when the lactate/albumin ratio chosen as a cutoff was 0.9061
Elevated lactate/albumin ratio predicts in-hospital mortality in hospitalized cirrhotics with acute-on-chronic hepatic failure.
Mutant KRAS is a druggable target for pancreatic cancer Khvalevsky, Elina Zorde; Gabai, Racheli; Rachmut, Itzhak Haim ...
Proceedings of the National Academy of Sciences - PNAS,
12/2013, Letnik:
110, Številka:
51
Journal Article
Recenzirano
Odprti dostop
Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic ...target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial–mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.
Despite encouraging data gathered in inflammatory bowel diseases (IBD) patients, Vedolizumabs' (VDZ) safety profile in pregnancy is not established.
Data of 330 consecutive pregnancies with IBD was ...prospectively collected.
Women with IBD were treated with: VDZ (n = 24), anti-tumor necrosis factors (n = 82) or conventional therapy (n = 224). Gravidity and parity were similar among the 3 groups. The VDZ group was comprised mostly of Crohn's disease patients who were all not naïve to biological treatment. They had significantly higher conception rates during active disease (P < 0.05), with fewer flares during pregnancy.
Although further study is needed, VDZ appears of low risk during pregnancy.
Early detection of colorectal cancer (CRC) improves prognosis, yet many CRCs are diagnosed following symptoms. The aim of this study was to determine which CRC-related symptoms or signs can predict ...an advanced CRC in the pre-operative stage.
Retrospective analysis of 300 patients who underwent surgery for CRC between the years 2008 and 2019. Patients' symptoms prior to CRC diagnosis were documented. Primary endpoint was the association of signs or/and symptoms with CRC diagnosis at TNM stages of 2-4 (i.e., highly advanced), compared to TNM score of 0-1 (i.e., locally advanced).
Three hundred patients, 91 with locally advanced and 209 with highly advanced CRC, were enrolled. There was a significant correlation between highly advanced CRC, compared to locally advanced, regarding tumor size (4.8 vs. 2.6 cm, p<0.001), presentation of any symptom prior to diagnosis (77% vs. 54%, p<0.001), anemia (46% vs. 29%, p=0.004), and severe anemia (17% vs. 4%, p=0.002). Mean hemoglobin was 12.2 ± 2.2 and 13.1 ± 1.8 in the highly advanced compared to locally advanced CRC, respectively, p<0.001. Anemia correlated with the T stage of the tumor: 21% of patients diagnosed at stages 0-1 had anemia, 39% at stage 2, 44% at stage 3, and 66% at stage 4 (p=0.001).
Anemia is the only finding that correlates with highly advanced CRC, in the pre-operative stage. When CRC has been diagnosed, the presence of anemia, at any level, may be considered in determining prognosis at the pre-operative stage. Physicians should be aware that when anemia is present, the risk for highly advanced CRC increases, and therefore should pursue with CRC detection.
Colorectal cancer is a leading cause of death. Colonoscopy is the criterion standard for detection and removal of precancerous lesions and has been shown to reduce mortality. The polyp miss rate ...during colonoscopies is 22% to 28%. DEEP DEtection of Elusive Polyps (DEEP2) is a new polyp detection system based on deep learning that alerts the operator in real time to the presence and location of polyps. The primary outcome was the performance of DEEP2 on the detection of elusive polyps.
The DEEP2 system was trained on 3611 hours of colonoscopy videos derived from 2 sources and was validated on a set comprising 1393 hours from a third unrelated source. Ground truth labeling was provided by offline gastroenterologist annotators who were able to watch the video in slow motion and pause and rewind as required. To assess applicability, stability, and user experience and to obtain some preliminary data on performance in a real-life scenario, a preliminary prospective clinical validation study was performed comprising 100 procedures.
DEEP2 achieved a sensitivity of 97.1% at 4.6 false alarms per video for all polyps and of 88.5% and 84.9% for polyps in the field of view for less than 5 and 2 seconds, respectively. DEEP2 was able to detect polyps not seen by live real-time endoscopists or offline annotators in an average of .22 polyps per sequence. In the clinical validation study, the system detected an average of .89 additional polyps per procedure. No adverse events occurred.
