Antonino Agrusa

Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4

We investigated the mechanisms involved in the resistance to cell death observed in epithelial cancers. Here, we identify that primary epithelial cancer cells from colon, breast and lung carcinomas express high levels of the antiapoptotic proteins PED, cFLIP, Bcl-xL and Bcl-2. These cancer cells produced interleukin-4 (IL-4), which amplified the expression levels of these antiapoptotic proteins and prevented cell death induced upon exposure to TRAIL or other drug agents. IL-4 blockade resulted in a significant decrease in the growth rate of epithelial cancer cells and sensitized them, both in vitro and in vivo, to apoptosis induction by TRAIL and chemotherapy via downregulation of the antiapoptotic factors PED, cFLIP, Bcl-xL and Bcl-2. Furthermore, we provide evidence that exogenous IL-4 was able to upregulate the expression levels of these antiapoptotic proteins and potently stabilized the growth of normal epithelial cells rendering them apoptosis resistant. In conclusion, IL-4 acts as an autocrine survival factor in epithelial cells. Our results indicate that inhibition of IL-4/IL-4R signaling may serve as a novel treatment for epithelial cancers.

Aurora-A Is Essential for the Tumorigenic Capacity and Chemoresistance of Colorectal Cancer Stem Cells

Colorectal cancer stem cells (CR-CSC) are responsible for the generation and maintenance of intestinal tumors and are highly resistant to conventional chemotherapeutic agents. Aurora-A, a serine-threonine kinase involved in mitosis regulation, plays multiple key functions in tumor initiation and progression. We found that Aurora-A is overexpressed in primary colorectal tumor cells, in the CR-CSC fraction, and in stem cell-derived differentiated cells, compared with normal colon tissue. Aurora-A expression was functionally linked to centrosome amplification in CR-CSC, as indicated by the decrease in cells with multiple centrosomes that followed Aurora-A silencing. Knockdown of Aurora-A resulted in growth inhibition of CR-CSC, alteration of cell cycle kinetics, and downregulation of the expression levels of antiapoptotic Bcl-2 family members, strongly sensitizing to chemotherapy-induced cell death. Moreover, Aurora-A silencing compromised the ability to form tumor xenografts in immunocompromised mice and reduced the migratory capacity of CR-CSC. Altogether, these results indicate that Aurora-A is essential for CR-CSC regeneration and resistance to cytotoxic stimuli and suggest that therapies directed against Aurora-A may effectively target the stem cell population in colorectal cancer.

Role and outcomes of laparoscopic cholecystectomy in the elderly

INTRODUCTION Laparoscopic cholecystectomy is the standard of treatment for gallstones disease and acute colecystitis. The prevalence of this disease increases with age and the population is aging in industrialized countries. So, in this study we report our experience in the treatment of gallstone disease in elderly patients, particularly analyzing the outcomes of laparoscopic approach. METHODS Between January 2010 and May 2014 we performed a total of 1227 cholecystectomies. In this retrospective study age group was the primary independent variable: 351 patients were 65-79 years of age and 65 were 80 years of age or older. RESULTS Only 65 patients (5.3%) of all population had primary open cholecystectomy, but the rate in young group was 3.7% respect the highest frequency (9.2%) in the elderly group. The conversion rate was higher (1.2%) in the older group but there was no significant difference with younger group. LC in emergency setting was performed in 10.3% of young patients and in 13.8% of elderly group. CONCLUSION Laparoscopic cholecystectomy is a feasible and safe procedure in elderly patients and might be performed during the same hospitalization like definitive treatment of gallstone disease. The old age and subsequent comorbidity are the fundamental predictor of surgical outcomes. Elective treatment should be recommended when repeated gallstone symptoms have occurred in the elderly patient before the development of acute cholecystitis and related complications.

Damage to the vascular structures in inguinal hernia specimens.

BackgroundFew scientific reports to date describe the histological modification of structures outlining a hernia opening. This article is focused on the identification of the pathological changes in vascular structures in tissues excised from cadavers with inguinal hernia. A deeper comprehension of this topic could lead to essential improvements in the detection of hernia genesis.Materials and methodsDifferent kinds of hernia, including indirect, direct and mixed, were identified in 30 autopsied subjects. Tissue samples were resected for histological study from abdominal wall structures close to the hernia opening. Histological examination focused on the detection of structural changes in arteries and veins. The results were compared with tissue specimens excised from equivalent sites of the inguinal area in a control group of 15 fresh cadavers without hernia.ResultsSignificant modification of vascular structures were identified in the tissue specimens examined. The veins demonstrated parietal fibrosis, perivascular edema and vascular dilation due to congestion and stasis. The arterial structures detected showed thickening of the media due to medial hyperplasia, ranging from luminal sub-occlusion to a manifest artery occlusion. These findings are present independent of hernia type in cadavers with inguinal hernia. These pathological changes were lacking in the control group of cadavers without hernia.ConclusionsThe notable changes in vascular structures described in the report could be the result of a steady compressive effect exerted by the abdominal viscera in the inguinal area. These pathological changes could represent one of the factors involved in the weakening of the inguinal region leading to hernia protrusion.

