Malignant gastric outlet obstruction: Which is the best therapeutic option?

Malignant gastric outlet obstruction(MGOO) is a clinical condition characterized by the mechanical obstruction of the pylorus or the duodenum due to tumor compression/infiltration, with consequent reduction or impossibility of an adequate oral intake. MGOO is mainly secondary to advanced pancreatic or gastric cancers, and significantly impacts on patients' survival and quality of life.Patients suffering from this condition often present with intractable vomiting and severe malnutrition, which further compromise therapeutic chances. Currently,palliative strategies are based primarily on surgical gastrojejunostomy and endoscopic enteral stenting with self-expanding metal stents. Several studies have shown that surgical approach has the advantage of a more durable relief of symptoms and the need of fewer re-interventions, at the cost of higher procedure-related risks and longer hospital stay. On the other hand, enteral stenting provides rapid clinical improvement, but have the limit of higher stent dysfunction rate due to tumor ingrowth and a subsequent need of frequent reinterventions. Recently, a third way has come from interventional endoscopic ultrasound, through the development of endoscopic ultrasound-guided gastroenterostomy technique with lumen-apposing metal stent. This new technique may ideally encompass the minimal invasiveness of an endoscopic procedure and the long-lasting effect of the surgical gastrojejunostomy, and brought encouraging results so far, even if prospective comparative trial are still lacking. In this Review, we described technical aspects and clinical outcomes of the above-cited therapeutic approaches, and discussed the open questions about the current management of MGOO.     

Is a Preoperative Assessment of the Early Recurrence of Pancreatic Cancer Possible after Complete Surgical Resection?

Background/Aims

The prognosis of pancreatic adenocarcinoma (PAC) is poor. The serum carbohydrate antigen 19-9 (CA 19-9) level has been identified as a prognostic indicator of recurrence and reduced overall survival. The aim of this study was to identify preoperative prognostic factors and to create a prognostic model able to assess the early recurrence risk for patients with resectable PAC.

Methods

A series of 177 patients with PAC treated surgically at the St. Andrea Hospital of Rome between January 2003 and December 2011 were reviewed retrospectively. Univariate and multivariate analyses were utilized to identify preoperative prognostic indicators.

Results

A preoperative CA 19-9 level >228 U/mL, tumor size >3.1 cm, and the presence of pathological preoperative lymph nodes statistically correlated with early recurrence. Together, these three factors predicted the possibility of an early recurrence with 90.4% accuracy. The combination of these three preoperative conditions was identified as an independent parameter for early recurrence based on multivariate analysis (p=0.0314; hazard ratio, 3.9811; 95% confidence interval, 1.1745 to 15.3245).

Conclusions

PAC patient candidates for surgical resection should undergo an assessment of early recurrence risk to avoid unnecessary and ineffective resection and to identify patients for whom palliative or alternative treatment may be the treatment of choice.     

