Eldo E. Frezza

Adipose tissue: the new endocrine organ? A review article.

Fat is either white or brown, the latter being found principally in neonates. White fat, which comprises adipocytes, pre-adipocytes, macrophages, endothelial cells, fibroblasts, and leukocytes, actively participates in hormonal and inflammatory systems. Adipokines include hormones such as leptin, adiponectin, visfatin, apelin, vaspin, hepcidine, chemerin, omentin, and inflammatory cytokines, including tumor necrosis factor alpha (TNF), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator protein (PAI). Multiple roles in metabolic and inflammatory responses have been assigned to adipokines; this review describes the molecular actions and clinical significance of the more important adipokines. The array of adipokines evidences diverse roles for adipose tissue, which looms large in the mediators of inflammation and metabolism. For this reason, treating obesity is more than a reduction of excess fat; it is also the treatment of obesity’s comorbidities, many of which will some day be treated by drugs that counteract derangements induced by adipokine excesses.

Laparoscopic Vertical Sleeve Gastrectomy for Morbid Obesity. The Future Procedure of Choice

I report the general experience of performing sleeve gastrectomy defined as “a partial gastrectomy that results in removal of most of the stomach,” as a first-stage procedure for morbidly and super-obese people. I also explore its potential as a single procedure evaluating its advantages and disadvantages. This procedure is designed to reduce the size of the stomach and its distention, whereby the patient feels full sooner and their appetite is decreased. Some posit-increased satiety results from the decreased ghrelin, secreted by the fundus, which is resected during this procedure. The advantages of sleeve gastrectomy are as follows: the stomach is reduced without loss of function, pyloric preservation prevents dumping, it requires only 1 day in the hospital, it provides an effective first-stage procedure for super-obese patients, it is useful in patients with disorders such as anemia or Crohns disease, which preclude intestinal bypass, it can be performed laparoscopically, even in patients who weigh over 500 lbs, no band adjustment is required, it does not result in malabsorption, and it provides a good educational teaching base for doctors lacking experience in the treatment of gastric ulcers. The disadvantages include the risk of stapling complications and its irreversibility.

Quantitative evaluation and modeling of two-dimensional neovascular network complexity: the surface fractal dimension

BackgroundModeling the complex development and growth of tumor angiogenesis using mathematics and biological data is a burgeoning area of cancer research. Architectural complexity is the main feature of every anatomical system, including organs, tissues, cells and sub-cellular entities. The vascular system is a complex network whose geometrical characteristics cannot be properly defined using the principles of Euclidean geometry, which is only capable of interpreting regular and smooth objects that are almost impossible to find in Nature. However, fractal geometry is a more powerful means of quantifying the spatial complexity of real objects.MethodsThis paper introduces the surface fractal dimension (Ds) as a numerical index of the two-dimensional (2-D) geometrical complexity of tumor vascular networks, and their behavior during computer-simulated changes in vessel density and distribution.ResultsWe show that Dssignificantly depends on the number of vessels and their pattern of distribution. This demonstrates that the quantitative evaluation of the 2-D geometrical complexity of tumor vascular systems can be useful not only to measure its complex architecture, but also to model its development and growth.ConclusionsStudying the fractal properties of neovascularity induces reflections upon the real significance of the complex form of branched anatomical structures, in an attempt to define more appropriate methods of describing them quantitatively. This knowledge can be used to predict the aggressiveness of malignant tumors and design compounds that can halt the process of angiogenesis and influence tumor growth.

Usefulness of cancer-testis antigens as biomarkers for the diagnosis and treatment of hepatocellular carcinoma

Despite advances in our cellular and molecular knowledge, hepatocellular carcinoma (HCC) remains one of the major public health problems throughout the world. It is now known to be highly heterogeneous: it encompasses various pathological entities and a wide range of clinical behaviors, and is underpinned by a complex array of gene alterations that affect supra-molecular processes.Four families of HCC tumour markers have been recently proposed: a) onco-fetal and glycoprotein antigens; b) enzymes and iso-enzymes; c) cytokines and d) genes. A category of tumour-associated antigens called cancer-testis (CT) antigens has been identified and their encoding genes have been extensively investigated. CT antigens are expressed in a limited number of normal tissues as well as in malignant tumors of unrelated histological origin, including the liver. Given that cancers are being recognized as increasingly complex, we here review the role of CT antigens as liver tumour biomarkers and their validation process, and discuss why they may improve the effectiveness of screening HCC patients and help in determining the risk of developing HCC.

