In-cell Catalysis by Tethered Organo-Osmium Complexes Generates Selectivity for Breast Cancer Cells.

Anticancer agents that exhibit catalytic mechanisms of action offer a unique multi-targeting strategy to overcome drug resistance. Nonetheless, many in-cell catalysts in development are hindered by deactivation by endogenous nucleophiles. We have synthesised a highly potent, stable Os-based 16-electron half-sandwich ('piano stool') catalyst by introducing a permanent covalent tether between the arene and chelated diamine ligand. This catalyst exhibits antiproliferative activity comparable to the clinical drug cisplatin towards triple-negative breast cancer cells and can overcome tamoxifen resistance. Speciation experiments revealed Os to be almost exclusively albumin-bound in the extracellular medium, while cellular accumulation studies identified an energy-dependent, protein-mediated Os accumulation pathway, consistent with albumin-mediated uptake. Importantly, the tethered Os complex was active for in-cell transfer hydrogenation catalysis, initiated by co-administration of a non-toxic dose of sodium formate as a source of hydride, indicating that the Os catalyst is delivered to the cytosol of cancer cells intact. The mechanism of action involves the generation of reactive oxygen species (ROS), thus exploiting the inherent redox vulnerability of cancer cells, accompanied by selectivity for cancerous cells over non-tumorigenic cells.

Gastric perforation after endoscopic treatment of a Dieulafoy's lesion.

Dieulafoy's vascular malformation is an underdiagnosed cause of massive, often recurrent upper gastrointestinal hemorrhage. Attempted endoscopic treatment of Dieulafoy's lesion has been recommended prior to surgery in many instances, but may occasionally be employed as primary therapy in patients that are not considered good "operative risks." Although generally considered safe and effective therapy for nonvariceal hemorrhage, combination therapy by injection and thermocoagulation techniques may result in perforation. We present a patient with a Dieulafoy's lesion of the stomach that illustrates both the efficacy and risks of combination endoscopic therapy for nonvariceal gastrointestinal hemorrhage.

A comparison of nonionic versus ionic contrast media: results of a prospective, multicenter study. Midwest Pancreaticobiliary Study Group.

BACKGROUND: Pancreatitis is one of the most common complications associated with ERCP. Multiple factors have been implicated for this potentially serious complication. Numerous suggestions for minimizing risks at ERCP have been offered, one of which is to use nonionic, low osmolarity contrast agents for pancreatic injection. Results of previous studies comparing different contrast media have been inconclusive. METHODS: To evaluate the role contrast material plays in the development of post-ERCP pancreatitis, the Midwest Pancreaticobiliary Group performed a prospective double-blind controlled study. A total of 1,979 consecutive ERCP patients were enrolled, and 1,659 patients with pancreatic duct injections were divided into subgroups according to the complexity of the ERCP. Post-ERCP pancreatitis was compared between similar groups. Patients were randomized to receive injections of nonionic, low osmolarity contrast or standard ionic contrast media. RESULTS: The overall incidence of post-procedural pancreatitis was 10.2%. Those with diagnostic ERCP had the lowest incidence at 5.6%. Therapeutic procedures (12.3%) and sphincter of Oddi manometry (15.2%) had higher rates. Those injected with standard (ionic) contrast had an incidence of 10.4% and after injection with lower osmolar (nonionic) contrast, there was a 10% post-procedural pancreatitis rate. CONCLUSIONS: Patients with more complex procedures develop pancreatitis more frequently. The use of low osmolar (nonionic) contrast media does not decrease the incidence of post-ERCP pancreatitis.

Observer variation and reproducibility of endoscopic ultrasonography.

