Geriatric nutritional risk index as an easy‐to‐use assessment tool for nutritional status in hepatocellular carcinoma treated with atezolizumab plus bevacizumab

Posted on 3 October 2023 by

Abstract

Aim

The present study focused on Geriatric Nutritional Risk Index (GNRI), which is based on bodyweight and serum albumin, and known as an easy-to-use nutritional assessment tool in clinical settings, to elucidate the prognostic predictive ability of GNRI in patients treated with atezolizumab plus bevacizumab (Atez/Bev) for hepatocellular carcinoma (HCC).

Methods

A total of 525 HCC patients treated with Atez/Bev, based on their classification of unsuitable status for curative treatments and/or transarterial catheter chemoembolization, were enrolled (Child–Pugh A:B:C = 484:40:1, Barcelona Clinic Liver Cancer stage 0:A:B:C:D = 7:25:192:283:18). Prognosis was evaluated retrospectively using GNRI.

Results

Atez/Bev was used in 338 of the present cohort as first-line systemic chemotherapy (64.4%). Median progression-free survival based on GNRI indicating normal, mild decline, moderate decline, and severe decline was 8.3, 6.7, 5.3, and 2.4 months, respectively, whereas median overall survival was 21.4, 17.0, 11.5. and 7.3 months, respectively (both p < 0.001). The concordance index (c-index) values of GNRI for predicting prognosis (progression-free survival/overall survival) were superior to those of Child–Pugh class and albumin-bilirubin grade (0.574/0.632 vs. 0.527/0.570 vs. 0.565/0.629). As a subanalysis, muscle volume loss was observed in 37.5% of 256 patients with computed tomography data available. Along with GNRI decline, frequency of muscle volume loss became progressively larger (normal vs. mild vs. moderate vs. severe = 17.6% vs. 29.2% vs. 41.2% vs. 57.9%, p < 0.001), and a GNRI value of 97.8 was predictive of its occurrence (AUC 0.715, 95% CI 0.649–0.781; specificity/sensitivity = 0.644/0.688).

Conclusion

These findings indicate that GNRI is an effective nutritional prognostic tool for predicting prognosis and muscle volume loss complication in HCC patients treated with Atez/Bev.

Tumor steatosis and glutamine synthetase expression in patients with advanced hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy

Posted on 3 October 2023 by

Abstract

Aim

The anti-programmed death-ligand 1 antibody atezolizumab and vascular endothelial growth factor-neutralizing antibody bevacizumab in combination (Atezo + Bev) have become the first-line therapy in advanced hepatocellular carcinoma (HCC). Distinct types of tumor immune microenvironment (TIME) and their associations with specific molecular subclasses and driver gene mutations have been identified in HCC; however, these insights are mainly based on surgically resected early-stage tumors. The current study aimed to reveal the biology and TIME of advanced HCC and their significance in predicting clinical outcomes of Atezo + Bev therapy.

Methods

Thirty-three patients with advanced HCC who were scheduled for treatment with Atezo + Bev therapy were included in this study. Pretreatment tumor biopsy, pre- and posttreatment diffusion-weighted magnetic resonance imaging (MRI) with nine b values (0–1500 s/mm²), and other clinicopathologic factors were analyzed.

Results

Compared with resectable HCC, advanced HCC was characterized by higher proliferative activity, a higher frequency of Wnt/β-catenin-activated HCC, and lower lymphocytic infiltration. Prognostically, two metabolism-related factors, histopathologically determined tumor steatosis and/or glutamine synthetase (GS) expression, and MRI-determined tumor steatosis, were the most significant prognostic indicators for progression-free survival (PFS) and overall survival after Atezo + Bev therapy. Furthermore, changes in the pre- and posttreatment true diffusion coefficients on MRI, which might reflect changes in TIME after treatment, were significantly associated with better PFS.

Conclusions

The biology and TIME of HCC were strikingly different in advanced HCC compared with those of surgically resected HCC. Two metabolism-related factors, pathologically determined tumor steatosis and/or GS expression, and MRI-determined tumor steatosis, were found to be the most significant prognostic indicators for Atezo + Bev therapy in advanced HCC.

Serial increase and high alpha‐fetoprotein levels predict the development of hepatocellular carcinoma in 6 months

Posted on 3 October 2023 by

A combination of a serial AFP-increase of ≥10% every 3–6 months with an AFP level of ≥20 ng/ml may predict the risk of HCC in 6 months. Regular AFP surveillance helps to detect HCC at early stage and should be included in the surveillance test for HCC.

