•FOXO1 impairs HCC progression indirectly through macrophages.•FOXO1 transcriptional target IRF-1 increased tumor cells NO expression.•NO recruits macrophages and suppressing IL-6 releasing from ...it.•The shaped macrophages inhibited HCC progression by inhibiting IL-6/STAT3 activation.
Tumor heterogeneity dominates tumor biological behavior and shapes the tumor microenvironment. However, the mechanisms of tumor genetic features modulate immunity response were not clearly clarified. Tumor associated macrophages (TAMs) exert distinct immune functions in the progression of hepatocellular carcinoma (HCC) based on the inducible phenotype. FOXO family members sense changes in the extracellular or intracellular environment by activating a series of signaling pathways. FOXO1, a transcription factor that a common suppressor in hepatocellular carcinoma, correlated with a better tumor biological behavior in HCC through shaping macrophages anti-tumour response. Here, we found that human HCC tissue microarray (TMA) slides were employed to showed tumor derived FOXO1 negatively related with distribution of protumour macrophages. This phenomenon was confirmed in mouse xenograft model and in vitro. HCC-derived FOXO1 inhibits tumorigenesis not only by targeting tumor cells but also by synchronizing with re-educated macrophages. These effects may be partially dependent on FOXO1 transcriptionally modulates IRF-1/nitrio oxide (NO) axis in exerting effects in macrophages and decreasing IL-6 releasing from macrophages in tumor microenvironment indirectly. This feedback suppressed the progression of HCC by inactivation of IL-6/STAT3 in HCC. It implicates the potential role of FOXO1 in the therapeutic effects for modulating immune response by targeting macrophages.
Display omitted
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
OBJECTIVE:To perform a systematic review of worldwide literature on laparoscopic liver resections (LLR) and compare short-term outcomes against open liver resections (OLR) by meta-analyses.
SUMMARY ...BACKGROUND DATA:There are no updated pooled data since 2009 about the current status and short-term outcomes of LLR worldwide.
PATIENTS AND METHODS:All English language publications on LLR were screened. Descriptive worldwide data and short-term outcomes were obtained. Separate analyses were performed for minor-only and major-only resection series, and series in which minor/major resections were not differentiated. Apparent case duplications were excluded.
RESULTS:A set of 463 published manuscripts were reviewed. One hundred seventy-nine single-center series were identified that accounted for 9527 LLR cases worldwide. Minor-only, major-only, and combined major–minor series were 61, 18, and 100, respectively, including 32, 8, and 43 comparative series, respectively. Of the total 9527 LLR cases reported, 6190 (65%) were for malignancy and 3337 (35%) were for benign indications. There were 37 deaths reported (mortality rate = 0.4%). From the meta-analysis comparing case-matched LLR to OLR (N = 2900 cases), there was no increased mortality and significantly less complications, transfusions, blood loss, and hospital stay observed in LLR vs OLR.
CONCLUSIONS:This is the largest review of LLR available to date with over 9000 cases published. It confirms growing safety when performed in selected patients and by trained surgeons, and suggests that LLR may offer improved patient short-term outcomes compared with OLR. Improved levels of evidence, standardized reporting of outcomes, and assuring proper training are the next challenges of laparoscopic liver surgery.
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
by treating mice with DNAse lead to decreased tumor growth, decreased NET formation and higher levels of functioning T cells.
, 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
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.
PURPOSE:Time to surgery (TTS) is of concern to patients diagnosed with cancer and their physicians. Controversy surrounds the impact of TTS on colon cancer survival. There are limited national data ...evaluating the association; thus, our aim was to estimate the overall survival (OS) impact from increasing TTS for patients with colon cancer.
METHODS:Using the National Cancer Data Base (NCDB), we assessed OS as a function of time between diagnosis and surgery by evaluating intervals encompassing <7, 7 to 30, 31 to 60, 61 to 90, 91 to 120, and 121 to 180 days in length. All patients were diagnosed with nonmetastatic colon cancer and underwent surgery as initial treatment. Our main outcome was OS as a function of time between diagnosis and surgery, after adjusting for patient, demographic, and tumor-related factors using Cox regression models and propensity score-based weighting.
RESULTS:A total of 514,103 patients diagnosed between 1998 and 2012 were included. Individuals having <7, 7 to 30, 31 to 60, 61 to 90, 91 to 120, and 121 to 180 days between diagnosis and surgery comprised 35.4%, 45%, 15.1%, 2.9%, 1%, and 0.6% of the patients, respectively. There was a steady increase in median TTS across the years. On multivariable analysis, TTS >30 days or within the first week independently increased mortality risk. There was a significant increase in mortality with TTS 31 to 60 hazard ratio (HR) 1.13, 61 to 90 (HR 1.49), <7 (HR 1.56), 91 to 120 (HR 2.28), and 121 to 180 (HR 2.46) compared to surgery performed 7 to 30 days after diagnosis (P < 0.001).
