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1.
Artigo em Inglês | MEDLINE | ID: mdl-34866343

RESUMO

BACKGROUND: Although the number of minimally invasive liver resection (MILR) has been steadily increasing in many institutions, minimally invasive anatomic liver resection (MIALR) remains a complicated procedure that has not been standardized. We present the results of a survey among expert liver surgeons as a benchmark for standardizing MIALR. METHOD: We administered this survey to 34 expert liver surgeons who routinely perform MIALR. The survey contained questions on personal experience with liver resection, inflow/outflow control methods, and identification techniques of intersegmental/sectional planes (IPs). RESULTS: All 34 participants completed the survey; 24 experts (70%) had more than 11 years of experience with MILR, and over 80% of experts had performed over 100 open resections and MILRs each. Regarding the methods used for laparoscopic or robotic anatomic resection, the Glissonean approach (GA) was a more frequent procedure than the hilar approach (HA). Although hepatic veins were considered essential landmarks, the exposure methods varied. The top three techniques that the experts recommended for identifying IPs were creating a demarcation line, indocyanine green (ICG) negative staining method, and intraoperative ultrasound. CONCLUSION: MIALR remains a challenging procedure; however, a certain degree of consensus exists among expert liver surgeons.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34866349

RESUMO

BACKGROUND: The Brisbane 2000 Terminology for Liver Anatomy and Resections, based on Couinaud's segments, did not address how to identify segmental borders and anatomic territories of less than one segment. Smaller anatomic resections including segmentectomies and subsegmentectomies, have not been well defined. The advent of minimally invasive liver resection has enhanced the possibilities of more precise resection due to a magnified view and reduced bleeding, and minimally invasive anatomic liver resection (MIALR) is becoming popular gradually. Therefore, there is a need for updating the Brisbane 2000 system, including anatomic segmentectomy or less. An online "Expert Consensus Meeting: Precision Anatomy for Minimally Invasive HBP Surgery (PAM-HBP Surgery Consensus)" was hosted on February 23, 2021. METHODS: The Steering Committee invited 34 international experts from around the world. The Expert Committee (EC) selected 12 questions and 2 future research topics in the terminology session. The EC created 7 tentative definitions and 5 recommendations based on the experts' opinions and the literature review performed by the Research Committee. Two Delphi Rounds finalized those definitions and recommendations. RESULTS: This paper presents 7 definitions and 5 recommendations regarding anatomic segmentectomy or less. In addition, two future research topics are discussed. CONCLUSIONS: The PAM-HBP Surgery Consensus has presented the Tokyo 2020 Terminology for Liver Anatomy and Resections. The terminology has added definitions of liver anatomy and resections that were not defined in the Brisbane 2000 system.

3.
Can J Gastroenterol Hepatol ; 2021: 5212953, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34888264

RESUMO

Introduction: Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver malignancies and is currently the fourth most common cause of cancer-related death worldwide. Due to varying underlying etiologies, the prognosis of HCC differs greatly among patients. It is important to develop ways to help stratify patients upon initial diagnosis to provide optimal treatment modalities and follow-up plans. The current study uses Artificial Neural Network (ANN) and Classification Tree Analysis (CTA) to create a gene signature score that can help predict survival in patients with HCC. Methods: The Cancer Genome Atlas (TCGA-LIHC) was analyzed for differentially expressed genes. Clinicopathological data were obtained from cBioPortal. ANN analysis of the 75 most significant genes predicting disease-free survival (DFS) was performed. Next, CTA results were used for creation of the scoring system. Cox regression was performed to identify the prognostic value of the scoring system. Results: 363 patients diagnosed with HCC were analyzed in this study. ANN provided 15 genes with normalized importance >50%. CTA resulted in a set of three genes (NRM, STAG3, and SNHG20). Patients were then divided in to 4 groups based on the CTA tree cutoff values. The Kaplan-Meier analysis showed significantly reduced DFS in groups 1, 2, and 3 (median DFS: 29.7 months, 16.1 months, and 11.7 months, p < 0.01) compared to group 0 (median not reached). Similar results were observed when overall survival (OS) was analyzed. On multivariate Cox regression, higher scores were associated with significantly shorter DFS (1 point: HR 2.57 (1.38-4.80), 2 points: 3.91 (2.11-7.24), and 3 points: 5.09 (2.70-9.58), p < 0.01). Conclusion: Long-term outcomes of patients with HCC can be predicted using a simplified scoring system based on tumor mRNA gene expression levels. This tool could assist clinicians and researchers in identifying patients at increased risks for recurrence to tailor specific treatment and follow-up strategies for individual patients.

