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BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a highly fatal cancer characterized by high intra-tumor heterogeneity (ITH). A panoramic understanding of its tumor evolution, in relation to its clinical trajectory, may provide novel prognostic and treatment strategies. METHODS: Through the Asia-Pacific Hepatocellular Carcinoma trials group (NCT03267641), we recruited one of the largest prospective cohorts of patients with HCC, with over 600 whole genome and transcriptome samples from 123 treatment-naïve patients. RESULTS: Using a multi-region sampling approach, we revealed seven convergent genetic evolutionary paths governed by the early driver mutations, late copy number variations and viral integrations, which stratify patient clinical trajectories after surgical resection. Furthermore, such evolutionary paths shaped the molecular profiles, leading to distinct transcriptomic subtypes. Most significantly, although we found the coexistence of multiple transcriptomic subtypes within certain tumors, patient prognosis was best predicted by the most aggressive cell fraction of the tumor, rather than by overall degree of transcriptomic ITH level - a phenomenon we termed the 'bad apple' effect. Finally, we found that characteristics throughout early and late tumor evolution provide significant and complementary prognostic power in predicting patient survival. CONCLUSIONS: Taken together, our study generated a comprehensive landscape of evolutionary history for HCC and provides a rich multi-omics resource for understanding tumor heterogeneity and clinical trajectories. IMPACT AND IMPLICATIONS: This prospective study, utilizing comprehensive multi-sector, multi-omics sequencing and clinical data from surgically resected hepatocellular carcinoma (HCC), reveals critical insights into the role of tumor evolution and intra-tumor heterogeneity (ITH) in determining the prognosis of HCC. These findings are invaluable for oncology researchers and clinicians, as they underscore the influence of distinct evolutionary paths and the 'bad apple' effect, where the most aggressive tumor fraction dictates disease progression. These insights not only enhance prognostic accuracy post-surgical resection but also pave the way for personalized treatment strategies tailored to specific tumor evolutionary and transcriptomic profiles. The coexistence of multiple subtypes within the same tumor prompts a re-appraisal of the utilities of depending on single samples to represent the entire tumor and suggests the need for clinical molecular imaging. This research thus marks a significant step forward in the clinical understanding and management of HCC, underscoring the importance of integrating tumor evolutionary dynamics and multi-omics biomarkers into therapeutic decision-making. CLINICAL TRIAL NUMBER: NCT03267641 (Observational cohort).
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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
BACKGROUND: An updated systematic review and meta-analysis was conducted to compare radiofrequency ablation (RFA) versus repeat hepatectomy (RH) for patients with recurrent hepatocellular carcinoma (rHCC) after a previous liver resection. METHODS: PubMed, EMBASE, and Cochrane databases were searched from inception to October 2021 for randomized controlled trials and propensity-score matched studies. Individual participant survival data of disease-free survival (DFS) and overall survival (OS) were extracted and reconstructed followed by one-stage and two-stage meta-analysis. Secondary outcomes were major complications and length of hospital stay (LOHS). RESULTS: A total of seven studies (1317 patients) were analysed. In both one-stage and two-stage meta-analysis, there was no significant difference in OS between the RFA and RH cohorts (Hazard Ratio (HR) 1.15, 95% CI 0.98-1.36, P = 0.094 and HR 1.12, 95% CI 0.77-1.64, P = 0.474 respectively), while the RFA group had a higher hazard rate of disease recurrence compared to the RH group (HR 1.30, 95% CI 1.13-1.50, P < 0.001 and HR 1.31, 95% CI 1.09-1.57, P = 0.013, respectively). RFA was associated with fewer major complications and shorter LOHS versus RH (Odds Ratio 0.34, 95% CI 0.15-0.76, P = 0.009 and Weighted Mean Difference - 4.78, 95% CI - 6.30 to - 3.26, P < 0.001, respectively). CONCLUSIONS: RH may be associated with superior DFS for rHCC, at the expense of higher morbidity rate and longer LOHS. However, OS is comparable between both modalities. As such, these techniques may be utilized as complementary strategies depending on individual patient and disease factors. Large-scale, randomized, prospective studies are required to corroborate these findings.
