Alpha- synuclein immunoreactivity in the enteric nervous system of human small intestine

Alpha-synuclein (α-syn) is a 140 amino acid protein, belonging to the synuclein family, expressed in mammalian neurons. Structural alterations of α-syn as well as its overexpression have been related to the onset and the progression of several human neurodegenerative diseases, as Parkinson’s diseases (PD). Indeed, α-syn aggregates are the main component of the Lewy bodies (Lbs), considered as pathological hallmarks of neurodegenerative diseases [1-2], known as synucleinopathies. PD is a multicentric neurodegenerative process that affects several neuronal structures in the central and peripheral nervous system, among which is the enteric nervous system (ENS). Remarkably, recent reports have shown that the lesions in the ENS occurred at very early stage of the disease, even before the involvement of the central nervous system. So, the ENS could be critical in the pathophysiology of PD [3-4] and the pathological alterations within the ENS could be involved in the gastrointestinal dysfunction frequently encountered by parkinsonian patients. Although at present Lbs, as well as α-syn pathological aggregates, have been evidenced throughout the autonomic nervous system projecting to the gut of patients affected by PD or other neurodegenerative diseases, however data on the distribution of α-syn in human normal ENS are lacking. Our study focused on the immunohistochemical distribution of α-syn in the ENS of proximal tract of human normal small intestine. Surgical specimens of duodenum and proximal jejunum, collected from patients submitted to a pancreaticoduodenectomy, were fixed and paraffin embedded. Intestinal slices underwent immunohistochemical procedure using monoclonal anti α-syn antibody. Alpha-syn immunoreactive (ir) structures were detected along both myenteric and submucosal plexuses as well as in the circular and longitudinal muscular layers. We found perivascular α-syn-ir fibers in the submucosa and a dense ir periglandular network projecting up to the axis of the villi in the mucosa. The immunohistochemical distribution pattern of α-syn has been compared with that of major enteric neurotransmitters. Our preliminary observations confirm a physiological role of α-syn in the ENS, and may contribute to clarify its role in the peripheral nervous system. References [1] Spillantini et al, Nature 1997; 388:839-40. [2] Arima et al, Brain Res 1998; 808:93-100. [3] Braak et al, Neurosci Lett 2006; 396:67-72. [4] Wakabayashi et al, Acta Neuropathol 2010; 120:1-12

Endocrine cells distribution in human proximal small intestine: an immunohistochemical and morphometrical study

Atrophy of the pancreatic remnant after pancreaticoduodenectomy might be consequent to deregulation of pancreatic endocrine stimuli after duodenal removal. Relative technical surgical solution could be the anastomosis of the 1st jejunal loop to the stomach and the 2nd to the pancreatic stump. Data on the distribution of endocrine cells within the proximal intestine might represent the lacking tile of the problem. Our aims were to investigate the distribution pattern of serotonin, cholecystokinin and secretin cells in the duodenum, the 1st and 2nd jejunal loops of humans. Bowel specimens of ten patients submitted to pancreaticoduodenectomy were collected; immunohistochemical reactions and morphometric analyses were performed. A general ab-oral decrease of enteroendocrine cells was found. The rate of serotonin cells showed a significant 30.67±8.13% reduction starting from the 1st jejunal loop versus duodenum. The rate of both cholecystokinin and secretin cells in the duodenum was superimposable to that in the 1st jejunal loop, with a significant 62.88±4.80% loss of cholecystokinin and 39.5±9.31% of secretin cells in the 2nd loop. After removal of duodenum, preservation of the 1st jejunal loop could impact the function of pancreatic remnant maintaining the physiological enteroendocrine stimulus for pancreatic secretion that can compensate, at least in part for the abolished duodenal hormonal release

Pancreaticojejuno Anastomosis after Pancreaticoduodenectomy: Brief Pathophysiological Considerations for a Rational Surgical Choice

Introduction. The best pancreatic anastomosis technique after pancreaticoduodenectomy (PD) is still debated. Pancreatic fistula (PF) is the most important complication but is also related to postoperative bleedings and pancreatic remnant involution. We support pancreaticojejuno anastomosis (PJ) advantages describing our technique with brief technical considerations. Materials and Methods. 89 consecutive patients underwent PD with suprapyloric gastric resection and double loop reconstruction. Pancreaticojejunal end-to-end anastomosis was done by simple invagination with a single layer of interrupted pledget-supported Ticron stitches. Results. Pancreatic fistula occurred in seven patients (7.8%): six cases of grade A fistula resolved spontaneously, and in only one case of grade B fistula percutaneous drainage was necessary. Postoperative hemorrhage occurred in only two (2.2%) of 89 patients. Conclusion. Pancreaticojejunostomy with minor changes in anastomotic techniques can contribute to improvement of the outcome of Roux-en-Y reconstruction regarding PF and other related complications. The particular reconstruction reported seems also to preserve the pancreatic exocrine function