4.
Life Sci ; : 120214, 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34890591

RESUMO

AIMS: Although separate blockage of either IL33/ST2 or PD-L/PD-1 axes has been shown to be beneficial in many tumors, co-blockage of IL33/ST2 and PD-L/PD-1 hasn't been studied yet. MAIN METHODS: 4T1 breast cancer and CT26 colon cancer were inducted in BALB/C wild type (WT) and BALB/C ST2 knockout mice, after which mice underwent anti PD-1 and anti IL-33 treatment. KEY FINDINGS: Co-blockage of IL33/ST2 and PD-L/PD-1 delayed tumor appearance and slowed tumor growth. Enhanced NK cell cytotoxicity against 4T1 tumor cells in ST2 knockout anti-PD-1 treated mice was associated with overexpression of miRNA-150 and miRNA-155, upregulation of NFκB and STAT3, increased expression of activation markers and decreased expression of immunosuppressive markers in splenic and primary tumor derived NK cells. NK cells from ST2 knockout anti-PD-1 treated mice tend to proliferate more and are less prone to apoptosis. Accumulation of immunosuppressive myeloid derived suppressor cells and regulatory T cells was significantly impaired in spleen and primary tumor of ST2 knockout anti-PD-1 treated mice. SIGNIFICANCE: Co-blockage of IL3/ST2 and PD-L/PD-1 axes impedes tumor progression more efficiently than single blockage of either axes, thus offering potential new approach to immunotherapy of tumors.

5.
Front Immunol ; 12: 785222, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899751

RESUMO

While neutrophil extracellular traps (NETs) are important for directly promoting cancer growth, little is known about their impact on immune cells within the tumor microenvironment (TME). We hypothesize that NETs can directly interact with infiltrating T cells to promote an immunosuppressive TME. Herein, to induce a NET-rich TME, we performed liver Ischemia/Reperfusion (I/R) in an established cancer metastasis model or directly injected NETs in subcutaneous tumors. In this NET-rich TME, the majority of CD4+ and CD8+ tumor infiltrating lymphocytes expressed multiple inhibitory receptors, in addition these cells showed a functional and metabolic exhausted phenotype. Targeting of NETs in vivo by treating mice with DNAse lead to decreased tumor growth, decreased NET formation and higher levels of functioning T cells. In vitro, NETs contained the immunosuppressive ligand PD-L1 responsible for T cell exhaustion and dysfunction; an effect abrogated by using PD-L1 KO NETs or culturing NETs with PD-1 KO T cells. Furthermore, we found elevated levels of sPDL-1 and MPO-DNA, a NET marker, in the serum of patients undergoing surgery for colorectal liver metastases resection. Neutrophils isolated from patients after surgery were primed to form NETs and induced exhaustion and dysfunction of human CD4+ and CD8+ T cells. We next targeted PD-L1 in vivo by injecting a blocking antibody during liver I/R. A single dose of anti-PD-L1 during surgery lead to diminished tumors at 3 weeks and functional T cells in the TME. Our data thus reveal that NETs have the capability of suppressing T cell responses through metabolic and functional exhaustion and thereby promote tumor growth. Furthermore, targeting of PD-L1 containing NETs at time of surgery with DNAse or anti-PD-L1 lead to diminished tumor growth, which represents a novel and viable strategy for sustaining immune competence within the TME.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34752621

