The association between tumour heterogeneity and immune evasion mechanisms in hepatocellular carcinoma and its clinical implications.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. The emergence of combination therapy, atezolizumab (anti-PDL1, immune checkpoint inhibitor) and bevacizumab (anti-VEGF) has revolutionised the management of HCC. Despite this breakthrough, the best overall response rate with first-line systemic therapy is only about 30%, owing to intra-tumoural heterogeneity, complex tumour microenvironment and the lack of predictive biomarkers. Many groups have attempted to classify HCC based on the immune microenvironment and have consistently observed better outcomes in immunologically "hot" HCC. We summarised possible mechanisms of tumour immune evasion based on the latest literature and the rationale for combination/sequential therapy to improve treatment response. Lastly, we proposed future strategies and therapies to overcome HCC immune evasion to further improve treatment outcomes of HCC.

Gender survival differences in hepatocellular carcinoma: Is it all due to adherence to surveillance? A study of 1716 patients over three decades.

Background and Aims: Hepatocellular carcinoma (HCC) is one of the commonest causes of cancer-related death worldwide. Whether gender is an independent factor for HCC survival is debatable. We studied the influence of gender on the clinical characteristics of HCC and on survival. Methods: The study cohort comprised patients with HCC seen in our department from 1988 to 2021. Clinical data were prospectively collected. We studied and compared demography, HCC characteristics, and survival between females and males. Survival analysis was censored on October 31, 2015. Results: There were 1716 HCC patients. 343 (20.0%) were females. Females were significantly older at diagnosis (median 69 vs 62 years, P < 0.001). More females were diagnosed via regular HCC surveillance (37.9% vs 29.6%, P = 0.003). Hence, as expected, females had less-advanced HCC at diagnosis with smaller median tumor diameter (30 vs 39.5 mm, P = 0.038), lower frequency of portal vein tumor thrombus (19.4% vs 33.4%, P < 0.001), less distant metastases (7.7% vs 11%, P = 0.043), and earlier Barcelona Clinic Liver Cancer (BCLC) stages (0/A, 39.7% vs 28.4%, P < 0.001). On multivariable analysis, HCC diagnosis via surveillance but not female gender was an independent predictor of improved HCC survival. Conclusions: In this large cohort of multi-ethnic Asian patients, females with HCC were significantly more adherent to surveillance and hence presented with less advanced HCC with correspondingly better overall survival than males. The gender difference in survival is likely due to females having better adherence to HCC surveillance. Surveillance to diagnose early-stage HCC remains crucial in improving outcomes.

Clinical spectrum of non-alcoholic fatty liver disease in patients with diabetes mellitus.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is increasingly widespread with an overall global estimated prevalence of 25%. Type 2 diabetes Mellitus (T2DM) is a key contributor to NAFLD progression and predicts moderate-severe liver fibrosis and mortality. However, there is currently no uniform consensus on routine NAFLD screening among T2DM patients, and the risk factors of NAFLD and advanced fibrosis among T2DM patients remain to be clarified fully. AIM: We explored the prevalence, clinical spectrum, and risk factors of NAFLD and liver fibrosis among T2DM patients. METHODS: This is a cross-sectional study that enrolled subjects from a primary care clinic and a diabetes centre in Singapore. Subjects aged 21 to 70 years of all ethnic groups with an established T2DM diagnosis were included. Subjects with chronic liver diseases of other aetiologies were excluded. All subjects underwent transient elastography for hepatic steatosis and fibrosis assessment. Their demographics, anthropometric measurements and clinical parameters were collected. Statistical analysis was performed using STATA/SE16.0 software. RESULTS: Among 449 enrolled T2DM subjects, 436 with complete data and valid transient elastography results were analysed. Overall, 78.72% (344/436) of the T2DM subjects had NAFLD, of which 13.08% (45/344) had increased liver stiffness. Higher ALT level (OR = 1.08; 95% CI: 1.03-1.14; p = 0.004), obesity (BMI ≥ 27.5 kg/m2, OR = 2.64; 95% CI: 1.28-5.44; p = 0.008) and metabolic syndrome (OR = 4.36; 95% CI 1.40-13.58; p = 0.011) were independent factors associated with increased CAP (NAFLD). Higher AST level (OR = 1.06; 95% CI: 1.02-1.11; p = 0.008), CAP value (OR = 1.02; 95% CI: 1.00-1.03; p = 0.003), lower platelet count (OR = 0.99; 95% CI: 0.98-1.00; p = 0.009) and concomitant hypertension (OR = 4.56; 95% CI: 1.18-17.62; p = 0.028) were independent factors associated with increased liver stiffness. CONCLUSIONS: Our study demonstrated a considerably high prevalence of NAFLD among T2DM patients, with the proportion of advanced liver fibrosis among T2DM NAFLD patients much higher than the general population. Given that NAFLD is largely asymptomatic, increased awareness and vigilance for identifying NAFLD and increased liver stiffness among T2DM patients should be advocated.