Analysis of the results of sleeve gastrectomy for morbid obesity and the role of ghrelin

To evaluate the effectiveness of laparoscopic sleeve gastrectomy (LSG), a relatively new bariatric surgical procedure associated with duodenal switch (DS), we analyzed the findings of ten published studies on LSG. No relationship was found between the excess weight loss and the size of the bougie or the follow-up period. The amount of gastric fundus removed may be an important consideration because most ghrelin-producing cells are in the fundus; however, there is insufficient evidence that lowered ghrelin is the sole reason for the resulting weight loss after this procedure. Laparoscopic sleeve gastrectomy is still considered experimental by many, but the initial results are promising, with one study even suggesting long-term results comparable with those of other bariatric procedures. Ghrelin may play a role in the weight loss associated with LSG, but is unlikely to be the sole reason for its success.

A Simple Venous Thromboembolism Prophylaxis Protocol for Patients Undergoing Bariatric Surgery

Objective: Pulmonary embolism is a leading cause of death for bariatric patients. Numerous regimens have been proposed, but a comprehensive, simple approach is lacking. This study provides a simple, easily implemented prophylaxis regimen.

AKAP‐4: a novel cancer testis antigen for multiple myeloma

Purpose Immunotherapy promises to be a more gentle and successful cancer treatment when compared with current standard treatments. Multiple myeloma (MM) is still a fatal hematologic malignancy that represents approximately 1% of all cancers and 2% of all cancer deaths. Approximately 50,000 Americans currently have MM. The research to discover new suitable cancer targets is needed to improve the effects of immunotherapy. The AKAP family9s protein provides an organizing center about which various protein kinases and phosphatases can be assembled to create solid-state signaling devices that can signal, be modulated, and be trafficked within the cell. A member of this family, AKAP-4, is the focus of our study. Human AKAP-4 is a structural protein of the sperm fibrous sheath that also functions to anchor protein kinase A to this structure via the regulatory subunit of the kinase, and seems to be involved in sperm motility. Our aim was to investigate the presence of AKAP-4 as a novel cancer testis antigen target in MM patients. Methods We evaluated the expression of AKAP-4 mRNA in a normal panel of tissues and in 15 MM patients either by PCR and immunocytochemistry. The normal control investigated tissues were kidney, ovary, skeletal muscle, mammary, brain, heart, colon, stomach, liver, lung, pancreas, spleen, trachea, and bone marrow. Summary The analysis of the mRNA expression of AKAP-4 showed that none of the normal tissues produced any positive band signals, whereas 6 of the 15 investigated patients (40%) showed a positive band signal. The immunohistochemical approach to the normal tissue panel showed no staining in any of the evaluated organs, except for the control, the testis. Five of the 15 MM investigated cases (33.3%) showed positive cytoplasmic staining. Conclusion To our knowledge, we established for the first time that AKAP-4 is expressed at the transcriptional level in MM cases, with a rate of 40%, whereas it is not expressed in normal tissues. Immunocytochemical data confirmed the PCR observations even if with a slightly lower percentage rate (33.3%). Since AKAP-4 has yet not been studied in MM, this is the first study that gives evidence of its aberrant expression in MM and suggests its use as possible novel cancer testis antigen target in MM.