Abstract

Aim

Alpha-fetoprotein (AFP) checkup with abdominal ultrasonography for hepatocellular carcinoma (HCC) surveillance remains controversial. We evaluated a serial AFP-increase and high AFP levels in the prediction of HCC.

Methods

At-risk patients with chronic liver disease underwent HCC surveillance with trimonthly AFP measurement were included and categorized into HCC and non-HCC groups. Their AFP levels at 12, 9, and 6 months (−6M) before the outcome date were evaluated. Group-based trajectory analysis and multivariable regression analysis were performed to identify AFP trajectories as risk predictors for HCC.

Results

Overall, 2776 patients were included in the HCC (n = 326) and non-HCC (n = 2450) groups. Serial AFP levels were significantly higher in the HCC than the non-HCC groups. Trajectory analysis identified AFP-increase group (11%) increased 24-fold risks of HCC compared with the AFP-stable (89%) group. Compared with patients without the AFP-increase, a serial 3-month AFP-increase ≥10% elevated HCC risk by 12.1-fold (95% CI: 6.5–22.4) in 6 months, and the HCC risks increased 13–60 fold in patients with cirrhosis, hepatitis B, or C receiving antiviral therapy, or AFP levels <20 ng/ml. Combining serial AFP-increase ≥10% and AFP ≥20 ng/ml at −6M significantly increased 41.7-fold (95% CI: 13.8–126.2) HCC risks. In patients who underwent biannual AFP checkups, those with both 6-month AFP-increase ≥10% and AFP ≥20 ng/ml increased 22.1-fold (95% CI: 12.52–39.16) HCC risks in 6 months. Most HCCs were detected at an early stage.

Conclusions

Serial 3–6-month AFP-increase of ≥10% previously and AFP level of ≥20 ng/ml significantly increased HCC risks in 6 months.

Impact of liver fibrosis on the relative abundance of a urease‐positive Streptococcus salivarius group from saliva in patients with chronic liver disease

Posted on 3 October 2023 by

Abstract

Aim

We performed genomic analysis to study the relative abundance of a urease-positive Streptococcus salivarius group isolated from the saliva of patients with chronic liver disease.

Methods

Male and female patients with chronic liver disease aged over 20 years were included. First, we assessed the frequency and type of the S. salivarius group isolated from oral saliva using molecular biology techniques based on 16S rRNA and dephospho-coenzyme A kinase gene sequencing. Next, we assessed the correlation between the urease positivity rate in the S. salivarius group isolated from oral saliva and liver fibrosis based on chronic liver disease. Urease-positive strains were identified by the urease test using urea broth (Difco, Franklin Lakes, NJ, USA). Liver fibrosis was evaluated by the liver stiffness measurement value based on magnetic resonance elastography.

Results

A total of 45 patients identified using the multiplex polymerase chain reaction for the 16S rRNA gene were tested using the multiplex polymerase chain reaction for the dephospho-coenzyme A kinase gene. Confirming the strains detected in each of the 45 patients, urease-positive S. salivarius was detected in 28 patients (62%), urease-negative S. salivarius in 25 patients (56%), and urease-positive Streptococcus vestibularis in 12 patients (27%). There was no patient with urease-negative S. vestibularis. The urease-positive rate of the S. salivarius group in the cirrhosis and non-cirrhosis groups were 82.2% and 39.2%, respectively. The liver cirrhosis group had a higher urease positivity rate than the non-cirrhotic group (p < 0.001).

Conclusions

Liver fibrosis influences the frequency of a urease-positive S. salivarius group isolated from oral saliva.

Determinants of the effectiveness of bezafibrate combined with ursodeoxycholic acid in patients with primary biliary cholangitis

Posted on 3 October 2023 by

This study focused on patients with primary biliary cholangitis (PBC) who did not respond well to the usual treatment with ursodeoxycholic acid (UDCA), and received a combination therapy with UDCA and bezafibrate (BZF). The study explored factors that could predict the outcomes of patients who received a combination therapy of two drugs. The results showed that certain indicators, such as high bilirubin levels and advanced histological stage, were associated with the patients' survival without requiring liver transplantation. The study emphasizes the need for early diagnosis of PBC to improve the effectiveness of the combination treatment.