CONCLUSIONS:TTS is independently associated with OS and this represents a public health issue that should be addressed at a national level. Although time is required for evaluation before surgery, efforts to reduce TTS should be pursued.
The inducible nitric oxide synthase (iNOS) is associated with more aggressive solid tumors, including hepatocellular carcinoma (HCC). Notch signaling in cancer stem cells promotes cancer progression ...and requires Notch cleavage by ADAM (a disintegrin and metalloprotease) proteases. We hypothesized that iNOS/NO promotes Notch1 activation through TACE/ADAM17 activation in liver cancer stem cells (LCSCs), leading to a more aggressive cancer phenotype. Expression of the stem cell markers CD24 and CD133 in the tumors of patients with HCC was associated with greater iNOS expression and worse outcomes. The expression of iNOS in CD24⁺CD133⁺ LCSCs, but not CD24⁻CD133⁻ LCSCs, promoted Notch1 signaling and stemness characteristics in vitro and in vivo, as well as accelerating HCC initiation and tumor formation in the mouse xenograft tumor model. iNOS/NO led to Notch1 signaling through a pathway involving the soluble guanylyl cyclase/cGMP/PKG-dependent activation of TACE/ADAM17 and up-regulation of iRhom2 in LCSCs. In patients with HCC, higher TACE/ADAM17 expression and Notch1 activation correlated with poor prognosis. These findings link iNOS to Notch1 signaling in CD24⁺CD133⁺ LCSCs through the activation of TACE/ADAM17 and identify a mechanism for how iNOS contributes to progression of CD24⁺CD133⁺ HCC.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Background
Laparoscopic liver resection is rapidly expanding with more than 9500 cases performed worldwide. While initial series reported non-anatomic resection of benign peripheral hepatic lesions, ...approximately 50–65 % of laparoscopic liver resections are now being done for malignant tumors, primarily hepatocellular carcinoma (HCC) or colorectal cancer liver metastases (mCRC).
Methods
We performed a literature review of published studies evaluating outcomes of major laparoscopic liver resection, defined as three or more Couinaud segments.
Results
Initial fears of adverse oncologic outcomes or tumor seeding have not been demonstrated, and dozens of studies have reported comparable 5-year disease-free and overall survival between laparoscopic and open resection of HCC or mCRC in case-cohort and propensity score-matched analyses. Increased experience has led to laparoscopic anatomic liver resections including laparoscopic major hepatectomy. A steep learning curve of 45–60 cases is evident for laparoscopic hepatic resection.
Conclusion
Laparoscopic major hepatectomy is safe and effective in the treatment of benign and malignant liver tumors when performed in specialized centers with dedicated teams. Comparable to other complex laparoscopic surgeries, laparoscopic major hepatectomy has a learning curve of 45–60 cases.
Full text
Available for:
EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
Neutrophil infiltration and neutrophil extracellular traps (NET) in solid cancers are associated with poorer prognosis, but the mechanisms are incompletely understood. We hypothesized that NETs ...enhance mitochondrial function in tumor cells, providing extra energy for accelerated growth. Metastatic colorectal cancer tissue showed increased intratumoral NETs and supranormal preoperative serum MPO-DNA, a NET marker. Higher MPO-DNA correlated with shorter survival. In mice, subcutaneous tumor implants and hepatic metastases grew slowly in PAD4-KO mice, genetically incapable of NETosis. In parallel experiments, human cancer cell lines grew slower in nu/nu mice treated with DNAse, which disassembles NETs. PAD4-KO tumors manifested decreased proliferation, increased apoptosis, and increased evidence of oxidative stress. PAD4-KO tumors had decreased mitochondrial density, mitochondrial DNA, a lesser degree of ATP production, along with significantly decreased mitochondrial biogenesis proteins PGC1α, TFAM, and NRF-1.
, cancer cells treated with NETs upregulated mitochondrial biogenesis-associated genes, increased mitochondrial density, increased ATP production, enhanced the percentage of cancer cells with reduced mitochondrial membrane potential, and increased the oxygen consumption rate. Furthermore, NETs increased cancer cells' expression of fission and fusion-associated proteins, DRP-1 and MFN-2, and mitophagy-linked proteins, PINK1 and Parkin. All of which were decreased in PAD4-KO tumors. Mechanistically, neutrophil elastase released from NETs activated TLR4 on cancer cells, leading to PGC1α upregulation, increased mitochondrial biogenesis, and accelerated growth. Taken together, NETs can directly alter the metabolic programming of cancer cells to increase tumor growth. NETs represent a promising therapeutic target to halt cancer progression. SIGNIFICANCE: Neutrophils through the release of NETs facilitate the growth of stressed cancer cells by altering their bioenergetics, the inhibition of which induces cell death.
To provide a review of the world literature on laparoscopic liver resection.
Initially described for peripheral, benign tumors resected by nonanatomic wedge resections, minimally invasive liver ...resections are now being performed more frequently, even for larger, malignant tumors located in challenging locations. Although a few small review articles have been reported, a comprehensive review on laparoscopic liver resection has not been published.
