RESUMEN
We employed scRNA sequencing to extensively characterize the cellular landscape of human liver from development to disease. Analysis of â¼212,000 cells representing human fetal, hepatocellular carcinoma (HCC), and mouse liver revealed remarkable fetal-like reprogramming of the tumor microenvironment. Specifically, the HCC ecosystem displayed features reminiscent of fetal development, including re-emergence of fetal-associated endothelial cells (PLVAP/VEGFR2) and fetal-like (FOLR2) tumor-associated macrophages. In a cross-species comparative analysis, we discovered remarkable similarity between mouse embryonic, fetal-liver, and tumor macrophages. Spatial transcriptomics further revealed a shared onco-fetal ecosystem between fetal liver and HCC. Furthermore, gene regulatory analysis, spatial transcriptomics, and in vitro functional assays implicated VEGF and NOTCH signaling in maintaining onco-fetal ecosystem. Taken together, we report a shared immunosuppressive onco-fetal ecosystem in fetal liver and HCC. Our results unravel a previously unexplored onco-fetal reprogramming of the tumor ecosystem, provide novel targets for therapeutic interventions in HCC, and open avenues for identifying similar paradigms in other cancers and disease.
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Carcinoma Hepatocelular/patología , Células Endoteliales/metabolismo , Microambiente Tumoral/genética , Adulto , Animales , Carcinoma Hepatocelular/genética , Línea Celular , Modelos Animales de Enfermedad , Células Endoteliales/patología , Femenino , Receptor 2 de Folato/metabolismo , Perfilación de la Expresión Génica/métodos , Humanos , Hígado/patología , Neoplasias Hepáticas/genética , Macrófagos/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Receptores Notch/genética , Receptores Notch/metabolismo , Transducción de Señal/genética , Transcriptoma/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Hepatocellular carcinoma (HCC) often develops following chronic hepatitis B virus (HBV) infection and responds poorly to immune checkpoint blockade. Here, we examined the antigen specificities of HCC-infiltrating T cells and their relevance to tumor control. Using highly multiplexed peptide-MHC tetramer staining of unexpanded cells from blood, liver, and tumor tissues from 46 HCC patients, we detected 91 different antigen-specific CD8+ T cell populations targeting HBV, neoantigen, tumor-associated, and disease-unrelated antigens. Parallel high-dimensional analysis delineated five distinct antigen-specific tissue-resident memory T (Trm) cell populations. Intratumoral and intrahepatic HBV-specific T cells were enriched for two Trm cell subsets that were PD-1loTOXlo, despite being clonally expanded. High frequencies of intratumoral terminally exhausted T cells were uncommon. Patients with tumor-infiltrating HBV-specific CD8+ Trm cells exhibited longer-term relapse-free survival. Thus, non-terminally exhausted HBV-specific CD8+ Trm cells show hallmarks of active involvement and effective antitumor response, implying that these cells could be harnessed for therapeutic purposes.
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Linfocitos T CD8-positivos/inmunología , Carcinoma Hepatocelular/inmunología , Memoria Inmunológica/inmunología , Neoplasias Hepáticas/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Antígenos de Neoplasias/inmunología , Carcinoma Hepatocelular/patología , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Proteínas del Grupo de Alta Movilidad/metabolismo , Humanos , Neoplasias Hepáticas/patología , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/prevención & control , Receptor de Muerte Celular Programada 1/metabolismo , Células Tumorales CultivadasRESUMEN
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.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Escape del Tumor , Microambiente Tumoral , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/tratamiento farmacológico , Microambiente Tumoral/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Evasión InmuneRESUMEN
BACKGROUND: No adjuvant treatment has been established for patients who remain at high risk for hepatocellular carcinoma recurrence after curative-intent resection or ablation. We aimed to assess the efficacy of adjuvant atezolizumab plus bevacizumab versus active surveillance in patients with high-risk hepatocellular carcinoma. METHODS: In the global, open-label, phase 3 IMbrave050 study, adult patients with high-risk surgically resected or ablated hepatocellular carcinoma were recruited from 134 hospitals and medical centres in 26 countries in four WHO regions (European region, region of the Americas, South-East Asia region, and Western Pacific region). Patients were randomly assigned in a 1:1 ratio via an interactive voice-web response system using permuted blocks, using a block size of 4, to receive intravenous 1200 mg atezolizumab plus 15 mg/kg bevacizumab every 3 weeks for 17 cycles (12 months) or to active surveillance. The primary endpoint was recurrence-free survival by independent review facility assessment in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04102098. FINDINGS: The intention-to-treat population included 668 patients randomly assigned between Dec 31, 2019, and Nov 25, 2021, to either atezolizumab plus bevacizumab (n=334) or to active surveillance (n=334). At the prespecified interim