Abstract

Background and Aims

For patients with primary biliary cholangitis (PBC) exhibiting suboptimal responses to ursodeoxycholic acid (UDCA), obeticholic acid (OCA), and bezafibrate (BZF) are currently used and shown to improve long-term outcomes. Nevertheless, we encounter patients who die or undergo liver transplantation (LT) even with combination treatment. In this study, we explored prognostic indicators in patients receiving combination treatment of UDCA and BZF.

Methods

We took advantage of the Japanese PBC registry and enrolled patients who received both UDCA and BZF therapy in 2000 or later. The covariates investigated included baseline covariates as well as treatment covariates. Two main outcomes (all-cause death or LT and liver-related death or LT) were assessed using multivariable-adjusted Cox proportional hazards models.

Results

In total, 772 patients were included. The median follow-up was 7.1 years. Using the Cox regression model, bilirubin (hazard ratio [HR] 6.85, 95% confidence interval [CI] 1.73–27.1, p = 0.006), alkaline phosphatase (HR 5.46, 95% CI 1.32–22.6, p = 0.019), and histological stage (HR 4.87, 95% CI 1.16–20.5, p = 0.031) were found associated with LT-free survival. For survival free from liver disease-related death or LT, albumin (HR 7.72, 95% CI 1.48–40.4, p = 0.016) and bilirubin (HR 14.5, 95% CI 2.37–88.5, p = 0.004) were found significantly associated.

Conclusion

In patients with PBC receiving combination therapy, prognostic variables were similar to those in patients receiving UDCA monotherapy. These results indicate the importance of diagnosing patients with PBC at an earlier stage because of the reduced effectiveness of BZF at advanced stages.

Recent prevalence and characteristics of patients with hepatitis delta virus in Hokkaido, Japan

Posted on 3 October 2023 by

Although hepatitis delta virus (HDV) co-infection with hepatitis B virus (HBV) is a global health concern, the global prevalence of HDV infections remains unknown due to insufficient data in many countries. In Japan, HDV prevalence has not been updated for over 20 years. The objective of our study was to investigate the recent prevalence of HDV infections in Hokkaido, Japan. We found that the current prevalence of HDV infections in Japanese patients with HBV was 1.7% (10/601). These patients experienced rapid liver fibrosis progression, highlighting the importance of routine HDV testing.

Abstract

Aim

Although hepatitis delta virus (HDV) coinfection with hepatitis B virus (HBV) is a global health concern, the global prevalence of HDV infections remains unknown due to insufficient data in many countries. In Japan, HDV prevalence has not been updated for over 20 years. We aimed to investigate the recent prevalence of HDV infections in Japan.

Methods

We screened 1264 consecutive patients with HBV infection at Hokkaido University Hospital between 2006 and 2022. Patients' serums were preserved and subsequently tested for HDV antibody (immunoglobulin-G). Available clinical information was collected and analyzed. We compared the changes in liver fibrosis using the Fibrosis-4 (FIB-4) index between propensity-matched patients with and without the evidence of anti-HDV antibodies and corrected for baseline FIB-4 index, nucleoside/nucleotide analog treatment, alcohol intake, sex, HIV coinfection, liver cirrhosis, and age.

Results

After excluding patients without properly stored serums and those lacking appropriate clinical information, 601 patients with HBV were included. Of these, 1.7% of patients had detectable anti-HDV antibodies. Patients with anti-HDV antibody serum positivity had a significantly higher prevalence of liver cirrhosis, significantly lower prothrombin time, and a higher prevalence of HIV coinfection than those who demonstrated serum anti-HDV antibody negativity. A propensity-matched longitudinal analysis revealed that liver fibrosis (FIB-4 index) progressed more rapidly in patients with positive results for anti-HDV antibody tests.

Conclusions

The recent prevalence of HDV infections in Japanese patients with HBV was 1.7% (10/601). These patients experienced rapid liver fibrosis progression, highlighting the importance of routine HDV testing.