Terminal ligature of inferior thyroid artery branches during total thyroidectomy for multinodular goiter is associated with higher postoperative calcium and PTH levels

PURPOSE To evaluate the impact of truncal versus terminal branch ligature of the inferior thyroid artery (ITA) on postoperative calcium and PTH plasma levels in patients undergoing total thyroidectomy for multinodular goiter. METHODS A prospective randomized study was performed comparing a group of patients that underwent either truncal ligature of the ITA (group 1) or terminal ligature of ITA branches (group 2). RESULTS A series of 126 consecutive patients with non-toxic euthyroid multinodular goiter underwent total thyroidectomy. Truncal ligature of the ITA was performed in 63 patients (group 1) and terminal branch ITA ligature in 63 patients (group 2). Postoperative ionized serum calcium (mmol/L) at 24 hours was significantly lower in group 1 than in group 2 patients (1.22 ± 0.06 vs. 1.25 ± 0.05, P<0.05) and at 48 hours (1.20 ± 0.05 vs. 1.23 ± 0.05, P<0.05). Mean postoperative PTH levels (pg/mL) at 4 hours after thyroidectomy were significantly lower in group 1 than in group 2 patients (22.32 ± 11.64 vs. 25.82 ± 12.87, P=0.044). Mean hospital stay (hours) was higher in group 1 than in group 2 patients (87.47 ± 41.04 vs. 70.34 ± 24.82, P<0.05). CONCLUSION This study shows that terminal ligature of ITA branches during total thyroidectomy for multinodular goiter is associated with higher mean postoperative calcium and PTH levels, and shorter hospital stay. However, no significant difference in terms of permanent hypoparathyroidism was observed between the two groups.

Laparoscopic management of interstitial pregnancy: the “purse-string” technique

We report five cases of interstitial pregnancy, treated between 2004 and 2010, to evaluate surgical and obstetric outcome of laparoscopic cornual resection with a “purse‐string” technique. A hemostatic suture was passed at the base of the mass in a purse‐string fashion prior to resection, to minimize intraoperative blood loss. Subsequent pregnancies were analysed, with a mean follow‐up time of 48 months. The mean operating time was 39 min and mean blood loss 47 mL. Three of four patients who desired children delivered at term uneventfully. Laparoscopic cornual resection with a “purse‐string” technique appears to be useful for treatment of early interstitial pregnancy. The technique ensures effective and safe treatment, with satisfactory obstetric outcome.

Whipple’s pancreaticoduodenectomy: Surgical technique and perioperative clinical outcomes in a single center

INTRODUCTION Pancreatic cancer is the fourth cause of death from cancer in Western countries. The radical surgical resection is the only curative option for this pathology. The prevalence of this disease increases with age in population. The causes of pancreatic cancer are unknown, but we consider risk factors like smoke and tobacco usage, alcohol consumption coffee, history of diabetes or chronic pancreatitis. In this study we report our experience in the treatment of resectable pancreatic cancer and periampullary neoplasms with particular attention to evaluate the evolution of surgical technique and the clinical postoperative outcomes. METHODS In our Department between January 2010 and December 2014 we performed a total of 97 pancreaticoduodenectomy. We considered only resectable pancreatic cancer and periampullary neoplasms defined by absence of distant metastases, absence of local tumor extension to the celiac axis and hepatic artery as the lack of involvement of the superior mesenteric vasculature. None of these patients received neoadjuvant chemotherapy. RESULTS The mean age of these patients was 64.5 years. Jaundice was the commonest presenting symptom associated to anorexia and weight loss. The mean operative time was 295 min (± 55 min). The mean blood loss was 450 ml and median blood transfusion was 1 units. 12.1% of patients had an intra-abdominal complication. The commonest complication was Delayed Gastric Emptying responsable of increased length of hospital stay and readmission rate. Postoperative pancreatic fistula of grade C occurred in 4 patients. 2 patients developed a postpancreatectomy hemorrhage. Perioperative mortality was 4.1%. CONCLUSION Pancreaticoduodenectomy is a complex surgical technique and the associated high morbidity and mortality resulted in initial reluctance to adopt this surgery for the management of pancreatic and periampullary tumors. Surgical outcomes of pancreatic surgery are better at high-volume experienced center reporting mortality rates below 5%. We perform an end-to-side duct-to-mucosa pancreaticojejunostomy with routinely use of internal pancreatic stent. However no one technique has been shown to definitely be the solution to the problem of postoperative pancreatic fistula. At our center we have a reasonable volume and our data are comparable to literature data.