analysis (Oct 21, 2022), median duration of follow-up was 17·4 months (IQR 13·9-22·1). Adjuvant atezolizumab plus bevacizumab was associated with significantly improved recurrence-free survival (median, not evaluable [NE]; [95% CI 22·1-NE]) compared with active surveillance (median, NE [21·4-NE]; hazard ratio, 0·72 [adjusted 95% CI 0·53-0·98]; p=0·012). Grade 3 or 4 adverse events occurred in 136 (41%) of 332 patients who received atezolizumab plus bevacizumab and 44 (13%) of 330 patients in the active surveillance group. Grade 5 adverse events occurred in six patients (2%, two of which were treatment related) in the atezolizumab plus bevacizumab group, and one patient (<1%) in the active surveillance group. Both atezolizumab and bevacizumab were discontinued because of adverse events in 29 patients (9%) who received atezolizumab plus bevacizumab. INTERPRETATION: Among patients at high risk of hepatocellular carcinoma recurrence following curative-intent resection or ablation, recurrence-free survival was improved in those who received atezolizumab plus bevacizumab versus active surveillance. To our knowledge, IMbrave050 is the first phase 3 study of adjuvant treatment for hepatocellular carcinoma to report positive results. However, longer follow-up for both recurrence-free and overall survival is needed to assess the benefit-risk profile more fully. FUNDING: F Hoffmann-La Roche/Genentech.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Adulto , Humanos , Bevacizumab/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/cirugía , Espera Vigilante , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugíaRESUMEN
Alterations in metabolic pathways are a hallmark of cancer. A deeper understanding of the contribution of different metabolites to carcinogenesis is thus vitally important to elucidate mechanisms of tumor initiation and progression to inform therapeutic strategies. Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide and its altered metabolic landscape is beginning to unfold with the advancement of technologies. In particular, characterization of the lipidome of human HCCs has accelerated, and together with biochemical analyses, are revealing recurrent patterns of alterations in glycerophospholipid, sphingolipid, cholesterol and bile acid metabolism. These widespread alterations encompass a myriad of lipid species with numerous roles affecting multiple hallmarks of cancer, including aberrant growth signaling, metastasis, evasion of cell death and immunosuppression. In this review, we summarize the current trends and findings of the altered lipidomic landscape of HCC and discuss their potential biological significance for hepatocarcinogenesis.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/metabolismo , Lipidómica , Carcinogénesis/genética , Transformación Celular NeoplásicaRESUMEN
BACKGROUND AND AIMS: Hypoxia is one of the central players in shaping the immune context of the tumor microenvironment (TME). However, the complex interplay between immune cell infiltrates within the hypoxic TME of HCC remains to be elucidated. APPROACH AND RESULTS: We analyzed the immune landscapes of hypoxia-low and hypoxia-high tumor regions using cytometry by time of light, immunohistochemistry, and transcriptomic analyses. The mechanisms of immunosuppression in immune subsets of interest were further explored using in vitro hypoxia assays. Regulatory T cells (Tregs) and a number of immunosuppressive myeloid subsets, including M2 macrophages and human leukocyte antigen-DR isotype (HLA-DRlo ) type 2 conventional dendritic cell (cDC2), were found to be significantly enriched in hypoxia-high tumor regions. On the other hand, the abundance of active granzyme Bhi PD-1lo CD8+ T cells in hypoxia-low tumor regions implied a relatively active immune landscape compared with hypoxia-high regions. The up-regulation of cancer-associated genes in the tumor tissues and immunosuppressive genes in the tumor-infiltrating leukocytes supported a highly pro-tumorigenic network in hypoxic HCC. Chemokine genes such as CCL20 (C-C motif chemokine ligand 20) and CXCL5 (C-X-C motif chemokine ligand 5) were associated with recruitment of both Tregs and HLA-DRlo cDC2 to hypoxia-high microenvironments. The interaction between Tregs and cDC2 under a hypoxic TME resulted in a loss of antigen-presenting HLA-DR on cDC2. CONCLUSIONS: We uncovered the unique immunosuppressive landscapes and identified key immune subsets enriched in hypoxic HCC. In particular, we identified a potential Treg-mediated immunosuppression through interaction with a cDC2 subset in HCC that could be exploited for immunotherapies.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Linfocitos T Reguladores , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Granzimas/metabolismo , Linfocitos T CD8-positivos , Receptor de Muerte Celular Programada 1/metabolismo , Ligandos , Microambiente Tumoral , Terapia de Inmunosupresión , Hipoxia/metabolismo , Células Dendríticas/metabolismo , Antígenos HLARESUMEN