RESUMO

CONTEXT: First-degree relatives of women with polycystic ovary syndrome (PCOS) present hormonal and metabolic alterations compared to girls unrelated to PCOS. It is unknown whether glucose intolerance in the PCOS proband confers a more severe metabolic predisposition on their first-degree relatives. OBJECTIVE: To determine whether glucose tolerance status in women with PCOS is associated with worsened glucose metabolism and sex hormone levels in their peripubertal daughters or sisters. DESIGN: Cross-sectional study. SETTING: Seven academic centers in North America, South America and Europe. PATIENTS: Sixty-four pairs of women with PCOS and their daughters or younger sisters aged between 8 and 14 years were recruited. Twenty-five mothers or older sisters with PCOS were glucose intolerant (GI) and 39 were normal glucose tolerant (NGT). INTERVENTION: None. MAIN OUTCOME MEASURES: Beta-cell function estimated by the insulin secretion-sensitivity index-2 (ISSI-2) during an oral glucose tolerance test and by the disposition index (DI) during a frequently sampled iv glucose tolerance test. Free testosterone and 17-hydroxyprogesterone (17-OHP) levels. RESULTS: Being related to a GI PCOS proband was associated with a lower ISSI-2 (p-value=0.032) after adjusting for ethnicity, body mass index z-score, and pubertal stage. They also had higher free testosterone (p-value=0.011) and 17-OHP levels compared to girls with an NGT proband, the latter becoming significant after adjusting for confounders (p-value=0.040). CONCLUSIONS: Compared to first-degree female relatives of women with PCOS and NGT, first-degree relatives of women with PCOS and GI display lower beta-cell function and hyperandrogenemia, putting them at higher risk of GI and PCOS development.

8.
Artigo em Inglês | MEDLINE | ID: mdl-34779150

RESUMO

BACKGROUND: The concept of minimally invasive anatomic liver resection (MIALR) is gaining popularity. However, specific technical skills need to be acquired to safely perform MIALR. The "Expert Consensus Meeting: Precision Anatomy for Minimally Invasive HBP Surgery (PAM-HBP Surgery Consensus)" was developed as a special program during the 32nd meeting of the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS). METHODS: Thirty-four international experts gathered online for the consensus. A Research Committee performed a comprehensive literature review, classifying studies according to the Scottish Intercollegiate Guidelines Network method. Based on the literature review and experts' opinions, tentative recommendations were drafted and circulated among experts using online Delphi Rounds. Finally, formulated recommendations were presented online in the Expert Consensus Meeting of the JSHBPS on February 23rd, 2021. The final recommendations were validated and finalized by the 2nd Delphi Round in May 2021. RESULTS: Seven clinical questions were selected, and 22 recommendations were formulated. All recommendations reached more than 85% consensus among experts at the final Delphi Round. CONCLUSIONS: The Expert Consensus Meeting for safely performing MIALR has presented a set of clinical guidelines based on available literature and experts' opinions. We expect these guidelines to have a favorable effect on the safe implementation and development of MIALR.

