Sorafenib and triptolide as combination therapy for hepatocellular carcinoma.

INTRODUCTION: Sorafenib is the only drug approved by the Food and Drug Administration for metastatic hepatocellular carcinoma (HCC). Triptolide, a diterpene triepoxide, exhibits antineoplastic properties in multiple tumor cell types. In this study, we examined the effects of these agents and their combination on HCC in vitro and in vivo models. METHODS: HuH-7 and PLC/PRF/5 cells were treated with triptolide (50 nM), sorafenib (1.25 or 2.5 µM), or a combination of both. Cell viability assay (CCK-8), caspase 3&7 activation, and nuclear factor κB assays were performed. For in vivo studies, 40 mice were implanted with subcutaneous HuH7 tumors and divided into four treatment groups (n = 10); saline control, sorafenib 10 mg/kg PO daily (S), Minnelide (a prodrug of triptolide) 0.21 mg/kg intraperitoneally7 daily (M), and combination of both (C). Tumor volumes were assessed weekly. RESULTS: The combination of triptolide and sorafenib was superior to either drug alone in inducing apoptosis and decreasing viability, whereas triptolide alone was sufficient to decrease nuclear factor κB activity. After 2 weeks of treatment, tumor growth inhibition rates were S = 59%, M = 84%, and C = 93%, whereas tumor volumes in control animals increased by 9-fold. When crossed over to combination treatment, control mice tumor growth volumes plateaued over the following 4 weeks. CONCLUSION: The combination of sorafenib and triptolide is superior to single drug treatment in increasing cell death and apoptosis in vitro. Combining sorafenib with Minnelide inhibited tumor growth with greater efficacy than single-agent treatments. Importantly, in vivo combination treatment allowed for using a lesser dose of sorafenib (10 mg/kg), which is less than 10% of currently prescribed dose for HCC patients. Therefore, combination treatment could have translational potential in the management of HCC.

Triptolide-mediated cell death in neuroblastoma occurs by both apoptosis and autophagy pathways and results in inhibition of nuclear factor-kappa B activity.

BACKGROUND: Neuroblastoma is an aggressive pediatric malignancy with significant chemotherapeutic resistance. We assessed triptolide as a potential therapy. METHODS: SH-SY5Y and IMR-32 neuroblastoma cell lines were treated with triptolide. Viability, intracellular calcium, caspase activation, protein, and mRNA levels were measured. Autophagy was evaluated with confocal microscopy. Nuclear factor-kappa B (NF-κB) activation was measured using a dual luciferase assay. RESULTS: Triptolide treatment resulted in death in both cell lines within 72 hours, with sustained increases in intracellular calcium. IMR-32 cells underwent cell death by apoptosis. Conversely, light chain 3II (LC3II) protein levels were elevated in SH-SY5Y cells, which is consistent with autophagy. Confocal microscopy confirmed increased LC3 puncta in SH-SY5Y cells compared with control cells. Heat shock pathway protein and mRNA levels decreased with treatment. NF-κB assays demonstrated inhibition of tumor necrosis factor (TNF)-α-induced activity with triptolide. CONCLUSIONS: Triptolide treatment induces cell death in neuroblastoma by different mechanisms with multiple pathways targeted. Triptolide may serve a potential chemotherapeutic role in advanced cases of neuroblastoma.

Who's covering our loved ones: surprising barriers in the sign-out process.

BACKGROUND: The aims of this study were to characterize obstacles affecting current sign-out practices and to evaluate the potential impact of standardized sign-out guidelines. METHODS: In June 2011, detailed guidelines for transitions of care were implemented, and a 29-item multiple-choice survey was developed to assess sign-out practices, attitudes, and barriers to effective communication. Surveys were administered to residents and nurses at 3 time points. Comparisons between time points were assessed using t tests and χ(2) tests (α = .05). RESULTS: Guideline implementation achieved nonsignificant improvements in satisfaction with sign-outs, perceptions of patient safety, adequacy of information provided in sign-out, and patient knowledge by on-call residents. On follow-up, concerns surfaced regarding less complete sign-out processes due to new duty-hour restrictions. CONCLUSIONS: Guideline implementation mildly improved perceptions of safety and adequacy of sign-out; however, persistent barriers to continuity of care remain. Sign-out standardization may not adequately ensure patient safety, and further efforts to improve handoff processes are in need.

Comparing apples to apples: a call for unification of complication reporting across health systems.