BACKGROUND: Conventional differential expression (DE) testing compares the grouped mean value of tumour samples to the grouped mean value of the normal samples, and may miss out dysregulated genes in small subgroup of patients. This is especially so for highly heterogeneous cancer like Hepatocellular Carcinoma (HCC). METHODS: Using multi-region sampled RNA-seq data of 90 patients, we performed patient-specific differential expression testing, together with the patients' matched adjacent normal samples. RESULTS: Comparing the results from conventional DE analysis and patient-specific DE analyses, we show that the conventional DE analysis omits some genes due to high inter-individual variability present in both tumour and normal tissues. Dysregulated genes shared in small subgroup of patients were useful in stratifying patients, and presented differential prognosis. We also showed that the target genes of some of the current targeted agents used in HCC exhibited highly individualistic dysregulation pattern, which may explain the poor response rate. DISCUSSION/CONCLUSION: Our results highlight the importance of identifying patient-specific DE genes, with its potential to provide clinically valuable insights into patient subgroups for applications in precision medicine.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Pronóstico , Regulación Neoplásica de la Expresión GénicaRESUMEN
INTRODUCTION: Our primary objective was to determine if receiving intraoperative blood transfusion was a significant prognostic factor for overall and recurrence-free survival after curative resection of hepatic cellular carcinoma (HCC). METHODOLOGY: Between 2001 and 2018, 1092 patients with histologically proven primary HCC who underwent curative liver resection were retrospectively reviewed. Primary study endpoints were recurrence-free survival (RFS) and overall survival (OS). The main analysis was undertaken using propensity-score matching (PSM) to minimize confounding and selection biases in the comparison of patients with or without transfusion. RESULTS: There were 220 patients who received and 666 patients who did not receive intraoperative blood transfusion. The PSM cohort consisted of 163 pairs of patients. After PSM, the only perioperative outcome that appeared to significantly affect whether patients would receive blood transfusion was median blood loss (p = 0.001). In the PSM cohort, whether patients received blood transfusion was neither associated with OS (p = 0.759) nor RFS (p = 0.830). When the volume of blood transfusion was analyzed as a continuous variable, no significant dose-response relationship between blood transfusion volume and HR for OS and RFS was noted. CONCLUSION: Intraoperative blood transfusion had no significant impact on the survival outcomes in patients who receive curative resection in primary HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Hepatectomía , Estudios Retrospectivos , Transfusión Sanguínea , Puntaje de Propensión , Recurrencia Local de Neoplasia/patología , PronósticoRESUMEN
The objective of this research was to evaluate how different feeding strategies based on various pasture availability (PA) treatments within intensive seasonal production systems affected pasture production and utilization, sward quality, and the milk production, body weight (BW), and body condition score (BCS) of dairy cows. The performance data were obtained from a 3-yr experiment conducted previously (2018-2020, inclusive). In total, records from 208 spring-calving dairy cows were available for analysis. The animals were randomly allocated to 1 of 3 PA grazing treatments in spring that varied in average pasture cover (measured as herbage mass available above 3.5 cm) that was established via different pasture management strategies in the previous autumn. Thus, the opening average pasture cover across all paddocks on February 1 was 1,100 kg of dry matter (DM)/ha for high pasture availability (HPA), 880 for medium pasture availability (MPA), and 650 for low pasture availability (LPA), respectively. The measurements were taken over an 8-wk period during the first grazing rotation in spring, commencing on February 16 (±2 d) and finishing when all paddocks were grazed once on April 12 (±5 d). Paddocks that were part of the HPA treatment showed the highest pregrazing herbage masses and pregrazing sward heights (1,645 kg of DM/ha and 8.2 cm, respectively) compared with MPA (1,412 kg of DM/ha and 7.5 cm, respectively) and LPA (1,170 kg of DM/ha and 6.9 cm, respectively). Owing to the differences in PA, daily herbage allowance was greatest for HPA (11.7 kg of DM/cow), intermediate for MPA (10.2 kg of DM/cow), and lowest for LPA (8.8 kg of DM/cow), with the remaining feed deficit composed of additional daily grass silage supplementation (0.8, 1.5, and 2.8 kg of DM/cow for HPA, MPA, and LPA, respectively), while the daily concentrate and daily total feed allowance were equal between treatments during spring (2.7 and 15.0 kg of DM/cow). Despite salient differences in fresh pasture used, complementing pasture intake with grass silage did not affect daily or cumulative milk, solids-corrected milk, fat, or protein yield or milk constituents. Similarly, BW and BCS were also unaffected by PA treatment. The results highlight the importance of high spring pasture utilization and grazing efficiency achievable with higher pregrazing herbage masses, which also allow larger animal intakes from grazed pasture as the cheapest feed source during spring. Moreover, targeting an adequate pasture supply at the commencement of calving increases the grazing days per hectare and lowers the requirement for supplementary feed on farm, particularly when facing increasing variability in climatic conditions.
