Clinical significance of postoperative complications after pancreatic surgery in time-to-complication and length of postoperative hospital stay: a retrospective study.

PURPOSE: We retrospectively analyzed pancreatectomy patients and examined the occurrence rate and timing of postoperative complications (time-to-complication; TTC) and their impact on the length of postoperative hospital stay (POHS) to clarify their characteristics, provide appropriate postoperative management, and improve short-term outcomes in the future. METHODS: A total of 227 patients, composed of 118 pancreaticoduodenectomy (PD) and 109 distal pancreatectomy (DP) cases, were analyzed. We examined the frequency of occurrence, TTC, and POHS of each type of postoperative complication, and these were analyzed for each surgical procedure. Complications of the Clavien-Dindo (CD) classification Grade II or higher were considered clinically significant. RESULTS: Clinically significant complications were observed in 70.3% and 36.7% of the patients with PD and DP, respectively. Complications occurred at a median of 10 days in patients with PD and 6 days in patients with DP. Postoperative pancreatic fistula (POPF) occurred approximately 7 days postoperatively in both groups. For the POHS, in cases without significant postoperative complications (CD ≤ I), it was approximately 22 days for PD and 11 days for DP. In contrast, when any complications occurred, POHS increased to 30 days for PD and 19 days for DP (each with additional 8 days), respectively. In particular, POPF prolonged the hospital stay by approximately 11 days for both procedures. CONCLUSION: Each postoperative complication after pancreatectomy has its own characteristics in terms of the frequency of occurrence, TTC, and impact on POHS. A correct understanding of these factors will enable timely therapeutic intervention and improve short-term outcomes after pancreatectomy.

Re-consideration of Lymph Node Metastasis in Pancreatic Cancer Patients Following Radical Resection: A Retrospective Study.

BACKGROUND/AIM: Perioperative chemotherapy has become more common in patients with pancreatic cancer (PC), and the significance of lymph node (LN) metastasis and the role of surgical resection in PC have gradually evolved. In the present study, we reconsidered the significance of LN metastasis for patients with PC. PATIENTS AND METHODS: We analyzed 142 PC patients who underwent radical resection at our hospital between September 2012 and December 2021. Patients were divided into three groups based on the performance of preoperative chemotherapy, as follows: up-front surgery (US, n=109), neoadjuvant chemotherapy (NAC, n=22), and conversion surgery (CS, n=11). The characteristics of patients with LN metastasis in the US group were clarified, and a prognostic analysis was performed. The prognostic impact of LN metastasis in the NAC/CS group was examined and compared to that in the US group. RESULTS: Multivariate analysis revealed that high CA19-9 levels, large tumor size, and positive lymphatic invasion were significantly associated with LN metastasis. LN metastasis and portal vein invasion were independent poor prognostic factors in multivariate analysis. Patients without LN metastasis in the NAC group tended to have a better prognosis than those in the US group; however, the prognosis of patients with LN metastasis was similar between the two groups. In the CS and US groups, the prognosis was comparable for patients with and without LN metastasis. CONCLUSION: LN metastasis is a notably poor prognostic factor for PC patients, even after NAC, and more aggressive perioperative treatments may be considered for these patients.

C-H▪▪▪S Hydrogen Bonds in Ampicillin and Amoxicillin Crystals Investigated by Sulfur K-Edge X-Ray Absorption Near-Edge Structure Spectroscopy and Single-Crystal X-Ray Structure Analysis.

Sulfur K-edge X-ray absorption near-edge structure (XANES) spectroscopy was evaluated for its ability to detect non-conventional C-H▪▪▪S hydrogen bonds in crystals of the sulfur-containing penam antibiotics ampicillin and amoxicillin. The XANES spectra of the nearly isomorphous crystals of ampicillin trihydrate and amoxicillin trihydrate were very similar, whereas that of ampicillin anhydrate displayed unique features. Single-crystal X-ray structure analyses revealed that the C-H▪▪▪S hydrogen bond geometries and the chemical types of the hydrogen donors differed between the isomorphous trihydrate crystals and ampicillin anhydrate crystal. These observations demonstrate that the shapes of the sulfur K-edge XANES spectra are dependent on the nature of the C-H▪▪▪S hydrogen bonds. Sulfur K-edge XANES spectroscopy shows promise for use in the detection and analysis of non-covalent interactions, including hydrogen bonds to sulfur atoms, within active pharmaceutical ingredients.