Severe intestinal bleeding due to left-sided portal hypertension after pancreatoduodenectomy with portal resection and splenic vein ligation

Pancreatoduodenectomy (PD) with portal vein (PV)/superior mesenteric vein (SMV) resection is well accepted for pancreatic head cancer because of the improvement in margin-negative resection and survival rates, without increasing postoperative morbidity and mortality in high volume centers. There is controversy in the surgical literature regarding the safety of splenic vein (SV) ligation during a PD with PV-SMV resection. Simple SV ligation has been associated with the development of left-sided portal hypertension, gastrointestinal bleeding and hypersplenism over the long term. We report a rare case of severe intestinal bleeding due to left-sided portal hypertension in patient who underwent a PD with PV-SMV confluence segmental resection and splenic ligation, preserving left gastric vein and inferior mesenteric vein, for cephalic pancreatic adenocarcinomas, seven months previously

Endocrine cells distribution pattern in the proximal small intestine of patients submitted to pancreaticoduodenectomy

The best surgical technique for pancreatic anastomosis after pancraticoduodenectomy (PD) is still debate. It is estimated that the atrophy of the pancreatic remnant is the common evolution after one year after surgical PD [1]. This may also be a consequence of deregulation of pancreatic neurohumoral stimulatory factors after duodenal removal. After PD, in order to maintain the pancreatic exocrine function, has been proposed the recostruction with two jejunal loops [2]: the first jejunal loop to the stomach, and the second jejunal loop to the pancreatic stump (end-to-end pancreatic jejunostomy), and following a hepatic jejunostomy. At the end, the intestinal continuity is restored by an entero-entero anastomosis [3]. Gastric preservation might favour an adequate weight gain after surgery due to higher caloric intake and normal acid secretion acts as a physiologic stimulus to promote the secretion of secretin and cholecystokinin (CCK). Our aims were to investigate the distribution pattern of serotonin-, secretin- and CCK cells in proximal small intestine. Specimens from duodenal, first and second jejunal loop taking from seven male patients submitted to PD were collected and immunohistochemical reaction and morphometrical analysis were performed. We found a general decrease of enteroendocrine cells in the second jejunal loop with a significant reduction of CCK-cells. So after removal of the duodenal source of secretin and CCK, preservation of the first jejunal loop that comes anastomized to the stomach, restores the alimentary circuit and maintain the physiological jejunal secretion of secretin and CCK subsequent to alimentary transit and can compensate (at least in part) for the abolished duodenal hormonal release. This operative procedure may preserve the exocrine and endocrine pancreatic secretion through the maintenance of physiological stimuli

Increased HMGB1 expression and release by mononuclear cells following surgical/anesthesia trauma

Introduction: High mobility group box 1 (HMGB1) is a key mediator of inflammation that is actively secreted by macrophages and/or passively released from damaged cells. The proinflammatory role of HMGB1 has been demonstrated in both animal models and humans, since the severity of inflammatory response is strictly related to serum HMGB1 levels in patients suffering from traumatic insult, including operative trauma. This study was undertaken to investigate HMGB1 production kinetics in patients undergoing major elective surgery and to address how circulating mononuclear cells are implicated in this setting. Moreover, we explored the possible relationship between HMGB1 and the proinflammatory cytokine interleukin-6 (IL-6). Methods: Forty-seven subjects, American Society of Anesthesiologists physical status I and II, scheduled for major abdominal procedures, were enrolled. After intravenous medication with midazolam (0.025 mg/Kg), all patients received a standard general anesthesia protocol, by thiopentone sodium (5 mg/Kg) and fentanyl (1.4 mu g/Kg), plus injected Vecuronium (0.08 mg/Kg). Venous peripheral blood was drawn from patients at three different times, t(0): before surgery, t(1): immediately after surgical procedure; t(2): at 24 hours following intervention. Monocytes were purified by incubation with anti-CD14-coated microbeads, followed by sorting with a magnetic device. Cellular localization of HMGB1 was investigated by flow cytometry assay; HMGB1 release in the serum by Western blot. Serum samples were tested for IL-6 levels by ELISA. A one-way repeated-measures analysis ANOVA was performed to assess differences in HMGB1 concentration over time, in monocytes and serum. Results: We show that: a) cellular expression of HMGB1 in monocytes at t(1) was significantly higher as compared to t(0); b) at t(2), a significant increase of HMGB1 levels was found in the sera of patients. Such an increase was concomitant to a significant down-regulation of cellular HMGB1, suggesting that the release of HMGB1 might partially derive from mononuclear cells; c) treatment of monocytes with HMGB1 induced in vitro the release of IL-6; d) at t(2), high amounts of circulating IL-6 were detected as compared to t(0). Conclusions: This study demonstrates for the first time that surgical/anesthesia trauma is able to induce an early intracellular upregulation of HMGB1 in monocytes of surgical patients, suggesting that HMGB1 derives, at least partially, from monocytes

Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

Tregs can contribute to tumor progression by suppressing antitumor immunity. Exceptionally, in human colorectal cancer (CRC), Tregs are thought to exert beneficial roles in controlling pro-tumor chronic inflammation. The goal of our study was to characterize CRC-infiltrating Tregs at multiple levels, by phenotypical, molecular and functional evaluation of Tregs from the tumor site, compared to non-tumoral mucosa and peripheral blood of CRC patients. The frequency of Tregs was higher in mucosa than in blood, and further significantly increased in tumor. Ex vivo, those Tregs suppressed the proliferation of tumor-infiltrating CD8+ and CD4+ T cells. A differential compartmentalization was detected between Helioshigh and Helioslow Treg subsets (thymus-derived versus peripherally induced): while Helioslow Tregs were enriched in both sites, only Helioshigh Tregs accumulated significantly and specifically in tumors, displayed a highly demethylated TSDR region and contained high proportions of cells expressing CD39 and OX40, markers of activation and suppression. Besides the suppression of T cells, Tregs may contribute to CRC progression also through releasing IL-17, or differentiating into Tfr cells that potentially antagonize a protective Tfh response, events that were both detected in tumor-associated Tregs. Overall, our data indicate that Treg accumulation may contribute through multiple mechanisms to CRC establishment and progression

Severe bleeding from esophageal varices resistant to endoscopic treatment in a non cirrhotic patient with portal hypertension

A non cirrhotic patient with esophageal varices and portal vein thrombosis had recurrent variceal bleeding unsuccessfully controlled by endoscopy and esophageal transection. Emergency transhepatic portography confirmed the thrombosed right branch of the portal vein, while the left branch appeared angulated, shifted and stenotic. A stent was successfully implanted into the left branch and the collateral vessels along the epatoduodenal ligament disappeared. In patients with esophageal variceal hemorrhage and portal thrombosis if endoscopy fails, emergency esophageal transection or nonselective portocaval shunting are indicated. The rare patients with only partial portal thrombosis can be treated directly with stenting through an angioradiologic approach

A prognostic score for predicting survival in patients with pancreatic head adenocarcinoma and distal cholangiocarcinoma

Background/aim: Survival of patients with pancreatic cancer remains poor despite improvements in therapeutic strategies. This study aims to create a novel preoperative score to predict prognosis in patients with tumors of the pancreaticobiliary head. Patients and methods: Data on 190 patients who underwent to pancreaticoduodenectomy at Sapienza University of Rome from January 2010 to December 2018 were retrospectively analyzed. After exclusion criteria, 101 patients were considered eligible for retrospective study. Preoperative biological, clinical and radiological parameters were considered. Results: Pancreatic ductal adenocarcinoma [hazard ratio (HR)=1.995, 95% confidence intervaI (CI)=1.1-3.3; p=0.01], carbohydrate antigen 19.9 (CA 19.9) >230 U/ml (HR=2.414, 95% CI=2.4-1.5, p<0.0001) and Wirsung duct diameter >3 mm (HR=1.592, 95% CI=1.5-0.9; p=0.08) were the only parameters associated with poor prognosis. Through these parameters, a prognostic score (PHT score) was developed which predicted worst survival when exceeding 2 and better survival when ≤2. Conclusion: The PHT score may have a potential impact on predicting overall survival and consequently modulate the timing and type of treatment (up-front surgery vs. neoadjuvant therapy) patients are offered

Metastatic renal cell carcinoma invading liver, duodenum and ivc, surgical treatment and literature review. A case report

Renal Cell Carcinoma has a biologic predisposition for direct vascular invasion: intravascular tumor thrombus is found in 5% to 20% of the cases inside the renal vein or the inferior vena cava. Despite new and effective conservative therapy such as targeted therapy and immunotherapy, cytoreductive nephrectomy and palliative nephrectomy continues to have an important role in T4 patient. The patient selection for cytoreductive nephrectomy should be done carefully. This report present an unique case of metastatic RCC with invasion of the duodenum, liver and retrohepatic IVC, the adopted surgical approach and a review of the literature. Complete surgical extirpation is possible in cases of RCC invading other organs such as pancreas, duodenum, liver, retroperitoneum and IVC. In this scenario, to narrow the possible intraoperative complication, a multidisciplinary approach and equipe is recommended