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Dieta , Lactancia , Bovinos , Femenino , Animales , Estaciones del Año , Dieta/veterinaria , Industria Lechera/métodos , Leche/metabolismo , Poaceae , Peso Corporal , Alimentación Animal/análisisRESUMEN
The objective of this study was to investigate the effect of increasing stocking rate (SR) and extending grazing season (GS) length on pasture and animal productivity on a marginal, poorly draining soil type. The study was a multiyear (2017 to 2020, inclusive) whole farm systems evaluation with a 2 × 2 factorial experimental arrangement of treatments. The systems evaluated comprised 2 GS lengths, average (AGS; 205 d) and extended (EGS; 270 d), and the 2 whole farm stocking rates were medium (2.5 cows/ha) and high (2.9 cows/ha). We used this study design to create 4 grazing system intensities (500, 600, 700, and 800 cow grazing days per hectare per year). In 2017, cows were randomly allocated to 1 of the 4 whole farm systems precalving and remained on the same treatments for the duration of the study. We found no significant differences in total average annual pasture production [14,133 ± 538 kg of dry matter (DM) per hectare] or sward chemical composition between GS and SR treatments over the 4-yr period, with the exception of average crude protein content, which was lower for EGS (211 g/kg DM) compared with AGS (218 g/kg DM). Grazed pasture production was significantly increased in EGS treatments (+758 kg of DM/ha) compared with AGS (9,917 kg of DM/ha), whereas conserved silage DM production was greater for AGS (+716 kg of DM/ha) compared with EGS (3,583 kg of DM/ha). Neither GS nor SR had a significant effect on daily or cumulative lactation milk and fat plus protein production per cow (5,039 and ±440 kg, respectively). Increasing SR resulted in increased milk fat plus protein yield per hectare based on increased grazed pasture utilization. These results add further credence to the important additive contributions of both extended grazing and SR intensification to achieve high levels of grazed pasture utilization and milk production per hectare while reducing supplementary feed requirements within spring-calving grazing systems.
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Alimentación Animal , Leche , Femenino , Bovinos , Animales , Leche/metabolismo , Estaciones del Año , Industria Lechera/métodos , Lactancia , Proteínas de la Leche/metabolismo , Dieta/veterinariaRESUMEN
Selection for feed efficiency, the ratio of output (e.g., milk yield) to feed intake, has traditionally been limited on commercial dairy farms by the necessity for detailed individual animal intake and performance data within large animal populations. The objective of the experiment was to evaluate the effects of individual animal characteristics (animal breed, genetic potential, milk production, body weight (BW), daily total dry matter intake (TDMI), and energy balance) on a cost-effective production efficiency parameter calculated as the annual fat and protein (milk solids) production per unit of mid-lactation BW (MSperBWlact). A total of 1,788 individual animal intake records measured at various stages of lactation (early, mid, and late lactation) from 207 Holstein-Friesian and 200 Jersey × Holstein-Friesian cows were used. The derived efficiency traits included daily kilograms of milk solids produced per 100 kg of BW (dMSperBWint) and daily kilograms of milk solids produced per kilogram of TDMI (dMSperTDMI). The TDMI per 100 kg of BW was also calculated (TDMI/BWint) at each stage of lactation. Animals were subsequently either ranked as the top 25% (Heff) or bottom 25% (Leff) based on their lactation production efficiency (MSperBWlact). Dairy cow breed significantly affected animal characteristics over the entire lactation and during specific periods of intake measurements. Jersey crossbred animals produced more milk, based on a lower TDMI, and achieved an increased intake per kilogram of BW. Similarly, Heff produced more milk over longer lactations, weighed less, were older, and achieved a higher TDMI compared with the Leff animals. Both Jersey × Holstein-Friesian and Heff cows achieved superior production efficiency due to lower maintenance energy requirements, and consequentially increased milk solids production per kilogram of BW and per kilogram of TDMI at all stages of lactation. Indeed, within breed, Heff animals weighed 20 kg less and produced 15% more milk solids over the total lactation than Leff. In addition, Heff achieved increased daily milk solids yield (+0.16 kg) and milk solids yield per kilogram of TDMI (+ 0.23 kg/kg DM) during intake measurement periods. Moreover, the strong and consistently positive correlations between MSperBWlact and detailed production efficiency traits (dMSperBWint, dMSperTDMI) reported here demonstrate that MSperBWlact is a robust measure that can be applied within commercial grazing dairy systems to increase the selection intensity for highly efficient animals.