Role of podoplanin and Kupffer cells in liver injury after ischemia-reperfusion in mice.

AIM: To investigate the relationship between the intrahepatic expression of podoplanin (PDPN) and Kupffer cells (KCs) in ischemia-reperfusion (I/R) liver damage. METHODS: C57Bl/6 mice were injected with 200 µl of clodronate liposomes (macrophage depletion; MDP group) to deplete KCs or control liposomes (control group) via the ophthalmic vein plexus 24 h prior to ischemia. Animals were subjected to 90 min of partial hepatic ischemia (70%), followed by reperfusion, and were then killed at designated time points. Serum and liver tissues were harvested for further analyses. RESULTS: Serum ALT levels, mortality rates, and the percentage of necrotic area in liver sections were significantly higher in the MDP group than in the control group. PDPN was expressed in the lymphatic epithelium, interlobular bile duct epithelium, and in some hepatocytes in each group. Its expression in hepatocytes was down-regulated in the MDP group. The accumulation of platelets in the sinusoid was reduced 6 h after I/R in the MDP group. Tissue HGF and IGF-1 levels decreased in the MDP group. CONCLUSIONS: These results suggest that KCs play a key role in the activation of platelets through direct contact with PDPN-positive hepatocytes in I/R livers.

Early Drain Removal Regardless of Drain Fluid Amylase Level Might Reduce Risk of Postoperative Pancreatic Fistula.

BACKGROUND/AIM: Drains are frequently placed at the time of distal pancreatectomy (DP) to evacuate pancreatic juice and intra-abdominal exudate and obtain information on abdominal cavity status. However, the timing of drain removal remains debatable. Meanwhile, prolonged drain placement might increase the risk of postoperative pancreatic fistula (POPF), with a prevalence of 5-40%. Therefore, we examined the effect of removing the drain within postoperative day (POD) 3 on the risk of POPF development. PATIENTS AND METHODS: A total of 108 consecutive patients who underwent DP between April 2015 and March 2020 were examined and divided into two groups according to the day of drain removal; hence, for some patients, the drain was removed on POD 1 (POD 1 group) and for others on POD 3 (POD 3 group). Furthermore, risk factors, including drain fluid amylase (DFA) levels, for developing POPF were investigated. RESULTS: The overall rate of clinically relevant POPF was 4.6% and did not significantly differ between the POD 1 and POD 3 groups [4.5% and 4.9%, respectively (p=0.924)]. DFA levels on POD 1 did not significantly differ between patients with and without POPF. On POD 3 and POD 5, C-reactive protein (CRP) levels were significantly higher in patients with POPF than in those without (p=0.03 and p<0.001, respectively). CONCLUSION: Early drain removal regardless of DFA level may reduce the risk of developing POPF. CRP measured on POD 3 and POD 5 appeared to be a useful predictor of clinically relevant POPF.

[Nab-Paclitaxel plus Gemcitabine for Patients with Recurrence after Resection for Adenocarcinoma of the Pancreas].

PURPOSE: The purpose of this study was to clarify the predictors of efficacy of nab-paclitaxel plus gemcitabine(GnP)for patients with recurrence after resection for adenocarcinoma of the pancreas. METHOD: Patients who had received GnP at our hospital were divided into 2 groups; effective group and non-effective group and we compared them. In addition, we compared the therapeutic effect of patients between well-differentiated adenocarcinoma and moderately differentiated adenocarcinoma. Furthermore, we compared the efficacy depending on the time of recurrence. RESULTS: In patients with well-differentiated adenocarcinoma, the disease control rate was 93.6% and progression free survival was 8.6 months, whereas those in patients with moderately differentiated adenocarcinoma were 57.1% and 4.4 months, respectively. Patients who recurred at 7 months or later, had a better therapeutic response than the patients who recurred within 6 months after surgery. CONCLUSIONS: GnP may be effective in patients with well-differentiated adenocarcinoma and in patients who recurred at 7 months or later.

