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Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy. We found that loss of transcriptionally active p73 (TAp73), a p53 family member, impacted PDA development. In two relevant and specific engineered pancreatic cancer mouse models, we observed that TAp73 deficiency reduced survival and enhanced epithelial-to-mesenchymal transition (EMT). Through proteomic analysis of conditioned media from TAp73 wild-type (WT) and deficient pancreatic tumor cells, we identified a secreted protein, biglycan (BGN), which is necessary and sufficient to mediate this pro-EMT effect. Interestingly, BGN is modulated by and modulates the transforming growth factor-β (TGF-β) pathway, a key regulator of the EMT process. We further examined this link and revealed that TAp73 impacts the TGF-β pathway by direct regulation of BGN expression and Sma and Mad-related proteins (SMADs) expression/activity. Absence of TAp73 leads to activation of TGF-β signaling through a SMAD-independent pathway, favoring oncogenic TGF-β effects and EMT. Altogether, our data highlight the implication of TAp73 in the aggressiveness of pancreatic carcinogenesis through modulation of the TGF-β signaling. By suggesting TAp73 as a predictive marker for response to TGF-β inhibitors, our study could improve the classification of PDA patients with a view to offering combined therapy involving TGF-β inhibitors.

Esophageal carcinoma is the eighth most frequent cancer worldwide and the sixth cancer-related cause of death. Here we propose a new meta-analysis to identify the most appropriate approach for resectable adenocarcinoma of the distal esophagus and cardia (Siewert 1-2). A systematic literature search was performed independently by 2 of the manuscript's authors using PubMed, EMBASE, Scopus and the Cochrane Library Central. The following criteria were set for inclusion in this meta-analysis: 1) studies comparing transthoracic esophagectomy and transhiatal esophagectomy for adenocarcinoma of the esophagus; 2) studies reporting at least 1 perioperative outcome; and 3) if more than 1 study was reported by the same institute, only the most recent or the highest quality study was included. A total of 6 articles dated between 1996 and 2012 fulfilled the selection criteria and were therefore included in this meta-analysis; this pool of articles consisted of 2 prospective and 4 retrospective studies. A statistically significant difference favoring the transthoracic procedure was noted regarding the number of retrieved lymph nodes, 5-year disease-free survival rate and 5-year overall survival rate (p = 0.001, p = 0.05 and p = 0.03, respectively). In conclusion, transthoracic esophagectomy for adenocarcinoma of the distal esophagus and esophagogastric junction (Siewert 1-2) appears to be superior to the transhiatal approach in terms of oncological outcomes.

Despite developments in panic disorder (PD) research, a significant percentage of patients do not benefit from conventional treatments. Interpersonal factors have been identified as potential predictors of treatment failures. We aimed to evaluate assertiveness in a sample of patients with PD and its implications for treatment. Forty-six symptomatic patients with PD and 46 college students responded to assessment scales regarding assertiveness and clinical data. Seventy-five percent of the patients had a secondary diagnosis of agoraphobia. We found that the PD group was characterized as nonassertive and slightly less assertive than control subjects. Furthermore, the deficit in the level of assertiveness correlated with the severity of the PD. The diagnosis of agoraphobia was correlated with unassertiveness (p< 0.05). Agoraphobia predisposes individuals to dependency and insecurity about their ability to overcome anxiogenic situations. These data demonstrate the importance of managing assertiveness in patients with PD accompanied by agoraphobia.

The differential diagnosis between vegetative state and minimally conscious state is still complex and the development of an evaluation systems is one of the challenging tasks for researchers and professionals. The Coma Recovery Scale-revised is considered the gold standard for clinical/behavioral assessment and for the differential diagnosis of patients with disorder of consciousness. However, the scale presents some limitations in that (i) scores may partially overlap between different diagnoses and (ii) there is an underlying assumption that if a patient is able to show higher-level behaviors, he/she is also able to show lower-level responses. In the present study, a procedure to calculate a modified Coma Recovery Scale-revised score is presented that attempts to avoid these problems. To exemplify this new scoring approach, 60 patients with disorder of consciousness were studied and the results showed the usefulness of the Modified Score.

