This paper reviews the literature on global value chain configuration, providing an overview of this topic. Specifically, we review the literature focusing on the concept of the global value chain ...and its activities, the decisions involved in its configuration, such as location, the governance modes chosen and the different ways of coordinating them. We also examine the outcomes of a global value chain configuration in terms of performance and upgrading. Our aim is to review the state of the art of these issues, identify research gaps and suggest new lines for future research that would advance our understanding of how firms are implementing new ways of organizing and managing activities on a global scale."
This overview presents the updated European Association of Urology (EAU) guidelines for non–muscle-invasive bladder cancer (NMIBC), TaT1, and carcinoma in situ (CIS).
To provide practical ...recommendations on the clinical management of NMIBC with a focus on clinical presentation and recommendations.
A broad and comprehensive scoping exercise covering all areas of the NMIBC guidelines has been performed annually since the last published version in 2017. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries. Previous guidelines were updated, and the level of evidence and grade of recommendation were assigned.
Tumours staged as Ta, T1, and/or CIS are grouped under the heading of NMIBC. Diagnosis depends on cystoscopy and histological evaluation of the tissue obtained by transurethral resection (TURB) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TURB is essential for the patient’s prognosis and correct diagnosis. Where the initial resection is incomplete, where there is no muscle in the specimen, or where a T1 tumour is detected, a second TURB should be performed within 2–6 wk. The risks of both recurrence and progression may be estimated for individual patients using the European Organisation for Research and Treatment of Cancer (EORTC) scoring system. Stratification of patients into low-, intermediate-, and high-risk groups is pivotal to the recommendation of adjuvant treatment. In patients with tumours presumed to be at a low risk and in those presumed to be at an intermediate risk with a low previous recurrence rate and an expected EORTC recurrence score of <5, one immediate chemotherapy instillation is recommended. Patients with intermediate-risk tumours should receive 1 yr of full-dose bacillus Calmette-Guérin (BCG) intravesical immunotherapy or instillations of chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for 1–3 yr is indicated. In patients at the highest risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is recommended in BCG-unresponsive tumours. The extended version of the guidelines is available at the EAU website: https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/.
These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice.
The European Association of Urology Non–muscle-invasive Bladder Cancer (NMIBC) Panel has released an updated version of their guidelines, which contains information on classification, risk factors, diagnosis, prognostic factors, and treatment of NMIBC. The recommendations are based on the current literature (until the end of 2018), with emphasis on high-level data from randomised clinical trials and meta-analyses. Stratification of patients into low-, intermediate-, and high-risk groups is essential for deciding appropriate use of adjuvant intravesical chemotherapy or bacillus Calmette-Guérin (BCG) instillations. Surgical removal of the bladder should be considered in case of BCG-unresponsive tumours or in NMIBCs with the highest risk of progression.
The European Association of Urology guidelines on non–muscle-invasive bladder cancer (TaT1 and CIS) present updated information on the diagnosis and treatment of this disease. Recent findings are provided for their routine application in clinical practice.
Gastro‐oesophageal varices are the major clinical manifestations of cirrhosis and portal hypertension. Although less frequent than oesophageal varices (EV), bleeding from gastric varices (GV) is ...generally more severe and associated with higher mortality and a greater risk to rebleed. According to Sarin's classification, GVs are categorized into four types based on their location within the stomach and relationship with EV. Currently, treatment options for the management of GV include beta‐blockers, endoscopic band ligation, endoscopic cyanoacrylate injection, EUS‐guided coil/cyanoacrylate injection, transjugular intrahepatic portosystemic shunts and balloon‐occluded retrograde transvenous obliteration. The best treatment strategy of GV remains controversial because of the heterogeneity of GV, lack of high‐quality data and suboptimal trial design of the studies available. The proper treatment algorithm may require adequate endoscopic and imaging evaluation by a multidisciplinary team with multiple treatment options available. This review describes the hemodynamic features of GV, pharmacological, endoscopic and interventional radiological treatment options for GV.
This overview presents the updated European Association of Urology (EAU) guidelines for muscle-invasive and metastatic bladder cancer (MMIBC).
To provide practical evidence-based recommendations and ...consensus statements on the clinical management of MMIBC with a focus on diagnosis and treatment.