To investigate interobserver variation and reproducibility of endosonographic findings, both experienced and inexperienced endosonographers evaluated depth of tumor invasion (T stage) and presence of lymph node metastasis (N stage) in 50 patients with nonobstructing esophageal carcinoma. Results were compared with the findings by surgical pathology of the resected specimens. The kappa statistic (kappa) was used to assess interobserver and intraobserver agreement and consistency of accurate interpretation (reproducibility) for the two groups. Agreement between the experienced endosonographers was excellent (kappa = > .75) for T1 and T4 lesions, good (kappa = .61) for T3 lesions, but only poor (kappa = > .46) for T2 lesions. The overall agreement between the experienced endosonographers was equally good for both T and N stages. Agreement between the inexperienced endosonographers was poor for all T stages but was good for lymph node metastasis (kappa = .52). For experienced endosonographers, endosonographic reproducibility of histologically confirmed T4 lesions was excellent, followed closely by T3 and T2 lesions; T1 tumors were frequently interpreted differently by the same endosonographer. Reproducibility of N stage determinations was excellent for N0 lymph nodes and good for N1 nodes. Thus, for experienced endosonographers, interobserver agreement was excellent for all T stages except T2, whereas reproducibility of determination of depth of tumor invasion was good to excellent for T2, T3, and T4 lesions but poor for T1 lesions. As yet poorly defined operator and machine-dependent factors that cause misinterpretation of T1 and T2 tumors will require additional study.

A cost-effectiveness analysis of biliary anastomosis with or without T-tube after orthotopic liver transplantation.

Biliary reconstruction continues to be a major source of morbidity following orthotopic liver transplantation. We wished to determine if choledochocholedochostomy without a T-tube was associated with fewer biliary complications and was less costly than choledochocholedochostomy with a T-tube. A retrospective cohort study of patients who underwent liver transplantation was performed. Patients were stratified into two groups: group I had bile duct reconstruction with T-tube and group II did not have a T-tube. The results were interpreted on an intention-to-treat analysis. We identified 147 adult patients who underwent initial liver transplantation. There were 76 patients in group I and 71 patients in group II. There were no statistical differences between the two groups regarding underlying cause of liver disease, patient age, gender or United Network for Organ Sharing status. As the decision to use a T-tube was made at the time of surgery, the two groups may not be strictly comparable. The mean hospital stay was longer in group I (31.1 +/- 27.9d) than in group II (18.8 +/- 15.5d) (p = 0.001). Biliary complications were statistically more frequent in patients from group I patients (25/76, 32.9%) than in patients from group II (11/71, 15.5%) (p = 0.01). There was a trend for the costs associated with diagnostic and therapeutic procedures for the management of biliary complications to be greater for group I than for group II, although this was not statistically significant (p = 0.235). Our study suggests choledochocholedochostomy without T-tube reconstruction is the preferred strategy for biliary reconstruction in orthotopic liver transplantation. It is not only associated with fewer biliary complications, but also less costly than using choledochocholedochostomy over a T-tube. Randomized prospective studies are needed to confirm our results.

Endoscopic management of biliary leaks after T-tube removal in liver transplant recipients: nasobiliary drainage versus biliary stenting.

This study presents the long-term sequelae of endoscopic retrograde cholangiopancreatography (ERCP)-managed biliary leakage in patients who underwent orthotopic liver transplantation (OLT) and compares the relative efficacy, safety, and charges of nasobiliary drainage (NBD) versus biliary stenting (BS). We identified all orthotopic liver transplant recipients from January 1, 1993, to December 31, 1997, who had undergone ERCP for biliary leakage. Clinical outcome and charges were calculated on an intention-to-treat basis according to initial endoscopic therapy. Of the 1,166 adult OLTs performed during the study period, 442 patients underwent elective T-tube removal. ERCP was attempted in 69 patients (16%) who developed biliary leakage after T-tube removal. Three patients (5%) in whom initial ERCP was unsuccessful underwent surgery. NBD and BS were used as primary therapy in 45 (68%) and 21 patients (32%), respectively. Three patients initially treated with NBD required reendoscopy or surgery compared with 6 patients initially treated with BS (P <.05). Although not statistically significant, there was a trend toward greater expense in the BS group compared with the NBD group. ERCP is a safe and effective method of managing biliary leakage after T-tube removal in orthotopic liver transplant recipients. However, our results suggest NBD is the preferred method because recurrent leaks were more common in patients treated initially with BS. With prompt use of ERCP, surgery is rarely needed for this complication of OLT.