Anastomosis technique for pancreatojejunostomy and early removal of drainage tubes may reduce postoperative pancreatic fistula.

BACKGROUND: Postoperative pancreatic fistula (POPF) is one of the most serious complications after pancreaticoduodenectomy (PD). Various factors have been reported as POPF risks, but the most serious of these is soft pancreas. To reduce POPF occurrences, many changes to the PD process have been proposed. This study evaluates short-term results of anastomosis technique for PD. METHODS: In total, 123 patients with soft pancreases who had undergone PD at Yamanashi University between January 2012 and August 2020 were retrospectively analyzed. We divided these patients into two groups depending on the time PD was performed: a conventional group (n = 67) and a modified group (n = 56). RESULTS: The rate of clinically relevant POPF was significantly lower in the modified group than that in the conventional group (5.4% vs 22.4%, p value < 0.001), with there being only one case of POPF in the modified group. There were no cases of POPF-related hemorrhaging in the modified group. On the third day after the operation, the amylase levels in the drainage fluid for the modified group became less than half (1696 vs 650 U/L). Multivariate analysis showed that the modified method was the independent predictors to prevent clinical POPF (p value = 0.002). CONCLUSIONS: Our novel anastomosis technique for pancreatojejunostomy reduced POPF in PD, especially in cases where the patient had a soft pancreas.

Changes in Function and Dynamics in Hepatic and Splenic Macrophages in Non-Alcoholic Fatty Liver Disease.

BACKGROUND: The aim of this study was to investigate the populations and functions of hepatic and splenic macrophages (Mfs) in non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: Experiment 1: Wild-type and STAM® mice were given chow or high-fat diets for designated periods. In isolated Mfs, phagocytosis and cytokine production were assessed. Immunohistochemistry for CD68 and F4/80 and expression of CD14 and CD16 were assessed. Experiment 2: Bone marrow cells harvested from enhanced green fluorescent protein (EGFP) mice were transplanted into wild-type mice with or without splenectomy after total body irradiation that was kept on methionine- and choline-deficient diets. RESULTS: Experiment 1: The number of CD68-positive cells and the percentage of F4/80-positive/CD68-positive cells increased with the progression of NAFLD. Production of TNF-α and IL-6 by hepatic Mfs was greater than that by splenic Mfs in mice with NASH. The number of CD14+CD16- Mfs increased in the spleen and decreased in the liver in animals that had progressed to NASH. Furthermore, the number of CD14+CD16+ hepatic Mfs was increased in animals that had progressed to NASH with fibrosis. Experiment 2: EGFP-positive cells were observed in the liver after transplantation. In the splenectomy group, EGFP-positive Mfs were also observed; however, the number was significantly less than that in the sham operation group. CONCLUSION: The populations and functions of hepatic and splenic Mfs are altered during the progression of NAFLD. In addition, increased hepatic Mfs during the progression of NAFLD may migrate from bone marrow to the liver via the spleen.

Pituitary Adenylate Cyclase-Activating Polypeptide Prevents Mortality Caused by Septic Peritonitis in Mice.