Age-related neurodegenerative diseases (NDDs) are associated with the aggregation and propagation of specific pathogenic protein species (e.g., Aβ, α-synuclein). However, whether disruption of synaptic homeostasis results from protein misfolding per se rather than accumulation of a specific rogue protein is an unexplored question. Here, we show that error-prone translation, with its frequent outcome of random protein misfolding, is sufficient to recapitulate many early features of NDDs, including perturbed Ca2+signaling, neuronal hyperexcitability, and mitochondrial dysfunction. Mice expressing the ribosomal ambiguity mutation Rps9 D95N exhibited disrupted synaptic homeostasis resulting in behavioral changes reminiscent of early Alzheimer disease (AD), such as learning and memory deficits, maladaptive emotional responses, epileptiform discharges, suppressed circadian rhythmicity, and sleep fragmentation, accompanied by hippocampal NPY expression and cerebral glucose hypometabolism. Collectively, our findings suggest that random protein misfolding may contribute to the pathogenesis of age-related NDDs, providing an alternative framework for understanding the initiation of AD.

In pancreatic ductal adenocarcinoma (PDAC), signaling from stromal cells is implicated in metastatic progression. Tumor-stroma cross-talk is often mediated through extracellular vesicles (EVs). We previously reported that EVs derived from cancer-associated stromal fibroblasts (CAFs) that are abundant in annexin A6 (ANXA6+EVs) support tumor cell aggressiveness in PDAC. Here, we found that the cell surface glycoprotein and tetraspanin CD9 is a key component of CAF-derived ANXA6+EVs for mediating this cross-talk. CD9 was abundant on the surface of ANXA6+CAFs isolated from patient PDAC samples and from various mouse models of PDAC. CD9 colocalized with CAF markers in the tumor stroma, and CD9 abundance correlated with tumor stage. Blocking CD9 impaired the uptake of ANXA6+EVs into cultured PDAC cells. Signaling pathway arrays and further analyses revealed that the uptake of CD9+ANXA6+EVs induced mitogen-activated protein kinase (MAPK) pathway activity, cell migration, and epithelial-to-mesenchymal transition (EMT). Blocking either CD9 or p38 MAPK signaling impaired CD9+ANXA6+EV–induced cell migration and EMT in PDAC cells. Analysis of bioinformatic datasets indicated that CD9 abundance was an independent marker of poor prognosis in patients with PDAC. Our findings suggest that CD9-mediated stromal cell signaling promotes PDAC progression.

This work presents a new approach for establishing a relationship between the temperature and the spatial position, for infinite cylindrical fins, providing an innovative tool for this class of phenomena. The results are valid even for nonlinear heat transfer processes, especially those in which the thermal conductivity depends on the local temperature. Exact formulas for the temperature distribution as well as for the total heat flux are provided in a simple and systematic way.

Transanal stapled procedures are increasingly being used. Several postoperative complications can be referred to their application, including those related to the presence of retained staples at the level of the staple line.

Pancreatic surgery remains the only established curative treatment for pancreatic cancer. Radical antegrade pancreatosplenectomy (RAMPS) is a modification of the standard retrograde pancreatosplenectomy (SRPS) developed to achieve a complete N1 node resection and R0 resection (posterior extent). The aim of this study is to compare the short-, mid-, and long-term outcomes of RAMPS and SRPS. From a database that included 143 consecutive patients who underwent resection for pancreatic carcinoma at the St. Andrea Hospital, University of Rome, 25 patients who underwent pancreatosplenectomy were retrospectively reviewed. Among these 25 patients, eight (32%) underwent RAMPS (Group 1) and 17 (68%) underwent SRPS (Group 2). Clinicopathologic and oncological characteristics of the RAMPS group were compared with those of the SRPS group. RAMPS was longer than SRPS (315 vs265 minutes, respectively, P< 0.001). No differences were encountered for perioperative outcomes (estimated blood loss, intraoperative blood transfusions, postoperative morbidity and mortality, and hospital stay). The margin status rates were similar: noteworthy, the two patients with positive tangential margins belonged to Group 2. No between-group differences in survival were encountered: the actuarial 5-year overall survival for Groups 1 and 2 were 26 and 29 per cent, respectively (P= 0.6608; hazard ratio, 1.2621; 95% confidence interval, 0.4462 to 3.5699). RAMPS and SRPS did not differ statistically in terms of perioperative outcomes. RAMPS seems to allow better control of tangential margins; however, no difference was found in actuarial survival compared with standard pancreatosplenectomy.

Postoperative pain after stapled hemorrhoidopexy is cause for considerable concern and may be related to contracture of continence muscles.

