Comparative efficacy of novel combination strategies for unresectable hepatocellular carcinoma: A network metanalysis of phase III trials.

BACKGROUND: Dual programmed cell death-1 and vascular endothelial growth factor pathway inhibition is the novel standard of care for patients with unresectable hepatocellular carcinoma. Direct comparisons between first-line treatments are lacking. METHOD: We conducted a literature search in MEDLINE (https://pubmed.ncbi.nlm.nih.gov), the Cochrane library (https://www.cochranelibrary.com) and Embase (www.embase.com) between January 2007 and February 2022. We included phase III randomised controlled trials that tested immune-checkpoint inhibitors or tyrosine kinase inhibitors, including sorafenib, lenvatinib and donafenib, and evaluated as primary end-point overall survival (OS) or progression-free survival (PFS). Studies testing loco-regional therapies were excluded. The primary end-point was to compare the efficacy of first-line options in terms of OS and PFS. We extracted Hazard ratios (HR) and 95% confidence intervals (95% CI) for OS and PFS and performed a frequentist network meta-analysis with fixed effect multivariable meta-regression models. The research protocol was registered in PROSPERO, an international prospective register of systematic reviews (registration code CRD42022312489). FINDINGS: Literature review yielded 13709 results, after duplicates removal and exclusion of not relevant studies, 70 papers were available for screening. After full-text review, 9 studies were eligible for analysis. Atezolizumab plus bevacizumab reduced the risk of death compared to placebo (HR 0·40; 95% CI 0·28-0·57), sorafenib (HR 0·58; 95% CI 0·42-0·80), lenvatinib (HR 0·63; 95% CI 0·44-0·89), atezolizumab plus cabozantinib (HR 0·64; 95% CI 0·43-0·97), nivolumab (HR 0·68; 95% CI 0·48-0·98) and donafenib (HR 0·69; 95% CI 0·48-0·99). Atezolizumab plus bevacizumab was not statistically superior to durvalumab plus tremelimumab (HR 0·74; 95% CI 0·52-1·06) and sintilimab plus IBI305 (HR 1·02; 95% CI 0·67-1·55) in reducing the risk of death. Efficacy was associated with a higher risk of grade 3 adverse events.

Lumen reconstruction with magnetic compression anastomosis technique in a patient with complete esophageal stricture.

Background: Complete esophageal obstruction (CEO) is a rare condition of which treatment options are challenging. Surgery is the main treatment with high morbidity and mortality rates. Magnetic compression anastomosis (MCA) is a novel technique developed to restore lumen patency in gastrointestinal and biliary tracts. However, MCA experience is limited in respect of esophageal strictures. Case Report: We present a 26-year-old patient having CEO. Magnets are inserted endoscopically to both sides of the obstructed area via oral and retrograde (through the gastrostomy tract) route. On day 8, magnets stuck together and were removed endoscopically through the oral route. Subsequently, sessions of balloon dilatations and triamcinolone injection were performed. The patient's complaint of aphagia resolved after the treatment process. Conclusion: In conclusion, MCA is an alternative technique that can be used to restore lumen patency in esophageal strictures and also avoids complications of surgical interventions.

Novel immunotherapy combinations in clinical trials for hepatocellular carcinoma: will they shape the future treatment landscape?

INTRODUCTION: Underlying liver disease and the intrinsic chemoresistance have historically hampered the development of efficacious treatments in HCC. However, in the last few years, immunotherapy-based combinations have emerged as efficacious therapeutic strategy in this setting. This paper critically summarizes the recent therapeutic progress in the systemic treatment of HCC. AREA COVERED: This paper examines the preclinical rationale of the following combinations in HCC: dual checkpoint inhibitors, immune checkpoint inhibitors plus anti-angiogenic agents, and immune checkpoint inhibitors plus tyrosine kinase inhibitors. Results of recent clinical studies are presented, along with a brief overview of ongoing and future trials. EXPERT OPINION: The approval of atezolizumab plus bevacizumab and the positive results of the HIMALAYA trial have broadened the therapeutic scenario for advanced HCC, opening, at the same time, new challenges. First of all, predictive biomarkers to allocate patients to the best treatment are eagerly required; second, specific studies are urgently needed to define the use of new combinations in patients usually excluded from clinical trials, e.g. those with deranged liver function and HIV or transplant recipients. Finally, with new combinations being translated into earlier stages, profound changes are soon expected in the adjuvant and neoadjuvant setting.

