MEDICAL AND SURGICAL TREATMENT OF CHRONIC ANAL FISSURE: PROSPECTIVE LONG-TERM RESULTS

Background: we previously assessed the efficacy of different medical and surgical treatments for chronic anal fissure (CAF). In this prospective audit we present longer-term results of this study in a larger series.Patients and Methods: From 01/04 to 09/08, 294 patients with typical CAF were enrolled. All patients were treated with 0.2% nitroglycerin ointment (GTN) or anal dilators (DIL) for 8 weeks. Those patients in which no improvement in symptoms was observed after 8 weeks were crossed to the other treatment (GTN or DIL) or switched to a combination of the two. Persisting symptoms after 12 weeks or recurrence were indications for either botulinum toxin injection into the internal sphincter and fissurectomy (BTX) or LIS. Primary end-point was fissure healing at last follow-up. Secondary end-points were symptomatic improvement, need for lateral internal sphincterotomy (LIS), and side effects. Differences between treatment groups were evaluated by chi square test. Results: patients' demographics, fissure characteristics and treatment results are resumed in Table 1. Mean follow-up was 36±17 months. Recurrence rate after 12 weeks treatment was similar between GTN and DIL (11.5% vs 9.3%). Overall fissure healing after medical treatment was 69.7% without significant differences between GTN (57.2%), DIL (66.9%) or a combination of the two (59.5%). Side effects (GTN) or severe discomfort (DIL) were observed in 13.2% of the patients. Thirty patients were treated with BTX and 64 underwent LIS (including BTX failures). At the end of the follow-up healing rates were 83.3% after BTX and 100% after LIS. No morbidity or postoperative incontinence were observed in both surgical groups.Conclusions: This study confirms that LIS is far more effective than medical treatments for CAF. However, BTX injection/fissurectomy as first line treatment may significantly increase the healing rate while avoiding any risk of incontinence. Table 1: patients' demographics, fissure characteristics and treatment results. GTN DIL GTN/DIL BTX/Fissurectomy LIS Number 173 121 42 30 64 Mean Age (years) 41 43 43 38 45 Sex (M/F) 80/93 52/69 28/14 11/19 27/32 Fissure position Ant 19 18 8 2 15 Post 145 97 32 26 47 Both/other 9 6 2 2 2 Single treatment (12 weeks) success N/% 95/173 (54.9%) 75/121 (61%) NA NA NA Recurrence 11/95 (11.5%) 7/75 (9.3%) NA NA NA After cross-over healing N/% 20/50 (40%) 16/32 (50%) 17/42 (40.4%) NA NA Recurrence 5/20 (25%) 3/16 (18.7%) 4/17 (23.5%) NA NA Overall success N/% 99/173 (57.2%) 81/121 (66.9%) 25/42 (59.5%) 25/30 (83.3%) 64/64 (100%) NA= not applicabl