The majority of existing functional MRI studies on olfactory perception have addressed the relationship between stimulus features and the intensity of activity in separate regions considered in isolation. However, anatomical studies as well as neurophysiological recordings in rats and insects suggest that odor features may also be represented in a sparse manner through the simultaneous activity of multiple cortical areas interacting as a network. Here, we aimed to map the interdependence of neural activity among regions of the human brain, representing functional connectivity, during passive smelling. Seventeen healthy participants were scanned while performing a blocked-design task alternating exposure to two unpleasant odorants and breathing fresh air. High efferent connectivity was detected for the piriform cortex and the amygdala bilaterally. By contrast, the medial orbitofrontal cortex was characterized by high afferent connectivity, notably in the absence of an overall change in the intensity of hemodynamic activity during olfactory stimulation. Our results suggest that, even in the context of an elementary task, information on olfactory stimuli is scattered by the amygdala and piriform cortex onto an anatomically sparse representation and then gathered and integrated in the medial orbitofrontal cortex.

Laparoscopic low anterior rectal resection (LLAR), allowing better visualization and rectal mobilization, can reduce postoperative pain and recovery. A Contour Curved Stapler (CCS) is a very helpful device because of its curved profile that consents better access into the pelvic cavity and allows to perform rectal closure and section in one shot, especially in the presence of a narrow pelvis, complex anatomy, or large tumors. We developed an original technique of laparoscopic rectal resection using CCS. Between 2005 and 2009, in 36 cases, we performed LLAR with a three-trocar technique, starting with mobilization of left colonic flexure followed by the section of inferior mesenteric vessels. The rectum was prepared up to the levator ani with total mesorectal excision. The Lapdisc® was inserted trough a suprapubic midline incision, allowing the CCS stapler placement into the pelvic cavity. After the rectal section, the anastomosis was then performed with a circular stapler. Ileostomy was performed if neoadjuvant radiotherapy and chemotherapy have been carried out or if the anastomosis was below 4 cm from the anal verge. Mean operative time was 135 minutes and no intra- or postoperative bleeding occurred. In 27 patients we performed temporary ileostomy. In two cases we observed anastomotic leakage; one of these patients already had ileostomy. No anastomotic stenosis occurred after one-year follow-up. This procedure simplifies the section of the lower rectum, reduces leaking rate resulting from technical difficulties, and does not nullify the benefits of laparoscopy.

Hartmann's procedure is still performed in those cases in which colorectal anastomosis might be unsafe. Reversal of Hartmann's procedure (HR) is considered a major surgical procedure with a high morbidity (55 to 60%) and mortality rate (0 to 4%). To decrease these rates, laparoscopic Hartmann's reversal procedure was successfully experienced. We report our totally laparoscopic Hartmann's reversal technique. Between 2004 and 2010 we performed 27 HRs with a totally laparoscopic approach. The efficacy and safety of this technique were demonstrated evaluating the operative data, postoperative complications, and the outcome of the patients. There were no open conversions or major intraoperative complications. Anastomotic leaking occurred in one patient requiring an ileostomy; one patient needed a blood transfusion and one had a nosocomial pneumonia. The mean postoperative hospitalization was 5.7 days. Laparoscopic HR is a feasible and safe procedure and can be considered a valid alternative to open HR.

Gastrointestinal stromal tumors are the most common mesenchymal tumors of the gastrointestinal tract and occur rarely in the duodenum. Splenic angiosarcoma is an aggressive neoplasm with an extremely poor prognosis.

Liver resection is considered the therapeutic gold standard for primary and metastatic liver neoplasms. The reduction of postoperative complications and mortality has resulted in a more aggressive approach to hepatic malignancies. For the most part, results of liver surgery have been published by highly experienced institutions, but the observations of highly specialized units results may not reflect the current status of hepatic surgery, underestimating mortality and complications. The objective of this study is to evaluate morbidity and mortality as a result of liver resection for primary and metastatic lesions, analyzing a large number of studies with a meta-analytic process taking into account the overdispersion of data. An extensive literature search has been conducted, and 148 papers published between January 2000 and April 2008, including a total of 36,629 patients from both high-volume and low volume institutions, were included in the meta-analysis. A beta binomial model was used to provide a robust estimate of the summary event rate by pooling overdispersion binomial data from different studies. Overall morbidity and mortality after liver surgery were 29.32 per cent and 3.15 per cent, respectively. Significantly higher postoperative mortality was observed after liver resection for hepatocellular carcinomas and primary hepatic tumors. The application of a beta binomial model to correct for overdispersion of liver surgery data showed significantly higher postoperative mortality rates in patients with hepatocellular carcinomas or primary hepatic tumors after liver resection.