New Frontiers in the Medical Therapy of Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver tumor, and it rates fourth as a cause of cancer-related death. The presence of underlying liver disease and poor chemosensitivity pose major treatment challenges in the management of HCC. However, in the last few years, the therapeutic scenario has substantially changed, and immunotherapy in the form of immune checkpoint inhibitors (ICPIs) has become an essential therapeutic strategy in this field. SUMMARY: After controversial results of monotherapy, ICPIs have been mainly investigated in association with antiangiogenic agents or as dual checkpoint inhibition. The combination of atezolizumab plus bevacizumab has become the new therapeutic standard for unresectable HCC. Currently, a number of ICPI-based combinations are being studied in phase III clinical trials as front-line therapy for advanced HCC, with growing interest in integration of early-stage disease management in the form of adjuvant or neoadjuvant therapies. With most of the trials investigating ICPIs as first-line treatment, the second-line scenario relies mainly on tyrosine kinase inhibitors, which however have not been formally trialed after ICPIs. KEY MESSAGES: In this review, we summarize the main therapeutic advances in the systemic management of HCC focusing on the most relevant ongoing trials. We also discuss the main issues arising from a such rapidly evolving field including therapeutic sequencing and patient stratification.

ALBI grade: Evidence for an improved model for liver functional estimation in patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) usually arises in the context of a chronically damaged liver. Liver functional estimation is of paramount importance in clinical decision making. The Child-Pugh score (CPS) can be used to categorise patients into 3 classes (A to C) based on the severity of liver functional impairment according to 5 parameters (albumin, bilirubin, prothrombin time, presence of ascites and hepatic encephalopathy). The albumin-bilirubin (ALBI) grade has emerged as an alternative, reproducible and objective measure of liver functional reserve in patients with HCC, defining worsening liver impairment across 3 grades (I to III). The ALBI score can identify different subgroups of patients with different prognoses across the diverse Barcelona Clinic Liver Cancer stages and CP classes, making it an appealing clinical predictor. In patients treated with potentially curative approaches (resection, transplantation, radiofrequency ablation, microwave ablation), ALBI grade has been shown to correlate with survival, tumour relapse, and post-hepatectomy liver failure. ALBI grade also predicts survival, toxicity and post-procedural liver failure in patients treated with transarterial chemoembolisation, radioembolisation, external beam radiotherapy as well as multi-kinase inhibitors (sorafenib, lenvatinib, cabozantinib, regorafenib) and immune checkpoint inhibitor therapy. In this review, we summarise the body of evidence surrounding the role of ALBI grade as a biomarker capable of optimising patient selection and therapeutic sequencing in HCC.

Spinal cord arterio-venous shunts: From classification to therapeutic management.

Spinal Cord Arterio-Venous shunts (SCAVSs) are a rare disease. The aim of this paper is to describe how we classify and consider management of SCAVSs in relation to the location of the shunt focusing mainly on intradural SCAVSs. The anatomical features of the SCAVSs together with data provided by MRI and CT scans allow identification of four types of SCAVSs: paraspinal, epidural, dural and intradural ones. Clinical and neuroradiologic characteristics are described for each entity as well as the therapeutic endovascular management at our institution between 2002 and 2020. The therapeutic management of SCAVSs, and in particular of intradural shunts, remains mainly based on endovascular treatment as a first-choice approach. Understanding properly the lesional and regional vascular anatomy is mandatory to plan an appropriate therapeutic strategy and obtain good clinical results stable at long term follow up.

[Therapeutic and endovascular management of cerebral mycotic aneurysms]. / Traitement interventionnel des anévrismes mycotiques cérébraux.

Infective endocardites are associated with both ischemic and hemorrhagic neurological complications and also with cerebral abscesses and the development of "mycotic" aneurysms, which are detected in about 5 % of patients in the acute and sub-acute phase of the infection. Data about their natural history and their hemorrhagic risk are scarce and fragmented. The therapeutic management is represented by the medical treatment of the infection with interventional abstention, the surgical treatment and the endovascular approach by selective embolization of the aneurysm. No evidence is provided concerning the superiority of a specific approach. Mycotic aneurysms remain a diagnostic and therapeutic challenge and their management is necessarily based on a multidiscplinary approach.