A broad and comprehensive scoping exercise covering all areas of the MMIBC guideline has been performed annually since its 2017 publication (based on the 2016 guideline). Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries, resulting in yearly guideline updates. A level of evidence and a grade of recommendation were assigned. Additionally, the results of a collaborative multistakeholder consensus project on advanced bladder cancer (BC) have been incorporated in the 2020 guidelines, addressing those areas where it is unlikely that prospective comparative studies will be conducted.
Variant histologies are increasingly reported in invasive BC and are relevant for treatment and prognosis. Staging is preferably done with (enhanced) computerised tomography scanning. Treatment decisions are still largely based on clinical factors. Radical cystectomy (RC) with lymph node dissection remains the recommended treatment in highest-risk non–muscle-invasive and muscle-invasive nonmetastatic BC, preceded by cisplatin-based neoadjuvant chemotherapy (NAC) for invasive tumours in “fit” patients. Selected men and women benefit from sexuality sparing RC, although this is not recommended as standard therapy. Open and robotic RC show comparable outcomes, provided the procedure is performed in experienced centres. For open RC 10, the minimum selected case load is 10 procedures per year. If bladder preservation is considered, chemoradiation is an alternative in well-selected patients without carcinoma in situ and after maximal resection. Adjuvant chemotherapy should be considered if no NAC was given. Perioperative immunotherapy can be offered in clinical trial setting. For fit metastatic patients, cisplatin-based chemotherapy remains the first choice. In cisplatin-ineligible patients, immunotherapy in Programmed Death Ligand 1 (PD-L1)-positive patients or carboplatin in PD-L1–negative patients is recommended. For second-line treatment in metastatic disease, pembrolizumab is recommended. Postchemotherapy surgery may prolong survival in responders. Quality of life should be monitored in all phases of treatment and follow-up. The extended version of the guidelines is available at the EAU website: https://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-metastatic/.
This summary of the 2020 EAU MMIBC guideline provides updated information on the diagnosis and treatment of MMIBC for incorporation into clinical practice.
The European Association of Urology Muscle-invasive and Metastatic Bladder Cancer (MMIBC) Panel has released an updated version of their guideline, which contains information on histology, staging, prognostic factors, and treatment of MMIBC. The recommendations are based on the current literature (until the end of 2019), with emphasis on high-level data from randomised clinical trials and meta-analyses and on the findings of an international consensus meeting. Surgical removal of the bladder and bladder preservation are discussed, as well as the use of chemotherapy and immunotherapy in localised and metastatic disease.
Radical cystectomy with urinary diversion remains the mainstay of managing muscle-invasive bladder cancer (MIBC). The use of neoadjuvant chemotherapy (NAC) has improved overall survival rates, but selection of patients who will benefit most from NAC remains challenging. In case bladder-preserving strategies are considered, patient stratification according to their risk profile is imperative and management should be discussed in a multidisciplinary team. As yet, there are no validated prognostic molecular markers to guide the clinical management of MIBC. In a metastatic setting, cisplatin-based chemotherapy remains the first choice in fit patients. In unfit patients, based on interim results from two on-going clinical trials, first-line treatment with pembrolizumab or atezolizumab for urothelial cancer is restricted to Programmed Death Ligand 1-positive patients only.
Background and Aims
Sustained virologic response (SVR) to interferon (IFN)‐free therapies ameliorates portal hypertension (PH); however, it remains unclear whether a decrease in hepatic venous ...pressure gradient (HVPG) after cure of hepatitis C translates into a clinical benefit. We assessed the impact of pretreatment HVPG, changes in HVPG, and posttreatment HVPG on the development of hepatic decompensation in patients with PH who achieved SVR to IFN‐free therapy. Moreover, we evaluated transient elastography (TE) and von Willebrand factor to platelet count ratio (VITRO) as noninvasive methods for monitoring the evolution of PH.
Approach and Results
The study comprised 90 patients with HVPG ≥ 6 mm Hg who underwent paired HVPG, TE, and VITRO assessments before (baseline BL) and after (follow‐up FU) IFN‐free therapy. FU HVPG but not BL HVPG predicted hepatic decompensation (per mm Hg, hazard ratio, 1.18; 95% confidence interval, 1.08‐1.28; P < 0.001). Patients with BL HVPG ≤ 9 mm Hg or patients who resolved clinically significant PH (CSPH) were protected from hepatic decompensation. In patients with CSPH, an HVPG decrease ≥ 10% was similarly protective (36 months, 2.5% vs. 40.5%; P < 0.001) but was observed in a substantially higher proportion of patients (60% vs. 24%; P < 0.001). Importantly, the performance of noninvasive methods such as TE/VITRO for diagnosing an HVPG reduction ≥ 10% was inadequate for clinical use (area under the receiver operating characteristic curve AUROC, < 0.8), emphasizing the need for HVPG measurements. However, TE/VITRO were able to rule in or rule out FU CSPH (AUROC, 0.86‐0.92) in most patients, especially if assessed in a sequential manner.