We conducted a literature search using Pubmed, screening all English publications on laparoscopic liver resections. All data were analyzed and apparent case duplications in updated series were excluded from the total number of patients. Tumor type, operative characteristics, perioperative morbidity, and oncologic outcomes were tabulated.
A total of 127 published articles of original series on laparoscopic liver resection were identified, and accounted for 2,804 reported minimally invasive liver resections. Fifty percent were for malignant tumors, 45% were for benign lesions, 1.7% were for live donor hepatectomies, and the rest were indeterminate. Of the resections, 75% were performed totally laparoscopically, 17% were hand-assisted, and 2% were laparoscopic-assisted open hepatic resection (hybrid) technique, with the remainder being other techniques or conversions to open hepatectomies. The most common laparoscopic liver resection was a wedge resection or segmentectomy (45%) followed by anatomic left lateral sectionectomy (20%), right hepatectomy (9%), and left hepatectomy (7%). Conversion from laparoscopy to open laparotomy and from laparoscopy to hand-assisted approach occurred in 4.1% and 0.7% of reported cases, respectively. Overall mortality was 9 of 2,804 patients (0.3%), and morbidity was 10.5%, with no intraoperative deaths reported. The most common cause of postoperative death was liver failure. Postoperative bile leak was observed in 1.5% of cases. For cancer resections, negative surgical margins were achieved in 82% to 100% of reported series. The 5-year overall and disease-free survival rates after laparoscopic liver resection for hepatocellular carcinoma were 50% to 75% and 31% to 38.2%, respectively. The 3-year overall and disease-free survival rates after laparoscopic liver resection for colorectal metastasis to the liver were 80% to 87% and 51%, respectively.
In experienced hands, laparoscopic liver resections are safe with acceptable morbidity and mortality for both minor and major hepatic resections. Oncologically, 3- and 5-year survival rates reported for hepatocellular carcinoma and colorectal cancer metastases are comparable to open hepatic resection, albeit in a selected group of patients.
OBJECTIVE:To define the current status of “difficult” LLR, a global database was created and investigated.
BACKGROUND:In the Second International Consensus Conference in 2014, minor LLR was ...considered as a standard practice and major LLR remained an innovative procedure. Since then, no updates on worldwide trends have been available.
METHODS:A questionnaire on all consecutive patients who underwent difficult LLR (major hepatectomy, posterosuperior segmentectomy, sectionectomy, living donor hepatectomy, tumor size ≥10 cm, Child–Pugh grade ≥B, combined with biliary reconstruction, and Iwate criteria difficulty score ≥7) in 2014–2018 was distributed via email to 65 high-volume LLR centers worldwide. Individual data on patient and tumor demographics, surgical information, and short-term outcomes were obtained to create a large-scale international registry for analyses.
RESULTS:Overall, 58 centers in 19 countries performed 4478 difficult LLR (median, 58.5; range, 5–418) during the study period. Hepatocellular carcinoma accounted for ≥40% of all indications. Half of the patients underwent major hepatectomy, followed by sectionectomy, posterosuperior segmentectomy, and living donor hepatectomy. In the vast majority of procedures, Clavien–Dindo grade ≥IIIa complication rates of ≈10% and 90-day mortality rates of ≈1% were achieved. Left or right trisectionectomy had the worst Clavien–Dindo grade ≥IIIa complication rate of ≥10% and 90-day mortality rate of 5%–10%. No significant correlation was observed between center volume and short-term outcomes.
CONCLUSIONS:Total 4478 patients underwent difficult LLR worldwide in 2014–2018. Most procedures are safe and feasible when conducted in specialized centers.
To compare textbook outcomes (TO) of open live donor right hepatectomy (RH) versus open right hepatic lobectomy for cancer in a single Western center and to identify clinical factors associated with ...failure to achieve a TO.
TO, a composite quality measure that captures multiple aspects of perioperative care, has not been thoroughly studied in open RH. We hypothesized that TO rates after RH for live donor transplant could represent the "best-achievable" results of this operation and could serve as the benchmark for RH performed for an oncologic indication.
A prospective database was reviewed to compare TO rates after RH for live donor purposes versus RH for cancer at a single center from 2010 to 2020. A TO was defined as achieving 7 metrics: no perioperative transfusion, no major postoperative complications, no significant bile leak, no unplanned transfer to the ICU, no 30-day mortality, no 30-day readmission, and no R1 margins for cancer cases.
Among 686 RH patients (371 live donor and 315 cancer cases), a TO was achieved in 92.2% of RH donors and 53.7% of RH cancer cases. Live donor patients tended to be younger, healthier, and thinner. Among donors, increased intraoperative blood loss, and in cancer cases, male sex, tumor size, and increased intraoperative blood loss were associated with TO failure.
A TO can be achieved in over 90% of patients undergoing living donor RH and in approximately half of RH cancer cases. These metrics represent a new benchmark for "real-world" TO after open RH.
PDF