An association between hospital surgical volume and short- and long-term outcomes after pancreatic surgery has been demonstrated. Identification of specific factors contributing to this relationship is difficult. In this study, the authors evaluated if margin status can be identified as a measure of surgical quality, affecting overall survival, as a function of hospital pancreaticoduodenectomy volume. A systematic review of the literature was performed. Two models for analysis were created, dividing the 18 studies identified into quartiles and two quantiles based on the average annual hospital pancreatectomy volume. Regression modeling and analysis of variance were used to find an association between hospital volume, margin status, and survival. Increasing hospital volume was associated with a significantly increased negative margin status rate: 55 per cent for low-volume, 72 per cent for medium-volume, 74.3 per cent for high-volume, and 75.7 per cent for very high-volume centers (P= 0.008). The negative margin status rates were 64 per cent and 75.1 per cent for volume centers with less and more than 12 pancreaticoduodenectomies/year, respectively (P= 0.04). Low-volume centers negatively affected both margin positive resection and 5-year survival rates, compared with high-volume centers. Margin status rate after pancreaticoduodenectomy could, therefore, be considered a measure of quality for selection of hospitals dedicated to pancreatic surgery.

In the last 10 years, stapled hemorrhoidectomy has gained worldwide consensus. We studied a day-surgery stapled hemorrhoidopexy protocol to allow shorter recovery time and cost reduction. From 2003 to 2008, we performed 292 outpatient stapled hemorrhoidopexies under spinal or local anesthesia including symptomatic Grade III and IV hemorrhoid disease. We used PPH 01 to PPH 03 staplers. We assessed early and late postoperative pain with a Visual Analog Scale, whereas clinical postoperative examinations were performed at sev7en days, 6 months, and 1, 3, and 5 years after surgery. The mean surgery time was approximately 18 minutes (range, 13 to 39 minutes). Of 292 patients, 39 were not dischargeable for urine retention, severe pain, or mild bleeding. Four other patients were rehospitalized within 8 days for bleeding. Twenty-one patients reported transient fecal urgency, whereas nobody reported anal incontinence. We can conclude that stapled hemorrhoidopexy is a safe and effective procedure if performed in a day-surgery unit. The complication rate is comparable to that of inpatient procedures.

Minimally invasive adrenalectomy (MIA) is both feasible and safe with either transperitoneal or retroperitoneal entry. However, only a few studies have rigorously compared these two techniques. The aim of the current study is to compare transperitoneal and retroperitoneal adrenalectomy to detect significant differences in patient selection and perioperative outcomes. Between 1995 and 2009, 171 patients underwent MIA through transperitoneal (n = 127) or retroperitoneal access (n = 44). The respective cohorts were then examined retrospectively through matched and unmatched comparisons. Multivariate analyses of intraoperative blood loss, postoperative morbidity, and length of hospital stay were performed. Surgical indications were benign lesions (70.2%), malignant tumors (11.1%), and pheochromocytomas (18.7%). The postoperative morbidity rate was 15.8 per cent, but mortality was null. The rate of conversion to open surgery was 5.3 per cent. Blood loss and operative time were significantly lower with the transperitoneal approach, whereas time to oral intake was shorter for the retroperitoneal group. Tumor size less than 4.5 cm was associated with less blood loss, shorter hospital stay, and lower postoperative morbidity. Laparoscopic and retroperitoneal routes are both effective and safe for excising adrenal lesions. In the present study, however, laparoscopic adrenalectomy demonstrated shorter operative times with less blood loss. Regardless of this, we remain cautious in recommending one procedure preferentially. Other important measures of clinical outcome such as required pain control, ease of patient recovery, and cost considerations were not included in this analysis. Further randomized trials, with large patient numbers, are therefore desirable for defining an optimal surgical method.

Postoperative pancreatic fistula (POPF) is the most frequent complication after pancreaticoduodenectomy, results in increased morbidity and mortality, and adversely affects length of stay and costs. Reported rates of postoperative pancreatic fistula vary from 0 per cent up to more than 30 per cent. Plenty of randomized trails and meta-analysis were published to analyze the ideal procedure, technique of anastomosis, and perioperative management of patients undergoing pancreaticoduodenectomy; however, results are often discordant and clear evidence on the ideal management and surgical technique to reduce POPF rate is not yet provided. This collective review examined the current evidence about risk factors contributing to postoperative pancreatic fistula and delineates methods of diagnosis and treatment of this universally dreaded complication.