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Alimentación Animal , Dieta , Femenino , Bovinos , Animales , Dieta/veterinaria , Industria Lechera , Lactancia/genética , Leche/metabolismo , Peso CorporalRESUMEN
INTRODUCTION: The presence of previous abdominal surgery (PAS) has traditionally been considered to add difficulty to and increase risk of complications of laparoscopic procedures. This study aims to analyse the impact of non-liver-related PAS on the difficulty of minimally invasive liver resections (MILRs). MATERIALS AND METHODS: After exclusion of patients with concomitant major surgical procedures as well as previous liver resections, 515 consecutive patients undergoing MILR in Singapore General Hospital from 2006 to 2019 were analysed, consisting of 161 MILR in patients with previous abdominal surgery (WPAS) and 354 MILR in patients without previous abdominal surgery (WOPAS). Propensity score-matched (PSM) comparison was performed between WPAS and WOPAS groups. In addition, subgroup analysis was made comparing previous upper or lower abdominal surgery and open versus minimally invasive approach of PAS. Outcomes measured include those associated with operative difficulty such as open conversion rates, operative time, blood loss, as well as morbidity and mortality rates. RESULTS: MILR outcomes in patients WPAS are not inferior to those WOPAS. Overall open conversion rate was 8.2%, higher in patients WOPAS compared to patients WPAS (11.9% versus 3.5%, p = 0.015). Operating time (p = 0.942), blood loss (p = 0.063), intraoperative blood transfusion (p = 0.750), length of hospital stay (p = 0.206), morbidity (p = 0.217) and 30- and 90-day mortality (p = 1 & p = 0.367) were comparable between the two groups and subgroup analysis. CONCLUSION: Outcomes of MILR in patients with previous non-liver-related abdominal surgery are not inferior to patients without previous abdominal surgery.
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Laparoscopía , Neoplasias Hepáticas , Hepatectomía/efectos adversos , Hepatectomía/métodos , Humanos , Laparoscopía/efectos adversos , Laparoscopía/métodos , Tiempo de Internación , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/cirugía , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Tempo Operativo , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Puntaje de Propensión , Estudios RetrospectivosRESUMEN
Emerging evidence suggests that hepatocytes are primarily maintained by self-renewal during normal liver homeostasis, as well as in response to a wide variety of hepatic injuries. However, how hepatocytes in distinct anatomic locations within the liver lobule are replenished under homeostasis and injury-induced regeneration remains elusive. Using a newly developed bacterial artificial chromosome (BAC)-transgenic mouse model, we demonstrate that Lgr5 expression in the liver is restricted to a unique subset of hepatocytes most adjacent to the central veins. Genetic lineage tracing revealed that pericentral Lgr5+ hepatocytes have a long lifespan and mainly contribute to their own lineage maintenance during postnatal liver development and homeostasis. Remarkably, these hepatocytes also fuel the regeneration of their own lineage during the massive and rapid regeneration process following two-thirds partial hepatectomy. Moreover, Lgr5+ hepatocytes are found to be the main cellular origin of diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) and are highly susceptible to neoplastic transformation triggered by activation of Erbb pathway. Our findings establish an unexpected self-maintaining mode for a defined subset of hepatocytes during liver homeostasis and regeneration, and identify Lgr5+ pericentral hepatocytes as major cells of origin in HCC development.
