Gastrectomy history as a predictor of post-hepatectomy complications.

PURPOSE: The effect of a history of gastrectomy on patients undergoing hepatectomy is unclear. We investigated the relationship between postoperative complications of Clavien-Dindo grade III or higher and a history of gastrectomy in patients undergoing hepatectomy. METHODS: The subjects of this retrospective analysis were 474 consecutive patients who underwent hepatectomy at our institute for hepatic malignancy, classified into groups of those with or without a history of gastrectomy and those with or without postoperative complications. We compared the clinicopathological factors between the groups. RESULTS: There were no hospital deaths. Gastrectomy history was identified in 22 patients (4.6%) and was significantly associated with advanced age, low body mass index, male sex, decreased serum albumin level, decreased hemoglobin level, low PNI, low CONUT score, high incidence of postoperative complications, and longer hospital stay. Multivariate analyses revealed that the independent risk factors for postoperative complications were gastrectomy history, an albumin-bilirubin score of 2/3, primary liver cancer, high serum creatinine level, advanced age, and prolonged operation time. CONCLUSIONS: Gastrectomy history was an independent predictor of postoperative complications in patients undergoing hepatectomy for hepatic malignancies. Patients with a history of gastrectomy were likely to suffer postoperative bile leakage and pneumonia.

Does intraoperative and postoperative analgesia cause bile leakage after hepatectomy?

PURPOSE: To evaluate the effect of morphine or morphine equivalents on the risk of bile leakage (BL) after hepatectomy. METHODS: The subjects of this retrospective study were 379 patients who underwent hepatectomy without biliary reconstruction and biliary decompression tube insertion at Gunma University between 2016 and 2020. Clinical BL was defined as International Study Group of Liver Surgery post-hepatectomy bile leakage Grade B or C. RESULTS: Intra- and post-operative analgesia comprised intravenous patient-controlled analgesia (IV-PCA) with fentanyl (n = 58), epidural analgesia with fentanyl (n = 157), epidural analgesia with morphine (n = 151), and epidural analgesia with ropivacaine or levobupivacaine (n = 13). Clinical BL was diagnosed in 14 of the 379 (3.7%) patients. The significant risk factors for clinical BL were hepatocellular carcinoma (HCC), elevated serum total bilirubin, high indocyanine green retention at 15 min, elevated Mac-2-binding protein glycosylated isomer, prolonged duration of surgery, and a large volume of blood loss. There was no significant correlation of clinical BL with intra- and post-operative analgesia and total oral morphine equivalents. CONCLUSION: Intra- and post-operative IV-PCA and epidural analgesia were not related to clinical BL after hepatectomy. Based on our data, fentanyl and morphine can be administered safely as epidural or intravenous analgesic agents.

Prediction with functional liver volume assessment to achieve the resection limit after portal vein embolization in patients scheduled major hepatectomy.

BACKGROUND: Preoperative portal vein embolization (PVE) stimulates liver hypertrophy and improves the safety of major hepatectomy. It is essential to predict the future remnant liver volume (FRLV) and resection limit following PVE. Previously, we reported that evaluating functional FRLV (fFRLV) using EOB-MRI could predict post-hepatectomy liver failure. In this study, we investigated the usefulness of fFRLV in predicting the achieving of adequate resection limit for safe hepatectomy following PVE. METHODS: We included 55 patients who underwent PVE and were scheduled for major hepatectomy. We calculated the liver-to-muscle ratio in the remnant liver and fFRLV using EOB-MRI. We investigated the pre-PVE variables in determining the nonachievement of the resection limit. RESULTS: The median observation period between PVE and the first evaluation was 21 days, and the median growth rate of FRLV was 26.4%. In 54.5% of patients, the resection limit of fFRLV (615 mL/m2) was achieved. In logistic regression and receiver-operating characteristic analyses, pre-PVE fFRLV (p < 0.001, area under the curve: 0.852) was the reliable predictor of achieving the resection limit; the cutoff value of pre-PVE fFRLV was 446 mL/m2. CONCLUSION: Pre-PVE fFRLV can be useful in predicting the achievement of adequate resection limit following PVE.

High membrane expression of CMTM6 in hepatocellular carcinoma is associated with tumor recurrence.

CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6) maintains membrane PD-L1 expression by controlling its endosomal recycling. However, in patients with hepatocellular carcinoma (HCC), the correlation among CMTM6, B7 family ligands, and CD8-positive cytotoxic T lymphocytes (CTLs), and the molecular function of CMTM6 in HCC have not been established. We performed immunohistochemistry to evaluate the relationships among CMTM6 expression, clinicopathological factors, B7 family ligands expression, and CTL infiltration in HCC samples. Moreover, we established CMTM6-knockout human HCC cell lines to evaluate the function of human CMTM6 in immune regulation and tumor viability. CMTM6 expression was positively associated with membrane B7 family ligands expression and CTL infiltration in HCC samples. High CMTM6 expression in HCC tissues was associated with the expression of the proliferation marker Ki-67 and shorter recurrence-free survival. In vitro analysis showed the downregulation of membrane B7 family ligands and proliferation potency in the CMTM6-knockout human HCC cell line. High membrane CMTM6 expression was associated with tumor recurrence and proliferation via the regulation of membranous B7 family ligands expression. Thus, CMTM6 might be a biomarker to predict the risk of HCC recurrence and a therapeutic target to suppress tumor growth and increase CTL activity.

FDG-PET for preoperative evaluation of tumor invasion in ampullary cancer: A retrospective analysis.

BACKGROUND: Tumor invasion is the most significant prognostic factor in ampullary cancer and is thus a crucial factor in decision making for treatment. Endoscopic ultrasound can be performed to evaluate tumor invasion, but its diagnostic accuracy varies depending on the endoscopist. This study aimed to assess the usefulness of fluorodeoxyglucose positron emission tomography (FDG-PET) for preoperatively predicting tumor invasion in ampullary cancer. METHODS: We retrospectively evaluated 44 patients with ampullary cancer (adenoma, n = 6; adenocarcinoma, n = 38) who underwent surgical resection. The SUVmax of the ampullary tumor site was assessed using FDG-PET, and the correlation among tumor invasion, lymph node metastasis, and other clinicopathological factors was evaluated. RESULTS: The SUVmax of the ampullary tumor site gradually increased depending on the extent of tumor invasion (p = 0.0075). Moreover, the SUVmax was significantly different between ≤T1a and ≥T1b, which is an indication for endoscopic papillectomy or surgical resection (p = 0.0015). The SUVmax of the ampullary section was significantly correlated with lymph node metastasis (p = 0.035). CONCLUSION: The SUVmax of the ampullary tumor site is correlated with tumor invasion and lymph node metastasis in ampullary cancer. Thus, FDG-PET can be a useful modality for preoperative staging and treatment strategy.

Hepatic stellate cell as a Mac-2-binding protein-producing cell in patients with liver fibrosis.

BACKGROUND: Mac-2 binding protein (M2BP) glycosylated isomer (M2BPGi) is a serum marker of liver fibrosis; M2BPGi is a glycosylated form of M2BP. Hepatocytes and hepatic stellate cells (HSCs) have been studied to determine the source of M2BP. This study proposes to identify the origin of M2BP in fibrotic liver. METHODS: Using liver fibrosis tissue specimens from 15 patients with liver cancer, M2BP mRNA and M2BP were detected by in situ hybridization and immunohistochemistry, respectively. The expression levels of M2BP mRNA were evaluated with scores of 3, 2, and 1. Fluorescent in situ hybridization was carried out to evaluate the distribution of M2BP mRNA and the activated-HSC marker αSMA mRNA; multicolor fluorescent immunohistochemistry was used for protein localization of M2BP, αSMA, and CD68. The Kruskal-Wallis test analyzed the relationship between M2BP mRNA expression and existing serum fibrosis markers. RESULTS: M2BP mRNA was expressed in spindle-shaped cells along the fibrous septa and in the perisinusoidal area of the fibrotic liver. The HSC markers αSMA mRNA and M2BP mRNA were colocalized in the spindle-shaped cells; on the protein level, M2BP was expressed in Kupffer cells. M2BP mRNA expression was positively correlated with serum M2BPGi levels. Aspartate transaminase-to-platelet ratio index, Fibrosis-4, hyaluronic acid, and the 15-minute indocyanine green retention rate were significantly correlated with M2BP mRNA expression. CONCLUSIONS: M2BP mRNA transcription in fibrotic liver was primarily observed in HSCs but not at the M2BP level, which suggests that HSCs might produce and introduce M2BP to Kupffer cells and serum.