MEDICAL AND SURGICAL TREATMENT OF CHRONIC ANAL FISSURE: PROSPECTIVE LONG-TERM RESULTS

Background: we previously assessed the efficacy of different medical and surgical treatments for chronic anal fissure (CAF). In this prospective audit we present longer-term results of this study in a larger series.Patients and Methods: From 01/04 to 09/08, 294 patients with typical CAF were enrolled. All patients were treated with 0.2% nitroglycerin ointment (GTN) or anal dilators (DIL) for 8 weeks. Those patients in which no improvement in symptoms was observed after 8 weeks were crossed to the other treatment (GTN or DIL) or switched to a combination of the two. Persisting symptoms after 12 weeks or recurrence were indications for either botulinum toxin injection into the internal sphincter and fissurectomy (BTX) or LIS. Primary end-point was fissure healing at last follow-up. Secondary end-points were symptomatic improvement, need for lateral internal sphincterotomy (LIS), and side effects. Differences between treatment groups were evaluated by chi square test. Results: patients' demographics, fissure characteristics and treatment results are resumed in Table 1. Mean follow-up was 36±17 months. Recurrence rate after 12 weeks treatment was similar between GTN and DIL (11.5% vs 9.3%). Overall fissure healing after medical treatment was 69.7% without significant differences between GTN (57.2%), DIL (66.9%) or a combination of the two (59.5%). Side effects (GTN) or severe discomfort (DIL) were observed in 13.2% of the patients. Thirty patients were treated with BTX and 64 underwent LIS (including BTX failures). At the end of the follow-up healing rates were 83.3% after BTX and 100% after LIS. No morbidity or postoperative incontinence were observed in both surgical groups.Conclusions: This study confirms that LIS is far more effective than medical treatments for CAF. However, BTX injection/fissurectomy as first line treatment may significantly increase the healing rate while avoiding any risk of incontinence. Table 1: patients' demographics, fissure characteristics and treatment results. GTN DIL GTN/DIL BTX/Fissurectomy LIS Number 173 121 42 30 64 Mean Age (years) 41 43 43 38 45 Sex (M/F) 80/93 52/69 28/14 11/19 27/32 Fissure position Ant 19 18 8 2 15 Post 145 97 32 26 47 Both/other 9 6 2 2 2 Single treatment (12 weeks) success N/% 95/173 (54.9%) 75/121 (61%) NA NA NA Recurrence 11/95 (11.5%) 7/75 (9.3%) NA NA NA After cross-over healing N/% 20/50 (40%) 16/32 (50%) 17/42 (40.4%) NA NA Recurrence 5/20 (25%) 3/16 (18.7%) 4/17 (23.5%) NA NA Overall success N/% 99/173 (57.2%) 81/121 (66.9%) 25/42 (59.5%) 25/30 (83.3%) 64/64 (100%) NA= not applicabl

vulnerabilités et capabilités

Collectif dirige par mylene baum sur le lien entre vulnerabilités clinique et caapbilisations de patient

Type 2 transglutaminase is involved in the autophagy-dependent clearance of ubiquitinated proteins

Eukaryotic cells are equipped with an efficient quality control system to selectively eliminate misfolded and damaged proteins, and organelles. Abnormal polypeptides that escape from proteasome-dependent degradation and aggregate in the cytosol can be transported via microtubules to inclusion bodies called 'aggresomes', where misfolded proteins are confined and degraded by autophagy. Here, we show that Type 2 transglutaminase (TG2) knockout mice display impaired autophagy and accumulate ubiquitinated protein aggregates upon starvation. Furthermore, p62-dependent peroxisome degradation is also impaired in the absence of TG2. We also demonstrate that, under cellular stressful conditions, TG2 physically interacts with p62 and they are localized in cytosolic protein aggregates, which are then recruited into autophagosomes, where TG2 is degraded. Interestingly, the enzyme's crosslinking activity is activated during autophagy and its inhibition leads to the accumulation of ubiquitinated proteins. Taken together, these data indicate that the TG2 transamidating activity has an important role in the assembly of protein aggregates, as well as in the clearance of damaged organelles by macroautophagy

Pazopanib and sunitinib trigger autophagic and non-autophagic death of bladder tumour cells.

Background: Tyrosine kinase inhibitors (TKI) such as sunitinib and pazopanib display their efficacy in a variety of solid tumours. However, their use in therapy is limited by the lack of evidence about the ability to induce cell death in cancer cells. Our aim was to evaluate cytotoxic effects induced by sunitinib and pazopanib in 5637 and J82 bladder cancer cell lines. Methods: Cell viability was tested by MTT assay. Autophagy was evaluated by western blot using anti-LC3 and anti-p62 antibodies, acridine orange staining and FACS analysis. Oxygen radical generation and necrosis were determined by FACS analysis using DCFDA and PI staining. Cathepsin B activation was evaluated by western blot and fluorogenic Z-Arg-Arg-AMC peptide. Finally, gene expression was performed using RT–PCR Profiler array. Results: We found that sunitinib treatment for 24 h triggers incomplete autophagy, impairs cathepsin B activation and stimulates a lysosomal-dependent necrosis. By contrast, treatment for 48 h with pazopanib induces cathepsin B activation and autophagic cell death, markedly reversed by CA074-Me and 3-MA, cathepsin B and autophagic inhibitors, respectively. Finally, pazopanib upregulates the a-glucosidase and downregulates the TP73 mRNA expression. Conclusion: Our results showing distinct cell death mechanisms activated by different TKIs, provide the biological basis for novel molecularly targeted approaches