9.
Am Surg ; 87(11): 1766-1774, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34766506

RESUMO

INTRODUCTION: Resection of colorectal liver metastases provides the best chance for survival in patients with Stage IV colorectal cancer; however, hepatic recurrence is frequent and the main cause of death. Multiple epidemiological studies have documented an association between metformin and anti-neoplastic effects in a variety of cancers. Given the vast literature, we evaluated the incidence on recurrence and survival of patients on metformin who undergo surgery for colorectal liver metastasis (CRLM). METHODS: We selected 270 consecutive patients with known CRLM who underwent hepatic metastases resection at our institution between January 1st 2012 and December 31st 2019. Patients were divided based on their use of metformin (n = 62) or no metformin (n = 208). Adjusted analysis of recurrence-free (RFS) and overall survival (OS) was performed. RESULTS: Patients on metformin had significantly longer RFS (HR: .44, 95% CI: .26-.75, P < .002; Median RFS: 49 months vs 33 months) and OS (HR .60, 95% CI .31-.97, P < .048, Median OS: 72 months vs 60 months). Additional factors associated with shorter RFS on univariate analysis included the following: CEA > 200 ng/ml (HR: 2.23, 95% CI 1.21-4.03, P < .010), positive liver margin (HR: 3.70, 95% CI 2.27-6.03, P < .001), and >1 tumor (HR: 1.98, 95% CI 1.26-3.09, P < .003). Liver margin remained a significant factor for predicting shorter OS (HR: 4.99, 95% CI 2.49-10.0, P < .001). CONCLUSION: In this study, we found that patients with CRLM on metformin have prolonged RFS and OS postliver resection. Further prospective randomized trials need to be carried out to evaluate the anti-neoplastic effect of metformin in diabetic and non-diabetic cancer patients.

10.
Artigo em Inglês | MEDLINE | ID: mdl-34806126

RESUMO

PURPOSE: The aim of this study was to examine the link between psychological, behavioral, and social factors and survival in patients diagnosed with gastrointestinal cancer. METHODS: A cohort of gastrointestinal cancer patients were administered a battery of questionnaires that assessed trauma, depression, social support, sleep, diet, exercise, quality of life, tobacco and alcohol use, pain, and fatigue. Analyses included Pearson's correlations, analyses of variance, Kaplan Meier survival, and Cox regression analyses. RESULTS: Of the 568 patients, the majority were male (57.9%) and Caucasian (91.9%), with a mean age of 61 (S.D. = 10.7). The level of perceived social support was comparable to patients with other medical conditions. Sociodemographic predictors of social support included the number of years of education (r = 0.109, p = 0.05), marital status (F(6,387) = 5.465, p ≤ 0.001), and whether the patients' income met the family's basic needs (F(1,377) = 25.531, p < 0.001). Univariate analyses revealed that older age (p < 0.001), male gender (p = 0.007), being black (p = 0.005), diagnosis of hepatocellular carcinoma (p = 0.046), higher body mass index (p = 0.022), larger tumor size (p = 0.032), initial treatment including chemotherapy rather than surgery (p < 0.001), and lower level of perceived social support (p = 0.037) were associated with poorer survival. Using multivariate Cox regression and adjusting for all factors found to be significant in univariate survival analyses, older age (p = 0.024) and lower perceived social support (HR = 0.441, 95% CI = 0.233, 0.833; p = 0.012) were the factors that remained significantly associated with poorer survival. CONCLUSION: There are several biological and psychosocial factors that predict cancer mortality. Social support appears to be a robust factor affecting mortality in gastrointestinal cancer patients.

12.
Cancers (Basel) ; 13(16)2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34439258

RESUMO

This is an early clinical analysis of the DEEPGENTM platform for cancer detection. Newly diagnosed cancer patients and individuals with no known malignancy were included in a prospective open-label case-controlled study (NCT03517332). Plasma cfDNA that was extracted from peripheral blood was sequenced and data were processed using machine-learning algorithms to derive cancer prediction scores. A total of 260 cancer patients and 415 controls were included in the study. Overall, sensitivity for all cancers was 57% (95% CI: 52, 64) at 95% specificity, and 43% (95% CI: 37, 49) at 99% specificity. With 51% sensitivity and 95% specificity for all stage 1 cancers, the stage-specific sensitivities trended to improve with higher stages. Early results from this preliminary clinical, prospective evaluation of the DEEPGENTM liquid biopsy platform suggests the platform offers a clinically relevant ability to differentiate individuals with and without known cancer, even at early stages of cancer.