Impact of preoperative nutritional support and rehabilitation therapy in patients undergoing pancreaticoduodenectomy.

BACKGROUND: Sarcopenia is closely associated with morbidity after pancreatic surgery. We investigated the impact of preoperative nutritional support and rehabilitation on patients undergoing pancreaticoduodenectomy. METHODS: This was a retrospective analysis of 101 patients who underwent pancreaticoduodenectomy. Skeletal muscle (SM) loss was defined using the SM index (cutoff level: 42 cm2/m2 in men and 38 cm2/m2 in women). A total of 33 and 30 patients received preoperative nutrition and prehabilitation, respectively. The neutrophil-to-lymphocyte ratio (NLR), Prognostic Nutritional Index (PNI), and modified Glasgow Prognostic Score (mGPS) values were calculated during the first visit and immediately before surgery. RESULTS: SM loss was present in 65 of 101 patients and was significantly correlated with female sex, older age, lower body mass index, and low PNI. Preoperative nutritional support and prehabilitation prevented the decrease in PNI values in patients with SM loss. The NLR significantly improved in patients with SM loss who received nutritional support and prehabilitation. In patients with SM loss, the lack of preoperative nutrition and prehabilitation was an independent risk factor for postoperative pancreatic fistula. CONCLUSIONS: Preoperative nutritional support and prehabilitation may reduce the incidence of pancreatic fistula in patients with SM loss and improve the surgical outcomes of patients undergoing pancreaticoduodenectomy.

Association between intraoperative and postoperative epidural or intravenous patient-controlled analgesia and pancreatic fistula after distal pancreatectomy.

PURPOSE: This study aimed to elucidate the association between postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP) and clinicopathological factors and intraoperative and postoperative epidural or intravenous patient-controlled analgesia (IV-PCA). METHODS: We reviewed data of 116 patients who underwent distal pancreatectomy at Gunma University Hospital from October 2000 to October 2019. Clinical POPF was defined as the International Study Group of Pancreatic Fistula grade B or C. RESULTS: Intraoperative and postoperative analgesia included fentanyl-mediated IV-PCA (n = 37, 32%), fentanyl-mediated epidural analgesia (n = 39, 34%), and morphine-mediated epidural analgesia (n = 40, 34%). All patients had received analgesia. Clinical POPF occurred in 34 of the 116 (29%) DP cases. Male sex (P = 0.035) and the length of operation time (P = 0.0070) were significant risk factors of clinical POPF. Furthermore, a thick pancreas was more likely to cause clinical POPF than a thin one (P = 0.052). No statistically significant difference was found between other factors, including intraoperative and postoperative analgesia (P = 0.95), total median oral morphine equivalents (P = 0.23), and clinical POPF. CONCLUSION: Intraoperative and postoperative epidural analgesia and IV-PCA are not associated with clinical POPF after DP. Our results suggest that morphine and fentanyl can be used as IV-PCA or epidural analgesia.

Mac-2-binding protein glycan isomer enhances the aggressiveness of hepatocellular carcinoma by activating mTOR signaling.

BACKGROUND: Wisteria floribunda agglutinin (WFA)+ Mac-2-binding protein (M2BPGi) is a novel serum marker for liver fibrosis. Although an elevated serum level of M2BPGi can predict development of hepatocellular carcinoma (HCC), the effect of M2BPGi on HCC remains unclear. There are no reports about the association of M2BPGi with HCC aggressiveness. We aimed to clarify the significance of M2BPGi in HCC. METHODS: The protein expression of M2BPGi and galectin-3, a ligand of M2BP, and the mRNA expression of M2BP were evaluated in surgically resected human HCC samples. M2BPGi-regulating signals in HCC cells were investigated using transcriptome analysis. The effects of M2BPGi on HCC properties and galectin-3/mTOR signaling were evaluated. RESULTS: M2BPGi and galectin-3 proteins co-localised in HCC cells, while M2BP mRNA was detected in cirrhotic liver stromal cells. mTOR signaling was upregulated in M2BPGi-treated HCC cells. Moreover, M2BPGi treatment induced tumour-promoting effects on HCC in vitro by activated mTOR signaling. In addition, M2BPGi bound to galectin-3 to induce membranous galectin-3 expression in HCC cells. In vivo, M2BPGi enhanced the growth of xenografted HCC. CONCLUSIONS: M2BPGi is produced in stromal cells of the cirrhotic liver. Furthermore, M2BPGi enhances the progression of HCC through the galectin-3/mTOR pathway.

