Meta-Analysis of the Risk of Immune-Related Adverse Events With Anticytotoxic T-Lymphocyte-Associated Antigen 4 and Antiprogrammed Death 1 Therapies.

We assessed the risks of immune-related adverse events with anticytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and antiprogrammed death 1 (PD1) therapies by meta-analysis. Twenty-one studies including 11,144 patients were found. Anti-CTLA4 therapy was associated with a significantly higher risk of overall immune-related adverse events: diarrhea, immune-related colitis, pruritus, and rash compared to control therapies (relative risk (RR) = 2.43, 2.10, 11.39, 3.88, 3.87, 95% confidence interval (CI) = 1.77-3.34, 1.52-2.45, 6.30-20.59, 2.37-6.37, 2.39-6.27, P < 0.001 for all outcomes). Anti-PD1 therapy was associated with a significantly higher risk of pruritus (RR = 4.01, 95% CI = 1.97 to 8.17, P < 0.001); however, it did not increase the risks of other adverse events. Anti-CTLA4 and anti-PD1 therapies have distinct features of immune-related adverse events. The results of our study would aid the surveillance and management of immune-related adverse events in patients receiving these therapies.

Systematic review with meta-analysis: the efficacy and safety of CT-P13, a biosimilar of anti-tumour necrosis factor-α agent (infliximab), in inflammatory bowel diseases.

BACKGROUND: Biosimilars of anti-tumour necrosis factor (TNF)-α agents have now become clinically available for the treatment of inflammatory bowel diseases (IBD). AIM: To perform a systematic review and meta-analysis to evaluate the efficacy and safety of biosimilars of anti-TNF-α agents in patients with IBD. METHODS: Electronic databases were searched. The outcomes were the pooled rates of clinical response or remission, sustained clinical response or remission, and adverse events in patients with IBD induced with or switched to biosimilars of anti-TNF-α agents. RESULTS: Eleven observational studies reporting outcomes in 829 patients treated with biosimilar of infliximab (CT-P13) were identified. The pooled rates of clinical response among Crohn's disease (CD) and ulcerative colitis (UC) at 8-14 weeks were 0.79 (95% confidence interval (CI) = 0.65-0.88) and 0.74 (95% CI = 0.65-0.82), respectively, and at 24-30 weeks were 0.77 (95% CI = 0.63-0.86) and 0.77 (95% CI = 0.67-0.85) respectively. Adverse events were rare (CD, 0.08 (95% CI = 0.02-0.26); UC, 0.08 (95% CI = 0.03-0.17)). The pooled rates of sustained clinical response among CD and UC after switching from infliximab to CT-P13 at 30-32 weeks were 0.85 (95% CI = 0.71-0.93) and 0.96 (95% CI = 0.58-1.00), respectively, and at 48-63 weeks were 0.75 (95% CI = 0.44-0.92) and 0.83 (95% CI = 0.19-0.99) respectively. Adverse events were rare (CD, 0.10, 95% CI = 0.02-0.31; UC, 0.22, 95% CI = 0.04-0.63). CONCLUSIONS: CT-P13 was associated with excellent clinical efficacy and safety profile, supporting its use in the treatment of IBD.

Characterization of ouabain-induced noradrenaline and acetylcholine release from in situ cardiac autonomic nerve endings.