PGC-1β promotes enterocyte lifespan and tumorigenesis in the intestine

The mucosa of the small intestine is renewed completely every 3–5 d throughout the entire lifetime by small populations of adult stem cells that are believed to reside in the bottom of the crypts and to migrate and differentiate into all the different populations of intestinal cells. When the cells reach the apex of the villi and are fully differentiated, they undergo cell death and are shed into the lumen. Reactive oxygen species (ROS) production is proportional to the electron transfer activity of the mitochondrial respiration chain. ROS homeostasis is maintained to control cell death and is finely tuned by an inducible antioxidant program. Here we show that peroxisome proliferator-activated receptor-γ coactivator-1β (PGC-1β) is highly expressed in the intestinal epithelium and possesses dual activity, stimulating mitochondrial biogenesis and oxygen consumption while inducing antioxidant enzymes. To study the role of PGC-1β gain and loss of function in the gut, we generated both intestinal-specific PGC-1β transgenic and PGC-1β knockout mice. Mice overexpressing PGC-1β present a peculiar intestinal morphology with very long villi resulting from increased enterocyte lifespan and also demonstrate greater tumor susceptibility, with increased tumor number and size when exposed to carcinogens. PGC-1β knockout mice are protected from carcinogenesis. We show that PGC-1β triggers mitochondrial respiration while protecting enterocytes from ROS-driven macromolecule damage and consequent apoptosis in both normal and dysplastic mucosa. Therefore, PGC-1β in the gut acts as an adaptive self-point regulator, capable of providing a balance between enhanced mitochondrial activity and protection from increased ROS production.The intestine represents the interface between the organism and its luminal environment and is constantly challenged by mechanical stress, diet-derived toxins and oxidants, and endogenously generated reactive oxygen species (ROS), which can induce serious damage to all biological molecules and cell structures (1). To preserve cellular integrity and tissue homeostasis, the intestine possesses self-renewing capacity via the continuous migration of new enterocytes that undergo differentiation from the crypt to the apical compartment of the villus, where they become competent to apoptosis and are shed into the lumen. ROS accumulation within intestinal epithelial cells promotes apoptotic cell death in the differentiated compartment (2). The mitochondrial electron transport chain is a major site of ROS production in the cells. Under physiological conditions, the balance between ROS generation and detoxification is controlled by a set of cellular enzymes including superoxide dismutase and catalase. Important components of the ROS-scavenging pathways are linked to mitochondrial oxidative metabolism via the peroxisome proliferator-activated receptor-γ coactivators 1α and 1β (PGC-1α and PGC-1β), apparently enabling cells to maintain normal redox status in response to changing oxidative capacity (3). PGC-1α and PGC-1β are master regulators of mitochondrial biogenesis and oxidative metabolism as well as antioxidant defense. Both PGC-1α and PGC-1β are preferentially expressed in tissues with high oxidative capacity where they participate, through mitochondrial biogenesis, in the metabolic response to high energy demand (4), such as cold-adapted thermogenesis in brown adipose tissue (5), fiber-type switching in striated muscle (6), and fatty acid β oxidation and gluconeogenesis in liver during a fasting state (7, 8). The increase in mitochondrial biogenesis and activity stimulated by PGC-1 proteins may cause an increase in the production of ROS. However, PGC-1α also has been shown to increase the expression of the major mitochondrial antioxidant enzyme superoxide dismutase 2 (Sod2) (3, 9). Therefore, PGC-1α is able to upgrade aerobic energy metabolism while preserving ROS homeostasis, by simultaneously promoting ROS formation and detoxification. Recently, it has been shown in Drosophila that the PGC-1α homolog spargel is able to induce mitochondrial function and oxygen consumption, which is coupled to the induction of scavenger systems and ROS reduction, finally leading to increased longevity (10). On the other hand, in the differentiated intestinal epithelium of mice, PGC-1α induces mitochondrial biogenesis and oxygen consumption, but it is not able to induce the ROS-scavenging apparatus, thus promoting ROS-dependent apoptotic cell death (2).PGC-1β is highly similar to PGC-1α, both in amino acid sequence and ability to regulate several metabolic pathways (8, 11). Therefore, in the present study we focus on the function of PGC-1β in the intestinal epithelium, giving special attention to the effect of this coactivator in enterocyte homeostasis. We first show that PGC-1β is highly expressed in intestinal epithelium with an almost ubiquitous pattern of localization along the entire crypt–villus axis. To study its activation, we generated mice overexpressing PGC-1β selectively in the enterocytes. We show that in these cells PGC-1β enhances mitochondrial biogenesis and respiration and induces a parallel increase in antioxidant enzymes, such as Sod2 and glutathione peroxidase 4 (Gpx4), as well as peroxiredoxins. As a result, the intestinal morphology is severely affected, with significant increases in enterocyte longevity and mucosal villi length. Concomitantly, PGC-1β overexpression leads to a significant increase in tumor number and size in two distinct models of intestinal carcinogenesis. Moreover, to confirm the role of PGC-1β activity in the intestine, we also generated intestinal-specific PGC-1β (iPGC-1β) knockout mice that, in line with the evidence from transgenic mice, show reduced expression of several metabolic pathways and mitochondrial antioxidant systems as well as decreased susceptibility to tumors. Indeed, tumors may use adaptive mechanisms to keep their ROS burden within a range that permits their growth and survival. In such contest, PGC-1β acts as a gatekeeper of redox status, allowing enterocyte survival and, in cancer-promoting conditions, tumor progression.     