Diagnostic utility of oxidative and non-oxidative markers for spontaneous bacterial peritonitis in non-malign ascites.

OBJECTIVE: In this study, we aimed to investigate the diagnostic availability of oxidant and antioxidant parameters in ascites for spontaneous bacterial peritonitis (SBP). MATERIAL AND METHODS: This study was carried out between July and October 2018 with 25 patients with SBP and 24 patients without SBP. Patients with acute infection, those taking vitamin supplements and antioxidant medication, smoking and drinking alcohol, and patients without ascites culture were excluded from the study. RESULTS: In patients with SBP compared those without SBP median paraoxonase (3.1 vs 15.6 ; p <0.001), median stimulated paraoxonase (12.6 vs 53.1 ; p <0.001), median arylesterase (769,9 vs 857,5 ; p = 0,003) and median catalase (10 vs 22,2 ; p = 0,003) were found to be lower and median myeloperoxidase (8.1 vs 1.1 ; p <0.001) were found to be higher. There was a positive correlation between paraoxonase levels and stimulated paraoxonase levels, arylesterase levels and catalase levels, there was a negative correlation between paraoxonase levels and myeloperoxidase levels. Paraoxonase levels 3.7 and lower, stimulated paraoxonase levels 25.8 and lower, arylesterase levels 853.4 and lower, catalase levels 11.8 and lower and myeloperoxidase levels 2.7 and more predicted the the presence of SBP with high specificity and high sensitivity. Paraoxonase and stimulated paraoxo-nase levels were found to have superior performance in predicting the presence of SBP compared to arylesterase levels (p <0.05). CONCLUSION: In this study it was shown that paraoxonase, stimulated paraoxonase, arylesterase, catalase and myeloperoxidase activities can be used for the diagnosis and severity of SBP.

Arterial stiffness is associated independently with liver stiffness in biopsy-proven nonalcoholic fatty liver disease: a transient elastography study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has been associated with an increased arterial stiffness. However, the question as to whether an association exists between the extent of vascular and liver stiffness in patients with biopsy-proven NAFLD remains open. In this study, we sought to investigate whether pulse wave velocity (PWV) and augmentation index (AIx) - two common indices of arterial stiffness - are associated with (a) liver stiffness measurement (LSM) on transient elastography (TE) and (b) histological liver fibrosis. PATIENTS AND METHODS: We examined 125 patients with biopsy-proven NAFLD and 55 age-matched and sex-matched controls. Arterial stiffness of the brachial artery was measured using a Mobil-O-Graph arteriography system. LSM was assessed using TE, whereas the presence of advanced fibrosis (F ≥ 3) was determined on histology. RESULTS: Patients with NAFLD had higher PWV [median: 7.2 (6.3-8.2) and 6.2 (5.5-6.7) m/s, respectively, P < 0.001] and AIx (mean: 21.3 ± 13.5 and 17.2 ± 11.9%, respectively, P=0.01) compared with the controls. LSM showed positive correlations with both PWV (ρ = 0.300; P<0.01) and AIx (ρ = 0.223, P = 0.02). Both indices of arterial stiffness were higher in patients with advanced fibrosis than in those with nonadvanced fibrosis (F ≤ 2). CONCLUSION: The severity of arterial and liver stiffness increases in parallel in patients with biopsy-proven NAFLD. Systematic risk assessment for reducing arterial stiffness is recommended in the presence of TE-determined advanced fibrosis.

The physiopathological effects of quercetin on oxidative stress in radiation of 4.5 g mobile phone exposed liver tissue of rat.

OBJECTIVE: The study was aimed to evaluate the physiopathological consideration of the effects of electromagnetic field (EMF) from the radiation of 4.5 G mobile phones on the liver tissue of rats and quercetin (Qu) applied as an antioxidant for reducing these effects. METHODS: Male Wistar-Albino rats were divided into four groups with 8 rats in each group. Group 1 (control group), Group 2 (sham group), Group 3 (EMF group) and Group 4 (EMF + Qu). From the animals sacrificed at the end of the 30th day; liver tissues were taken for histopathological and immunohistochemical examinations. RESULTS: In the liver tissue of the electromagnetic field group; dilatation of sinusitis was determined to be higher than in the sham group. It was concluded that the concentration of caspase-3 and TNF-α immunopositive cells was in the EMF group (+3) level and also the immunostaining was stronger, it caused an increase in malondialdehyde level, the difference between the groups was statistically significant, in terms of superoxide dismutase, catalase activities, the difference was not significant. CONCLUSION: It was determined that 2600 MHz EMF exposure caused damage to the liver, 100 mg/kg/day quercetin was not sufficient to prevent this damage (Tab. 5, Fig. 15, Ref. 27).