Gamma-radiation upregulates MHC class I/II and ICAM-I molecules in multiple myeloma cell lines and primary tumors

SummaryThe γ-irradiation of normal cells causes an increased synthesis of specific proteins. However, few studies have described the effects of high doses of irradiation on the expression of cell surface antigens in tumor cells. This study analyzed the effects of high doses of γ-irradiation on the surface antigen expression of Major Histocompatability Complex (MHC) class I/II and intercellular adhesion molecule-1 (ICAM-I) in human multiple myeloma (MM) cell lines ARP-1, ARK-RS, and 10 MM primary tumors. The expression of surface antigens was evaluated by fluorescence-activated cell sorter analysis at different time points, following the exposure to high doses of γ-irradiation. Doses of 10,000 and 15,000 cGy were no0105 sufficient to totally block cell replication in both cell lines and primary tumors; cell replication was able to be inhibited completely only at 18,000 cGy. Lower doses (10,000 cGy) and lethal doses of irradiation (i.e., 15,000 and 18,000 cGy) increased the expression of all surface antigens present on the cells before irradiation. Essentially, such upregulation was shown to be dose dependent, with higher radiation doses resulting in higher antigen expression. Furthermore, when the kinetics of this upregulation were studied 3 and 6 d after irradiation, there was a constant increase in antigen expression in MM cells. These findings suggest that upregulation of costimulatory molecules, such as of MHC class I/II antigens and ICAM-1 molecules in MM patients treated by γ-radiation, can increase the immunogenicity of the tumor cells. In light of these findings, radiotherapy combined with immunotherapy might be considered in relapsing patients after receiving the standard treatment.

Sperm protein 17 is expressed in human nervous system tumours

BackgroundHuman sperm protein 17 (Sp17) is a highly conserved protein that was originally isolated from a rabbit epididymal sperm membrane and testis membrane pellet. It has recently been included in the cancer/testis (CT) antigen family, and shown to be expressed in multiple myeloma and ovarian cancer. We investigated its immunolocalisation in specimens of nervous system (NS) malignancies, in order to establish its usefulness as a target for tumour-vaccine strategies.MethodsThe expression of Sp17 was assessed by means of a standardised immunohistochemical procedure [(mAb/antigen) MF1/Sp17] in formalin-fixed and paraffin embedded surgical specimens of NS malignancies, including 28 neuroectodermal primary tumours (6 astrocytomas, 16 glioblastoma multiforme, 5 oligodendrogliomas, and 1 ependymoma), 25 meningeal tumours, and five peripheral nerve sheath tumours (4 schwannomas, and 1 neurofibroma),.ResultsA number of neuroectodermal (21%) and meningeal tumours (4%) were found heterogeneously immunopositive for Sp17. None of the peripheral nerve sheath tumours was immunopositive for Sp17. The expression pattern was heterogeneous in all of the positive samples, and did not correlate with the degree of malignancy.ConclusionThe frequency of expression and non-uniform cell distribution of Sp17 suggest that it cannot be used as a unique immunotherapeutic target in NS cancer. However, our results do show the immunolocalisation of Sp17 in a proportion of NS tumour cells, but not in their non-pathological counterparts. The emerging complex function of Sp17 makes further studies necessary to clarify the link between it and immunopositive cells.

Laparoscopic Sleeve Gastrectomy After Gastric Banding Removal: A Feasibility Study:

Background and objectives. Laparoscopic adjustable gastric banding (LAGB) is a commonly performed bariatric procedure. When LAGB fails, restrictive procedures such as gastric bypass have been performed. Laparoscopic sleeve gastrectomy (LSG) has been suggested as an alternative, but it has not yet been fully studied. Evaluated in this report are the experiences of patients who underwent LSG, a restrictive procedure, as a rescue procedure for failed LAGB. Methods. From June 2002 to June 2007, charts of patients who underwent LAGB were reviewed to find those who had undergone LSG as a rescue procedure. Results. Of 294 patients who underwent LAGB, 10 later underwent LSG. Median excess weight loss (EWL) prior to LSG had been 34%; after LSG, median EWL was 55%. Before LSG was performed, patients had a median 11.5 comorbidities, all of which improved after LSG. No major complications or deaths resulted. Conclusion. The results suggest LSG might be a reasonable choice for patients who fail LAGB. A formal study comparing LSG with other rescue procedures should be performed.