The purpose of this study was to investigate whether pituitary adenylate cyclase-activating polypeptide (PACAP) prevents mortality due to sepsis in mice. Mice were given PACAP at designated time points before or after cecal ligation and puncture (CLP), and organ injury and mortality were investigated. Serum inflammatory and anti-inflammatory cytokine levels were assessed after CLP. Plasma corticosterone and adrenocorticotropic hormone levels were also measured. Isolated tissue macrophages (Mfs) were incubated with or without PACAP, and production of cytokines was measured. Activation of NF-κB was investigated in tissue Mfs isolated from CLP animal in the presence and absence PACAP in vitro. PACAP treatment significantly prevented acute lung injury and mortality after CLP. Plasma endotoxin levels and bacterial load were not different between PACAP-treated and nontreated groups. Increased serum TNF-α and HMGB1 levels in animals treated with vehicle were significantly blunted in PACAP-treated animals after CLP. Furthermore, serum IL-10 levels were significantly greater in the PACAP-treated group compared with the vehicle group. Production of HMGB1 and TNF-α by isolated hepatic Mfs was significantly inhibited in the presence of PACAP, whereas production of IL-10 by isolated hepatic Mfs and interstitial lung Mfs was significantly increased. Plasma corticosterone and adrenocorticotropic hormone levels were significantly greater in the animals treated with PACAP compared with vehicle after CLP. Activation of NF-κB was significantly inhibited by PACAP in the hepatic Mfs compared with other tissue Mfs. PACAP prevents mortality due to septic peritonitis by inhibiting inflammation via NF-κB activation and possible effects on the brain.

Effects of Medium-chain Triglycerides Administration in Chemically-induced Carcinogenesis in Mice.

AIM: The aim of this study was to investigate the effects of medium-chain triglycerides (MCTs) on chemically-induced hepatic carcinogenesis (HCC) in mice. MATERIALS AND METHODS: In a first set of experiments, mice were treated with diethylnitrosoamine intraperitoneally at two weeks of age. They were fed chow containing MCT or a normal chow diet and sacrificed after 28 weeks. Incidence of hepatic tumor was compared between the two groups. Expression of oxidative stress, and inflammatory cytokines and chemokines in liver tissues were examined. In a second set of experiments, the histopathological findings of the intraperitoneal adipose tissue were assessed, and expression of adipocytokines in the fat tissue was measured. In a third set of experiments, plasma ß-hydroxybutyrate (HB) concentration was measured in both animals fed chow containing MCT and a normal chow diet. Mouse HCC cells were co-cultured with ß-HB, and the numbers of tumor cells were counted at days 3 and 7. RESULTS: In the first set of experiments, the tumor count observed in the control group was significantly blunted in the MCT group. Maximum tumor diameter also decreased in the MCT group compared to the control group. The expression of inflammatory cytokines and chemokines was significantly decreased by MCT. Furthermore, expression of 4-hydroxynonenal was lower in the MCT group compared to the control group. In the second set of experiments, hypertrophy of the adipocytes was suppressed, and the concentration of adiponectin and leptin in the adipose tissue decreased by MCT. In the third set of experiments, plasma ß-HB concentration increased in the MCT group as expected. ß-HB significantly inhibited the proliferation of HCC cells. CONCLUSION: MCT administration markedly suppresses the incidence of chemically-induced HCC by inhibition of inflammation and increase of ketone bodies.

[Investigation of Lateral Lymph Node Dissection for Rectal Cancer in Our Department].

No clear policy has been established in Japan for proper lymph node dissection for rectal cancer. In our department, we examined the frequency of lateral lymph node metastasis, its treatment outcomes, and whether lateral dissection can narrow down necessary cases. In 10 years from 2003 to 2013, 98 cases of lower rectal cancer surgically treated in our department were examined. The clinicopathological factors in these cases were examined, and the risk factors were examined based on their correlation with the presence or absence of lateral lymph node metastasis. Based on the postoperative prognostic analysis, the dissection effect index(metastasis positive rate×5-year survival rate in cases with positive metastases)was also examined. Forty-three lateral lymph node dissections were performed. Cases involving a circumferential resection margin (CRM)of 1mm or less had significantly more lateral lymph node metastases. In the prognostic analysis, the 5-year survival rate of lateral lymph node metastasis-positive cases was 19%, and the dissection effect index was 3.5. It was suggested that CRM-positive patients had a higher risk of lateral lymph node metastasis before surgery. However, considering the results of this study and the results of JCOG0212, the presence or absence of lateral lymph node metastasis may be a prognostic predictor, although the prognostic improvement effect by dissection is considered to be limited.