Determination of IL-6, TNF-α and VEGF levels in the serums of patients with colorectal cancer.

Cytokines are multifunctional polypeptides synthesized by different body cells. They have clinical significance in terms of disease diagnosis, treatment and prevention. Cytokines TNF-α and IL-6 play an important role in the growth and differentiation of cells.Vascular Endothelial Growth Factor (VEGF) is excessively produced in epithelial, mesenchymal, and particularly in tumor cells. Studies have shown that the increased serum concentrations of IL-6, TNF-α, VEGF are strongly associated with colorectal cancer  and directly with the clinical stage of the disease. This can be used to diagnose cancer and to identify patients with a bad prognosis who can avail themselves of a more aggressive treatment. The present study investigated the role of cytokines in the development of cancer by comparing preoperative serum cytokine levels of patients suffering from colorectal cancer with those of the healthy control group. The prognostic significance of the data obtained has also been evaluated. For this purpose, IL-6, TNF-α and VEGF levels in 60 serums, 30 preoperatively taken from patients with colorectal cancer and 30 from a healthy control group at Çanakkale Onsekiz Mart University General Surgery Clinic, were determined by ELISA kits. The statistical analyses of the obtained data were evaluated on SPSS, a statistical package program. In this study, no significant difference was obtained between the mean scores concerning the IL-6 and VEGF serums of the colorectal cancer and healthy group (p>.05). But a statistically significant decrease was observed in the TNF-α serum level of the colorectal cancer group in comparison with the control group (p= .016; p < .05).

Cytomegalovirus and Epstein-Barr virus reactivation in the intensive care unit.

AIM: The purpose of this work was to evaluate the reactivation of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in immunocompetent patients in the intensive care unit (ICU) and to identify risk factors associated with reactivation. MATERIALS AND METHODS: In this observational prospective study, 60 adult immunocompetent patients who stayed at least 7 days in an ICU were evaluated. During hospitalization, the viral load was monitored at admission and on day 7 with polymerase chain reaction to detect viral reactivation and weekly thereafter on days 14, 21, and 28 if hospitalization continued. RESULTS: The mean age of patients was 63.3 years (±23.4 years) and 34 (56.7 %) of them were male. Mean APACHE II scores for patients was 25 at admission. Of these patients, 28 were hospitalized in the internal ICU and 32 were hospitalized in the anesthesiology ICU. CMV/EBV reactivation was found in 17 individuals (12 for EBV, 3 for CMV, and 2 for both). The median high-sensitive C-reactive protein value in patients with CMV reactivation was significantly higher than in those patients without CMV reactivation (p = 0.037). EBV reactivation was statistically higher in patients with mechanical ventilation compared to patients without mechanical ventilation (p = 0.023). EBV reactivation in patients with fever was found to be statistically higher than in the patients without fever (p = 0.035). CONCLUSION: There is a need for extended studies with a larger number of patients from specific groups to better understand the reactivation frequency and identify risk factors. EBV and CMV reactivation should be taken into consideration in critically ill patients with fever, without specific symptoms and unresponsive to the treatment.

Impact of Modified TICI 3 versus Modified TICI 2b Reperfusion Score to Predict Good Outcome following Endovascular Therapy.