AIM: Although ouabain modulates autonomic nerve ending function, it is uncertain whether ouabain-induced releasing mechanism differs between in vivo sympathetic and parasympathetic nerve endings. Using cardiac dialysis, we examined how ouabain induces neurotransmitter release from autonomic nerve ending. METHODS: Dialysis probe was implanted in left ventricle, and dialysate noradrenaline (NA) or acetylcholine (ACh) levels in the anaesthetized cats were measured as indices of neurotransmitter release from post-ganglionic autonomic nerve endings. RESULTS: Locally applied ouabain (100 microm) increased in dialysate NA or ACh levels. The ouabain-induced increases in NA levels remained unaffected by cardiac sympathetic denervation and tetrodotoxin (Na+ channel blocker, TTX), but the ouabain-induced increases in ACh levels were attenuated by TTX. The ouabain-induced increases in NA levels were suppressed by pretreatment with desipramine (NA transport blocker) and augmented by reserpine (vesicle NA transport blocker). In contrast, the ouabain-induced increases in ACh levels remained unaffected by pretreatment with hemicholinium-3 (choline transport blocker) but suppressed by vesamicol (vesicle ACh transport blocker). The ouabain-induced increases in NA levels were suppressed by pretreatment with omega-conotoxin GVIA (N-type Ca2+ channel blocker), verapamil (L-type Ca2+ channel blocker) and TMB-8 (intracellular Ca2+ antagonist). The ouabain-induced increases in ACh levels were suppressed by pretreatment with omega-conotoxin MVIIC (P/Q-type Ca2+ channel blocker), and TMB-8. CONCLUSIONS: Ouabain-induced NA release is attributable to the mechanisms of regional exocytosis and/or carrier-mediated outward transport of NA, from stored NA vesicle and/or axoplasma, respectively, while the ouabain-induced ACh release is attributable to the mechanism of exocytosis, which is triggered by regional depolarization. At both sympathetic and parasympathetic nerve endings, the regional exocytosis is because of opening of calcium channels and intracellular calcium mobilization.

Statistical analysis in the differentiation between cases of serious acute pancreatitis and generalized peritonitis due to a perforated peptic ulcer.

Serious acute pancreatitis was considered by the authors as one of the diseases which must be distinguished from generalized peritonitis due to perforated peptic ulcer. An attempt was made to differentiate between these two conditions without reference to two factors, namely amylase value and intraperitoneal free air. Differential diagnosis by linear discriminant analysis, making full use of information such as the history of the present illness, general and abdominal findings and laboratory data, was undertaken. This resulted in a satisfactory predictive value, at least for sample cases. Lastly, items which seem to be important for differentiation between the diseases are discussed.

The importance of postoperative choledochoscopy for management of retained biliary tract stones.

From 1974-8, 808 postoperative choledochoscopy procedures, conducted by insertion of choledochofiberscope into the biliary tract through the sinus tract after the T-tube had been removed, were carried out in 292 patients at Teikyo University Hospital, Tokyo, Japan. In this series, 104 with retained biliary tract stones were encountered, and complete removal of stones was successfully carried out in 101, using postoperative choledochoscopy. Any failures of removal of retained biliary tract stones were attributed to improper insertion of the T-tube. The T-tube, of at least 18 French calibers should be inserted into the common bile duct at a right angle so as to obviate a tortuous sinus tract. THe follow-up study in cases of complete extraction of the retained biliary tract stones showed that this approach is most effective. Recurrent stone with a silk nidus was found in one patient in whom postoperative choledochoscopy had been performed one year previously. Reoperation was carried out in this particular case. All other patients have remained asymptomatic. Finally, we advise routine use of postoperative choledochoscopy as an adjunct to the T-tube cholangiography, in order to prevent the possibility of retained biliary tract stones.

Intrahepatic stones and postoperative choledochoscopy.

In 35 out of 38 cases of patients suffering from intrahepatic stones, complete removal of the stones has been carried out with repeated postoperative choledochoscopies, the average being 14.5. A follow-up study revealed that 34 cases remain asymptomatic and are leading a normal social life. The remaining one case died from pancreas carcinoma 22 months after successfully removing the entire stones. With the successful results using postoperative choledochoscopy, we believe that the endoscopy is the preferred approach insofar as it can relieve symptoms, prolong life and render cure in some cases, although it may be only palliative in others. This safer and more reliable procedure as opposed to the blind technique which is carried out under fluoroscopic control should be routinely used for management of intrahepatic stones.