Including genomic information in the genetic evaluation of production and reproduction traits in South African Merino sheep

Posted on 3 October 2023 by

Abstract

Genomic selection (GS) has become common in sheep breeding programmes in Australia, New Zealand, France and Ireland but requires validation in South Africa (SA). This study aimed to compare the predictive ability, bias and dispersion of pedigree BLUP (ABLUP) and single-step genomic BLUP (ssGBLUP) for production and reproduction traits in South African Merinos. Animals in this study originated from five research and five commercial Merino flocks and included between 54,072 and 79,100 production records for weaning weight (WW), yearling weight (YW), fibre diameter (FD), clean fleece weight (CFW) and staple length (SL). For reproduction traits, the dataset included 58,744 repeated records from 17,268 ewes for the number of lambs born (NLB), number of lambs weaned (NLW) and the total weight weaned (TWW). The single-step relationship matrix, H, was calculated using PreGS90 software combining 2811 animals with medium density (~50 K) genotypes and the pedigree of 88,600 animals. Assessment was based on single-trait analysis using ASREML V4.2 software. The accuracy of prediction was evaluated according to the ‘LR-method’ by a cross-validation design. Validation candidates were assigned according to Scenario I: born after a certain time point; and Scenario II: born in a particular flock. In Scenario I, the genotyping rate for the reference population between 2006 and the 2013 cut-off point approached 7% of animals with phenotypes and 20% of their sires. For reproduction traits, about 20% of ewes born between 2006 and 2011 cut-off were genotyped, along with 15% of their sires. Genotyping rates in the validation set of Scenario I were 3.7% (production) and 11.4% (reproduction) for candidates and 35% of their sires. Sires were allowed to have progeny in both the reference and validation set. In Scenario I, ssGBLUP increased the accuracy of prediction for all traits except NLB, ranging between +8% (0.62–0.67) for FD and +44% (0.36–0.52) for WW. This showed a promising gain in accuracy despite a modestly sized reference population. In the ‘across flock validation’ (Scenario II), overall accuracy was lower, but with greater differences between ABLUP and ssGBLUP ranging between +17% (0.12–0.14) for TWW and +117% (0.18–0.39) for WW. There was little indication of severe bias, but some traits were prone to over dispersion and the use of genomic information did not improve this. These results were the first to validate the benefit of genomic information in South African Merinos. However, because production traits are moderately heritable and easy to measure at an early age, future research should be aimed at best exploiting GS methods towards genetic prediction of sex-limited and/or lowly heritable traits such as NLW. GS methods should be combined with dedicated efforts to increase genetic links between sectors and improved phenotyping by commercial flocks.

Performance and bone characteristics of broilers fed diets supplemented with vitamin A at different concentrations

Posted on 2 October 2023 by

Abstract

This work evaluated the influence of vitamin A on performance, organ weight, and bone and skin characteristics in broilers (Cobb 500) at 21 and 42 days of age. A total of 1920 chickens were distributed in a randomised design, considering six vitamin A supplementation levels (0, 6000, 16,000, 26,000, 36,000, and 46,000 IU kg⁻¹), with 16 replicates and 20 chickens per experimental unit, established due to rising the range of vitamin levels observed in the literature to evaluate the effect of vitamin A on broilers. At 22 days, half of the replicates from each treatment continued receiving the initial diet, and the other eight repetitions received diets without vitamin A (0 IU kg⁻¹) until 42 days. The level of vitamin A influenced feed intake (FI) and body weight gain (BWG) until 21 days for all treatments. Broilers at 21 days of age had a more significant BWG at a vitamin A supplementation level of 28,209 IU kg⁻¹. At 42 days, vitamin A influenced the BWG and FI of broilers at treatments that were not supplemented after 21 days. Treatments supplemented up to 42 days showed quadratic responses to vitamin A for BWG, FI, and feed conversion. The vitamin A levels influenced the relative weights of the small intestine, pancreas, gizzard, abdominal fat, Seedor index, and breaking strength at 42 days, where the adequate supplementation of vitamin A improved these characteristics in broilers. Vitamin A supplementation from 22 to 42 days old did not affect broiler performance. An increased BWG was obtained when vitamin A supplementation occurred until 42 days, with supplementation of 29,375 IU kg⁻¹ and a lower response of feed conversion with the addition of 27,775 IU kg⁻¹.

Critical stage and key natural mortality factors of Hypothenemus hampei in commercial coffee plantations

Posted on 2 October 2023 by

Predators ants, parasitoids, entomopathogenic fungi, and malformations during the Hyphothenemus hampei life cycle caused 75.34% of the mortalities seen within their populations. Adult mortality is the principal factor that regulates the size of populations of this insect. Predatory ants were the key mortality factor for H. hampei.