Conclusions
Reassessment of HVPG after SVR improved prognostication in patients with pretreatment CSPH. An “immediate” HVPG decrease ≥ 10% was observed in the majority of these patients and was associated with a clinical benefit, as it prevented hepatic decompensation. These results support the use of HVPG as a surrogate endpoint for interventions that lower portal pressure by decreasing intrahepatic resistance.
Patients with treatment-naïve metastatic urothelial carcinoma are grouped according to platinum eligibility based on clear definitions. In general, first-line treatment consists of platinum-based ...chemotherapy in which cisplatin is to be preferred to carboplatin. Patients who are cisplatin ineligible but carboplatin eligible should receive carboplatin-gemcitabine combination chemotherapy. In case of positive programmed death ligand 1 (PD-L1) status, treatment with checkpoint inhibitors (atezolizumab or pembrolizumab) could be an alternative option.
Patients unfit for both cisplatin and carboplatin (platinum unfit) can be considered for immunotherapy (U.S. Food and Drug Administration approved irrespective of PD-L1 status and European Medicines Agency approved only for PD-L1 positive) or can receive best supportive care.
Treatment of metastatic urothelial carcinoma is currently undergoing a rapid evolution.
This overview presents the updated European Association of Urology (EAU) guidelines for metastatic urothelial carcinoma.
A comprehensive scoping exercise covering the topic of metastatic urothelial carcinoma is performed annually by the Guidelines Panel. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries, resulting in yearly guideline updates.
Platinum-based chemotherapy is the recommended first-line standard therapy for all patients fit to receive either cisplatin or carboplatin. Patients positive for programmed death ligand 1 (PD-L1) and ineligible for cisplatin may receive immunotherapy (atezolizumab or pembrolizumab). In case of nonprogressive disease on platinum-based chemotherapy, subsequent maintenance immunotherapy (avelumab) is recommended. For patients without maintenance therapy, the recommended second-line regimen is immunotherapy (pembrolizumab). Later-line treatment has undergone recent advances: the antibody-drug conjugate enfortumab vedotin demonstrated improved overall survival and the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib appears active in case of FGFR3 alterations.
This 2021 update of the EAU guideline provides detailed and contemporary information on the treatment of metastatic urothelial carcinoma for incorporation into clinical practice.
In recent years, several new treatment options have been introduced for patients with metastatic urothelial cancer (including bladder cancer and cancer of the upper urinary tract and urethra). These include immunotherapy and targeted treatments. This updated guideline informs clinicians and patients about optimal tailoring of treatment of affected patients.
Idiopathic portal hypertension (IPH) is a rare disorder characterized by clinical portal hypertension in the absence of a recognizable cause such as cirrhosis. Laboratory tests often reveal a ...preserved liver function with anemia, leukopenia, and thrombocytopenia due to splenomegaly. Imaging studies reveal signs of portal hypertension, whereas liver stiffness and portal pressure values are usually normal or slightly elevated. Liver biopsy is considered mandatory in order to rule out other causes of portal hypertension, mainly cirrhosis. Liver histology may only show subtle or mild changes, and the definite diagnosis of IPH often requires an expert pathologist and a high‐quality specimen. The most frequent clinical presentation is variceal bleeding. Ascites is rarely observed initially, although it may occasionally appear during follow‐up. Typical histological findings associated with IPH have been described in patients without portal hypertension, probably representing early stages of the disease. Although the pathophysiology of this entity remains largely unknown, it is frequently associated with underlying immunological disorders, bacterial infections, trace metal poisoning, medications, liver circulatory disturbances, and thrombotic events. The long‐term prognosis of patients with IPH, where ascites and the underlying condition are important prognostic factors, is better than in patients with cirrhosis. Treatments that modify the natural history of the disease remain an unmet need, and management of IPH is frequently restricted to control of portal hypertension–related complications.