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Carcinoma Hepatocelular , Ablación por Catéter , Neoplasias Hepáticas , Ablación por Radiofrecuencia , Ablación por Catéter/métodos , Hepatectomía/métodos , Humanos , Recurrencia Local de Neoplasia/patología , Ablación por Radiofrecuencia/métodos , Resultado del TratamientoRESUMEN
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: Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common primary liver cancers. With the increasing incidence of ICC over the past two decades in Asia, it is essential to differentiate between HCC and ICC. However, ICC may mimic the radiological appearance of HCC on computed tomography scans (CT) and magnetic resonance imaging (MRI), leading to misdiagnosis of ICC. The objective of this study is to evaluate and describe the association of specific pre-operative imaging characteristics (arterial enhancement, portal venous washout) in patients with histologically proven resected ICC in our centre. METHODS: Data on patients with histology-proven ICC and mixed hepatocellular-cholangiocarcinomas (HCC-CC) who had undergone surgical resection at Singapore General Hospital (SGH) were identified from a prospectively maintained database. Pre-operative cross-sectional imaging reports were analysed. RESULTS: Ninety-one patients underwent resection between 1 January 2000 and 31 December 2016. Among those with no risk factors for HCC, a significant percentage of patients with ICC (24.3%) show imaging characteristics of both arterial phase hyperenhancement and non-peripheral venous washout. Among patients with risk factors for HCC, between 20.0 and 33.3% of patients with pure ICC fulfilled the imaging criteria for HCC, and this proportion was generally even higher in the mixed HCC-CC group. CONCLUSIONS: A significant proportion of patients with pure ICC showed pre-operative imaging characteristics which fulfilled the diagnostic criteria for HCC. The differential of ICC should be borne in mind in populations where both malignancies are endemic.
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Neoplasias de los Conductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Hepáticas , Asia , Neoplasias de los Conductos Biliares/diagnóstico por imagen , Neoplasias de los Conductos Biliares/cirugía , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/cirugía , Colangiocarcinoma/diagnóstico por imagen , Colangiocarcinoma/cirugía , Medios de Contraste , Diagnóstico Diferencial , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Imagen por Resonancia Magnética , SingapurRESUMEN
BACKGROUND: Minimally invasive pancreatic surgeries (MIPS) are increasingly adopted worldwide. However, it remains uncertain if these reported experiences are reproducible throughout the world today. This study examines the safety and evolution of MIPS at a single institution in Southeast Asia. METHODS: This is a retrospective review of 150 consecutive patients who underwent MIPS between 2006 and 2018 of which 135 cases (90%) were performed since 2012. To determine the evolution of MIPS, the study population was stratified into 3 equal groups of 50 patients. Comparison was also made between pancreatoduodenectomies (PD), distal pancreatectomies (DP) and other pancreatic surgeries. RESULTS: One hundred and fifty patients underwent MIPS (103 laparoscopic, 45 robotic and 2 hand-assisted). Forty-three patients underwent PD, 93 DP and 14 other MIPS. There were 21 (14.0%) open conversions. There was an exponential increase in caseload over the study period. Comparison across the 3 time periods demonstrated that patients were significantly more likely to have a higher American Society of Anesthesiologists score, older, undergo PD and a longer operation time. The conversion rate decreased from 28% to 0% and increased again to 14% across the 3 time periods. Comparison between the various types of MIPS demonstrated that patients who underwent PD were significantly older, more likely to have symptomatic tumours, had longer surgery time, increased blood loss, increased frequency of extended pancreatectomies, increased frequency of hybrid procedures, longer post-operative stay, increased post-operative morbidity rate and increased post-operative major morbidity rate. CONCLUSION: The case volume of MIPS increased rapidly at our institution over the study period. Furthermore, although the indications for MIPS expanded to include more complex procedures in higher risk patients, there was no change in key perioperative outcomes.