Biologic response of inguinal hernia prosthetics: a comparative study of conventional static meshes versus 3D dynamic implants.

Despite improvements in prosthetics and surgical techniques, the rate of complications following inguinal hernia repair remains high. Among these, discomfort and chronic pain have become a source of increasing concern among surgeons. Poor quality of tissue ingrowth, such as thin scar plates or shrinking scars-typical results with conventional static implants and plugs-may contribute to these adverse events. Recently, a new type of 3D dynamically responsive implant was introduced to the market. This device, designed to be placed fixation-free, seems to induce ingrowth of viable and structured tissue instead of regressive fibrotic scarring. To elucidate the differences in biologic response between the conventional static meshes and this 3D dynamically responsive implant, a histological comparison was planned. The aim of this study was to determine the quality of tissue incorporation in both types of implants excised after short, medium, and long periods post-implantation. The results showed large differences in the biologic responses between the two implant types. Histologically, the 3D dynamic implant showed development of tissue elements more similar to natural abdominal wall structures, such as the ingrowth of loose and well-hydrated connective tissue, well-formed vascular structures, elastic fibers, and mature nerves, with negligible or absent inflammatory response. All these characteristics were completely absent in the conventional static implants, where a persistent inflammatory reaction was associated with thin, hardened, and shrunken fibrotic scar formation. Consequently, as herniation is a degenerative process, the 3D dynamic implants, which induce regeneration of the typical groin components, seem to address its pathogenesis.

Histological findings in direct inguinal hernia : Investigating the histological changes of the herniated groin looking forward to ascertain the pathogenesis of hernia disease.

BackgroundThe study is focused on recognizing the histological changes of the structures close to and around the hernia opening in patients having direct inguinal hernia.MethodsIn 15 patients with primary bilateral direct inguinal hernia who underwent a Stoppa open posterior inguinal hernia repair, tissue specimens from the abdominal wall surrounding a direct hernia border were excised for histological examination. These findings in patients with direct inguinal hernia were compared with tissue specimens excised from the fossa inguinalis media of cadavers without hernia.ResultsSignificant degenerative modifications such as fibrohyaline degeneration and fatty substitution of the muscle fibers were seen in the biopsy samples. Inflammatory infiltration with lympho-histiocitary elements, artery sub-occlusion and vascular congestion were also constantly identified. Noteworthy injuries of the nervous structures such as edema, degenerative fibrosis and atrophy were also detected. No comparable tissue damage was witnessed in the control samples.ConclusionPresence of inflammatory infiltration, vascular damage and regressive nerve lesions, as well as fibrohyaline degeneration and fatty dystrophy of the muscle fibers are the features seen within the examined structures surrounding the direct hernia opening. These findings could represent a reason for a structural and functional weakening of the inguinal region. Consequently, the described results lead the authors to depict these changes as a plausible cause of direct inguinal hernia protrusion.

Three-dimensional (3D) versus two-dimensional (2D) laparoscopic adrenalectomy: A case-control study

INTRODUCTION Laparoscopic adrenalectomy is today considered the gold standard of treatment for adrenal tumors. The development of high definition cameras does not eliminate the major limitation of two-dimensional (2D) laparoscopy: lack of depth perception and loss of spatial orientation. Tree-dimensional (3D) HD laparoscopy was developed as an alternative to conventional 2D laparoscopy. METHODS We report our experience with use of 3D vision system for laparoscopic adrenalectomy. Between January 2009 and March 2015 we performed a total of 52 laparoscopic adrenalectomies. In this case-control study we considered 13 laparoscopic adrenalectomies performed with three-dimensional (3D) vision system as case group. The last 26 procedures made with two-dimensional (2D) HD laparoscopic system represented the control group. We considered primary end-points: operative time, intraoperative complications and conversion rate. We evaluated also quality of depth perception and surgical strain. RESULTS Although the operative time for the entire surgical procedure was shorter in 3D group, there were no significant differences. The surgeon experienced better depth perception with 3D system and subjectively reported less strain using 3D vision system. Residents and medical students confirmed these data on surgical outcome. CONCLUSION 3D system vision does not seem to influence the operative time of laparoscopic adrenalectomy performed by experienced surgeon because the surgical technique request simple tasks. We obtain the better visualization in depth perception with effect on surgical precision. Comparative studies are necessary to verify if 3D can reduce perioperative complication with similar operative time.