13.
Front Immunol ; 12: 705465, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262574

RESUMO

Liver allograft recipients are more likely to develop transplantation tolerance than those that receive other types of organ graft. Experimental studies suggest that immune cells and other non-parenchymal cells in the unique liver microenvironment play critical roles in promoting liver tolerogenicity. Of these, liver interstitial dendritic cells (DCs) are heterogeneous, innate immune cells that appear to play pivotal roles in the instigation, integration and regulation of inflammatory responses after liver transplantation. Interstitial liver DCs (recruited in situ or derived from circulating precursors) have been implicated in regulation of both ischemia/reperfusion injury (IRI) and anti-donor immunity. Thus, livers transplanted from mice constitutively lacking DCs into syngeneic, wild-type recipients, display increased tissue injury, indicating a protective role of liver-resident donor DCs against transplant IRI. Also, donor DC depletion before transplant prevents mouse spontaneous liver allograft tolerance across major histocompatibility complex (MHC) barriers. On the other hand, mouse liver graft-infiltrating host DCs that acquire donor MHC antigen via "cross-dressing", regulate anti-donor T cell reactivity in association with exhaustion of graft-infiltrating T cells and promote allograft tolerance. In an early phase clinical trial, infusion of donor-derived regulatory DCs (DCreg) before living donor liver transplantation can induce alterations in host T cell populations that may be conducive to attenuation of anti-donor immune reactivity. We discuss the role of DCs in regulation of warm and liver transplant IRI and the induction of liver allograft tolerance. We also address design of cell therapies using DCreg to reduce the immunosuppressive drug burden and promote clinical liver allograft tolerance.

14.
Cancers (Basel) ; 13(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202373

RESUMO

Less morbidity is considered among the advantages of laparoscopic liver resection (LLR) for HCC patients. However, our previous international, multi-institutional, propensity score-based study of emerging laparoscopic repeat liver resection (LRLR) failed to prove this advantage. We hypothesize that these results may be since the study included complex LRLR cases performed during the procedure's developing stage. To examine it, subgroup analysis based on propensity score were performed, defining the proximity of the tumors to major vessels as the indicator of complex cases. Among 1582 LRLR cases from 42 international high-volume liver surgery centers, 620 cases without the proximity to major vessels (more than 1 cm far from both first-second branches of Glissonian pedicles and major hepatic veins) were selected for this subgroup analysis. A propensity score matching (PSM) analysis was performed based on their patient characteristics, preoperative liver function, tumor characteristics and surgical procedures. One hundred and fifteen of each patient groups of LRLR and open repeat liver resection (ORLR) were earned, and the outcomes were compared. Backgrounds were well-balanced between LRLR and ORLR groups after matching. With comparable operation time and long-term outcome, less blood loss (283.3±823.0 vs. 603.5±664.9 mL, p = 0.001) and less morbidity (8.7 vs. 18.3 %, p = 0.034) were shown in LRLR group than ORLR. Even in its worldwide developing stage, LRLR for HCC patients could be beneficial in blood loss and morbidity for the patients with less complexity in surgery.

