Hedgehog pathway inhibition as a therapeutic target in acute myeloid leukemia

Introduction: The Hedgehog (HH) pathway constitutes a collection of signaling molecules which critically influence embryogenesis. In adults, however, the HH pathway remains integral to the proliferation, maintenance, and apoptosis of adult stem cells including hematopoietic stem cells.

Areas covered: We discuss the current understanding of the HH pathway as it relates to normal hematopoiesis, the pathology of acute myeloid leukemia (AML), the rationale for and data from combination therapies including HH pathway inhibitors, and ultimately the prospects that might offer promise in targeting this pathway in AML.

Expert opinion: Efforts to target the HH pathway have been focused on impeding this disposition and restoring chemosensitivity to conventional myeloid neoplasm therapies. The year 2018 saw the first approval of a HH pathway inhibitor (glasdegib) for AML, though for an older population and in combination with an uncommonly-used therapy. Several other clinical trials with agents targeting modulators of HH signaling in AML and MDS are underway. Further study and understanding of the interplay between the numerous aspects of HH signaling and how it relates to the augmented survival of AML will provide a more reliable substrate for therapeutic strategies in patients with this poor-risk disease.     

Bile-pancreatic juice exclusion promotes Akt/NF-kB activation and chemokine production in ligation-induced acute pancreatitis

Using a unique surgical model (the donor rat model), we showed previously that duodenal replacement of bile-pancreatic juice, obtained fresh from a donor rat, ameliorates ligation-induced acute pancreatitis. We hypothesize that bile-pancreatic juice exclusion from gut exacerbates Akt/nuclear factor-kB (NF-kB) pathway activation and induces chemokine production in ligation-induced acute pancreatitis. We compared rats with bile-pancreatic duct ligation to those with duodenal bile-pancreatic juice replacement fresh from a donor rat beginning immediately before duct ligation. Sham control rats had ducts dissected but not ligated. Rats were killed 1 or 3 hours after operation (n=7/group). Akt activation (immunoblotting, immune-complex kinase assay, and ELISA), inhibitory protein I-kB (I-kB) activation (immunoblotting), and production of chemokines MCP-1 and RANTES (ELISA) were measured in pancreatic homogenates. NF-kB was quantitated in nuclear fractions using electrophoretic mobility shift assay. Duct ligation produced significant increases in pancreatic Akt, IkB, and NF-kB activation and production of MCP-1 and RANTES. Activation of the Akt/NF-kB pathway and increased MCP-1 and RANTES production in response to duct ligation were significantly reduced by bile-pancreatic juice replacement (ANOVA, P<0.05). Bile-pancreatic juice exclusion stimulates Akt/NF-kB pathway activation and increases chemokine production in ligation-induced acute pancreatitis. Presented at the annual meeting of The Society for Surgery of the Alimentary Tract, Chicago, Illinois, May 16, 2005 (poster).     

Abdominal aortic aneurysm repair and colonic infarction: a risk factor appraisal

OBJECTIVE: Colonic infarction is a recognized complication of abdominal aortic aneurysm (AAA) surgery. The clinical difficulty in establishing the diagnosis combined with the patient's poor physiological status is usually associated with a fatal outcome. We assessed our experience with this problem to identify a possible risk factor profile for these patients. METHOD: Patients records were identified from the operative logs, intensive care unit, Hospital Inpatient Enquiry system and vascular unit databases over a 6-year period. RESULTS: A total of 405 patients underwent AAA repair during this period; 140 as emergency ruptures. Nine patients were identified from the databases with known colonic infarction (2.2%). One was a woman. The mean age was 70 years. Seven patients had emergency ruptures (5%). Twenty independent risk factors were analysed using univariate and multivariate logistic regression models. Significant risk factors identified by using a multivariate analysis included the nature of the presenting patient, preoperative hypotension, prolonged cross-clamp time, intra-operative ischaemia and postoperative acidosis. Confirmatory diagnosis was made by colonoscopy in eight patients. One patient survived following the salvage surgery. The mean duration of survival was 10.5 days. The overall mortality was 89% of patients. CONCLUSION: In our unit infrarenal AAA repair has a 2.2% rate of colonic infarction. A definitive diagnosis is best made by colonoscopy. A risk factor profile for the development of colonic infarction may be constructed on the basis of specific clinical parameters. Earlier intervention on the basis of this profile may ultimately reduce the current excessive mortality.     

The effect of perioperative beta-blockade on the pulmonary function of patients undergoing major arterial surgery.

INTRODUCTION: Concern about the potential detrimental side-effects of beta-blockade on pulmonary function often dissuades against their perioperative use in patients undergoing major arterial surgery (especially in those with chronic obstructive pulmonary disease (COPD)). In this study we aimed to establish prospectively the clinical relevance of these concerns. METHODS: After ethics committee approval and individual informed consent, the pulmonary function of twenty patients (mean age 68.7 years (range 43-82), 11 males) scheduled to undergo non-emergency major vascular surgery was studied by recording symptoms and spirometry before and after institution of effective beta-blockade. Fifteen patients (75%) had significant smoking histories (mean pack years/patient=50), while 12 (60%) had COPD. RESULTS: All patients tolerated effective beta-blockade satisfactorily without developing either subjective deterioration in symptoms or significant change on spirometry. The mean change in FEV1 following adequate beta-blockade was 0.05+/-0.24 liters (95% CI -0.06 to +1.61), p=0.35, giving a mean percentage change of 3.18%+/-11.66 (95% CI -2.26 to 8.62). CONCLUSIONS: Previously held concerns about worsening pulmonary function through the short-term use of beta-blockers should not dissuade their perioperative usage in patients with peripheral vascular disease. Furthermore, the accuracy of pulmonary function tests in preoperative assessment and risk stratification also appears unaffected by this therapy.