BACKGROUND AND PURPOSE: The TICI score is widely used to evaluate cerebral perfusion before and after the endovascular treatment of stroke. Recent studies showing the effectiveness and safety of mechanical thrombectomy combine modified TICI 2b and modified TICI 3 to assess the technical success of endovascular treatment. The purpose of this study was to determine how much clinical outcomes differ between patients achieving modified TICI 2b and modified TICI 3 reperfusion. MATERIALS AND METHODS: We analyzed 222 consecutive patients with acute large intracranial artery occlusion of the anterior circulation having achieved modified TICI 2b or modified TICI 3 reperfusion after thrombectomy. The primary end point was the rate of favorable outcome defined as the achievement of a modified Rankin Scale score of 0-2 at 3 months. RESULTS: Patients with modified TICI 3 more often had favorable collateral circulation and atherosclerosis etiology, with a shorter time from onset to reperfusion than patients with modified TICI 2b (all P < .05). The number of total passes to achieve reperfusion was higher in the modified TICI 2b group (median, 2; interquartile range, 1-3, 1-9) versus (median, 1; interquartile range, 1-2, 1-8) in the modified TICI 3 group (P = .0002). Favorable outcome was reached more often for patients with modified TICI 3 than for those with modified TICI 2b (71.7% versus 50.5%, P = .001), with a similar difference when considering excellent outcome. In addition, patients with modified TICI 3 had a lower intracerebral hemorrhage rate (23.0% versus 45.0%, P < .001). CONCLUSIONS: Patients with modified TICI 3 reperfusion have better functional outcomes than those with modified TICI 2b. Given the improving reperfusion rates obtained with thrombectomy devices, future thrombectomy trials should consider modified TICI 2b and modified TICI 3 status separately.

A Direct Aspiration, First Pass Technique (ADAPT) versus Stent Retrievers for Acute Stroke Therapy: An Observational Comparative Study.

BACKGROUND AND PURPOSE: Mechanical thrombectomy with stent retrievers is now the standard therapy for selected patients with ischemic stroke. The technique of A Direct Aspiration, First Pass Technique for the Endovascular Treatment of Stroke (ADAPT) appears promising with a high rate of recanalization. We compared ADAPT versus stent retrievers (the Solitaire device) for efficacy and safety as a front-line endovascular procedure. MATERIALS AND METHODS: We analyzed 243 consecutive patients with large intracranial artery occlusions of the anterior circulation, treated within 6 hours with mechanical thrombectomy by either ADAPT or the Solitaire stent. Th primary outcome was complete recanalization (modified TICI ≥ 2b); secondary outcomes included complication rates and procedural and clinical outcomes. RESULTS: From November 2012 to June 2014, 119 patients were treated with stent retriever (Solitaire FR) and 124 by using the ADAPT with Penumbra reperfusion catheters. The median baseline NIHSS score was the same for both groups (Solitaire, 17 [interquartile range, 11-21] versus ADAPT, 17 [interquartile range, 12-21]). Time from groin puncture to recanalization (Solitaire, 50 minutes [range, 25-80 minutes] versus ADAPT, 45 minutes [range, 27-70 minutes], P = .42) did not differ significantly. However, compared with the Solitaire group, patients treated with ADAPT achieved higher final recanalization rates (82.3% versus 68.9%; adjusted relative risk, 1.18; 95% CI, 1.02-1.37; P = .022), though differences in clinical outcomes between the cohorts were not significant. Use of an adjunctive device was more frequent in the ADAPT group (45.2% versus 13.5%, P < .0001). The rate of embolization in new territories or symptomatic hemorrhage did not differ significantly between the 2 groups. CONCLUSIONS: Front-line ADAPT achieved higher recanalization rates than the Solitaire device. Further randomized controlled trials are warranted to define the best strategy for mechanical thrombectomy.

Splenic abscess in ulcerative colitis under anti tumor necrosis factor treatment.

Splenic abscess are rare conditions. Since morbidity and mortality rates are high, immediate diagnosis should be required. Here we presented an ulcerative colitis patients who develops splenic abscess under anti tumor necrosis factor treatment.

Lengthening temporalis myoplasty and brain plasticity: a functional magnetic resonance imaging study.

BACKGROUND: Lengthening temporalis myoplasty (LTM) is a technique developed since ten years for facial paralysis. A spontaneous smile is acquired after this surgery explains by brain plasticity and the aim of the study is to confirm this plasticity by functional magnetic resonance imaging. MATERIALS AND METHODS: A functional magnetic resonance imaging (fMRI) was performed at various time points in ten patients who were operated on LTM during one year. RESULTS: Two different areas were found to be involved in chewing and smiling. We observed changes in the areas involved in smiling and chewing three months after surgery, and these changes persisted for at least one year. CONCLUSIONS: Our findings thus confirm that brain plasticity underlies the clinical observation of acquisition of a spontaneous smile.