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BACKGROUND: Repeat liver resection (RLR) for recurrent HCC (rHCC) is a widely accepted treatment modality. However, early recurrence rate is high, frequently resulting in futile resection. We performed this study to evaluate preoperative factors, including the value of inflammatory indices, in predicting early (<1 year) recurrence in patients who underwent RLR for rHCC. This may help clinicians better select patients for RLR, while excluding cases in which RLR for rHCC would likely be futile. METHODS: This is a retrospective study of 80 patients where 90 operative cases of RLR and 84 cases of early recurrence (<1 year) post-RLR were evaluated. Preoperative predictors of early recurrence and overall survival (OS) were assessed. RESULTS: There were 31 (34.4%) early recurrences with a 5-year OS of 38.9%. Elevated platelet-to-lymphocyte ratio (PLR) >103.6 was a significant independent preoperative predictor of both early recurrence, relative risk (RR) 4.284 (P = 0.001) and OS, RR 2.139 (P = 0.027), while alphafetoprotein (AFP) ≥ 200 was a significant independent preoperative predictor of early recurrence only, RR 11.655 (P = 0.030). Patients were followed-up at a median of 14.3 months with 54.8% developing intrahepatic recurrences and 19.4% developing extrahepatic recurrences. CONCLUSION: Both, elevated PLR and AFP ≥ 200 were independent predictors of early (<1 year) recurrence after RLR for rHCC, while only an elevated PLR was an independent preoperative prognosticators of overall survival. Indication for RLR should be carefully discussed in patients with relapsed HCC with an elevated PLR, due to the potential of early recurrence and poor overall survival.
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Plaquetas , Carcinoma Hepatocelular/cirugía , Hepatectomía , Neoplasias Hepáticas/cirugía , Linfocitos , Recurrencia Local de Neoplasia/cirugía , Adulto , Anciano , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/mortalidad , Femenino , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Reoperación , Estudios RetrospectivosRESUMEN
BACKGROUND: Minimally invasive surgery (MIS) for Mirizzi syndrome (MS) remains a technically challenging procedure with a high open conversion rate. We critically evaluated the impact of the systematic adoption of MI-HBP surgery on the surgical outcomes of MS. METHODS: Ninety-five patients who underwent surgery for MS were retrospectively reviewed. Systematic adoption of advanced MI-HBP surgery started in 2012. The cohort was classified into a preadoption (2002-2012) (Era 1, n = 58) and post-adoption (2013-2017) (Era 2, n = 37). Furthermore, Era 2 was divided into a cohort operated by advanced minimally invasive surgeons (AMIS) (Era 2 AMIS, n = 19) and those by other surgeons (Era 2 others, n = 19). RESULTS: Comparison between Era 2 and Era 1 demonstrated a significant increase in the frequency of MIS attempted (89% vs 33%, p < 0.01), increase in the use of choledochoplasty (24% vs 2%, p < 0.01), increase operation time (180 min vs 150 min, p = 0.03) and significantly lower open conversion rate (24% vs 58%, p < 0.01). Comparison between Era 2 AMIS and Era 2 others demonstrated a significantly greater adoption of MIS (100% vs 78%, p = 0.046) with lower open conversion rate (5% vs 50%, p = 0.005). Comparison between all attempted MIS cases with open procedures demonstrated a significantly higher proportion of subtotal cholecystectomies performed (40% vs 23%, p = 0.04), choledochoplasty (17% vs 2%, p = 0.04) and shorter hospital stay (4 days vs 9 days, p < 0.01). CONCLUSIONS: Systematic adoption of advanced MI-HBP surgery allowed surgeons to perform MIS for MS more frequently and with a significantly lower open conversion rate. Patients who underwent successful MIS had the shortest hospital stay compared to patients who underwent open surgery or required open conversion.
