Animal Models of Barrett's Esophagus and Esophageal Adenocarcinoma–Past,Present, and Future

Esophageal adenocarcinoma is the fastest rising cancer in the United States. It develops from long‐standing gastroesophageal reflux disease which affects >20% of the general population. It carries a very poor prognosis with 5‐year survival <20%. The disease is known to sequentially progress from reflux esophagitis to a metaplastic precursor, Barrett''s esophagus and then onto dysplasia and esophageal adenocarcinoma. However, only few patients with reflux develop Barrett''s esophagus and only a minority of these turn malignant. The reason for this heterogeneity in clinical progression is unknown. To improve patient management, molecular changes which facilitate disease progression must be identified. Animal models can provide a comprehensive functional and anatomic platform for such a study. Rats and mice have been the most widely studied but disease homology with humans has been questioned. No animal model naturally simulates the inflammation to adenocarcinoma progression as in humans, with all models requiring surgical bypass or destruction of existing antireflux mechanisms. Valuable properties of individual models could be utilized to holistically evaluate disease progression. In this review paper, we critically examined the current animal models of Barrett''s esophagus, their differences and homologies with human disease and how they have shaped our current understanding of Barrett''s carcinogenesis.     

A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer

Lessons Learned

• The combination of trametinib and sorafenib has an acceptable safety profile, albeit at doses lower than approved for monotherapy.
• Maximum tolerated dose is trametinib 1.5 mg daily and sorafenib 200 mg twice daily.
• The limited anticancer activity observed in this unselected patient population does not support further exploration of trametinib plus sorafenib in patients with hepatocellular carcinoma.

BackgroundThe RAS/RAF/MEK/ERK signaling pathway is associated with proliferation and progression of hepatocellular carcinoma (HCC). Preclinical data suggest that paradoxical activation of the MAPK pathway may be one of the resistance mechanisms of sorafenib; therefore, we evaluated trametinib plus sorafenib in HCC.MethodsThis was a phase I study with a 3+3 design in patients with treatment‐naïve advanced HCC. The primary objective was safety and tolerability. The secondary objective was clinical efficacy.ResultsA total of 17 patients were treated with three different doses of trametinib and sorafenib. Two patients experienced dose‐limiting toxicity, including grade 4 hypertension and grade 3 elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/bilirubin over 7 days. Maximum tolerated dose was trametinib 1.5 mg daily and sorafenib 200 mg twice a day. The most common grade 3/4 treatment‐related adverse events were elevated AST (37%) and hypertension (24%). Among 11 evaluable patients, 7 (63.6%) had stable disease with no objective response. The median progression‐free survival (PFS) and overall survival (OS) were 3.7 and 7.8 months, respectively. Phosphorylated‐ERK was evaluated as a pharmacodynamic marker, and sorafenib plus trametinib inhibited phosphorylated‐ERK up to 98.1% (median: 81.2%) in peripheral blood mononuclear cells.ConclusionTrametinib and sorafenib can be safely administered up to trametinib 1.5 mg daily and sorafenib 200 mg twice a day with limited anticancer activity in advanced HCC.     

Derivation and spontaneous differentiation of human embryonic stem cells

Embryonic stem (ES) cells are unique cells derived from the inner cell mass of the mammalian blastocyst. These cells are immortal and pluripotent, retain their developmental potential after prolonged culture, and can be continuously cultured in an undifferentiated state. Many in vitro differentiation systems have been developed for mouse ES cells, including reproducible methods for mouse ES cell differentiation into haematopoietic and neural precursors, cardiomyocytes, insulin‐secreting cells, endothelial cells and various other cell types. The derivation of new human ES cell lines provides the opportunity to develop unique models for developmental research and for cell therapies. In this review we consider the derivation and spontaneous differentiation of human ES cells.     

Polyostotic fibrous dysplasia of the cervical spine: case report and review of the literature.

BACKGROUND CONTEXT: Multiple lytic lesions of the spine usually represent metastatic or infectious disease processes. PURPOSE: To describe an extremely rare presentation of an uncommon disease process. STUDY DESIGN/SETTING: Case report/university hospital. METHODS: We describe the management of a patient who presented with a pathological fracture of C3 and multiple lytic lesions of the cervical spine. RESULTS: After reconstructive surgery, the final pathological diagnosis was fibrous dysplasia. CONCLUSION: Fibrous dysplasia is rarely seen in the cervical spine and may mimic other pathological processes. The surgical and medical management of spinal fibrous dysplasia is described.     

Chronic lower extremity ischemia: a human model of ischemic tolerance.

