Atezolizumab plus bevacizumab versus sorafenib or atezolizumab alone for unresectable hepatocellular carcinoma: A systematic review

BACKGROUNDDespite the use of current standard therapy, the prognosis of patients with unresectable hepatocellular carcinoma (HCC) is poor, with median survival times of 40 mo for intermediate HCC (Barcelona Clinic Liver Cancer [BCLC] stage B) and 6–8 mo for advanced HCC (BCLC stage C). Although patients with early-stage HCC are usually suitable for therapies with curative intention, up to 70% of patients experience relapse within 5 years. In the past decade, the United States Food and Drug Administration has approved different immunogenic treatment options for advanced HCC, the most common type of liver cancer among adults. Nevertheless, no treatment is useful in the adjuvant setting. Since 2007, the multi-kinase inhibitor sorafenib has been used as a first-line targeted drug to address the increased mortality and incidence rates of HCC. However, in 2020, the IMbrave150 trial demonstrated that combination therapy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) and bevacizumab (anti-vascular endothelial growth factor [VEGF]) is superior to sorafenib, a single anti-programmed death 1/PD-L1 antibody inhibitor used as an anti-cancer monotherapy for HCC treatment.AIMTo conduct a systematic literature review to evaluate the evidence supporting the efficacy and safety of atezolizumab/bevacizumab as preferred first-line drug therapy over the conventional sorafenib or atezolizumab monotherapies, which are used to improve survival outcomes and reduce disease progression in patients with unresectable HCC and non-decompensated liver disease. METHODSA comprehensive literature review was conducted using the PubMed, Scopus, ScienceDirect, clinicaltrials.gov, PubMed Central, Embase, EuropePMC, and CINAHL databases to identify studies that met the inclusion criteria using relevant MeSH terms. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and risk of bias (RoB) were assessed using the Cochrane RoB 2 tool and Sevis.RESULTSIn the atezolizumab/bevacizumab group, an improvement in overall tumor response, reduction of disease progression, and longer progression-free survival were observed compared to monotherapy with either sorafenib or atezolizumab. Hypertension and proteinuria were the most common adverse events, and the rates of adverse events were comparable to those with the monotherapy. Of the studies, there were two completed trials and two ongoing trials analyzed using high quality and low bias. A more thorough analysis was only performed on the completed trials.CONCLUSIONTreatment of HCC with atezolizumab/bevacizumab combination therapy was confirmed to be an effective first-line treatment to improve survival in patients with unresectable HCC and non-decompensated liver disease compared to monotherapy with either sorafenib or atezolizumab.     

Analysis of Essential Viral Gene Functions after Highly Efficient Adenofection of Cells with Cloned Human Cytomegalovirus Genomes

Human cytomegalovirus (HCMV) has a large 240 kb genome that may encode more than 700 gene products with many of them remaining uncharacterized. Mutagenesis of bacterial artificial chromosome (BAC)-cloned CMV genomes has greatly facilitated the analysis of viral gene functions. However, the roles of essential proteins often remain particularly elusive because their investigation requires the cumbersome establishment of suitable complementation systems. Here, we show that HCMV genomes can be introduced into cells with unprecedented efficiency by applying a transfection protocol based on replication-defective, inactivated adenovirus particles (adenofection). Upon adenofection of several permissive cell types with HCMV genomes carrying mutations in essential genes, transfection rates of up to 60% were observed and viral proteins of all kinetic classes were found expressed. This enabled further analyses of the transfected cells by standard biochemical techniques. Remarkably, HCMV genomes lacking elements essential for viral DNA replication, such as the lytic origin of replication, still expressed several late proteins. In conclusion, adenofection allows the study of essential HCMV genes directly in BAC-transfected cells without the need for sophisticated complementation strategies.     

Factors affecting the quality of bowel preparation for colonoscopy in hard-to-prepare patients: Evidence from the literature

Adequate bowel cleansing is critical for a high-quality colonoscopy because it affects diagnostic accuracy and adenoma detection. Nevertheless, almost a quarter of procedures are still carried out with suboptimal preparation, resulting in longer procedure times, higher risk of complications, and higher likelihood of missing lesions. Current guidelines recommend high-volume or low-volume polyethylene glycol(PEG)/non-PEG-based split-dose regimens. In patients who have had insufficient bowel cleans...     