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Procedimientos Quirúrgicos del Sistema Digestivo/métodos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Síndrome de Mirizzi/cirugía , Adulto , Anciano , Femenino , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Several studies published mainly from pioneers and early adopters have documented the evolution of minimally invasive hepatectomy (MIH). However, questions remain if these reported experiences are applicable and reproducible today. This study examines the changing trends, safety, and outcomes associated with the adoption of MIH based on a contemporary single-institution experience. METHODS: This is a retrospective review of 400 consecutive patients who underwent MIH between 2006 and 2017 of which 360 cases (90%) were performed since 2012. To determine the evolution of MIH, the study population was stratified into four equal groups of 100 patients. Analyses were also performed of predictive factors and outcomes of open conversion. RESULTS: Four hundred patients underwent MIH of which 379 (94.8%) were totally laparoscopic/robotic. Eighty-eight (22.0%) patients underwent major hepatectomy and 160 (40.0%) had resection of tumors located in the posterosuperior segments. There were 38 (9.5%) open conversions. Comparison across the four groups demonstrated that patients were older, had higher ASA score, and had increased frequency of previous abdominal surgery and repeat liver resections. There was also an increase in the proportion of patients who underwent totally laparoscopic/robotic surgery, major liver resection, resection of ≥ 3 segments, and multiple resections. Comparison of outcomes demonstrated that there was a significant decrease in open conversion rate, longer operation time, and increased use of Pringles maneuver. The presence of cirrhosis and institution experience (1st 100 cases) were independent predictors of open conversion. Patients who required open conversion had significantly increased operation time, blood loss, blood transfusion rate, morbidity, and mortality. CONCLUSION: The case volume of MIH performed increased rapidly at our institution over time. Although the indications of MIH expanded to include higher risk patients and more complex hepatectomies, there was a decrease in open conversion rate and no change in other perioperative outcomes.
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Hepatectomía , Laparoscopía , Complicaciones Posoperatorias , Anciano , Conversión a Cirugía Abierta/estadística & datos numéricos , Femenino , Hepatectomía/efectos adversos , Hepatectomía/métodos , Hepatectomía/tendencias , Humanos , Laparoscopía/efectos adversos , Laparoscopía/métodos , Laparoscopía/tendencias , Tiempo de Internación , Cirrosis Hepática/cirugía , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Tempo Operativo , Evaluación de Procesos y Resultados en Atención de Salud , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Estudios Retrospectivos , Procedimientos Quirúrgicos Robotizados/efectos adversos , Singapur/epidemiologíaRESUMEN
BACKGROUND: Most studies analyzing the learning experience of laparoscopic liver resection (LLR) focused on the experience of one or two expert pioneering surgeons. This study aims to critically analyze the impact of individual surgeon experience on the outcomes of LLR based on the contemporary collective experiences of multiple surgeons at single institution. METHODS: Retrospective review of 324 consecutive LLR from 2006 to 2016. The cases were performed by 10 surgeons over various time periods. Four surgeons had individual experience with <20 cases, four surgeons with 20-30 cases, and two surgeons with >90 cases. The cohort was divided into two groups: comparing a surgeon's experience between the first 20, 30, 40, and 50 cases with patients treated thereafter. Similarly, we performed subset analyses for anterolateral lesions, posterosuperior lesions, and major hepatectomies. RESULTS: As individual surgeons gained increasing experience, this was significantly associated with older patients being operated, decreased hand-assistance, larger tumor size, increased liver resections, increased major resections, and increased resections of tumors located at the posterosuperior segments. This resulted in significantly longer operation time and increased use of Pringle maneuver but no difference in other outcomes. Analysis of LLR for tumors in the posterosuperior segments demonstrated that there was a significant decrease in conversion rates after a surgeon had experience with 20 LLR. For major hepatectomies, there was a significant decrease in morbidity, mortality, and length of stay after acquiring experience with 20 LLR. CONCLUSION: LLR can be safely adopted today especially for lesions in the anterolateral segments. LLR for lesions in the difficult posterosuperior segments and major hepatectomies especially in cirrhosis should only be attempted by surgeons who have acquired a minimum experience with 20 LLR.