[Effects of Preoperative Skeletal Muscle Mass on the Prognosis of Stageâ ¡ and â ¢ Colorectal Cancer].

INTRODUCTION: Some studies reported that the decrease in skeletal muscle mass worsens the immune and nutritional status and related to the poor prognosis in colorectal cancer. We examined the relationship of skeletal muscle mass, immune and nutritional index, and outcome in patients with colorectal cancer at our hospital. SUBJECTS AND METHODS: We retrospectively analyzed 196 patients of cStageⅡ andⅢ colorectal cancer who underwent curative surgery in our institution between 2007 and 2013. The cross-sectional area of the psoas muscle at the level of the third lumbar vertebra on preoperative computed tomography was assessed to calculate the psoas muscle index(PMI). Patients are divided into high PMIgroup(H-group)and low PMIgroup (L-group)with cut off value(6.36 cm / / 2/m2 for males and 3.92 cm2/m2 for females). Patient background, tumor factor, overall survival(OS), recurrence free survival(RFS)were examined retrospectively. RESULTS: There were 119 cases in H-group and 77 cases in L-group. Significant differences were recognized in gender, age, Alb value, BMI, and adjuvant chemotherapy between 2 groups. The 5-year survival rate was significantly different from 82.8% in H-group and 70.3% in L-group(p<0.01). The 5-year recurrence-free survival rate was 74.0%in the H-group, and 68.3%in the L-group (p=0.46). Univariate and multivariate analysis showed that age(OR: 1.90, p<0.01), high CEA(OR: 0.012, p<0.05), depth of invasion(OR: 2.19, p<0.05), lymph node metastasis(OR: 2.21, p<0.01), and preoperative low PMI(OR: 2.05, p<0.01), were significantly related to decrease of OS. CONCLUSION: Preoperative PMIsuggested to become prognostic factors in Stage Ⅱ and Ⅲ colorectal cancer.

M-CSF Receptor Antagonists Inhibit the Initiation and Progression of Hepatocellular Carcinoma in Mice.

BACKGROUND/AIM: The aim of this study was to investigate the effects of the macrophage colony-stimulating factor (M-CSF) receptor antagonist on hepatic carcinogenesis in mice. MATERIALS AND METHODS: Mice were injected with diethylnitrosamine (DEN) and treated with M-CSF receptor antagonist GW2580 (GW) or a saline vehicle just after (early treated group) or 2 weeks after (late treated group) DEN injection. Animals were sacrificed after 28 weeks and incidence of tumor was assessed. Isolated Kupffer cells were co-cultured with M-CSF in the presence or absence of GW, and the concentration of VEGF was measured. RESULTS: The incidence of tumors was significantly blunted both in the early- and the late-treated groups. In addition, angiogenesis within the tumor was also suppressed in both groups. The concentration of VEGF increased in Kupffer cells treated with M-CSF compared to those cultured without M-CSF. This increase was blunted by GW. CONCLUSION: M-CSF and its receptor could be novel molecular targets for hepatocellular carcinoma.

Long-term outcomes after surgical resection in patients with stage IV colorectal cancer: a retrospective study of 129 patients at a single institution.

BACKGROUND AND PURPOSE: Approximately 20% of all patients with colorectal cancer (CRC) are diagnosed at more advanced stages with synchronous distant metastasis, and the prognosis in these patients is usually poor. The aim of this study was to determine the factors that can identify subgroup(s) of patients with stage IV CRC who could benefit from curative (R0) resection of both primary and metastatic lesions. PATIENTS AND METHODS: A total of 126 patients with stage IV CRC who underwent surgical resection of primary tumor were retrospectively analyzed. Among these patients, 26 cases of R0 resection were further examined subsequently. Information on various clinicopathological factors of the patients were obtained from hospital records. Overall survival was estimated using the Kaplan-Meier method, and log-rank tests were used to compare survival distribution. All the factors with P < 0.05 in univariate analysis were analyzed in the Cox proportional hazards model. RESULTS: CEA negativity, left-sided tumor, R0 resection, differentiated histology, and nodal staging less than N1 were independent factors that predicted better prognosis in all the 126 patients with stage IV CRC. Tumor depth of T3 or less was significantly correlated with better survival in patients who had undergone R0 resection. CONCLUSION: Our findings demonstrate that it is possible to select patients in whom surgical resection would yield better prognosis, from a variety of patient subgroups with stage IV CRC.