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Hepatocitos/fisiología , Regeneración Hepática/fisiología , Receptores Acoplados a Proteínas G/metabolismo , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Diferenciación Celular/fisiología , Linaje de la Célula/fisiología , Proliferación Celular/fisiología , Modelos Animales de Enfermedad , Femenino , Hepatocitos/citología , Hepatocitos/metabolismo , Humanos , Hígado/fisiología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Transgénicos , Células Madre/citologíaRESUMEN
The objectives of this study are to evaluate the effects of (1) a potential interaction between supplement crude protein (CP) concentration and differing cow genotypes on milk production, (2) differing cow genotypes on milk production, and (3) decreasing the supplement CP concentration on milk production and N excretion during the main grazing season within a spring-calving herd. A 2 × 2 factorial arrangement experiment, with 2 feeding strategies [14%; n = 30 (lower CP; LCP) and 18%; n = 28 (higher CP; HCP) CP concentrate supplements] offered at varying levels according to pasture availability and days in milk (DIM) was conducted over the main grazing season from April 3 to September 3, 2019, at University College Dublin Lyons Farm. Cows were also grouped into 2 genotype groups: lower milk genotype; n = 30 [LM; milk kg predicted transmitting ability (PTA): 45 ± 68.6 (mean ± SD); fat kg PTA: 10 ± 4.9; and protein kg PTA: 7 ± 2.3] and higher milk genotype; n = 28 [HM; milk kg PTA: 203 ± 55.0; fat kg PTA: 13 ± 3.8; and protein kg PTA: 10 ± 2.4]. A total of 46 multiparous and 12 primiparous (total; 58) Holstein Friesian dairy cows were blocked on parity and balanced on DIM, body condition score, and Economic Breeding Index. Cows were offered a basal diet of grazed perennial ryegrass pasture. The N partitioning study took place from August 25 to 30, 2019 (187 ± 15.2 DIM). No interactions were observed for any milk production or milk composition parameter. No effect of supplement CP concentration was observed for any total accumulated milk production, daily milk production, or milk composition parameter measured. The HM cows had increased daily milk yield (+1.9 kg), fat and protein (+0.15 kg), and energy-corrected milk (+1.7 kg), compared with the LM cows. Furthermore, HM cows had decreased milk protein concentration (-0.1%) compared with LM cows. For the N partitioning study, cows offered LCP had increased pasture dry matter intake (PDMI; +0.9 kg/d), dietary N intake (+0.022 kg/d), feces N excretion (+0.016 kg/d), and decreased N partitioning to milk (-2%), and N utilization efficiency (-2.3%). In conclusion, offering cows LCP had no negative influence on milk production or milk composition over the main grazing season where high pasture quality was maintained. However, any potential negative effects of offering LCP on milk production may have been offset by the increased PDMI. Furthermore, offering cows LCP decreased N utilization efficiency due to the higher PDMI and feed N intake associated with cows on this treatment in our study.
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Alimentación Animal , Nitrógeno , Alimentación Animal/análisis , Animales , Bovinos , Dieta/veterinaria , Femenino , Lactancia , Leche , Embarazo , Estaciones del AñoRESUMEN
BACKGROUND: This study aims to compare the short- and long-term outcomes of patients undergoing minimally invasive liver resection (MILR) versus open liver resection (OLR) for nonrecurrent hepatocellular carcinoma (HCC). METHODS: Review of 204 MILR and 755 OLR without previous LR performed between 2005 and 2018. 1:1 coarsened exact matching (CEM) and 1:1 propensity-score matching (PSM) were performed. RESULTS: Overall, 190 MILR were well-matched with 190 OLR by PSM and 86 MILR with 86 OLR by CEM according to patient baseline characteristics. After PSM and CEM, MILR was associated with a significantly longer operation time [230 min (interquartile range [IQR], 145-330) vs. 160 min (IQR, 125-210), p < .001] [215 min (IQR, 135-295) vs. 153.5 min (120-180), p < .001], shorter postoperative stay [4 days (IQR, 3-6) vs. 6 days (IQR, 5-8), p = .001)] [4 days (IQR, 3-5) vs. 6 days (IQR, 5-7), p = .004] and lower postoperative morbidity [40 (21%) vs. 67 (35.5%), p = .003] [16 (18.6%) vs. 27 (31.4%), p = .036] compared to OLR. MILR was also associated with a significantly longer median time to recurrence (70 vs. 40.3 months, p = .014) compared to OLR after PSM but not CEM. There was no significant difference in terms of overall survival and recurrence-free survival. CONCLUSION: MILR is associated with superior short-term postoperative outcomes and with at least equivalent long-term oncological outcomes compared to OLR for HCC.
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Carcinoma Hepatocelular/cirugía , Hepatectomía/mortalidad , Laparoscopía/mortalidad , Neoplasias Hepáticas/cirugía , Procedimientos Quirúrgicos Mínimamente Invasivos/mortalidad , Anciano , Carcinoma Hepatocelular/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: At present, the majority of outcome studies of survival of hepatocellular carcinoma (HCC) post-liver resection (post-LR) present actuarial survival data, which often results in overestimation of survival. We sought to evaluate the actual 10-year survival post-LR for HCC and identify variables that are associated with long-term survival. METHODS: We performed a retrospective review of 600 consecutive patients who underwent primary LR for HCC from 2000 to 2010 at our institution. Twenty-eight patients (4.7%) with 90-day mortality and 125 patients who were lost to follow-up within 10 years were excluded leaving 447 patients who met the study criteria. RESULTS: There were 140 actual 10-year survivors of which 57 (40.7%) had a recurrence within 10 years. The actual 10-year overall survival (OS) rate of the 447 patients was 31.5% and the actual 10-year recurrence-free survival (RFS) was 18.6%. Multivariate analyses demonstrated that only age >65 years (OR, 0.29; p < .001) (OR, 0.973; p = .041) and presence of cirrhosis (OR. 0.37; p = .005) (OR, 0.31; p = .001) were independent factors negatively associated with actual 10-year OS and actual 10-year RFS, respectively. CONCLUSION: Approximately one-third of patients will survive over 10 years after LR for HCC. Amongst these 10-year survivors, 41% had developed recurrent cancer within 10-years of follow-up.