The chance finding at multislice computed tomography coronary angiography of myocardial bridging

Myocardial bridging is present when a segment of a major epicardial coronary artery, the ‘tunnelled artery’, runs intramurally through the myocardium. With each systole, the coronary artery is compressed. The pathophysiology of myocardial bridging is incompletely understood. With each systole, the coronary artery is compressed. Moreover, intravascular ultrasound analysis revealed a delayed relaxation after systolic compression, which may extend significantly into diastole. This explains both the impaired coronary flow reserve and ischemia. Evidence indicates that the intima beneath the bridge is protected from atherosclerosis, and the proximal segment is more susceptible to the development of atherosclerotic lesions because of haemodynamic disturbances. Myocardial bridging is sometimes associated with overt pathology, as well as it can just be an incidental finding without any significance. Myocardial bridging may cause angina pectoris, myocardial infarction, life threatening arrhythmias and even sudden cardiac death but most of them are harmless. Furthermore depressed left ventricular function, myocardial stunning, early death after cardiac transplantation has been also reported. Although the exact management is not well known, beta blockers seem to be the first choice. Stenting is controversial and one must think “twice” before stenting the bridged coronary artery. We report a case of chance finding at multislice computed tomography coronary angiography of two myocardial bridging. Also this case focuses attention on myocardial bridging and it confirms that multislice computed tomography coronary angiography technology represents a useful, noninvasive imaging method of its assessment.     

Nonalcoholic fatty liver disease is associated with increased GHBP and reduced GH/IGF-I levels

Introduction Nonalcoholic fatty liver disease (NAFLD) has been described in adult GH deficiency syndrome. Furthermore, chronic liver disease can be associated with significant changes in levels of IGF‐I, GH‐binding protein (GHBP), IGF‐binding proteins (IGFBPs) and acid‐labile subunit (ALS). However, the effect of liver steatosis on the GHBP production has not been investigated yet. Aim of the study To explore whether GH secretion and/or levels of IGF‐I, IGFBP‐3, ALS and GHBP could be altered in obese patients in relation to the presence of liver steatosis. Materials and methods A total of 115 obese patients (BMI > 30) were enrolled in the protocol (65 patients with liver steatosis and 50 age‐ and BMI‐matched controls). In all patients, the following parameters were studied: serum levels of glucose, insulin, the HOMA index, IGF‐I, GHBP, IGFBP‐3, ALS and GH after GHRH and arginine stimulation test. Results As expected, patients with NAFLD had blood glucose, insulin, HOMA‐R significantly higher than controls, indicating a more severe insulin‐resistance state in NAFLD. Furthermore, patients with NAFLD had higher levels of GHBP and IGFBP‐3 and lower GH peak and IGF‐I levels as compared to controls. No difference was found in ALS levels between the groups. In a multivariate analysis, GHBP was positively associated with hepatic steatosis while IGF‐1 was negatively associated with hepatic steatosis. Conclusions This study demonstrates that in patients with NAFLD, the GHBP levels are increased, and that the GH/IGF‐I axis is significantly altered probably leading to reduced IGF‐I bioavailability at tissue level.     

Validation of the Italian version of the Sunnybrook Facial Grading System

The Sunnybrook Facial Grading System (SFGS) is one of the most employed scales to assess the severity of facial palsy. The aim of our study was to produce an Italian version of the SFGS and of its explanatory criteria, and to test their measurement properties when employed by Italian physicians. A multidisciplinary committee translated and adapted the scale and its criteria into Italian. Six native Italian physicians, four of whom experienced in facial palsy and two novices, rated independently 29 videos of facial palsy patients twice. Internal consistency, agreement and repeatability were evaluated. The Italian version of the SFGS showed a high degree of internal consistency with a Cronbach’s α of 0.91. The test–retest reliability was high for both inter-rater and intra-rater measures with an ICC of 0.96 and 0.98, respectively. The scores given by the novice physicians were comparable with the scores given by the expert physicians. Our study suggests that the Italian version of the SFGS has excellent internal consistency and reproducibility, comparable to the original scale. Our study confirms in an independent case record the high measurement properties of SFGS and provides the first validated Italian scale for the assessment of facial palsy.