Surveillance strategies for precancerous gastric conditions after Helicobacter pylori eradication: There is still need for a tailored approach

Prevailing evidence declares that Helicobacter pylori (H. pylori) eradication therapy could shift precancerous gastric conditions (PGC) and positively confines gastric cancer (GC) risk during long-term endoscopic follow-up. Nonetheless, there is a yet unsolved controversy regarding the best-individualized surveillance strategies following H. pylori eradication, based on malignant risk stratification. This last dispute is due to the uncertainty of contemporary evidence and the role of H. pylori inflammatory changes in underestimating PGC at the index endoscopy. However, the current state of the art suggests that it is reasonable that high-quality endoscopy with histological assessment for the most accurate diagnosis of PGC may be delayed in selected high-risk patients without alarm signs for malignancy, following the eradication of H. pylori. Notwithstanding, these aspects need to be further examined in the next future to establish and optimize the most beneficial and cost-effective strategies for recognizing and managing H. pylori-positive patients with PGC in the short- and long-term follow-up. Accordingly, additional studies are yet required to sharpen the hazard stratification of patients with the greatest chance of GC evolution, also recognizing the evolving racial, ethnic, immigration factors and the necessity of novel biomarkers to limit GC development or accomplish a diagnosis of malignancy at an early stage.     

Viral Interference with Functions of the Cellular Receptor Tyrosine Phosphatase CD45

The receptor tyrosine phosphatase CD45 is expressed on the surface of almost all cells of hematopoietic origin. CD45 functions are central to the development of T cells and determine the threshold at which T and B lymphocytes can become activated. Given this pivotal role of CD45 in the immune system, it is probably not surprising that viruses interfere with the activity of CD45 in lymphocytes to dampen the immune response and that they also utilize this molecule to accomplish their replication cycle. Here we report what is known about the interaction of viral proteins with CD45. Moreover, we debate putative interactions of viruses with CD45 in myeloid cells and the resulting consequences—subjects that remain to be investigated. Finally, we summarize the evidence that pathogens were the driving force for the evolution of CD45.     

Helicobacter pylori-induced inflammation masks the underlying presence of low-grade dysplasia on gastric lesions

BACKGROUND Helicobacter pylori(H. pylori) infection has been associated with a long-term risk of precancerous gastric conditions(PGC) even after H. pylori eradication.AIM To investigate the efficacy of High-Resolution White-Light Endoscopy with Narrow-Band Imaging in detecting PGC, before/after H. pylori eradication.METHODS We studied 85 consecutive patients with H. pylori-related gastritis with/without PGC before and 6 mo after proven H. pylori eradication. Kimura-Takemoto modified and endoscopic grading of gastric intestinal metaplasia classifications, were applied to assess the endoscopic extension of atrophy and intestinal metaplasia. The histological result was considered to be the gold standard. The Sydney System, the Operative-Link on Gastritis-Assessment, and the OperativeLink on Gastric-Intestinal Metaplasia were used for defining histological gastritis, atrophy and intestinal metaplasia, whereas dysplasia was graded according to World Health Organization classification. Serum anti-parietal cell antibody and anti-intrinsic factor were measured when autoimmune atrophic gastritis was suspected.RESULTS After H. pylori eradication histological signs of mononuclear/polymorphonuclear cell infiltration and Mucosal Associated Lymphoid Tissue-hyperplasia, disappeared or decreased in 100% and 96.5% of patients respectively, whereas the Operative-Link on Gastritis-Assessment and Operative-Link on Gastric-Intestinal Metaplasia stages did not change. Low-Grade Dysplasia prevalence was similar on random biopsies before and after H. pylori eradication(17.6% vs 10.6%, P = 0.19), but increased in patients with visible lesions(0% vs 22.4%, P 0.0001). At a multivariate analysis, the probability for detecting dysplasia after resolution of H. pylori-related active inflammation was higher in patients with regression or reduction of Mucosal Associated Lymphoid Tissue hyperplasia, greater alcohol consumption, and anti-parietal cell antibody and/or anti-intrinsic factor positivity [odds ratio(OR) = 3.88, 95% confidence interval(CI): 1.31-11.49, P = 0.01; OR = 3.10, 95%CI: 1.05-9.12, P = 0.04 and OR = 5.47, 95%CI: 1.33-22.39, P 0.04, respectively].CONCLUSION High-Resolution White-Light Endoscopy with Narrow-Band Imaging allows an accurate diagnosis of Low-Grade Dysplasia on visible lesions after regression of H. pylori-induced chronic gastritis. Patients with an overlap between autoimmune/H. pylori-induced gastritis may require more extensive gastric mapping.     