BACKGROUND: Ischemic preconditioning (IPC) has been found in animals to have a protective effect against future ischemic injury to muscle tissue. Such injury is unavoidable during some surgical procedures. To determine whether chronic ischemia in the lower extremities would imitate IPC and reduce ischemic injury during vascular surgery, we designed a controlled clinical study. PATIENTS AND METHODS: Two groups of patients at a university-affiliated medical centre with chronic lower-extremity ischemia served as models of IPC: 6 patients awaiting femoral distal bypass (FDB) and 4 scheduled for aortobifemoral (ABF) bypass grafting for aortoiliac occlusive disease. Seven patients undergoing elective open repair of an infrarenal abdominal aortic aneurysm (AAA) were chosen as non-IPC controls. Three hematologic indicators of skeletal-muscle injury, lactate dehydrogenase (LDH), creatine kinase (CK) and myoglobin, were measured before placement of the proximal clamp, during surgical ischemia, immediately upon reperfusion, 15 minutes after and 1 hour after reperfusion, and during the first, second and third postoperative days. RESULTS: Baseline markers of skeletal-muscle injury were similar in all groups. In postreperfusion samples, concentrations of muscle-injury markers were significantly lower in the 2 PC groups than in the control group. For example, at day 2, LDH levels were increased by about 30% over baseline measures in the elective AAA (control) group, whereas levels in the FDB and ABF groups remained statistically unchanged from baseline. Myoglobin in controls had increased by 977%, but only by 160% in the FDB and 528% in the ABF groups. CK levels, in a similar trend, were 1432% higher in the control group and only 111% (FDB) and 1029% (ABF) in the study groups. Taken together, these data represent a significant level of protection. CONCLUSIONS: Patients with chronic lower-extremity ischemia suffered less severe ischemic injury after a period of acute ischemia than those with acute ischemia alone. Ischemic preconditioning is one proposed mechanism to help explain this protective effect.     

Zolpidem induced nocturnal sleep‐related eating disorder (NSRED) in a male patient

Nocturnal Sleep‐Related Eating Disorder (NSRED) is a well‐documented sleeping disorder where the person is reported to experience bizarre eating behavior during sleep. Although various causes are implicated in this disorder, role of drugs cannot be ruled out. Here we narrate an interesting rare case report of a drug‐induced new onset NSRED, where a 45‐year‐old man on zolipdem performed an unexpected and bizarre eating behavior during somnambulistic state, type of which has not been reported earlier in the literature. The case falls under even rarer category as such behavior in sleep is reported mainly in woman. © 2008 by Wiley Periodicals, Inc. Int J Eat Disord 2009     

Complex urethral disruptions: In pursuit of a successful reconstruction

OBJECTIVES: We analyzed the methods and outcomes of urethroplasty in men with complex urethral disruptions. METHODS: The medical records of 40 men with complex urethral disruptions were analyzed. Surgical methods were individualized according to stricture location, severity and length of the stricture, bladder neck characteristics and presence of complicating factors. Patients were divided into four groups based on the above characteristics. RESULTS: End-to-end urethroplasty performed in six patients with short bulbar strictures (<3 cm) was successful in all. Elaborated perineal repair was performed in 10 patients with intermediate (3-6 cm) strictures with or without complicating factors. Elaborated perineal repair with urethral substitution was performed in nine patients with long segment stricture (>6 cm). Abdominal transpubic repair was successfully applied to patients with rectourethral fistula or lacerated bladder neck. Success rate of anastomotic urethroplasty was 95% while over all success rate was 85%. CONCLUSION: Guidelines for urethral reconstruction of complex urethral disruptions are predicated on stricture length, location, bladder neck characteristics and associated complicating factors. End-to-end urethroplasty with stricture excision is highly reliable for short strictures for which previous operative repair have failed. Elaborated perineal repair is extremely versatile for intermediate and longer strictures with associated complicating factors. Abdominal transpubic urethroplasty is effective for patients with rectourethral fistula or lacerated bladder neck.     

Phospho-akt expression is associated with a favorable outcome in non-small cell lung cancer.

Akt, a Serine/Threonine protein kinase, mediates growth factor-associated cell survival. Constitutive activation of Akt (phosphorylated Akt, P-Akt) has been observed in several human cancers, including lung cancer and may be associated with poor prognosis and chemotherapy and radiotherapy resistance. The clinical relevance of P-Akt in non-small cell lung cancer (NSCLC) is not well described. In the present study, we examined 82 surgically resected snap-frozen and paraffin-embedded stage I to IIIA NSCLC samples for P-Akt and Akt by Western blotting and for P-Akt by immunohistochemistry. P-Akt protein levels above the median, measured using reproducible semiquantitative band densitometry, correlated with a favorable outcome (P = 0.007). Multivariate analysis identified P-Akt as a significant independent favorable prognostic factor (P = 0.004). Although associated with a favorable prognosis, high P-Akt levels correlated with high tumor grade (P = 0.02). Adenocarcinomas were associated with low P-Akt levels (P = 0.039). Akt was not associated with either outcome or clinicopathologic variables.Cytoplasmic (CP-Akt) and nuclear (NP-Akt) P-Akt tumor cell staining was detected in 96% and 42% of cases, respectively. Both CP-Akt and NP-Akt correlated with well-differentiated tumors (P = 0.008 and 0.017, respectively). NP-Akt also correlated with nodal metastases (P = 0.022) and squamous histology (P = 0.037).These results suggest P-Akt expression is a favorable prognostic factor in NSCLC. Immunolocalization of P-Akt, however, may be relevant as NP-Akt was associated with nodal metastases, a known poor prognostic feature in this disease. P-Akt may be a potential novel therapeutic target for the management of NSCLC.