[Effects of Preoperative Immune and Nutritional Indices on the Prognosis of pStage â ¡ and â ¢ Colorectal Cancer].

We examined the relationship between immune and nutritional indices and the outcome of colorectal cancer patients at our hospital. We retrospectively analyzed 196 patients with pStage Ⅱand Ⅲcolorectal cancer who underwent curative surgery in our institution between 2007 and 2013. The evaluation items were immune and nutritional indices, such as neutrophil/lym- phocyte ratio(NLR), platelet/lymphocyte ratio(PLR), lymphocyte/monocyte ratio(LMR), and the Onodera nutritional index (PNI). Moreover, we analyzed the relationship between immune and nutritional indices and outcome, overall survival(OS), and recurrence-free survival(RFS). Univariate and multivariate analyses showed that low LMR was significantly related to high mortality. Univariate analysis showed that high NLR, low LMR, and low PNIwere significantly related to a decrease in OS. Multivariate analysis showed that PNIwas an independent predictor of OS. LMR is suggested as a new predictor for postoperative complications. PNIis suggested as a new prognostic factor in pStageⅡand Ⅲcolorectal cancer.

[Efficacy of Surgery and Adjuvant Chemotherapy for Distal Cholangiocarcinoma].

INTRODUCTION: Surgery alone shows an insufficient result for distal cholangiocarcinoma, and postoperative adjuvant chemotherapy is commonly used. However, no definite opinion has yet been accepted. SUBJECTS AND METHODS: A group of 46 patients who underwent surgery for distal bile duct cancer and who received adjuvant chemotherapy including gemcitabine (GEM)(Group A)and surgery alone group(Group S)were compared for disease-free survival(DFS)and overall survival (OS). RESULTS: Although the median DFS was 718 days in Group A and 367 days in Group S(p=0.306)and the median OS was 1,171 days in Group A and 859 days in Group S(p=0.07), no significant difference was observed; however, the prognosis improved. CONCLUSION: Postoperative adjuvant chemotherapy may improve prognosis.

[Pathologic Complete Response of Advanced Gastric Cancer after Chemotherapy with S-1 and Oxaliplatin and Conversion Surgery-A Case Report].

A man in his 70s was admitted to our hospital for the treatment of gastric cancer type 3 located in the antrum of the stomach. Computed tomography revealed tumor invasion of the liver and metastatic lymph node invasion of the pancreatic head and splenic artery. The patient was diagnosed with unresectable T4bN3M0, Stage ⅢC advanced gastric cancer. As radical excision was impossible, the patient underwent chemotherapy with S-1 and oxaliplatin(SOX). After 13 courses of SOX, imaging showed reduction in the size of the primary tumor and disappearance or marked reduction in the size of the metastatic lymph nodes. Therefore, conversion surgery was attempted after 14 courses of SOX. Distal gastrectomy with D2 lymphadenectomy including station 14v was performed. Pathological examination demonstrated no viable tumor cells in the resected stomach specimen or dissected lymph nodes, confirming that a pathologic complete response(pCR)had been achieved.

Expression of podoplanin in stromal fibroblasts plays a pivotal role in the prognosis of patients with pancreatic cancer.

