Bile Duct Cancer: Preoperative Evaluation and Management

Cholangiocarcinomas (CCAs) are malignant tumors that can develop anywhere along the biliary tree. Almost 10% of cholangiocarcinomas arise from the intra-hepatic bile ducts (iCCA); 50–60% from the bifurcation of the hepatic duct (perhilar cholangiocarcinoma, pCCA); and 20–30% from the distal bile duct (dCCA). The 7th edition of the AJCC staging system, released in 2010, divides the tumors into two major categories: perihilar (pCCA) and distal (dCCA) cholangiocarcinoma, given the differences in anatomy of the bile duct and consideration of local factors related to resectability. There are separate histological classifications for intrahepatic and extrahepatic cholangiocarcinoma. The majority of CCAs (90%) are well or moderately differentiated adenocarcinomas. Other features include invasiveness with early neural, perineural, periductal and lymphatic infiltration (more than 50% of cases at diagnosis) and longitudinal subepithelial infiltration along the wall of the bile duct up to 2 cm proximally and 1 cm distally. In this chapter the extrhepatic bile duct cancers are analyzed

Palmitoylethanolamide dampens reactive astrogliosis and improves neuronal trophic support in a triple transgenic model of Alzheimer’s disease: in vitro and in vivo evidence

Alzheimer’s disease (AD) is a neurodegenerative disorder responsible for the majority of dementia cases in elderly people. It is widely accepted that the main hallmarks of AD are not only senile plaques and neurofibrillary tangles but also reactive astrogliosis, which often precedes detrimental deposits and neuronal atrophy. Such phenomenon facilitates the regeneration of neural networks; however, under some circumstances, like in AD, reactive astrogliosis is detrimental, depriving neurons of the homeostatic support, thus contributing to neuronal loss. We investigated the presence of reactive astrogliosis in 3×Tg-AD mice and the effects of palmitoylethanolamide (PEA), a well-documented anti-inflammatory molecule, by in vitro and in vivo studies. In vitro results revealed a basal reactive state in primary cortical 3×Tg-AD-derived astrocytes and the ability of PEA to counteract such phenomenon and improve viability of 3×Tg-AD-derived neurons. In vivo observations, performed using ultramicronized- (um-) PEA, a formulation endowed with best bioavailability, confirmed the efficacy of this compound. Moreover, the schedule of treatment, mimicking the clinic use (chronic daily administration), revealed its beneficial pharmacological properties in dampening reactive astrogliosis and promoting the glial neurosupportive function. Collectively, our results encourage further investigation on PEA effects, suggesting it as an alternative or adjunct treatment approach for innovative AD therapy

Intrahepatic Cholangiocarcinoma

Aim: The authors give a complete overview on this disease from epidemiology to treatment

Surgical and Interventional Management of Complications Caused by Pancreatitis

Acute pancreatitis has a broad clinical spectrum: from mild, self-limited disease to fulminant illness resulting in multi-organ failure leading to a prolonged clinical course with up to 30% mortality in case of infected necrosis. Management of local complications such as pseudocysts and walled-off necrosis may vary from clinical observation to interventional treatment procedures. Gram negative bacteria infection may develop in up to one-third of patients with pancreatic necrosis leading to a clinical deterioration with the onset of the systemic inflammatory response syndrome and organ failure. When feasible, an interventional treatment is indicated. Percutaneous or endoscopic drainage approach are the first choices. A combination of minimally invasive techniques (step-up approach) is possible in patients with large or multiple collections. Open surgical treatment has been revised both in the timing and in the operating modalities in the last decades. Since 1990s, the surgical treatment of infected necrosis shifted to a more conservative approach. Disruption of the main pancreatic duct is present in up to 50% of patients with pancreatic fluid collections. According to the location along the Wirsung, treatment may vary from percutaneous drainage, endoscopic retrograde pancreatography with sphincterectomy or stenting to traditional surgical procedures. Patients may suffer from vascular complications in up to 23% of cases. Tissue disruption provoked by lipolytic and proteolytic enzymes, iatrogenic complications during operative procedures, splenic vein thrombosis, and pseudoaneurysms are the pathophysiological determinants of bleeding. Interventional radiology is the first line treatment and when it fails or is not possible, an urgent surgical approach should be adopted. Chylous ascites, biliary strictures and duodenal stenosis are complications that, although uncommon and transient, may have different treatment modalities from non-operative, endoscopic to open surgery

Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation

Cholangiocarcinoma is an aggressive, strongly chemoresistant liver malignancy. Leukemia inhibitory factor (LIF), an IL-6 family cytokine, promotes progression of various carcinomas. To investigate the role of LIF in cholangiocarcinoma, we evaluated the expression of LIF and its receptor (LIFR) in human samples. LIF secretion and LIFR expression were assessed in established and primary human cholangiocarcinoma cell lines. In cholangiocarcinoma cells, we tested LIF effects on proliferation, invasion, stem cell-like phenotype, chemotherapy-induced apoptosis (gemcitabine+cisplatin), expression levels of pro-apoptotic (Bax) and anti-apoptotic (Mcl-1) proteins, with/without PI3K inhibition, and of pSTAT3, pERK1/2, pAKT. LIF effect on chemotherapy-induced apoptosis was evaluated after LIFR silencing and Mcl-1 inactivation. Results show that LIF and LIFR expression were higher in neoplastic than in control cholangiocytes; LIF was also expressed by tumor stromal cells. LIF had no effects on cholangiocarcinoma cell proliferation, invasion, and stemness signatures, whilst it counteracted drug-induced apoptosis. Upon LIF stimulation, decreased apoptosis was associated with Mcl-1 and pAKT up-regulation and abolished by PI3K inhibition. LIFR silencing and Mcl-1 blockade restored drug-induced apoptosis. In conclusion, autocrine and paracrine LIF signaling promote chemoresistance in cholangiocarcinoma by up-regulating Mcl-1 via a novel STAT3- and MAPK-independent, PI3K/AKT-dependent pathway. Targeting LIF signaling may increase CCA responsiveness to chemotherapy

Management of Acute and Chronic Pancreatitis

Pancreatitis is a major public health issue worldwide. There is geographical variation in the burden of acute and chronic pancreatitis (CP). Globally, the age-standardized prevalence rate increased from 1990 to 2017. Acute pancreatitis (AP) is now one of the most common reasons for hospitalization with a gastrointestinal condition. The essential requirements for the management of AP are accurate diagnosis, appropriate triage, high-quality supportive care, monitoring for and treatment of complications, and prevention of relapse. Clinicians should be aware of the time course and the best management of AP, identifying which patient will have a severe course allowing earlier triage to an intensive care unit and earlier initiation of effective therapy. CP is a pathologic fibroinflammatory syndrome of the pancreas in individuals with genetic, environmental, and other risk factors who develop persistent pathologic responses to parenchymal injury or stress. Diagnosing the underlying pathologic process early in the disease course and managing the syndrome to change the natural course of disease and minimize adverse disease effects are the managing paradigm. In this review, we consider recent changes in the management of acute and CP, as well as common misunderstandings and areas of ongoing controversy

Acute diverticulitis management: evolving trends among Italian surgeons. A survey of the Italian Society of Colorectal Surgery (SICCR)

Acute diverticulitis (AD) is associated with relevant morbidity/mortality and is increasing worldwide, thus becoming a major issue for national health systems. AD may be challenging, as clinical relevance varies widely, ranging from asymptomatic picture to life-threatening conditions, with continuously evolving diagnostic tools, classifications, and management. A 33-item-questionnaire was administered to residents and surgeons to analyze the actual clinical practice and to verify the real spread of recent recommendations, also by stratifying surgeons by experience. CT-scan remains the mainstay of AD assessment, including cases presenting with recurrent mild episodes or women of child-bearing age. Outpatient management of mild AD is slowly gaining acceptance. A conservative management is preferred in non-severe cases with extradigestive air or small/non-radiologically drainable abscesses. In severe cases, a laparoscopic approach is preferred, with a non-negligible number of surgeons confident in performing emergency complex procedures. Surgeons are seemingly aware of several options during emergency surgery for AD, since the rate of Hartmann procedures does not exceed 50% in most environments and damage control surgery is spreading in life-threatening cases. Quality of life and history of complicated AD are the main indications for delayed colectomy, which is mostly performed avoiding the proximal vessel ligation, mobilizing the splenic flexure and performing a colorectal anastomosis. ICG is spreading to check anastomotic stumps' vascularization. Differences between the two experience groups were found about the type of investigation to exclude colon cancer (considering the experience only in terms of number of colectomies performed), the size of the peritoneal abscess to be drained, practice of damage control surgery and the attitude towards colovesical fistula

Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity > 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI

The deleterious interplay between tumor epithelia and stroma in cholangiocarcinoma

Prognosis of cholangiocarcinoma, a devastating liver epithelial malignancy characterized by early invasiveness, remains very dismal, though its incidence has been steadily increasing. Evidence is mounting that in cholangiocarcinoma, tumor epithelial cells establish an intricate web of mutual interactions with multiple stromal components, largely determining the pervasive behavior of the tumor. The main cellular components of the tumor microenvironment (i.e. myofibroblasts, macrophages, lymphatic endothelial cells), which has been recently termed as 'tumor reactive stroma', are recruited and activated by neoplastic cells, and in turn, deleteriously mold tumor behavior by releasing a huge variety of paracrine signals, including cyto/chemokines, growth factors, morphogens and proteinases. An abnormally remodeled and stiff extracellular matrix favors and supports these cell interactions. Although the mechanisms responsible for the generation of tumor reactive stroma are largely uncertain, hypoxia presumably plays a central role. In this review, we will dissect the intimate relationship among the different cell elements cooperating within this complex 'ecosystem', with the ultimate goal to pave the way for a deeper understanding of the mechanisms underlying cholangiocarcinoma aggressiveness, and possibly, to foster the development of innovative, combinatorial therapies aimed at halting tumor progression