Nintedanib inhibits intrahepatic cholangiocarcinoma aggressiveness via suppression of cytokines extracted from activated cancer-associated fibroblasts.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a malignancy that is challenging to treat. Fibroblasts in ICC tissues have been identified as cancer-associated fibroblasts (CAFs) that promote the malignant behaviour of ICC cells. An antifibrotic drug nintedanib has been reported to suppress activated hepatic stellate cells in liver fibrosis. METHODS: We investigated whether nintedanib could suppress the cancer-promoting effect of CAFs derived from ICC tissues in vitro and in vivo. RESULTS: CAFs promoted the proliferation and invasion of ICC cells. Nintedanib suppressed activated CAFs expressing α-smooth muscle actin (α-SMA) and inhibited the ICC-promoting effects of CAFs. Nintedanib greatly reduced the levels of cancer-promoting cytokines, such as interleukin (IL)-6 (IL-6) and IL-8, secreted by CAFs. An in vivo study demonstrated that nintedanib reduced xenografted ICC growth and activated CAFs expressing α-SMA, and that combination therapy with nintedanib and gemcitabine against CAFs and ICC cells showed the strongest inhibition of tumour growth compared with the control and single-treatment groups. CONCLUSIONS: Nintedanib inhibited the cancer-promoting effect of CAFs via the suppression of CAF activation and secretion of cancer-promoting cytokines. Our findings suggest that therapeutic strategies combining conventional cytotoxic agents with nintedanib targeting CAFs are promising for overcoming refractory ICC with activated CAFs.

High Co-expression of Large Tenascin C Splice Variants in Stromal Tissue and Annexin A2 in Cancer Cell Membranes is Associated with Poor Prognosis in Pancreatic Cancer.

BACKGROUND: Pancreatic cancer tissue contains abundant stromal components, including extracellular matrix proteins such as tenascin C (TNC), which exists as large (TNC-L) and non-large splice variants. Here, we examined human pancreatic cancer specimens for the expression of total TNC (TNC-ALL) and TNC-L in the stroma and annexin A2 (ANXA2), a cell surface receptor for TNC, and evaluated their significance as prognostic markers for pancreatic cancer. METHODS: Expression of ANXA2, TNC-ALL, and TNC-L was examined in 106 pancreatic cancer tissues from patients who underwent curative resection and who had not received prior therapy or surgery. Protein expression was measured by immunohistochemistry and scored on a semi-quantitative scale. The relationships between protein expression, clinicopathological factors, and prognosis were evaluated by Cox proportional hazards analysis. RESULTS: TNC-ALL and TNC-L were detected mainly in the stroma, whereas ANXA2 was predominantly expressed in cancer cell membranes. TNC-ALL was also expressed in non-tumor pancreatic tissue. High levels of stromal TNC-L and membranous ANXA2, but not stromal TNC-ALL, were independently associated with cancer progression and poor prognosis. Moreover, high co-expression of stromal TNC-L and membranous ANXA2 was a superior indicator of poor prognosis compared with detection of TNC-ALL, TNC-L, or ANXA2 alone. CONCLUSIONS: Our data suggest that co-expression of stromal TNC-L and membranous ANXA2 is a poor prognostic marker compared with detection of TNC-L or ANXA2 alone for pancreatic cancer patients. Additionally, targeting of crosstalk between stromal TNC and cancer cell ANXA2 could be a promising therapeutic strategy to overcome refractory pancreatic cancer.

Diffusion-Weighted MRI Predicts Lymph Node Metastasis and Tumor Aggressiveness in Resectable Pancreatic Neuroendocrine Tumors.