Sustained virological response (SVR) improves survival in post‐liver transplant (LT) recurrent hepatitis C. However, the impact of SVR on fibrosis regression is not well defined. In addition, the ...performance of noninvasive methods to evaluate the presence of fibrosis and portal hypertension (PH) post‐SVR has been scarcely evaluated. We aimed to investigate the degree of fibrosis regression (decrease ≥1 METAVIR stage) after‐SVR and its associated factors in recurrent hepatitis C, as well as the diagnostic capacity of noninvasive methods in the assessment of liver fibrosis and PH after viral clearance. We evaluated 112 hepatitis C virus–infected LT recipients who achieved SVR between 2001 and 2015. A liver biopsy was performed before treatment and 12 months post‐SVR. Hepatic venous pressure gradient (HVPG), liver stiffness measurement (LSM), and Enhanced Liver Fibrosis (ELF) score were also determined at the same time points. Sixty‐seven percent of the cohort presented fibrosis regression: 43% in recipients with cirrhosis and 72%‐85% in the remaining stages (P = 0.002). HVPG, LSM, and ELF significantly decreased post‐SVR. Liver function significantly improved, and survival was significantly better in patients achieving fibrosis regression. Baseline HVPG and LSM as well as decompensations before therapy were independent predictors of fibrosis regression. One year post‐SVR, LSM had a high diagnostic accuracy to discard the presence of advanced fibrosis (AF) and clinically significant PH (AUROC, 0.902 and 0.888). Conclusion: In conclusion, SVR post‐LT induces fibrosis regression in most patients, leading to significant clinical benefits. Pretreatment HVPG and LSM are significant determinants of the likelihood of fibrosis regression. Finally, LSM accurately predicts the presence of AF and PH 1 year after SVR and thus can be used to determine monitoring strategies. (Hepatology 2018;67:1683‐1694).
This paper analyzes the relation between institutional regulative distance and the choice of international entry mode. The study contributes to existing literature by considering the relative ...positions of the origin and destination countries on this relation, examining the possibility that institutional distance may exert an asymmetric effect. The results, using a database of European firms and multilevel analysis techniques, indicate that entry in countries with lower levels of regulatory development than that of the origin is related to modes that require a lower resource commitment. Conversely, entry in countries with higher levels of regulatory development is related to higher resource commitment modes. These findings suggest that the direction of institutional distance is important for the choice of international entry mode.
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•Autophagy maintains liver endothelial cell homeostasis.•Autophagy deficiency in LSEC increases oxidative stress.•Autophagy regulates nitric oxide bioavailability and maintains LSEC ...phenotype.•Impairment of endothelial autophagy enhances endothelial dysfunction and exacerbates fibrosis.
Endothelial dysfunction plays an essential role in liver injury, yet the phenotypic regulation of liver sinusoidal endothelial cells (LSECs) remains unknown. Autophagy is an endogenous protective system whose loss could undermine LSEC integrity and phenotype. The aim of our study was to investigate the role of autophagy in the regulation of endothelial dysfunction and the impact of its manipulation during liver injury.
We analyzed primary isolated LSECs from Atg7control and Atg7endo mice as well as rats after CCl4 induced liver injury. Liver tissue and primary isolated stellate cells were used to analyze liver fibrosis. Autophagy flux, microvascular function, nitric oxide bioavailability, cellular superoxide content and the antioxidant response were evaluated in endothelial cells.
Autophagy maintains LSEC homeostasis and is rapidly upregulated during capillarization in vitro and in vivo. Pharmacological and genetic downregulation of endothelial autophagy increases oxidative stress in vitro. During liver injury in vivo, the selective loss of endothelial autophagy leads to cellular dysfunction and reduced intrahepatic nitric oxide. The loss of autophagy also impairs LSECs ability to handle oxidative stress and aggravates fibrosis.
Autophagy contributes to maintaining endothelial phenotype and protecting LSECs from oxidative stress during early phases of liver disease. Selectively potentiating autophagy in LSECs during early stages of liver disease may be an attractive approach to modify the disease course and prevent fibrosis progression.
Liver endothelial cells are the first liver cell type affected after any kind of liver injury. The loss of their unique phenotype during injury amplifies liver damage by orchestrating the response of the liver microenvironment. Autophagy is a mechanism involved in the regulation of this initial response and its manipulation can modify the progression of liver damage.
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