Energy metabolic pathways in neuronal development and function.

Neuronal development and function are known to be among the most energy-demanding functions of the body. Constant energetic support is therefore crucial at all stages of a neuron's life. The two main adenosine triphosphate (ATP)-producing pathways in cells are glycolysis and oxidative phosphorylation. Glycolysis has a relatively low yield but provides fast ATP and enables the metabolic versatility needed in dividing neuronal stem cells. Oxidative phosphorylation, on the other hand, is highly efficient and therefore thought to provide most or all ATP in differentiated neurons. However, it has recently become clear that due to their distinct properties, both pathways are required to fully satisfy neuronal energy demands during development and function. Here, we provide an overview of how glycolysis and oxidative phosphorylation are used in neurons during development and function.

AMPK adapts metabolism to developmental energy requirement during dendrite pruning in Drosophila.

To reshape neuronal connectivity in adult stages, Drosophila sensory neurons prune their dendrites during metamorphosis using a genetic degeneration program that is induced by the steroid hormone ecdysone. Metamorphosis is a nonfeeding stage that imposes metabolic constraints on development. We find that AMP-activated protein kinase (AMPK), a regulator of energy homeostasis, is cell-autonomously required for dendrite pruning. AMPK is activated by ecdysone and promotes oxidative phosphorylation and pyruvate usage, likely to enable neurons to use noncarbohydrate metabolites such as amino acids for energy production. Loss of AMPK or mitochondrial deficiency causes specific defects in pruning factor translation and the ubiquitin-proteasome system. Our findings distinguish pruning from pathological neurite degeneration, which is often induced by defects in energy production, and highlight how metabolism is adapted to fit energy-costly developmental transitions.

Unsupervised class discovery in pancreatic ductal adenocarcinoma reveals cell-intrinsic mesenchymal features and high concordance between existing classification systems.

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all common cancers. However, divergent outcomes exist between patients, suggesting distinct underlying tumor biology. Here, we delineated this heterogeneity, compared interconnectivity between classification systems, and experimentally addressed the tumor biology that drives poor outcome. RNA-sequencing of 90 resected specimens and unsupervised classification revealed four subgroups associated with distinct outcomes. The worst-prognosis subtype was characterized by mesenchymal gene signatures. Comparative (network) analysis showed high interconnectivity with previously identified classification schemes and high robustness of the mesenchymal subtype. From species-specific transcript analysis of matching patient-derived xenografts we constructed dedicated classifiers for experimental models. Detailed assessments of tumor growth in subtyped experimental models revealed that a highly invasive growth pattern of mesenchymal subtype tumor cells is responsible for its poor outcome. Concluding, by developing a classification system tailored to experimental models, we have uncovered subtype-specific biology that should be further explored to improve treatment of a group of PDAC patients that currently has little therapeutic benefit from surgical treatment.

[Whole laparoacopic trans-hiatal extended total gastrectomy with the Or-Vil device: preliminary results in the treatment of Siewert type II and III tumors]. / Gastrectomia totale "trans-hiatally extended" totalmente laparoscopica con Or-Vil" device: risultati preliminari nel trattamento dei tumori Siewert tipo II e III.

Adenocarcinoma of the gastro-oesophageal junction is progressively rising in western countries and, because of its poor prognosis, presents a real clinical challenge for the oncological surgeon. We evaluate our initial experience with wholly laparoscopic trans-hiatal extended total gastrectomy with the Or-Vil device for treating Siewert type II and III tumours of the gastro-oesophageal junction. Ten patients were enrolled in the present study; ASA score, stage of disease, length of surgery, estimated blood loss, number of lymph nodes harvested, length of proximal margin clearance, morbidity and mortality were analysed. Mortality was nil and morbidity 20%; the average proximal clearance margin was 5.7 cm and all margins were tumour-free (RO). The number of lymph nodes harvested was 38 +/- 19. Neither anastomotic fistulas nor major dehiscence were observed. In our initial experience, wholly laparoscopic trans-hiatal extended total gastrectomy for treating Siewert type II and III tumours of the gastro-oesophageal junction is safe, effective and, according to our preliminary results, oncologically correct, but it remains a complex, advanced laparoscopic procedure, requiring major skills and adequate experience. Prospective, randomised trials--possibly multicentric--are required to establish its efficacy in terms of long-term oncological outcomes.

Use of a dynamic self-regulating prosthesis (P.A.D.) in inguinal hernia repair: our first experience in 214 patients.

Numerous techniques exist for inguinal hernia treatment. Currently, open mesh tension-free repair is regarded as the repair method of choice. In particular Lichtenstein repair is the most common procedure performed, although several articles have reported long-lasting postoperative pain and a higher recurrence rate than originally reported. This study describes the P.A.D. (Protesi Autoregolantesi Dinamica) prosthesis implantation technique and reports postoperative complications and long-term results. From June 2002 to May 2005 a total of 214 patients underwent P.A.D. prosthesis inguinal repair. All patients were male, with a mean age of 51 years. All hernias were treated via an open inguinal approach using the original technique described by Valenti, with slight modifications. A total of 171'patients (80%) were available to follow-up 3 years after surgery. Early postoperative complications occurred in 14 patients (8.4%). Four patients (12.1%), who had undergone regional anaesthesia, developed urinary retention. Wound infection occurred in 3 patients (1.4%). There were two direct recurrences (0.93%) whereas chronic postoperative inguinal pain was reported in 4.2% of patients. Within the limitations of a short follow-up, our results show that the P.A.D. prosthesis procedure is a reliable technique with a low recurrence rate and low postoperative morbidity.

[Modulation of the extent of lymphadenectomy in early gastric cancer. Review of the literature and role of laparoscopy]. / Modulazione dell'estensione della linfadenectomia nell' "early gastric cancer". Review della letteratura e ruolo della laparoscopia.