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Supervivientes de Cáncer/estadística & datos numéricos , Carcinoma Hepatocelular/mortalidad , Hepatectomía/mortalidad , Neoplasias Hepáticas/mortalidad , Trasplante de Hígado/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Anciano , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Tasa de Supervivencia , Factores de TiempoRESUMEN
INTRODUCTION: The impact of liver cirrhosis on the difficulty of minimal invasive liver resection (MILR) remains controversial and current difficulty scoring systems do not take in to account the presence of cirrhosis as a significant factor in determining the difficulty of MILR. We hypothesized that the difficulty of MILR is affected by the presence of cirrhosis. Hence, we performed a 1:1 matched-controlled study comparing the outcomes between patients undergoing MILR with and without cirrhosis including the Iwate system and Institut Mutualiste Montsouris (IMM) system in the matching process. METHODS: Between 2006 and 2019, 598 consecutive patients underwent MILR of which 536 met the study inclusion criteria. There were 148 patients with cirrhosis and 388 non-cirrhotics. One-to-one coarsened exact matching identified approximately exact matches between 100 cirrhotic patients and 100 non-cirrhotic patients. RESULTS: Comparison between MILR patients with cirrhosis and non-cirrhosis in the entire cohort demonstrated that patients with cirrhosis were associated with a significantly increased open conversion rate, transfusion rate, need for Pringles maneuver, postoperative, stay, postoperative morbidity and postoperative 90-day mortality. After 1:1 coarsened exact matching, MILR with cirrhosis were significantly associated with an increased open conversion rate (15% vs 6%, p = 0.03), operation time (261 vs 238 min, p < 0.001), blood loss (607 vs 314 mls, p = 0.002), transfusion rate (22% vs 9%, p = 0.001), need for application of Pringles maneuver (51% vs 34%, p = 0.010), postoperative stay (6 vs 4.5 days, p = 0.004) and postoperative morbidity (26% vs 13%, p = 0.029). CONCLUSION: The presence of liver cirrhosis affected both the intraoperative technical difficulty and postoperative outcomes of MILR and hence should be considered an important parameter to be included in future difficulty scoring systems for MILR.
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Laparoscopía , Neoplasias Hepáticas , Hepatectomía , Humanos , Tiempo de Internación , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/cirugía , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios RetrospectivosRESUMEN
BACKGROUND: The management of post-liver resection recurrence is often the life-limiting factor in HCC treatment. While much has been published on intrahepatic recurrence and lung metastasis, there is a relative lack of data on intraabdominal extrahepatic metastasis (EHM). We sought to evaluate the outcomes of patients post-resection of intraabdominal EHM and assess preoperative factors predictive of early recurrence post-metastasectomy. METHODS: We performed a retrospective review of 25 consecutive patients who underwent metastasectomy for intraabdominal EHM from 2003 to 2016 at our institution. RESULTS: Of the 25 cases of EHM, 16 were in the peritoneum, 3 in the adrenal glands, 3 in the large bowel, 1 in the spleen, 1 in the pancreas and 1 in the omentum. Median overall survival was 27 months (IQR 15-89 months). Twenty-one patients (84%) developed recurrence post-metastasectomy of EHM of which 12 patients experienced early recurrence within 12 months. The median time to recurrence post-metastasectomy was 11(IQR 15.5) months. Multivariate analysis demonstrated both hepatitis B (11 (91.6%) versus 4 (44.4%), p = 0.00) status and high tumour grade (8 (66.6%) versus 3 (25%), p = 0.004) to be significant independent predictors of early recurrence. Patients who experienced early recurrence had a significantly shorter median overall survival (18 months (95% CI 12.9-23.0)) compared to those who did not (89 months (95% CI 24.8-153.1), p = 0.004). CONCLUSION: Patients with EHM who underwent metastasectomy had a median overall survival of 27 months. Hepatitis B positivity and high primary tumour grade were preoperative predictors of futile surgery. All 7 patients who had both hepatitis B and high tumour grade experienced early recurrence post-metastasectomy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias Pulmonares , Metastasectomía , Carcinoma Hepatocelular/cirugía , Humanos , Neoplasias Hepáticas/cirugía , Neoplasias Pulmonares/cirugía , Recurrencia Local de Neoplasia/cirugía , Estudios RetrospectivosRESUMEN