Surgery is the only effective treatment able to improve survival of patients with hilar cholangiocarcinoma (CCA). However, the significance of prognostic factors on overall survival is still debated. We evaluated early and long-term outcomes of patients resected for hilar cholangiocarcinoma over a 3-year period to determine the role of prognostic factors and their effect on overall survival. Medical records of patients with hilar CCA who underwent resection between January 2001 and December 2004 were retrospectively reviewed. Univariate and multivariate analysis was performed to identify prognostic factors associated with survival. Thirty-two of 45 patients underwent surgical resection with curative intent. Morbidity was 24.4 per cent; perioperative mortality was 0 per cent. Overall median survival was 22.3 months. Well-differentiated tumor grading and R0 resection were independently associated with better survival at multivariate analysis. Aggressive surgery, including biliary resection combined with major hepatectomy, is a safe procedure with low morbidity and mortality in a tertiary referral hepatobiliary center. The main aim of an aggressive surgical approach is to obtain a microscopic margin-negative resection, which is associated with better prognosis. Another important prognostic factor is tumor grading, which is independently associated with survival.

Gastric cancer remains one of the most common human malignancies with a poor prognosis. Apoptosis is known to be a programmed cell death and its inhibition is involved in the unregulated cellular growth that leads to neoplasms. Microvessel density (MVD) has been investigated as a promoting factor for angiogenesis with conflicting results about its relation to survival. The aim of our study was to search a correlation between these factors and some clinicopathological features and prognosis. Identification of apoptotic cells was performed applying the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique and recorded as apoptotic index (A.I.), whereas monoclonal antibodies were used for the study of MVD. A significant correlation was found between low and high A.I. and the subgroup of patients in Stages I and II (P < 0.02); 20 per cent of patients with a low A.I. showed an overall survival longer than 5 years versus44 per cent of patients with an high A.I. (P = 0.041). High MVD was significantly related to the T stage (P= 0.036) and to a poorer 5-year overall survival (P < 0.05). Further studies are required to confirm the role of apoptosis and MVD in the development and progression of gastric cancer.

The tumor, node, metastasis (TNM) system has become the principal method for assessing the extent of disease, determining prognosis in gastric cancer patients, and affecting the therapy strategies. The extent of lymph node metastasis is the most important prognostic factor. The aim of this study was to compare the N-classifications of the 4th and the 5th-6th TNM editions and to evaluate retrospectively the prognostic value of the 2002 TNM edition. We evaluated 344 patients who underwent curative total or subtotal gastrectomy. Nodal involvement was detected in 221 (64%) patients. Median follow-up period was 76 months. Thirty per cent of the old N1 patients were reclassified as pN2 (18.5%) and pN3 (11.3%). Eighty-eight per cent of the old N2 patients were reclassified as pN1 (75%) and pN3 (13.7%). In reclassifying the patients, statistically significant changes were reported between 1987 and 2002 TNM stage grouping, mainly in stage IIIB and IV. The 5-year survival rate per stage group did not statistically differ between the 4th and the 5th–6th editions, although a diminutive trend was registered in the IIIA stage. pTNM stage, nodal numerical stage, nodal topographical stage, and depth of tumor invasion resulted in significantly independent prognostic factors. Our data confirm the simplicity and easy application of the new stadiation and the better prognostic stratification of the N-stage. The pN3 group showed a worse prognosis independent of location. On the other hand, prognostic value of pN1 and pN2 stage is lower, probably depending on lymph node location. In multivariate analysis, the difference between old and new TNM staging is low. Hence, we suggest comparing lymph node location and number in larger series. In our series, in pT1 tumors, neither pN2 nor pN3 involvement was found. Hence, in our opinion, for correct N-staging, 10 lymph nodes in early gastric cancer and at least 16 in the other pT-stages seem sufficient for a real pN0 stadiation.

Gastroesophageal junction (GEJ) neoplasms have become more common over the past decade. Like mediastinal and abdominal lymph nodes and other gastric tumors, GEJ tumors spread to the retroperitoneal nodes. The TNM staging system does not consider this pattern and does not clinically distinguish GEJ tumors from gastric and esophageal cancers. The aim of the study is to compare the old and new TNM staging systems to assess whether the new TNM classifies lymph node involvement in these tumors as a prognostic factor. From January 1983 to December 1995, 438 patients underwent curative gastric resections for cancer at the Department of Surgery “P. Valdoni” of the University of Rome “La Sapienza.” Sixty-two had GEJ type II and III tumors according to the Siewert classification system. The old pN1 and new pN1 survival rates (P < 0.05) were statistically different; the old pN2 and new pN2 survival rates (P = 0.483) were not. The multivariate analysis of significant statistical prognostic factors showed that the pTNM staging in type II and type III GEJ tumors is the most important prognostic factor (P < 0.001), followed by the old pN and new pN (P < 0.001) and the pT (P < 0.005). Gender, age, Lauren type, and tumor location according to Siewert (II vs III) were not independently significant prognostic factors. This study concludes that the numbers and locations of metastatic lymph nodes are important prognostic factors that should be included in the next TNM edition.