Targeted therapy for hepatocellular carcinoma Huang, Ao; Yang, Xin-Rong; Chung, Wen-Yuan ...
Signal transduction and targeted therapy,
08/2020, Letnik:
5, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma (HCC). Sorafenib has been the mainstay of treatment for a decade and newer ...modalities were ineffective and did not confer any increased therapeutic benefit until the introduction of lenvatinib which was approved based on its non-inferiority to sorafenib. The subsequent success of regorafenib in HCC patients who progress on sorafenib treatment heralded a new era of second-line treatment and was quickly followed by ramucirumab, cabozantinib, and the most influential, immune checkpoint inhibitors (ICIs). Over the same period combination therapies, including anti-angiogenesis agents with ICIs, dual ICIs and targeted agents in conjunction with surgery or other loco-regional therapies, have been extensively investigated and have shown promise and provided the basis for exciting clinical trials. Work continues to develop additional novel therapeutic agents which could potentially augment the presently available options and understand the underlying mechanisms responsible for drug resistance, with the goal of improving the survival of patients with HCC.
Introduction
Malnutrition is a common sequela of chronic pancreatitis (CP). Alterations in body composition and the assessment of sarcopenia have gained the interest of clinicians in recent years. ...There is a scarcity of data currently available concerning sarcopenia in patients with CP. This review aims to investigate the prevalence and impact of sarcopenia in CP.
Methods
Embase and Medline databases were used to identify all studies that evaluated sarcopenia and outcomes in patients with chronic pancreatitis. Due to paucity of data, conference abstracts were included. PRISMA guidelines for systematic reviews were followed.
Results
Six studies, with a total of 450 individuals were reviewed. Three full-text studies and three conference abstracts met the predetermined eligibility criteria. The prevalence of sarcopenia in CP from all studies ranged from 17–62%. Pancreatic exocrine insufficiency was associated as an independent and significant risk factor for sarcopenia. Sarcopenia was found to be associated with a reduced quality of life, increased hospitalisation, and reduced survival. It was associated with significantly lower islet yield following total pancreatectomy with islet auto transplantation in CP.
Conclusion
The review of these existing studies amalgamates the limited data on sarcopenia and its impact on CP. It has shown that sarcopenia is exceedingly prevalent and an important risk factor in CP patients. The data presented emphasises that sarcopenia has a significant prognostic value and should be included in future prospective analyses in the outcomes of CP.
With the rising prevalence of obesity, there is a plethora of literature discussing the relationship between obesity and acute pancreatitis (AP). Evidence has shown a possible correlation between ...visceral adipose tissue (VAT) and AP incidence and severity. This systematic review explores these associations.
Eligible articles were searched and retrieved using Medline and Embase databases. Clinical studies evaluating the impact of VAT as a risk factor for AP and the association of the severity of AP and VAT were included.
Eleven studies, with a total of 2529 individuals were reviewed. Nine studies showed a statistically significant association between VAT and the severity of AP. Only four studies found VAT to be a risk factor for acute pancreatitis. Two studies showed VAT to be associated with an increased risk of local complications and two studies showed a correlation between VAT and mortality.
This is the first systematic review conducted to study the association between VAT and AP. The existing body of evidence demonstrates that VAT has a clinically relevant impact and is an important prognostic indicator of the severity of AP. However, it has not shown to be an independent risk factor to the risk of developing AP. The impact of VAT on the course and outcome of AP needs to be profoundly explored to confirm these findings which may fuel earlier management and better define the prognosis of patients with AP. VAT may need to be incorporated into prognostic scores of AP to improve accuracy.
Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a very poor prognosis. To date patient outcomes have not improved principally due to the limited number ...of patients suitable for surgical resections and the radiation and chemotherapy resistance of these tumours. In the last decade, a failure of conventional therapies has forced researchers to re-examine the environment of PDAC. The tumour environment has been demonstrated to consist of an abundance of stroma containing many cells but predominantly pancreatic stellate cells (PSCs). Recent research has focused on understanding the interaction between PSCs and PDAC cells in vitro and in vivo . It is believed that the interaction between these cells is responsible for supporting tumour growth, invasion and metastasis and creating the barrier to delivery of chemotherapeutics. Novel approaches which focus on the interactions between PDAC and PSCs which sustain the tumour microenvironment may achieve significant patient benefits. This manuscript reviews the current evidence regarding PSCs, their interaction with PDAC cells and the potential implication this may have for future therapies. Methods A PubMed search was carried out for the terms ‘pancreas cancer’ OR ‘pancreatic cancer’, AND ‘pancreatic stellate cells’, NOT ‘hepatic stellate cells’. All studies were screened and assessed for their eligibility and manuscripts exploring the relationship between PSCs and PDAC were included. The studies were subdivided into in vitro and in vivo groups. Results One hundred and sixty-six manuscripts were identified and reduced to seventy-three in vitro and in vivo studies for review. The manuscripts showed that PDAC cells and PSCs interact with each other to enhance proliferation, reduce apoptosis and increase migration and invasion of cancer cells. The pathways through which they facilitate these actions provide potential targets for future novel therapies. Conclusion There is accumulating evidence supporting the multiple roles of PSCs in establishing the tumour microenvironment and supporting the survival of PDAC. To further validate these findings there is a need for greater use of physiologically relevant models of pancreatic cancer in vitro such as three dimensional co-cultures and the use of orthotopic and genetically engineered murine (GEM) models in vivo.
Purpose
Recommendation for management of gallbladder polyps (GBPs) >1 cm is cholecystectomy. No consensus exists on management of GBPs <1 cm. This systematic review examines current evidence on ...management of GBPs.
Methods
MEDLINE, EMBASE and Cochrane library databases were searched from January 1991 to June 2013 using specified terms. A predefined protocol for data extraction was used to retrieve specified end points.
Results
Literature search yielded 43 manuscripts with a dataset of 11,685 patients with GBPs. M:F ratio was 1.3:1. Average age (range) was 49 years (32–83). Patients with malignant GBPs had an average (range) age of 58 (50–66) years with M:F ratio of 0.78:1. Cholesterol polyps constituted 60.5 % of GBPs followed by adenomas (15.2 %) and cancer (11.6 %). Malignant GBPs ≥1 cm, <1 cm and <5 mm constituted 8.5, 1.2 and 0 % of GBPs, respectively. Majority of patients requiring surgical intervention had laparoscopic cholecystectomy.
Conclusions
Presently employed policy of cholecystectomy for GBPs >1 cm is appropriate. For GBPs <1 cm, the authors
propose
(accepting existence of differing proposals) the following:
1. Surveillance may not be needed for GBPs <5 mm.
2. For GBPs between 5 and 10 mm, two scans at six monthly intervals is suggested and after that, tailor surveillance to age, growth and ethnicity. In the non-Asian population, if GBP remains the same size or number, discontinuation of surveillance may be considered. In the Asian population, if GBPs remain the same, yearly surveillance is continued for a suggested period of 3 years.
3. Discontinue surveillance if GBPs is/are smaller/ disappeared. Cholecystectomy is advised where size increases to >10 mm.
There is increasing evidence that peri-operative glucocorticosteroid can ameliorate the systemic response following major surgery. Preliminary evidence suggests peri-operative usage of ...glucocorticosteroid may decrease post-operative complications. These positive associations have been observed in a range of different operations including intra-abdominal, thoracic, cardiac, and orthopaedic surgery. This review aims to investigate the impact of peri-operative glucocorticosteroid in major pancreatic resections.
A systematic review based on a search in Medline and Embase databases was performed. PRISMA guidelines for systematic reviews were followed.
A total of five studies were analysed; three randomised controlled trials and two retrospective cohort studies. The total patient population was 1042. The glucocorticosteroids used were intravenous hydrocortisone or dexamethasone. Three studies reported significantly lower morbidity in the peri-operative glucocorticosteroid group. The number needed to treat to prevent one major complication with hydrocortisone is four patients. Two studies demonstrated that dexamethasone was associated with a statistically significantly improved median overall survival in pancreatic cancer.
