LKB1 and AMPK and the cancer-metabolism link - ten years after

The identification of a complex containing the tumor suppressor LKB1 as the critical upstream kinase required for the activation of AMP-activated protein kinase (AMPK) by metabolic stress was reported in an article in Journal of Biology in 2003. This finding represented the first clear link between AMPK and cancer. Here we briefly discuss how this discovery came about, and describe some of the insights, especially into the role of AMPK in cancer, that have followed from it. In September 2003, our groups published a joint paper [1] in Journal of Biology (now BMC Biology) that identified the long-sought and elusive upstream kinase acting on AMP-activated protein kinase (AMPK) as a complex containing LKB1, a known tumor suppressor. Similar findings were reported at about the same time by David Carling and Marian Carlson [2] and by Reuben Shaw and Lew Cantley [3]; at the time of writing these three papers have received between them a total of over 2,000 citations. These findings provided a direct link between a protein kinase, AMPK, which at the time was mainly associated with regulation of metabolism, and another protein kinase, LKB1, which was known from genetic studies to be a tumor suppressor. While the idea that cancer is in part a metabolic disorder (first suggested by Warburg in the 1920s [4]) is well recognized today [5], this was not the case in 2003, and our paper perhaps contributed towards its renaissance. The aim of this short review is to recall how we made the original finding, and to discuss some of the directions that these findings have taken the field in the ensuing ten years

A prospective comparison of ER, PR, Ki67 and gene expression in paired sequential core biopsies of primary, untreated breast cancer

BACKGROUND: Sequential biopsy of breast cancer is used to assess biomarker effects and drug efficacy. The preoperative "window of opportunity" setting is advantageous to test biomarker changes in response to therapeutic agents in previously untreated primary cancers. This study tested the consistency over time of paired, sequential biomarker measurements on primary, operable breast cancer in the absence of drug therapy. METHODS: Immunohistochemistry was performed for ER, PR and Ki67 on paired preoperative/operative tumor samples taken from untreated patients within 2 weeks of each other. Microarray analysis on mRNA extracted from formalin fixed paraffin embedded cores was performed using Affymetrix based arrays on paired core biopsies analysed using Ingenuity Pathway Analysis (IPA) and Gene Set Analysis (GSA). RESULTS: In 41 core/resection pairs, the recognised trend to lower ER, PR and Ki67 score on resected material was confirmed. Concordance for ER, PR and Ki67 without changing biomarker status (e.g. ER+ to ER-) was 90, 74 and 80 % respectively. However, in 23 paired core samples (diagnostic core v on table core), Ki67 using a cut off of 13.25 % was concordant in 22/23 (96 %) and differences in ER and PR immunohistochemistry by Allred or Quickscore between the pairs did not impact hormone receptor status. IPA and GSA demonstrated substantial gene expression changes between paired cores at the mRNA level, including reduced expression of ER pathway analysis on the second core, despite the absence of drug intervention. CONCLUSIONS: Sequential core biopsies of primary breast cancer (but not core versus resection) was consistent and is appropriate to assess the effects of drug therapy in vivo on ER, PR and Ki67 using immunohistochemistry. Conversely, studies utilising mRNA expression may require non-treatment controls to distinguish therapeutic from biopsy differences

ICAR: endoscopic skull‐base surgery

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2013 WSES guidelines for management of intra-abdominal infections

Peer reviewe

Burkitt lymphoma in Iraqi children. A distinctive form of sporadic disease with high incidence of EBV+cases and more frequent expression of MUM1/IRF4 protein in cases with head and neck presentation

Epstein-Barr virus (EBV)-related lymphoproliferative disorders are relatively common in Iraqi children. Burkitt lymphoma (BL) accounted for 40% of lymphoma cases. The mean age of 125 BL cases was 5.9 ± 3.1 years, and the male-to-female ratio was 3.6:1. Clinical presentation was abdominal in 66% and head and neck in 34%. Bone marrow involvement was higher (P < 0.001) in children with head and neck disease. Tumor cells had MYC translocation (96%) and were CD20+/CD10+/MYC+/BCL2−. MUM1/IRF4 staining was expressed by a fraction of tumor cells in 19 of 125 cases (15%) and was more frequent (P < 0.007) in head and neck disease (12/42; 29%). EBV-encoded RNA was positive in 100 of 125 (80%) BL cases

Epstein-Barr virus (EBV) positive classical Hodgkin lymphoma of Iraqi children: An immunophenotypic and molecular characterization of Hodgkin/Reed-Sternberg cells.

Background: Classical Hodgkin lymphoma (cHL) in children is often associated with EBV infection, more commonly in developing countries. Procedure: Here we describe the histological, immunohistochemical, and molecular features of 57 cases of HL affecting Iraqi children under 14 years of age. Results: Histologically, 51 cases were classified as cHL of Mixed Cellularity and Nodular Sclerosis subtypes (MC=69%; NS=31%), and 6 cases as Nodular Lymphocyte Predominant HL (NLP-HL). EBV infection of H/RS cells was demonstrated in 44 of 51 cases of cHL (86%), and was more common in MC than in NS (97% vs. 63%; P=0.0025). The immunophenotypic profile of H/RS cells was similar in MC and NS, and was not influenced by EBV infection; H/RS cells were consistently positive for PAX-5 and to a lesser degree for other B cell markers including CD20/CD79a, OCT-2, and BOB-1. Clonal IGH rearrangements were detected in 14 of 38 cHL (37%), with no significant difference between MC and NS cases, and with no association with the EBV status. Oligoclonal/monoclonal TCRγ rearrangements were present in 28 of 38 cases (74%), suggestive of restricted T cell responses. Conclusions: Our findings indicate that cHL occurring in Iraqi children is characterized by immunohistochemical and molecular features undistinguishable from those present in cHL occurring elsewhere in the world. Moreover, the high incidence of EBV-infected H/RS cells and frequent occurrence of restricted T cell responses might be indicative of a defective local immune response perhaps related to the very young age of the children. Pediatr Blood Cancer 2013;60:2068-2072

The Extended endoscopic endonasal transplanum transtuberculum approach to the anterior communicating artery complex : anatomic study

Background: When performing a transplanum transtuberculum approach, dealing with the anterior communicating artery (ACoA) complex is inevitable. The aim of this study is to provide quantitative anatomical information regarding the ACoA complex and its bony and neural relationships, when exposed through this approach. Method: The endoscopic endonasal transplanum transtuberculum approach was performed on ten human cadaver heads. In each specimen, radiological studies were performed. A three-dimensional model of the approach was reconstructed. Measured parameters were: exposure of the vessels; distance between the proximal anterior cerebral artery (A1) and the optic chiasm; dimension of the bone opening. The feasibility to perform clip placement was graded as "possible" or "not possible". Results: Dimension of bone opening varied from 88 to 53 mm(2). The ACoA was exposed for 3 mm ± 2 mm, A1 for 17 mm ± 9 mm, the distal anterior cerebral artery (A2) for 12 mm ± 3 mm, the recurrent artery of Heubner (RAH) for 16 mm ± 4 mm. Clip placement was possible on the ACoA, A2, and distal segment of A1 in all cases, and on the proximal segment of A1 in one instance. The distance between A1 and the optic chiasm measured 9 mm ± 2 mm. Conclusions: The ACoA, A2, and the distal segment of A1 can be visualized and controlled through the transplanum transtuberculum approach. The relationship between A1, gyrus rectus, and optic chiasm is the main determinant for the exposure and control of the vessel. The olfactory nerve can represent a surgical landmark for the identification of the A1 origin. The whole course of the RAH can be visualized trough this approach.9 page(s