OBJECTIVES: The aim of this study was to identify whether diffusion-weighted magnetic resonance imaging (DW-MRI) can predict the malignant behavior of preoperative well-differentiated pancreatic neuroendocrine tumors (PanNETs). METHOD: Forty patients with PanNETs who underwent pancreatectomy were enrolled in this study. The apparent diffusion coefficient (ADC) values were measured. Clinicopathological factors were compared in patients with high ADC and low ADC values and in patients with and without lymph node metastasis (LNM). RESULT: The low ADC group was significantly associated with higher Ki-67 index, higher mitotic count, larger tumor size, higher rate of LNM, and venous invasion. In patients with low ADC values, the incidence of LNMs was 33.3%. In patients with high ADC values, there were no patients with LNM being 0%. A significant negative correlation was found between the mean ADC values and the Ki-67 index and between the mean ADC values and the mitotic count. In multivariate analysis, neural invasion and mean ADC values ≤ 1458 were independent predictors of LNM. CONCLUSION: ADC values obtained using DW-MRI in the preoperative assessment of patients with PanNETs might be a useful predictor of malignant potential, especially LNM.

FDG-PET reflects tumor viability on SUV in colorectal cancer liver metastasis.

BACKGROUND: Liver resection is the most effective procedure for colorectal cancer liver metastasis (CRLM); however, early recurrence is an important problem that affects the postoperative prognoses of patients with CRLM. We previously suggested a therapeutic algorithm for CRLM using fluorodeoxyglucose-positron emission tomography (FDG-PET) and revealed the applicability of FDG-PET in predicting the prognosis after liver resection of CRLM. In this study, we assessed the correlation between FDG-PET and biological viability such as proliferation or metabolic activity. METHODS: We retrospectively evaluated 61 patients who underwent hepatectomy for CRLM. We assessed hypoxia inducible factor-1α (HIF-1α), pyruvate kinase isozyme M2 (PKM2), glucose transporter 1 (GLUT1), and Ki-67 expression via immunohistochemistry and evaluated the correlation between standardized uptake value (SUV) and these factors. RESULTS: High HIF-1α, PKM2, and GLUT1 expression were positively correlated with high SUV expression (P = 0.0444, 0.0296, and 0.0245, respectively). Ki-67 and SUV were also positively correlated (P = 0.00164). HIF-1α expression and PKM2 expression were significantly correlated (P = 0.0430), and PKM2 expression and GLUT1 expression were extremely significantly correlated (P < 0.0001). CONCLUSION: SUV reflected tumor proliferation or metabolic factors in CRLM. FDG-PET could be a useful modality for assessing tumor viability and may provide useful information regarding the appropriate treatment strategy for CRLM.

Efficiency of regional functional liver volume assessment using Gd-EOB-DTPA-enhanced magnetic resonance imaging for hepatocellular carcinoma with portal vein tumor thrombus.

PURPOSE: We investigated whether functional future remnant liver volume (fFRLV), assessed using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI), could evaluate regional liver function in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) and help establish the indication for hepatectomy. METHODS: The subjects of this study were 12 patients with PVTT [PVTT(+) group] and 58 patients without PVTT [PVTT(-) group], from among 191 patients who underwent hepatectomy of more than one segment for HCC. We calculated the liver-to-muscle ratio (LMR) in the remnant liver, using EOB-MRI and fFRLV. Preoperative factors and surgical outcome were compared between the groups. The LMR of the area occluded by PVTT was compared with that of the non-occluded area. RESULTS: The indocyanine green retention rate at 15 min (ICG-R15) and liver fibrosis indices were increased in the PVTT(+) group, but the surgical outcomes of patients in this group were acceptable, with no liver failure, no mortality, and no differences from those in the PVTT(-) group. The fFRLV in the PVTT(+) group was not significantly different from that in the PVTT(-) group (p = 0.663). The LMR was significantly lower in the occluded area than in the non-occluded area (p = 0.004), indicating decreased liver function. CONCLUSION: Assessing fFRLV using EOB-MRI could be useful for evaluating regional liver function and establishing operative indications for HCC with PVTT.

Albumin-Indocyanine Green Evaluation (ALICE) grade predicts bile leakage after hepatic resection.