Early gastric cancer is a gastric carcinoma confined to the mucosa or submucosa of the stomach, regardless of the presence of nodal involvement, which in any event is present only in about 20% of patients. This uncommon nodal involvement is a distinct clinical problem, because standard D2 lymphadenectomy constitutes overtreatment in more than 80% of patients. A review of the literature shows that the present surgical tendency for those patients who do not fulfill the Gotoda criteria (i.e. not amenable to an endoscopic mucosal or submucosal dissection) is to modulate the extent of the lymphadenectomy on the basis of the characteristics of the cancer: for mucosal early gastric cancers located in the upper third of the stomach, gastrectomy with D1 lymphadenectomy is sufficient; if located in the middle third the extent should be D1 +alpha (D1 + n. 7), while if located in the distal third, D1 +beta (D1 + n. 7,8a,9) is the best option. In all these cases, minimally invasive surgery can be a valid option, with results which are comparable to those of open surgery, but with all the advantages of the laparoscopic approach. For submucosal early gastric cancers, D1 +beta lymphadenectomy is indicated for neoplasia > 20 mm and of the protuberance type, while, for all other submucosal early gastric cancers (> 20 mm and of the depressed type, penetrating more than 500 micron into the submucosal layer, not differentiated, with lymphovascular invasion), standard D2 lymphadenectomy is the safest oncological procedure. In these cases, too, the laparoscopic approach can be a safe option, even if it requires greater laparoscopic skill.

[Five-year oncological results of laparoscopic versus open left hemicolectomy]. / Emicolectomia sinistra laparoscopica versus open: risultati oncologici a 5 anni.

Laparoscopic left hemicolectomy is still uncommon in surgical practice, because of both an unjustified fear of oncological inadequacy and technical difficulties with a steep learning curve. The aim of the present study was to analyse our 5-year experience with laparoscopic left hemicolectomy and its short- and long-term results. Thirty patients with non-metastatic non-infiltrating left colon cancer were treated laparoscopically and retrospectively compared to a group treated laparotomically and well matched for age, comorbidity and stage of disease in respect to the laparoscopic group. The duration of the laparoscopic procedures was longer, but intraoperative blood loss, passage of flatus and hospital stay were significantly less. Morbidity was similar and there was no 30 days mortality in either group. Specimen length and number of harvested lymph nodes were similar and 5-year cumulative survival curves showed no significant statistical difference (73.1% laparoscopic vs 70.8% open). Today, laparoscopic colon procedures are rarely performed, due both to fear of oncological inadequacy and to technical difficulties, yet several recent trials have presented evidence of safety, and oncological results comparable to those of the open counterpart. Our 5-year experience confirms these studies: our short- and long-term results show no statistical differences between the laparoscopic and "open" procedure. Laparoscopic left hemicolectomy is a safe, effective and oncologically adequate surgical procedure for non-metastatic non-infiltrating left colon cancer and is therefore a valid option for the surgical treatment of these neoplasms.

[Laparoscopic total mesorectal excision for extraperitoneal rectal cancer. Oncological outcome at 5 years]. / Total mesorectal excision laparoscopica per cancro del retto extraperitoneale. Outcome oncologico a 5 anni.

Total mesorectal excision (TME) is the cornerstone of surgical treatment for extraperitoneal rectal cancer. The aim of the present study was to analyse our five-year experience with laparoscopic TME, evaluating the overall five-year and disease-free survival rates. Twenty-five patients with low-middle rectal cancer were treated with laparoscopic TME. Patients with advanced rectal cancer were treated preoperatively with neoadjuvant radiochemotherapy. Five-year overall survival and disease-free survival were calculated according to the Kaplan-Meier method. Twenty-three ultralow anterior resections with Knight-Griffen anastomosis and 3 abdominoperineal resections were performed. At 30 days mortality was zero, while morbidity was 20% (all minor complications). The mean follow-up period was 30.5 months. Five-year overall survival was 80.2%, and five-year disease-free survival 80.9%. Our experience shows that laparoscopic TME is a safe and oncologically correct procedure. Oncologic outcomes were comparable to those reported in all major international experiences, and the results were very similar to those obtained with the laparotomic approach. However, it remains a complex technique, requiring an adequate learning curve. More prospective, randomised trials are needed in order to define laparoscopic TME as the new gold standard for the treatment of extraperitoneal rectal cancer.

[Laparoscopic versus open right hemicolectomy: 5-year oncology results]. / Emicolectomia destra laparoscopica versus open: risultati oncologici a 5 anni.

Laparoscopic right hemicolectomy has developed less markedly than rectosigmoid resection, probably because of the more complicated regional anatomy and greater difficulty in performing an adequate regional lymphectomy. The aim of the present study was to analyse our 5-year experience with laparoscopic right hemicolectomy. Twenty patients were enrolled with non-metastatic, non-infiltrating right colonic cancer, treated laparoscopically and compared to a group well matched for age, sex, comorbidity and stage of disease, treated laparotomically. The duration of the laparoscopic procedures was slightly longer, but intraoperative blood loss, passage of flatus and hospital stay were reduced compared to the laparotomic procedure. Morbidity was similar and there was no 30-day mortality in either group. Specimen length and number of harvested lymph nodes were similar and the 5-year cumulative survival curves showed no statistically significant difference (72.5% versus 72.2%). Our experience shows that laparoscopic right hemicolectomy is a safe, effective and oncologically adequate procedure, comparable in all respects to open hemicolectomy, but with all the advantages of the minimally invasive technique. Yet, it remains a complex surgical procedure, requiring skill and a long learning curve. Further studies, possibly prospective and randomised, are necessary to define the exact role of this technique for the treatment of non-metastatic, non-infiltrating right colonic cancer.