15.
Surg Oncol ; 38: 101610, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34091268

RESUMO

INTRODUCTION: There is currently no consensus regarding the best techniques or surgical strategies with which to maximize intercalary allograft reconstruction outcomes. The purpose of the current study was to assess which techniques and methods are being utilized by North American orthopaedic oncologists. METHODS: Members of the Musculoskeletal Tumor Society (MSTS) were invited to complete an anonymous online questionnaire. The survey presented participants with two clinical scenarios and interrogated them on their preferred type of allograft, method of compression and fixation, and additional techniques used. RESULTS: One hundred and twenty-six physicians completed the questionnaire. The majority studied in the United States (82%) and worked at an academic medical center (71%). Over half (54%) reported seeing over 10 primary bone tumors every year. Respondents were split between preferring a structural allograft alone or using a combined allograft-vascularized fibular graft. A majority indicated a preference for plate(s) and screw fixation but were divided between the use of two compression plates with a spanning plate, a single compression plate with a spanning plate, and two compression plates with an intramedullary nail. Screw fixation preferences were split between the use of unicortical locking only, bicortical locking only, and a combination of unicortical and bicortical locking. Almost equal percentages of respondents reported they would have used two, three, or four screws in both scenarios. Respondents were split between placing screws equidistantly and placing them peripherally within the allograft, adjacent to the allograft-host junction. DISCUSSION: There is no clear surgical preference for intercalary reconstruction following tumor extirpation within this sample of orthopaedic oncologists. The current survey demonstrates variability across nearly every aspect of allograft reconstruction, which may, in part, explain the wide spectrum of outcomes reported within the literature. Prospective studies are warranted to better evaluate technique-specific outcomes in an effort to maximize reconstructive longevity and minimize allograft related complications.

16.
Am J Surg ; 222(4): 731-738, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33840443

RESUMO

BACKGROUND: We compared the outcomes of laparoscopic hepatectomy (LH) vs. open hepatectomy (OH) for intrahepatic cholangiocarcinoma (iCCA). METHODS: A systematic review of the MEDLINE, EMBASE, Scopus, and Cochrane Library databases was performed using PRISMA guidelines (end-of-search date: 08-June-2020). Individual patient data on overall survival (OS) and recurrence-free survival (RFS) were extracted. Random-effects meta-analyses, and one- and two-stage survival analyses were conducted. RESULTS: Eight retrospective cohort studies comparing LH (n = 544) vs. OH (n = 2256) were identified. LH demonstrated lower overall complication (Risk ratio [RR] = 0.64, 95% confidence interval [CI]: 0.46-0.90; p = 0.01), surgical lymphadenectomy (RR = 0.74, 95% CI: 0.58-0.93; p = 0.01) and margin-positive resection (RR = 0.78, 95% CI: 0.62-0.99; p = 0.04) rates, and higher recurrence-free rate (RR = 1.24, 95% CI: 1.01-1.51; p = 0.04) vs. OH. In Cox regression, no difference was observed regarding OS (Hazard Ratio [HR] = 1.11, 95% CI: 0.65-1.91; p = 0.70) and RFS (HR = 1.19, 95% CI: 0.74-1.90; p = 0.47). CONCLUSION: The use of LH should be considered when feasible in well-selected iCCA patients by hepatobiliary surgeons with experience in minimally-invasive surgery.


Assuntos
Colangiocarcinoma/mortalidade , Colangiocarcinoma/cirurgia , Hepatectomia/métodos , Humanos , Laparoscopia , Tempo de Internação , Duração da Cirurgia , Complicações Pós-Operatórias , Análise de Sobrevida
17.
Gut ; 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849943

RESUMO

OBJECTIVE: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown. DESIGN: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS). RESULTS: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%). CONCLUSIONS: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.

18.
Br J Cancer ; 125(1): 101-111, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33772151

RESUMO

BACKGROUND: CHK1 is considered an oncogene with overexpression in numerous cancers. However, CHK1 signalling regulation in hepatocellular carcinoma (HCC) remains unclear. METHODS: CHEK1 mRNA, protein, pri-miR-195 and miR-195 expression in HCC tissue was determined by qPCR, WB and IF staining assay. Survival analyses in HCC with high- and low-CHEK1 mRNA expression was performed using TCGA database. Relative luciferase activity was investigated in HCC cells transfected with p-CHEK1 3'UTR. Apoptosis was detected by TUNEL assay. NK and CD8+ T cells were analysed by flow cytometry. RESULTS: CHK1 is increased in human HCC tumours compared with non-cancerous liver. High CHK1 predicts worse prognosis. IFN-γ suppresses CHK1 via IRF-1 in HCC cells. The molecular mechanism of IRF-1 suppressing CHK1 is post-transcriptional by promoting miR-195 binding to CHEK1 mRNA 3'UTR, which exerts a translational blockade. Upregulated IRF-1 inhibits CHK1, which induces apoptosis of HCC cells. Likewise, CHK1 inhibition augments cellular apoptosis in HCC tumours. This effect may be a result of increased tumour NK cell infiltration. However, IRF-1 expression or CHK1 inhibition also upregulates PD-L1 expression via increased STAT3 phosphorylation. CONCLUSIONS: IRF-1 induces miR-195 to suppress CHK1 protein expression. Both increased IRF-1 and decreased CHK1 upregulate cellular apoptosis and PD-L1 expression in HCC.