Impact of enhanced personal protective equipment on colonoscopy performance during the COVID-19 pandemic.

Background and study aims Using personal protective equipment (PPE) can reduce risk of disease transmission. During the COVID-19 pandemic, enhanced PPE (EPPE) is recommended when performing endoscopy. We aimed to evaluate the impact of EPPE on colonoscopy performance when compared to standard PPE (SPPE). Patients and methods A review of electronic medical records and endoscopy reports of consecutive patients who underwent colonoscopy during two similar one-month time periods (in 2019 and during the COVID-19 pandemic in 2020) was performed. SPPE was used in 2019 and EPPE was used in 2020. Patient clinical data and procedure-related information were captured and analyzed. The primary outcomes were time to cecum (TTC) and total procedure time. Secondary outcomes were adenoma detection rate (ADR), polyp detection rate (PDR) and cecal intubation rate (CIR). Statistical analysis was performed using STATA v16.1. Results Two hundred and forty-seven colonoscopy procedures were analyzed. Baseline demographics and indications for colonoscopy of patients in both groups were similar. There were no significant differences in median TTC (10.0 vs 10.0 min, P  = 0.524) or total procedure time (22.5 vs 23.0 min, P  = 0.946) between colonoscopy performed in SPPE and EPPE. The ADR, PDR and CIR were also similar. Conclusion Our findings suggest that use of EPPE does not affect colonoscopy performance.

Multi-Dimensional Nanostructures for Microfluidic Screening of Biomarkers: From Molecular Separation to Cancer Cell Detection.

Rapid screening of biomarkers, with high specificity and accuracy, is critical for many point-of-care diagnostics. Microfluidics, the use of microscale channels to manipulate small liquid samples and carry reactions in parallel, offers tremendous opportunities to address fundamental questions in biology and provide a fast growing set of clinical tools for medicine. Emerging multi-dimensional nanostructures, when coupled with microfluidics, enable effective and efficient screening with high specificity and sensitivity, both of which are important aspects of biological detection systems. In this review, we provide an overview of current research and technologies that utilize nanostructures to facilitate biological separation in microfluidic channels. Various important physical parameters and theoretical equations that characterize and govern flow in nanostructure-integrated microfluidic channels will be introduced and discussed. The application of multi-dimensional nanostructures, including nanoparticles, nanopillars, and nanoporous layers, integrated with microfluidic channels in molecular and cellular separation will also be reviewed. Finally, we will close with insights on the future of nanostructure-integrated microfluidic platforms and their role in biological and biomedical applications.

Pharmacological insight into neurotransmission origins of resting-state functional connectivity: α2-adrenergic agonist vs antagonist.

Resting-state functional connectivity MRI has emerged as a powerful tool for mapping large-scale neural networks based on synchronous BOLD signal; however, the neurobiological mechanisms are still unknown. To understand its neural substrates, especially the underlying neurotransmission, we applied pharmacological modulation with a receptor specific agonist and antagonist. Resting and evoked electrophysiology and BOLD signals in rat brains were measured under infusion of α2-adrenergic receptor agonist, medetomidine, the antagonist, atipamezole, and the vehicle individually. Both somatosensory BOLD activation and evoked potential were increased significantly under medetomidine compared to the vehicle while atipamezole slightly decreased both. The interhemispheric correlation at the resting state, in contrast, was suppressed by medetomidine but increased by atipamezole in regions with high receptor densities including the somatosensory cortex and thalamus. No change was seen in the caudate putamen, where receptor occupancy is low. The regional difference in connectivity was not related to cerebral blood flow, indicating that BOLD signal correlation is unlikely due to the vascular effects of the drugs. Resting intracortical recording exhibited agonist/antagonist dependent changes in beta and gamma bands that correlated with the BOLD functional connectivity measure. Our results confirm an important role of the adrenergic system on functional connectivity and suggest a neurotransmission basis of the phenomenon.