The formalization of assessment of surgical outcomes across health care systems for complex procedures is a significant problem in the surgical literature. Low and colleagues present support for the use of the Accordion Severity Grading System as a tool to provide simple and comprehensive assessment of postoperative complications.

Esophageal stenting in children: indications, application, effectiveness, and complications.

BACKGROUND: Use of esophageal stents is uncommon in children, and there are few reports. We report the first experience in predominantly small children and infants with retrievable, flexible stents designed for tracheobronchial use. OBJECTIVE: Evaluation of initial experience with placement of esophageal stents for benign esophageal disorders in children. DESIGN: A retrospective study. SETTING: A pediatric, academic, tertiary-referral center. PATIENTS: This study involved 7 pediatric patients. INTERVENTIONS: Covered tracheobronchial stents were endoscopically placed in pediatric patients with benign esophageal conditions. Removal involved using forceps to pull the purse-string suture into the endoscope channel and collapsing the top of the stent for easy removal. MAIN OUTCOME MEASUREMENTS: To evaluate the safety and feasibility of performing endoscopic stent placement in children and to establish criteria for early stent removal. RESULTS: Six of 7 patients benefitted from stenting. There were no complications of placement. Novel techniques were developed for difficult retrievals. One patient did not benefit from esophageal stent placement, because the stent migrated downward from the uppermost part of the esophagus. One patient had some gagging, which led to early removal of the stent. A stent was removed emergently in 1 patient for respiratory distress. LIMITATION: Small number of patients. CONCLUSIONS: Retrievable, covered stents are easily placed and removed from the esophagus in small children. They should be considered for severe unrelenting strictures, especially when associated with esophageal leaks. A need exists for development of esophageal stents designed for pediatric use.

Achievement of feeding milestones after primary repair of long-gap esophageal atresia.

OBJECTIVES: To determine the pattern of feeding milestones following primary repair of long-gap esophageal atresia (EA). METHOD: A questionnaire based upon well established feeding milestones was used. Children after long-gap EA repair, n=40, were compared from after primary repair to healthy children from birth, n=102. RESULTS: The age when surveyed of the EA group and controls was different: 6.2+/-4.7 (mean+/-standard deviation) years, range 1.1-20.9, versus 2.5+/-2.4 years, range 0.0-12.1, p=0.00. The esophageal gap length in the EA group was 5.1+/-1.2 cm and age at repair was 5.5+/-5.0 months. There was no statistically significant difference between the atresia group and controls for feeding milestones; Self feeding finger foods approached significance. There was, however, greater variability in the timing of milestones in the atresia group compared to controls. Feeding milestones were negatively correlated with age at primary repair: drinking with a covered sippy cup, rho=-0.51, p=0.01 and self feeding finger foods, rho=-0.36, p=0.04 were statistically significant. Drinking from a cup correlated with gestational age, rho=0.38, p=0.04, and negatively correlated to esophageal gap length, rho=-0.45, p=0.01. CONCLUSIONS: Despite delayed onset of feeding, major milestones after EA repair occurred in similar pattern to normal infants. An early referral for primary repair is beneficial for earlier acquisition of milestones for infants with long-gap EA.

Long-gap esophageal atresia treated by growth induction: the biological potential and early follow-up results.

This study had two purposes. The first was to determine whether the growth procedure would allow true primary repairs of the most severe end of the esophageal atresia (EA) spectrum with the longest gaps (LG) and most rudimentary lower esophageal segments. The second goal was to provide the first short- to mid-term (3-12 years) follow-up data on the esophageal function and quality of life (QOL) data on the patients in this series. From our series of 60 LG-EA patients who underwent a growth procedure, 42 had the true primary esophageal repair completed 3 years ago. Among these, 18 had gaps over 6 cm, and for 6, only a rudimentary lower esophagus existed well below the diaphragm. No patient was turned down and all had primary repairs. These results suggest that even the most rudimentary segment has the potential to achieve normal size and that the full EA spectrum can have a primary repair. Our follow-up studies indicated that the esophageal function of these previously grown segments was very good. All contacted (40) were eating normally with only 3 receiving supplemental g-tube feeds because of other significant defects. We have actively treated significant reflux and 41/42 had fundoplication. By endoscopy (N = 15) no esophagitis was visible, but on biopsy, mild inflammation was found in 3. No conditions were found which would suggest that there would be a late deterioration or adverse consequences would arise. Based on these ongoing evaluations, the outlook seems very favorable for a good long-term QOL.