Indications and outcomes of endoscopic resection for non-pedunculated colorectal lesions: A narrative review

In the last years, endoscopic techniques gained a crucial role in the treatment of colorectal flat lesions. At the same time, the importance of a reliable assessment of such lesions to predict the malignancy and the depth of invasion of the colonic wall emerged. The current unsolved dilemma about the endoscopic excision techniques concerns the necessity of a reliable submucosal invasive cancer assessment system that can stratify the risk of the post-procedural need for surgery. Accordingly, this narrative literature review aims to compare the available diagnostic strategies in predicting malignancy and to give a guide about the best techniques to employ. We performed a literature search using electronic databases (MEDLINE/PubMed, EMBASE, and Cochrane Library). We collected all articles about endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) registering the outcomes. Moreover, we analyzed all meta-analyses comparing EMR vs ESD outcomes for colorectal sessile or non-polypoid lesions of any size, preoperatively estimated as non-invasive. Seven meta-analysis studies, mainly Eastern, were included in the analysis comparing 124 studies and overall 22954 patients who underwent EMR and ESD procedures. Of these, eighty-two were retrospective, twenty-four perspective, nine case-control, and six cohorts, while three were randomized clinical trials. A total of 18118 EMR and 10379 ESD were completed for a whole of 28497 colorectal sessile or non-polypoid lesions > 5-10 mm in size. In conclusion, it is crucial to enhance the preoperative diagnostic workup, especially in deciding the most suitable endoscopic method for radical resection of flat colorectal lesions at risk of underlying malignancy. Additionally, the ESD necessitates further improvement because of the excessively time-consuming as well as the intraprocedural technical hindrances and related complications. We found a higher rate of en bloc resections and R0 for ESD than EMR for non-pedunculated colorectal lesions. Nevertheless, despite the lower local recurrence rates, ESD had greater perforation rates and needed lengthier procedural times. The prevailing risk for additional surgery in ESD rather than EMR for complications or oncologic reasons is still uncertain.     

Chronic functional constipation is strongly linked to vitamin D deficiency

BACKGROUND Few studies have examined intestinal motility disorders, which are disabling conditions associated with chronic functional constipation, whose pathogenesis is actually not well-defined.AIM To investigate the relationship between serum 25-hydroxyvitamin D levels and functional chronic constipation associated to intestinal motility disorders.METHODS We performed a prospective case-control study, from May-June to November2017. Glucose/lactulose breath tests, radiopaque markers(multiple capsule techniques) and wireless motility capsule analysis were used to assess colonicand oro-cecal transit time, after excluding small-intestinal bacterial overgrowth condition. Then, we measured 25-hydroxyvitamin D levels in patients with intestinal motility disorders and we further evaluated the influence of intestinal motility disorders on psychological symptoms/quality of life using validated questionnaires, the Irritable Bowel Syndrome Quality of life(IBS-QOL), the Short Form Health Survey 12, and the Hospital Anxiety and Depression Scale 14(HADS-14 A and HADS-14 D).RESULTS We enrolled 86 patients with chronic functional constipation associated to intestinal motility disorders and 86 matched healthy subjects. Patients with intestinal motility disorders had lower 25-hydroxyvitamin D levels(P < 0.001), and they showed a significant impairment of all health-related quality of life and psychological tests(IBS-QOL, Short Form Health Survey 12-Physical Component Summary, Short Form Health Survey 12-Mental Component Summary, HADS-14 A and HADS-14 D), as compared to the control group(P < 0.001), which significantly correlated with low vitamin D levels(r =-0.57, P < 0.001; r = 0.21, P = 0.01; r =-0.48, P < 0.001; r =-0.57, P < 0.001; r =-0.29, P < 0.001, respectively). At multivariate analysis vitamin D low levels remained a significant independent risk factor for the occurrence of intestinal motility disorder(odds ratio = 1.19; 95% confidence interval: 1.14-1.26, P < 0.001).CONCLUSION Vitamin D deficiency, anxiety and depression symptoms are commonly associated with chronic functional constipation induced by intestinal motility disorders. Vitamin D serum levels should be routinely measured in these patients.