PURPOSE: To investigate the role of podoplanin (PDPN) expression in invasive ductal carcinoma of the pancreas (IDCP) in humans. METHODS: Tumor samples were obtained from 95 patients with IDCP. Immunohistochemical staining was done to evaluate the expression of PDPN in cancer tissues. RESULTS: PDPN was detected predominantly in stromal fibroblasts, stained with α-smooth muscle actin. The cutoff value of PDPN-positive areas was calculated according to a histogram. There was no significant difference in clinicopathologic factors between patients with high vs. those with low PDPN expression. The high PDPN group showed significantly poorer disease-free and disease-specific survival rates than the low PDPN group. Among patients from the high PDPN group, those with lymph node metastases and those with a tumor larger than 20 cm in diameter had significantly poorer prognoses than similar patients from the low PDPN group. Multivariate Cox proportional hazards analysis indicated that a high expression of PDPN was an independent risk factor for disease-specific survival. CONCLUSIONS: PDPN expression in cancer-related fibrotic tissues is associated with a poor prognosis, especially in patients with large tumors or lymph node metastases.

Macrophage colony-stimulating factor expressed in non-cancer tissues provides predictive powers for recurrence in hepatocellular carcinoma.

AIM: To investigate the role of macrophage colony-stimulating factor (M-CSF) in patients with hepatocellular carcinoma (HCC) after surgery. METHODS: Expression of M-CSF, distribution of M2 macrophages (MΦs), and angiogenesis were assessed in the liver, including tumors and peritumoral liver tissues. The prognostic power of these factors was assessed. Mouse isolated hepatic MΦs or monocytes were cultured with media containing M-CSF. The concentration of vascular endothelial growth factor (VEGF) in media was assessed. Furthermore, the role of the M-CSF-matured hepatic MΦs on proliferation of the vascular endothelial cell (VEC) was investigated. RESULTS: A strong correlation between the expressions of M-CSF and CD163 was observed in the peritumoral area. Also, groups with high density of M-CSF, CD163 or CD31 showed a significantly shorter time to recurrence (TTR) than low density groups. Multivariate analysis revealed the expression of M-CSF or hepatic M2MΦs in the peritumoral area as the most crucial factor responsible for shorter TTR. Moreover, the expression of M-CSF and hepatic M2MΦs in the peritumoral area had better predictable power of overall survival. Values of VEGF in culture media were significantly greater in the hepatic MΦs compared with the monocytes. Proliferation of the VEC was greatest in the cells co-cultured with hepatic MΦs when M-CSF was present in media. CONCLUSION: M-CSF increases hepatocarcinogenesis, most likely by enhancing an angiogenic factor derived from hepatic MΦ and could be a useful target for therapy against HCC.

Interleukin-17A Plays a Pivotal Role in Chemically Induced Hepatocellular Carcinoma in Mice.

AIM: The aim of the present study was to investigate the role of interleukin (IL)-17A in the initiation and progression of hepatocellular carcinoma. METHODS: IL-17A deficient (KO) and wild-type (WT) mice were intraperitoneal injected with diethyl nitrosamine (DEN) to induce hepatocellular carcinoma, and the incidence of tumours was assessed 38 weeks later. In order to investigate the effects of DEN on hepatocytes in the acute phase of DEN administration, DEN-treated mice were sacrificed at designated time points. Serum and liver tissues were harvested for further analyses. RESULTS: The tumor incidence was approximately 65 % in WT mice, but was significantly lower (by 20 %) in KO mice. The number of tumours was also less in KO mice. Serum ALT levels increased in WT mice 7 days after the administration of DEN, but were significantly lower in KO mice. Furthermore, the number of neutrophils and Kupffer cells, and the expression of TNF-α and IL-6 were reduced in KO mice. The intrahepatic expression of the oxidative DNA damage marker 8-OHdG and lipid oxidative marker 4-HNE was markedly increased in WT mice, but was significantly lower in KO mice. In addition, the increase of cell proliferation, as assessed by Ki-67 immunohistochemistry, in WT mice was significantly reduced in KO mice. CONCLUSION: These results demonstrated that IL-17A plays a pivotal role in chemically induced hepatic carcinogenesis, which is most likely through inflammation-initiated oxidative DNA damage and cell proliferation.