Abstract

The coffee berry borer, Hypothenemus hampei (Ferrari) (Coleoptera: Scolytidae), is one of the most important coffee pests, and is present in almost all countries producing this crop, causing annual losses of US$350 million. Natural factors regulate H. hampei populations in coffee crops. Ecological life table analysis is a robust tool that allows the estimation of the mortality caused by these factors. Therefore, the main objective of this study was to determine the critical stage and the key mortality factors affecting H. hampei in the field. Data for constructing life tables were collected over 2 years in six coffee plantations in the regions of Paula Cândido and Viçosa, Minas Gerais State, Brazil. The average mortality of H. hampei was 75.34% ± 5.85%. The mortality at each developmental stage was 24.32% ± 2.83% (eggs), 7.29% ± 1.01% (first instar), 11.58% ± 1.46% (second instar), 9.68% ± 1.10% (third instar), 7.45% ± 1.01% (pupa), and 15.02% ± 1.29% (adult; n = 124). The mortality factors observed and quantified in this study were parasitism by Prorops nasuta (Hymenoptera: Bethylidae), predation by ants (Crematogaster spp., Pheidole spp. and Solenopsis spp.), physiological disorders and fungal infection by Beauveria bassiana and Metarhizium anisopliae. The critical mortality stage of H. hampei was the adult stage. The key factors for mortality of H. hampei adults were predatory ants, followed by B. bassiana and malformations (these insects had deformities in the head, wings, legs, or abdomen). This information is essential to conserve the activities of natural enemies and, thus maintain H. hampei natural mortality factors in coffee plantations, reducing damage to the crops and the need for excessive insecticide interventions.

Source‐sink patterns on coffee trees related to annual climate variability: An approach through stable isotopes analysis

Posted on 2 October 2023 by

This study highlights the importance of using stable isotope analysis as a reference point for long-term coffee ecophysiological studies. We have provided evidence to support the hypothesis that variations in the δ¹³C and δ¹⁵N values for the dry matter of bulk material from leaves, heterotrophic organs, and the cellulose in the growth tree rings of coffee trees have temporal and spatial patterns that suggest the differential use of substrates and signals the influence of the climate on the growth and phenology of the trees.

Abstract

Stable isotopic determination constitutes a useful tool to identify the processes that control the dynamics of the carbon and nitrogen flow in plants, unravelling the mechanisms of their differential investment under different environments. This work aimed to evaluate the spatiotemporal variation of source-sink patterns of coffee trees under field conditions in response to climatic conditions through the assessment of stable isotopes. For this purpose, stems, leaves, and fruit samples from coffee trees were collected following a temporal pattern based on the region's climatic characteristics and the plant's phenology and a spatial pattern considering different parts of the canopy. The carbon and nitrogen percentage content, the C/N ratio, and the carbon and nitrogen isotopic compositions (δ¹³C and δ¹⁵N) were determined for all samples. The basal portion of the orthotropic branch was also considered for the isotopic analysis of the tree's growth rings. The results obtained were correlated with the climatic variables of the region through a Pearson correlation analysis (p < .05). Coffee plants showed traditional δ¹³C values of C3 plants. Temporal δ¹³C variation was associated with the different growth rates between phenological stages and the use of substrates produced at different times under different environmental conditions leading to differences in photosynthetic discrimination. Spatial δ¹³C variation was observed with heterotrophic tissues isotopically heavier than leaves, with a significant decrease trend in δ¹³C values from the top (upper third) to the bottom (lower third), associated with ecophysiological differences between the canopy, isotopic fractionation processes downstream of photosynthetic carbon discrimination, and the fixation of C from other pools. Temporal δ¹⁵N variation was associated with the precipitation rates in the region and the fertilization distribution across the tree, while the spatial variation was with the plant's nitrogen assimilation and translocation patterns. The tree growth rings isotopic analyses showed isotopic differences between growth rings of the same plant addressed by the climatic conditions, with precipitation being the primary climatic determinant influencing the fixation and discrimination against ¹³C. Our results highlight the importance of using stable isotope analysis as a reference point for coffee ecophysiological studies to characterize how the temporal and spatial patterns of δ¹³C and δ¹⁵N emerge and signal the influence of climate on the source-sink relationship of coffee trees under field conditions.