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Hepatectomía/normas , Laparoscopía/normas , Hepatopatías/cirugía , Cirujanos , Adulto , Anciano , Femenino , Hepatectomía/mortalidad , Humanos , Laparoscopía/mortalidad , Hepatopatías/mortalidad , Masculino , Persona de Mediana Edad , Tempo Operativo , Evaluación de Resultado en la Atención de Salud , Estudios Retrospectivos , Cirujanos/normasRESUMEN
INTRODUCTION: This study aims to study the changing trends and outcomes associated with the adoption of minimally invasive distal pancreatectomy (MIDP) at a single centre. MATERIALS AND METHODS: Retrospective review of sixty consecutive patients who underwent MIDP from September 2006 to November 2016 at a single institution. To study the evolution of MIDP, the study population was divided into three groups consisting of twenty patients (Group I, Group II and Group III). RESULTS: Sixty patients underwent MIDP with 11 (18.3%) requiring open conversions. The median operation time was 305 (range: 85-775) min and the median post-operative stay was 6 (range: 3-73) days. Fifteen procedures were spleen-saving pancreatectomies. Major post-operative morbidity (>Grade 2) occurred in 12 (20.0%) patients and there was no mortality or reoperations. There were 33 (55.0%) pancreatic fistulas, of which 15 (25.0%) were Grade B fistulas of which 12 (20.0%) required percutaneous drainage. Comparison between the three groups demonstrated a statistically significant increase in the frequency of procedures performed, increase in robotic-assisted procedures and proportion of asymptomatic tumours resected. There also tended to be non-significant decrease in open conversion rates from 25% to 5% between the three groups and increase in tumour size resected from 24 to 40 mm. CONCLUSION: Comparison between the three groups demonstrated that MIDP was performed with increased frequency. There was a statistically significant increase in the frequency of resections performed for asymptomatic tumours and resections performed through robotic assistance. There was also a non-significant trend towards a decrease in open conversions and increase in the size of tumours resected.
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OBJECTIVE: This study aims to validate a previously reported recurrence clinical risk score (CRS). SUMMARY OF BACKGROUND DATA: Salvage transplantation after hepatocellular carcinoma (HCC) resection is limited to patients who recur within Milan criteria (MC). Predicting recurrence patterns may guide treatment recommendations. METHODS: An international, multicenter cohort of R0 resected HCC patients were categorized by MC status at presentation. CRS was calculated by assigning 1 point each for initial disease beyond MC, multinodularity, and microvascular invasion. Recurrence incidences were estimated using competing risks methodology, and conditional recurrence probabilities were estimated using the Bayes theorem. RESULTS: From 1992 to 2015, 1023 patients were identified, of whom 613 (60%) recurred at a median follow-up of 50 months. CRS was well validated in that all 3 factors remained independent predictors of recurrence beyond MC (hazard ratio 1.5-2.1, all P < 0.001) and accurately stratified recurrence risk beyond MC, ranging from 19% (CRS 0) to 67% (CRS 3) at 5 years. Among patients with CRS 0, no other factors were significantly associated with recurrence beyond MC. The majority recurred within 2 years. After 2 years of recurrence-free survival, the cumulative risk of recurrence beyond MC within the next 5 years for all patients was 14%. This risk was 12% for patients with initial disease within MC and 17% for patients with initial disease beyond MC. CONCLUSIONS: CRS accurately predicted HCC recurrence beyond MC in this international validation. Although the risk of recurrence beyond MC decreased over time, it never reached zero.
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Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Recurrencia Local de Neoplasia , Medición de Riesgo/métodos , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Invasividad Neoplásica , Reproducibilidad de los Resultados , Estudios RetrospectivosAsunto(s)
Calcinosis/patología , Quistes/patología , Bazo/patología , Enfermedades del Bazo/patología , Adulto , Calcinosis/diagnóstico por imagen , Calcinosis/cirugía , Quistes/diagnóstico por imagen , Quistes/cirugía , Femenino , Humanos , Laparoscopía , Bazo/diagnóstico por imagen , Bazo/cirugía , Esplenectomía , Enfermedades del Bazo/diagnóstico por imagen , Enfermedades del Bazo/cirugía , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: This study aimed to determine preoperative predictors of early (<1 year) mortality from disease recurrence after liver resection (LR) for huge (≥10 cm) HCC, with special emphasis on the importance of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and prognostic nutrition index (PNI). METHODS: Between 2000 to 2013, 166 patients underwent LR for huge HCC. Optimal cut-offs for alpha fetoprotein (AFP), NLR, PLR, and PNI were determined by plotting the receiver operator curves (ROC) in predicting early mortality and utilizing the Youden index. RESULTS: The 30-day/in-hospital postoperative mortality rate was 4.2%. The 5-year overall survival (OS) and the 5-year recurrence-free survival (RFS) was 43% and 24%, respectively. Early mortality from disease recurrence occurred in 35 of 159 (22%) patients. Multivariate analyses demonstrated that tumor rupture and high AFP (>1,085 ng/ml) were independent preoperative predictors of early mortality after LR for HCC, and both a low PNI (<41) and high AFP were independent predictors of early mortality for non-ruptured HCC. In 51 patients who had none of these three factors, only four (7.8%) patients experienced early mortality from disease recurrence. CONCLUSIONS: Spontaneous rupture, high AFP, and low PNI were predictors of early mortality from disease recurrence after LR for huge HCC. J. Surg. Oncol. 2016;113:621-627. © 2016 Wiley Periodicals, Inc.