This is the first systematic review conducted to investigate the significance of peri-operative glucocorticosteroid in patients undergoing pancreatic resection. This review shows a correlation of positive outcomes with the administration of glucocorticosteroid in the peri-operative setting following a major pancreatic resection.. More randomised clinical trials are required to confirm if this is a true effect, as it would have significant implications.
Numerous techniques have been described for fashioning gastrojejunostomy (GJ) in a Roux-en-Y gastric bypass. These include hand-sewn anastomosis (HSA) and mechanical anastomosis; the latter includes ...circular stapled anastomosis (CSA) or manual linear stapled anastomosis (mLSA). More recently, this list also includes powered linear stapled anastomosis (pLSA). The aim of this study was to analyse if addition of power to stapling would improve the integrity of GJ anastomosis in ex vivo porcine models.
The present study included five groups - mLSA1, mLSA2, HSA, CSA, and pLSA. Sequential infusions of methylene blue-coloured saline were performed into the GJ models. Pressure readings were recorded till the point of leak denoting burst pressure (BP). Total volume (TV) and site of leak were recorded. Compliance was calculated from the equation ΔTV/ΔBP.
Differences in pouch and intestinal thickness were not statistically significant between the models. BPs were higher in the mechanical anastomosis groups, i.e., pLSA 21 ± 9.85 mmHg, CSA 20.33 ± 5.78 mmHg, mLSA1 18 ± 4.69 mmHg and mLSA2 11 ± 2.94 mmHg, when compared to HSA 9.67 ± 3.79 mm Hg, which was found to be statistically significant (Kruskal-Wallis test, P = 0.03). Overall, the highest BP was recorded for powered stapling followed by circular, and then, linear stapling; however, this difference was not statistically significant (P = 0.86). There was no statistically significant difference among groups with regard to compliance (Kruskal-Wallis test, P = 0.082).
Despite the limited number of samples, mechanical anastomosis showed a statistically higher BP when compared to HSA, suggesting better anastomotic integrity. The pLSA group showed promising results with the highest BP recorded among all groups; however, this did not reach statistical significance.
Intraductal tubulopapillary neoplasms (ITPNs) of the pancreas and bile duct are contemporary entities. It is unclear on how to best manage patients with this diagnosis because little is known about ...its progression to cancer. This review provides an update on the current knowledge of ITPN of the pancreas and bile duct with an overview of clinical, radiological, histopathological, and molecular features, as well as the prognosis and management. Embase and Medline databases search were performed to identify studies that evaluated ITPN of the pancreas and bile duct. The infrequent exposure to this variant poses a diagnostic challenge. The diagnosis of ITPN is almost always made postoperatively because there are no characteristics on radiological studies to distinguish it from other cystic neoplasms of the pancreas. As ITPN has a favorable prognosis, it is crucial to establish an accurate diagnosis and differentiate it from other pancreatic and biliary variants. These neoplasms are considered to be precursor lesions to carcinomas, hence, surgery and close clinical surveillance are recommended. Further studies are essential to elucidate the natural history of ITPN, guide best treatment strategy and determine disease recurrence and survival.
Early and sensitive detection of islet graft damage is essential for improving posttransplant outcomes. MicroRNA 375 (miR375) has been reported as a biomarker of pancreatic β-cell death in small ...animal models.
The miR375 levels were measured in purified human islets, sera from patients with autologous and allogeneic islet transplantation as well as total pancreatectomy alone (nontransplanted group). The miR375 levels were also determined in a miniaturized in vitro tube model comprising human islets and autologous blood.
The miR375 expression level in islets was dose-dependent (P < 0.001) and significantly elevated after islet damage in plasma in the in vitro model (P = 0.003). Clinical analysis revealed that circulating miR375 levels in both autologous and allogeneic islet recipients were significantly elevated for 7 days after islet infusion, compared with the nontransplanted group (P = 0.005 and <0.001, respectively). Furthermore, miR375 detected the difference in islet graft damage among 3 different anti-inflammatory protocols for clinical autologous transplantation (P < 0.01).
Circulating miR375 can be a reliable biomarker to detect graft damage in clinical islet transplantation because serum C-peptide and proinsulin levels are difficult to interpret due to the influence of multiple factors, such as β-cell stress and physiological response.
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