PURPOSE: We investigated the predictors of bile leakage after hepatic resection. METHODS: The data of 270 consecutive patients who underwent curative hepatic resection in our institute between January, 2016 and April, 2019 were reviewed retrospectively. The patients were assigned to one of two groups according to the presence of bile leakage and the clinicopathological and surgical outcomes were analyzed. Bile leakage was defined by the International Study Group of Liver Surgery (ISGLS) grade. RESULTS: There were no hospital deaths. The median intraoperative blood loss volume was 167 ml. Bile leakage occurred in 12 patients (4.4%), as ISGLS grade A leakage in 1 and as ISGLS grade B leakage in 11. The mean hospital stay was significantly longer for patients with bile leakage. High-risk procedures, hepatocellular carcinoma, and Albumin-Indocyanine Green Evaluation (ALICE) grade 3 were independent predictors of ISGLS grade B or C postoperative bile leakage. In patients with three high-risk factors, the incidence of bile leakage was 53.9%. CONCLUSIONS: Based on this retrospective analysis, high-risk procedures, hepatocellular carcinoma, and ALICE grade 3 were independent predictors of bile leakage in patients undergoing hepatic resection. Thus, special care must be taken during surgery to prevent bile leakage in patients with these risk factors.

Functional remnant liver volumetry using Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) predicts post-hepatectomy liver failure in resection of more than one segment.

BACKGROUND: Gd-EOB-DTPA-enhanced magnetic resonance imaging (EOB-MRI) can be used for evaluating liver functional reserve. We assessed whether functional remnant liver volumetry (FRLV) using EOB-MRI predicted post-hepatectomy liver failure (PHLF) in resection of more than one segment. METHODS: We retrospectively analyzed 155 cases of hepatectomy of more than one segment. For assessment of FRLV, signal intensity (SI) of remnant liver was measured in T1-weighted images. Functional remnant liver score was derived by division of SI of liver by SI of muscle (or spleen), resulting in liver-to-muscle ratio (LMR) and liver-to-spleen ratio (LSR). FRLV were calculated by multiplying LMR (or LSR) and remnant liver volume. We investigated preoperative factors predicting PHLF (≥grade B) in study cohort (all cases except for portal vein embolization [PVE], n = 129) and validation cohort (PVE cases, n = 26). RESULTS: In study cohort, PHLF occurred in 5 patients (3.9%). In multivariate analysis, FRLV (LMR) was the most reliable predictor of PHLF (P = 0.013). The cutoff value of FRLV (LMR) predicting PHLF was 615 mL/m2 (AUC: 0.939). In validation cohort (n = 26), the cutoff value of FRLV (LMR) indicated reliable results, sensitivity (100%), specificity (77.3%), and accuracy (80.8%). CONCLUSIONS: FRLV using LMR could precisely predict PHLF of more than one segment, and was useful even in patients who underwent PVE.

Conophylline suppresses pancreatic cancer desmoplasia and cancer-promoting cytokines produced by cancer-associated fibroblasts.

Despite recent advances in cancer treatment, pancreatic cancer is a highly malignant tumor type with a dismal prognosis and it is characterized by dense desmoplasia in the cancer tissue. Cancer-associated fibroblasts (CAF) are responsible for this fibrotic stroma and promote cancer progression. We previously reported that a novel natural compound conophylline (CnP) extracted from the leaves of a tropical plant reduced liver and pancreatic fibrosis by suppression of stellate cells. However, there have been no studies to investigate the effects of CnP on CAF, which is the aim of this work. Here, we showed that CAF stimulated indicators of pancreatic cancer malignancy, such as proliferation, invasiveness, and chemoresistance. We also showed that CnP suppressed CAF activity and proliferation, and inhibited the stimulating effects of CAF on pancreatic cancer cells. Moreover, CnP strongly decreased the various cytokines involved in cancer progression, such as interleukin (IL)-6, IL-8, C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine ligand 12 (CXCL12), secreted by CAF. In vivo, CAF promoted tumor proliferation and desmoplastic formation in a mouse xenograft model, CnP reduced desmoplasia of tumors composed of pancreatic cancer cells + CAF, and combination therapy of CnP with gemcitabine remarkably inhibited tumor proliferation. Our findings suggest that CnP is a promising therapeutic strategy of combination therapy with anticancer drugs to overcome refractory pancreatic cancers.

Prognostic significance of neutrophil-lymphocyte ratio in resectable pancreatic neuroendocrine tumors with special reference to tumor-associated macrophages.