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Plaquetas/metabolismo , Carcinoma Hepatocelular/cirugía , Hepatectomía , Neoplasias Hepáticas/cirugía , Linfocitos/metabolismo , Neutrófilos/metabolismo , Estado Nutricional , Adulto , Anciano , Biomarcadores/metabolismo , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Femenino , Estudios de Seguimiento , Hepatectomía/mortalidad , Mortalidad Hospitalaria , Humanos , Recuento de Leucocitos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/etiología , Recurrencia Local de Neoplasia/mortalidad , Evaluación Nutricional , Recuento de Plaquetas , Pronóstico , Curva ROC , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento , Carga TumoralRESUMEN
BACKGROUND: Multimodal analgesia is now widely practised to minimise postoperative opioid consumption while optimising pain control. The aim of this meta-analysis was to assess the analgesic efficacy of erector spinae plane block (ESPB) in patients undergoing laparoscopic abdominal surgeries. This will be determined by perioperative opioid consumption, subjective pain scores, and incidences of postoperative nausea and vomiting. METHODS: The authors systemically searched electronic databases for randomised controlled trials (RCTs) published up to February 2023 comparing ESPB with other adjuvant analgesic techniques in laparoscopic abdominal surgeries. Nine randomised controlled trials encompassing 666 subjects were included in our study. RESULTS: ESPB was shown to reduce postoperative opioid consumption [mean difference (MD) of -5.95 mg (95% CI: -8.86 to -3.04; P <0.0001); I2 =89%], intraoperative opioid consumption MD of -102.4 mcg (95% CI: -145.58 to -59.21; P <0.00001); I2 =39%, and incidence of nausea [RR 0.38 (95% CI: 0.25-0.60; P <0.0001); I2 =0%] and vomiting [RR 0.32 (95% CI: 0.17-0.63; P =0.0009); I2 =0%] in laparoscopic abdominal surgeries. Subgroup analysis on laparoscopic colorectal surgeries further showed reduction in postoperative pain scores MD of -0.68 (95% CI: -0.94 to -0.41); P <0.00001; I2 =0%]. CONCLUSIONS: This study concludes that ESPB is a valuable technique with proven efficacy to potentially promote faster postoperative recovery through optimising pain control while minimising opioid requirements.
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Laparoscopía , Bloqueo Nervioso , Dolor Postoperatorio , Humanos , Laparoscopía/métodos , Laparoscopía/efectos adversos , Bloqueo Nervioso/métodos , Dolor Postoperatorio/prevención & control , Abdomen/cirugía , Músculos Paraespinales/inervación , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Manejo del Dolor/métodos , Náusea y Vómito Posoperatorios/prevención & control , Náusea y Vómito Posoperatorios/epidemiologíaRESUMEN
BACKGROUND: The slit-mesh technique for laparoscopic groin hernia repair remains controversial. We present the largest cohort of patients to date that have undergone laparoscopic hernia repair with this technique and aim to evaluate the impact of both techniques on postoperative recurrence and other secondary outcomes. METHODS: A retrospective, single-institution cohort study of patients who underwent a laparoscopic groin hernia repair over a 5.5-year period was performed. Univariate and multivariate analyses were performed to identify factors associated with recurrence, chronic pain, complications, length of stay, and operative time. A propensity score analysis also was performed. Time to recurrence was then subsequently plotted on a Kaplan-Meier survival analysis. RESULTS: In total, 611 laparoscopic groin hernia repairs (nonslit: n = 353; slit: n = 258) were reviewed. Mean follow-up duration was 6.6 months. On the multivariate analysis, body mass index was inversely correlated with recurrence (odds ratio, 0.792; 95% confidence interval, 0.656-0.956), whereas a slit mesh had lower recurrence (odds ratio, 0.228; 95% confidence interval, 0.064-0.809). In the propensity score-adjusted analysis, slit mesh remained significantly associated with reduced recurrence (adjusted odds ratio, 0.251; 95% confidence interval, 0.070-0.900), with no differences in chronic pain (adjusted odds ratio, 1.297; 95% confidence interval, 0.275-6.128) or postoperative complications (adjusted odds ratio, 1.808; 95% confidence interval, 0.429-7.620). Operative time also was reduced in the slit-mesh group (P = .009). CONCLUSIONS: The slit-mesh technique was associated with a reduced likelihood of postoperative recurrence and shorter operative time, with no impact on postoperative chronic pain or complications. A lower body mass index was also correlated with increased likelihood of postoperative recurrence.
RESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is a deadly cancer with a high global mortality rate, and the downregulation of GATA binding protein 4 (GATA4) has been implicated in HCC progression. In this study, we investigated the role of GATA4 in shaping the immune landscape of HCC. METHODS: HCC tumor samples were classified into "low" or "normal/high" based on GATA4 RNA expression relative to adjacent non-tumor liver tissues. The immune landscapes of GATA4-low and GATA4-normal/high tumors were analyzed using cytometry by time-of-flight, bulk/spatial transcriptomic analyses and validated by multiplex immunofluorescence. RESULTS: GATA4-low tumors displayed enrichment in exhausted programmed cell death protein 1+ T cells, immunosuppressive regulatory T cells, myeloid-derived suppressor cells, and macrophages, highlighting the impact of GATA4 downregulation on immunosuppression. Spatial and bulk transcriptomic analyses revealed a negative correlation between GATA4 and C-C Motif Chemokine Ligand 20 (CCL20) expression in HCC. Overexpressing GATA4 confirmed CCL20 as a downstream target, contributing to an immunosuppressive tumor microenvironment, as evidenced by increased regulatory T cells and myeloid-derived suppressor cells in CCL20-high tumors. Lastly, the reduced expression of GATA4 and higher expression of CCL20 were associated with poorer overall survival in patients with HCC, implicating their roles in tumor progression. CONCLUSIONS: Our study reveals that GATA4 downregulation contributes to an immunosuppressive microenvironment, driven by CCL20-mediated enrichment of regulatory T cells and myeloid-derived suppressor cells in HCC. These findings underscore the critical role of GATA4 reduction in promoting immunosuppression and HCC progression.
Asunto(s)
Carcinoma Hepatocelular , Quimiocina CCL20 , Regulación hacia Abajo , Factor de Transcripción GATA4 , Neoplasias Hepáticas , Microambiente Tumoral , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidad , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Factor de Transcripción GATA4/genética , Quimiocina CCL20/genética , Microambiente Tumoral/inmunología , Regulación Neoplásica de la Expresión Génica , Tolerancia Inmunológica , Células Supresoras de Origen Mieloide/inmunología , Masculino , Linfocitos T Reguladores/inmunologíaRESUMEN
Hepatocellular carcinoma (HCC) is the third deadliest and sixth most common cancer in the world. Histone-lysine N-methyltransferase EHMT2 (also known as G9a) is a histone methyltransferase frequently overexpressed in many cancer types, including HCC. We showed that Myc-driven liver tumours have a unique H3K9 methylation pattern with corresponding G9a overexpression. This phenomenon of increased G9a was further observed in our c-Myc-positive HCC patient-derived xenografts. More importantly, we showed that HCC patients with higher c-Myc and G9a expression levels portend a poorer survival with lower median survival months. We demonstrated that c-Myc interacts with G9a in HCC and cooperates to regulate c-Myc-dependent gene repression. In addition, G9a stabilises c-Myc to promote cancer development, contributing to the growth and invasive capacity in HCC. Furthermore, combination therapy between G9a and synthetic-lethal target of c-Myc, CDK9, demonstrates strong efficacy in patient-derived avatars of Myc-driven HCC. Our work suggests that targeting G9a could prove to be a potential therapeutic avenue for Myc-driven liver cancer. This will increase our understanding of the underlying epigenetic mechanisms of aggressive tumour initiation and lead to improved therapeutic and diagnostic options for Myc-driven hepatic tumours.