19.
Artigo em Inglês | MEDLINE | ID: mdl-33787072

RESUMO

BACKGROUND: The main aim of this survey was to analyze how liver surgeons perform liver resections and to define their conception of anatomic procedures within the incorporation of minimally invasive liver surgery (MILS). METHODS: The survey was distributed among liver surgeons. It mainly focused on personal experience on open and MILS, methods and landmarks, and experience on anatomic resections and Glissonean approach. RESULTS: A total of 445 valid answers from 54 countries was obtained. Surgeons performing MILS mainly have below 10 years of experience (81.8% of responders) and one third has never done complex MILS. New techniques, including indocyanine green demarcation are marginally used (<25%). More than 60% of surgeons do not make a full exposure of hepatic veins during MILS, mainly due to the risk of injury or not considering it to be of utility. Although 88% of responders agreed with the concept of anatomic resection as the "resection along the border/watersheds of each order division identified by the portal vein flow", only 55% of surgeons have ever performed MILS Glissonean approaches. CONCLUSIONS: Liver anatomy is not a static concept. Anatomic resections need training and precision. Standardization of complex anatomic resections by a minimally invasive approach should be encouraged.

20.
Cancer Lett ; 506: 95-106, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33689775

RESUMO

Interferon regulatory factor 1 (IRF-1) is a tumor suppressor gene in cancer biology with anti-proliferative and pro-apoptotic effect on cancer cells, however mechanisms of IRF-1 regulating tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remain only partially characterized. Here, we investigated that IRF-1 regulates C-X-C motif chemokine 10 (CXCL10) and chemokine receptor 3 (CXCR3) to activate anti-tumor immunity in HCC. We found that IRF-1 mRNA expression was positively correlated with CXCL10 and CXCR3 through qRT-PCR assay in HCC tumors and in analysis of the TCGA database. IRF-1 response elements were identified in the CXCL10 promoter region, and ChIP-qPCR confirmed IRF-1 binding to promote CXCL10 transcription. IRF-2 is a competitive antagonist for IRF-1 mediated transcriptional effects, and overexpression of IRF-2 decreased basal and IFN-γ induced CXCL10 expression. Although IRF-1 upregulated CXCR3 expression in HCC cells, it inhibited proliferation and exerted pro-apoptotic effects, which overcome proliferation partly mediated by activating the CXCL10/CXCR3 autocrine axis. In vitro and in vivo studies showed that IRF-1 increased CD8+ T cells, NK and NKT cells migration, and activated IFN-γ secretion in NK and NKT cells to induce tumor apoptosis through the CXCL10/CXCR3 paracrine axis. Conversely, this effect was markedly abrogated in HCC tumor bearing mice deficient in CXCR3. Therefore, the IRF-1/CXCL10/CXCR3 axis contributes to the anti-tumor microenvironment in HCC.


Assuntos
Carcinoma Hepatocelular/imunologia , Quimiocina CXCL10/fisiologia , Fator Regulador 1 de Interferon/fisiologia , Neoplasias Hepáticas/imunologia , Receptores CXCR3/fisiologia , Animais , Apoptose , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Quimiocina CXCL10/genética , Feminino , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas , Linfócitos T/imunologia
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