BACKGROUND: Recent studies have shown that the systemic inflammatory response induced by cancer leads to cancer progression. Neutrophil-to-lymphocyte ratio (NLR) is the most reliable marker to detect systemic inflammation. In this study, we investigated the significance of NLR in patients with well-differentiated pancreatic neuroendocrine tumors (PanNETs) according to the World Health Organization 2017 classification. METHODS: We retrospectively collected data for patients with PanNET who underwent pancreatic resection with curative intent between January 2008 and December 2017 at six institutions. Clinicopathological factors, recurrence, and immunohistochemical staining of tumor-associated macrophages (TAMs) were analyzed in a total of 55 patients in this study. RESULTS: High NLR (>3.41) in patients was significantly associated with higher white blood cell count, higher Ki-67 index, higher mitotic count, higher grade, higher incidence of lymph node metastasis, higher incidence of lymphatic and neural invasion, massive blood loss, and a large number of CD163-expressing TAMs. Recurrence-free survival of patients with high NLR was significantly poorer than that of patients with low NLR. Multivariate analysis identified high NLR, NET Grade 2 (G2) or Grade 3 (G3), and synchronous hepatic resection as independent risk factors for recurrence after curative resection. CONCLUSIONS: NLR is a promising predictor of recurrence after pancreatectomy that needs to be further investigated and that accumulation of TAMs in the tumor could be one of the causes of NLR elevation.

Preoperative Mac-2 binding protein glycosylation isomer level predicts postoperative ascites in patients with hepatic resection for hepatocellular carcinoma.

AIM: Postoperative ascites is one of the most common complications after hepatic resection and is related to liver fibrosis. Mac-2 binding protein glycosylation isomer (M2BPGi) is a reliable and non-invasive marker for assessing liver fibrosis. This study aimed to evaluate whether preoperative M2BPGi level can predict postoperative refractory ascites in patients with curative hepatic resection for hepatocellular carcinoma. METHODS: The present study retrospectively evaluated 59 patients between January 2016 and June 2018. We assessed the relationship between preoperative M2BPGi levels, expressed as the cut-off index, and postoperative ascites. RESULTS: The median M2BPGi level was 1.36 (range 0.34-11.56). Postoperative ascites occurred in seven patients (11.9%). Among them, refractory ascites, defined as diuretic-resistant ascites, occurred in four patients (6.8%). Uni- and multivariate analysis showed that preoperative M2BPGi level was the only independent risk factor of postoperative ascites (odds ratio 3.28, P = 0.033). The cut-off values of M2BPGi for postoperative ascites and refractory ascites were 2.41 and 3.10, respectively. Remarkably, there were no patients with postoperative ascites and refractory ascites when the preoperative M2BPGi levels were less than each cut-off value. CONCLUSION: Our results suggest that M2BPGi level is a reliable and non-invasive surrogate marker for predicting postoperative ascites before curative resection for hepatocellular carcinoma.

Left Lobe Mobilization Strategy of Right-Sided Major Hepatectomy for Treatment of a Tumor Causing Severe Inferior Vena Cava Compression: A Novel Strategy Using the Modified Liver-Hanging Maneuver.

BACKGROUND: Massive bleeding during major hepatectomy is associated with greater mortality and morbidity.1 Our previous study shows that inferior vena cava (IVC) compression by tumor and an anterior approach without the liver-hanging maneuver (LHM) are risk factors for massive bleeding.2 The LHM is useful for controlling bleeding in deeper parenchymal transection planes.3 However, severe compression of the IVC by tumor makes it difficult to insert a hanging tape.4 The study shows a novel modified LHM strategy for severe IVC compression to minimize intraoperative bleeding. METHODS: The procedure was disassembled into six steps: (1) the glissonian bifurcation is encircled using an extrahepatic approach (2) the hepatic ligaments are dissected, and the root of each hepatic vein trunk is exposed (3) the left lobe is fully mobilized, and the short hepatic veins are carefully dissected with a systematic procedure established from hemi-left lobe procurement in living donor liver transplantation5 (4) the tape is inserted from the space between the right and middle hepatic vein trunks into the glissonian bifurcation along the anterior surface of the IVC (5) liver parenchymal transection is performed with upward pulling of the tape (6) the right hepatic vein is dissected, and the right lobe is dissected from the diaphragm and the right hepatic ligaments. RESULTS: Right hepatectomy with this procedure was performed for two patients with IVC compressed by hepatocellular carcinoma. The operative times were respectively 483 and 396 min. The respective estimated blood losses were 1195 and 485 ml, without transfusion. Both patients had acceptable outcomes without complications. CONCLUSION: The novel modified LHM strategy ensured minimal bleeding in the resection of a huge liver tumor causing severe IVC compression.