Evolution of Endoscopic Lesions in Steroid-Refractory Acute Severe Ulcerative Colitis Responding to Infliximab or Cyclosporine

BACKGROUND/AIMS: Few data on the evolution of endoscopic findings are available in patients with acute severe ulcerative colitis (ASUC). The aim of this study was to describe this evolution in a prospective cohort. METHODS: Patients admitted for a steroid-refractory ASUC and included in a randomized trial comparing infliximab and cyclosporine were eligible if they achieved steroid-free clinical remission at day 98. Flexible sigmoidoscopies were performed at baseline, days 7, 42 and 98. Ulcerative colitis endoscopic index of severity (UCEIS) and its sub-scores - vascular pattern, bleeding and ulceration/erosion - were post-hoc calculated. Global endoscopic remission was defined by a UCEIS of 0, and partial endoscopic remission by any UCEIS sub-score of 0. RESULTS: Among the 55 patients analyzed (29 infliximab and 26 cyclosporine), 49 (83%) had UCEIS >= 6 at baseline at baseline. Partial endoscopic remission rates were higher for bleeding than for vascular pattern and for ulcerations/erosions at day 7 (20% vs. 4% and 5% (n = 55); p CONCLUSION: In steroid-refractory ASUC patients responding to a second-line medical therapy, endoscopic remission process started with bleeding remission and was not achieved in half the patients at day 98 for vascular pattern. Infliximab provided a higher endoscopic remission rate than cyclosporine at day 98.Peer reviewe

Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial.

BACKGROUND: The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy. METHODS: This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021. FINDINGS: Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded. INTERPRETATION: In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation. FUNDING: European Union's Horizon 2020

A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine.

Primary adenocarcinoma of the anal canal is a rare and aggressive gastrointestinal disease with unclear pathogenesis. Because of its rarity, no clear clinical practice guideline has been defined and a targeted therapeutic armamentarium has yet to be developed. The present article aimed at addressing this information gap by in-depth characterising the anal glandular neoplasms at the histologic, immunologic, genomic and epidemiologic levels. In this multi-institutional study, we first examined the histological features displayed by each collected tumour (n = 74) and analysed their etiological relationship with human papillomavirus (HPV) infection. The intratumoural immune cell subsets (CD4, CD8, Foxp3), the expression of immune checkpoints (PD-1, PD-L1), the defect in mismatch repair proteins and the mutation analysis of multiple clinically relevant genes in the gastrointestinal cancer setting were also determined. Finally, the prognostic significance of each clinicopathological variable was assessed. Phenotypic analysis revealed two region-specific subtypes of anal canal adenocarcinoma. The significant differences in the HPV status, density of tumour-infiltrating lymphocytes, expression of immune checkpoints and mutational profile of several targetable genes further supported the separation of these latter neoplasms into two distinct entities. Importantly, anal gland/transitional-type cancers, which poorly respond to standard treatments, displayed less mutations in downstream effectors of the EGFR signalling pathway (i.e., KRAS and NRAS) and demonstrated a significantly higher expression of the immune inhibitory ligand-receptor pair PD-1/PD-L1 compared to their counterparts arising from the colorectal mucosa. Taken together, the findings reported in the present article reveal, for the first time, that glandular neoplasms of the anal canal arise by HPV-dependent or independent pathways. These etiological differences leads to both individual immune profiles and mutational landscapes that can be targeted for therapeutic benefits

[How to find the cause of a chronic adult diarrhea]

National audienceChronic diarrhea can be defined as the passage of more than 3 loose stools per day during more than 4 weeks. Differential diagnosis include fecal incontinence (stool consistency is normal), rectal syndrome (passage of blood and mucus but no liquid or loose stools) and fecal impaction. The proposed guidelines are based upon a classification of chronic diarrhea that distinguishes colonic, small bowel, pancreatic, endocrine and miscellaneous causes of chronic diarrhea. It also takes into account the frequency of the many causes of chronic diarrhea. One of its main objectives is to ensure the proper diagnosis of severe causes of chronic diarrhea, notably colorectal neoplasia

The POCER Trial: Bet on Active Care

International audienc

[How to find the cause of a chronic adult diarrhea]

National audienceChronic diarrhea can be defined as the passage of more than 3 loose stools per day during more than 4 weeks. Differential diagnosis include fecal incontinence (stool consistency is normal), rectal syndrome (passage of blood and mucus but no liquid or loose stools) and fecal impaction. The proposed guidelines are based upon a classification of chronic diarrhea that distinguishes colonic, small bowel, pancreatic, endocrine and miscellaneous causes of chronic diarrhea. It also takes into account the frequency of the many causes of chronic diarrhea. One of its main objectives is to ensure the proper diagnosis of severe causes of chronic diarrhea, notably colorectal neoplasia

Non-surgical and non-chemical attempts to treat echinococcosis: do they work?

Cystic echinococcosis (CE) and alveolar echinococcosis (AE) are chronic, complex and neglected diseases. Their treatment depends on a number of factors related to the lesion, setting and patient. We performed a literature review of curative or palliative non-surgical, non-chemical interventions in CE and AE. In CE, some of these techniques, like radiofrequency thermal ablation (RFA), were shelved after initial attempts, while others, such as High-Intensity Focused Ultrasound, appear promising but are still in a pre-clinical phase. In AE, RFA has never been tested, however, radiotherapy or heavy-ion therapies have been attempted in experimental models. Still, application to humans is questionable. In CE, although prospective clinical studies are still lacking, therapeutic, non-surgical drainage techniques, such as PAIR (puncture, aspiration, injection, re-aspiration) and its derivatives, are now considered a useful option in selected cases. Finally, palliative, non-surgical drainage techniques such as US- or CT-guided percutaneous biliary drainage, centro-parasitic abscesses drainage, or vascular stenting were performed successfully. Recently, endoscopic retrograde cholangiopancreatography (ERCP)-associated techniques have become increasingly used to manage biliary fistulas in CE and biliary obstructions in AE. Development of pre-clinical animal models would allow testing for AE techniques developed for other indications, e.g. cancer. Prospective trials are required to determine the best use of PAIR, and associated procedures, and the indications and techniques of palliative drainage

Non-surgical and non-chemical attempts to treat echinococcosis: do they work?

Cystic echinococcosis (CE) and alveolar echinococcosis (AE) are chronic, complex and neglected diseases. Their treatment depends on a number of factors related to the lesion, setting and patient. We performed a literature review of curative or palliative non-surgical, non-chemical interventions in CE and AE. In CE, some of these techniques, like radiofrequency thermal ablation (RFA), were shelved after initial attempts, while others, such as High-Intensity Focused Ultrasound, appear promising but are still in a pre-clinical phase. In AE, RFA has never been tested, however, radiotherapy or heavy-ion therapies have been attempted in experimental models. Still, application to humans is questionable. In CE, although prospective clinical studies are still lacking, therapeutic, non-surgical drainage techniques, such as PAIR (puncture, aspiration, injection, re-aspiration) and its derivatives, are now considered a useful option in selected cases. Finally, palliative, non-surgical drainage techniques such as US- or CT-guided percutaneous biliary drainage, centro-parasitic abscesses drainage, or vascular stenting were performed successfully. Recently, endoscopic retrograde cholangiopancreatography (ERCP)-associated techniques have become increasingly used to manage biliary fistulas in CE and biliary obstructions in AE. Development of pre-clinical animal models would allow testing for AE techniques developed for other indications, e.g. cancer. Prospective trials are required to determine the best use of PAIR, and associated procedures, and the indications and techniques of palliative drainage