The importance of financial benchmarking has increased in recent years as European Union milk quota abolition has facilitated rapid change in the dairy sector. This study evaluates the association between usage frequency of a financial benchmarking tool [Profit Monitor (PM)] and farm changes on spring-calving pasture-based dairy farms. To this end, physical and financial data for 5,945 dairy farms, representing 20,132 farm years, for the years 2010 to 2018 were used. Farms were categorized by frequency of annual financial benchmarking over the 9-yr period into frequent PM users (7-9 yr), infrequent PM users (4-6 yr), low PM users (1-3 yr), and nonusers. We use a mixed model framework and econometric models to characterize farms and to explore characteristics and determinants of economic performance and user groups. The most frequent users of the financial benchmarking tool had the greatest increase in intensification (measured by change in farm stocking rate), productivity (measured by change in milk production per hectare), and financial performance (measured by change in farm gross output and net profit per hectare) across the study period. Infrequent and low PM users of the benchmarking tool were intermediate for all variables measured, whereas nonusers had the least change. Empirical results indicated that economic performance was positively associated with dairy specialization and pasture utilization for all groups. Despite considerable fluctuations over the observation period, the overall change in total farm net profit between 2010 and 2018 was greatest for the frequent PM users (an increase of 70%, or 37,639), followed by farms in the infrequent PM user category (a 71% increase corresponding to an increase of 28,008 in net profit); meanwhile, low PM user and nonuser categories showed increases of 69% (26,270) and 42% (10,977), respectively. The results of this study also clearly indicated the existence of a strong positive association between frequency of financial benchmarking and greater technical and financial efficiency. The econometric analysis revealed that financial benchmarking users are more likely than nonusers to have larger herds, and that regional differences exist in usage rates. Finally, the study concludes by suggesting that the development of simplified financial benchmarking technologies and their support are required to increase benchmarking frequency, which may also help to facilitate a more sustainable and resource efficient dairy industry.
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Benchmarking , Industria Lechera , Animales , Granjas , Leche , Estaciones del AñoRESUMEN
The objective of this study was to investigate the effect of altering autumn pasture availability and farm system intensity on the productivity of spring-calving dairy cows during autumn. A total of 144 Holstein-Friesian and Holstein-Friesian × Jersey crossbred dairy cows were randomly assigned to 2 whole farm system (FS) intensities and 3 autumn pasture availability (PA; measured above 3.5 cm) treatments in a 2 × 3 factorial arrangement. The 2 farm systems consisted of a medium intensity (MI: 2.75 cows/ha, target postgrazing sward height of 4.0-4.5 cm) and high intensity system (HI: 3.25 cows/ha, target postgrazing sward height of 3.5-4.0 cm, + 1.8 kg of concentrate dry matter [(DM)/cow per day]. Within each farm system treatment, cows were further subdivided into 3 different PA management strategies: high PA (HPA), medium PA (MPA), and low PA (LPA). The experimental period lasted for 11 wk from September 1 to housing of all animals on November 20 (±2 d) over 3 yr (2017-2019, inclusive). To establish the different average pasture covers for each PA treatment during autumn and in particular at the end of the grazing season, grazing rotation length was extended by +13 and +7 d for HPA and MPA, respectively, beyond that required by LPA (37 d). There were no significant FS × PA interactions for any of the pasture, dry matter intake, or milk production and composition variables analyzed. There were also no differences in pregrazing sward characteristics or sward nutritive value between FS with the exception of daily herbage allowance, which was reduced for HI system (12.2 vs. 14.2 kg of DM/cow). Milk and milk solid yield were greater for HI groups (15.9 and 1.55 kg/cow per day, respectively) compared with MI (15.4 and 1.50 kg/cow per day, respectively). Mean paddock pregrazing herbage mass was significantly higher with increased PA ranging from a mean of 1,297 kg of DM/ha for LPA to 1,718 and 2,111 kg of DM/ha of available pasture for MPA and HPA, respectively. Despite large differences in pregrazing herbage mass, there was no difference in cumulative pasture production and only modest differences in grazing efficiency and sward nutritive value between PA treatments. On average, closing pasture covers were 420, 650, and 870 kg of DM/ha for LPA, MPA, and HPA, respectively, on December 1. In addition to maintaining similar grazing season lengths and achieving big differences in availability of pasture on farm into late autumn, PA treatment had no significant effect on dry matter intake, milk production, and body condition score during the study period. The results of this study indicate that greater cow performance and pasture utilization can be achieved through a greater daily concentrate allocation along with an increased stocking rate. Moreover, the potential to adapt grazing management practices to increase the average autumn pasture cover in intensive grazing systems is highlighted. In addition, a high dependence on high-quality grazed pasture during late autumn can be ensured without compromising grazing season length while also allowing additional pasture to be available for the subsequent spring.