DEEP2 has a high sensitivity for polyp detection and was effective in increasing the detection of polyps both in colonoscopy videos and in real procedures with a low number of false alarms. (Clinical trial registration number: NCT04693078.)
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Abstract Eotaxin-1 (CCL-11) is a potent eosinophil chemoattractant that is considered a major contributor to tissue eosinophilia. Elevated eotaxin-1 levels have been described in various pathologic ...conditions, ranging from airway inflammation, to Hodgkin lymphoma, obesity and coronary artery disease. The main receptor for eotaxin-1 is CCR3; however, recent evidence indicates that eotaxin-1 may also bind to other receptors expressed by various cell types, suggesting a more widespread regulatory role for eotaxin-1 beyond the recruitment of eosinophils. Eotaxin-1 is also strongly associated with various gastrointestinal (GI) disorders. Although the etiology of inflammatory bowel disease (IBD) is still unknown, eotaxin-1 may play a key role in the development of mucosal inflammation. In this review, we summarize the biological context and effects of eotaxin-1, as well as its potential role as a therapeutic target, with a special focus on gastrointestinal inflammation.
Background
Fecal microbiota transplantation (FMT) is a new technique recently introduced to treat recurrent
Clostridium difficile
infection (CDI). Little is known about the efficacy and risks of FMT ...in elderly and ill patients.
Aim
To investigate FMT efficacy in ill and elderly patients compared to conventional treatment.
Methods
The study comprised two groups of patients between 2012 and 2016 with recurrent CDI at two medical centers in Israel. The study group received FMT and the controls conventional therapy. The primary end points were CDI recurrence, length of hospitalization, and short-term survival.
Results
Thirty-four patients altogether, (21 females, mean age 82 years) participated, 11 received FMT and 23 controls. Demographics and clinical characteristics were similar between the two groups. Comorbidity indexes, i.e., Charlson index was high in both groups. In the FMT group, 10/11 (90%) patients showed clinical improvement 3 days after initiating treatment compared to 9/23 (39%) in the control group,
p
= 0.02. Survival at 2 months did not differ between the groups (FMT 54%, Control 50%,
p
= 0.816), but mean survival in the FMT group was higher than in the control (12 vs. 4 months, respectively,
p
= 0.015). Two significant adverse events from the FMT group included suspected aspirations, both occurring during gastroscopy route of administration.
Conclusions
FMT is effective for elderly and very ill patients. Safety is a concern, but is rare even in patients with much comorbidity. Colonoscopy may be the preferred route of FMT infusion.
Purpose
Disease flare throughout gestation are not uncommon among women with inflammatory bowel diseases (IBD), and can substantially affect pregnancy outcomes. We aimed to evaluate the effect of ...prior pregnancy outcome on the risk of disease flare at subsequent pregnancy in women with IBD.
Methods
Women with IBD attending a multidisciplinary clinic for the preconception, antenatal and postnatal treatment were prospectively recruited during 2011–2018.
Results
Overall, 476 IBD women were followed during the study period. Of them, 69 (14.5%) had two pregnancies throughout follow-up period and constituted the study cohort. Among these 69 women, 48 (69.6%) had Crohn's disease and 21 (30.4%) ulcerative colitis. The median interpregnancy interval was 20 11–32 months. Overall, 34 (49.3%) women experienced disease flare at the subsequent pregnancy. In multivariate analysis, active disease at conception (odds ratio 95% CI: 25.65 (3.05, 25.52),
P
< 0.001) and history of disease flare at the previous pregnancy (odds ratio 95% CI: 4.21 (1.10, 16.58),
P
< 0.001) were the only independent predictors of disease relapse in current gestation. Rates of hospitalization during pregnancy (14.7% vs. 0,
P
= 0.02) and preterm delivery (32.4% vs. 5.7%,
P
= 0.006) were higher, and neonatal birth weight was lower (median 3039 vs. 3300 g,
P
= 0.03), in those with disease flare as compared to those with maintained remission.
Conclusion
History of disease relapse at previous gestation and periconception disease activity were found as important predictors of disease flare among IBD women. These data would facilitate adequate counseling and informed management decisions among reproductive-aged IBD women and their treating physicians.
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