Clinicopathological features of cholangiolocarcinoma and impact of tumor heterogeneity on prognosis: A single institution retrospective study.

Cholangiolocarcinoma (CLC) is an extremely rare tumor classified as a subtype of small duct-type intrahepatic cholangiocarcinoma (iCCA). There are few detailed reports on CLC and the prognostic impact of tumor heterogeneity is not clear. Between April 2006 and June 2022, of the 774 primary liver cancer resection cases who presented at Kanazawa University Hospital, 14 patients were pathologically diagnosed with CLC through immunohistochemical analysis of their molecular and biological features. Clinicopathological features and prognoses were evaluated retrospectively. Additionally, tumor heterogeneity was assessed and tumors were classified into pure and partial types according to the CLC component proportion in a single tumor. Chronic liver disease was observed in nine patients (64.3%). All tumors were mass-forming, and pathological R0 resection was achieved in 11 patients (78.6%). Tumor heterogeneity was classified as pure in 11 (78.6%) and partial in three (21.4%) patients. The median follow-up was 59.5 months (12-114 months). There was no difference in the 5-year disease-specific survival rates between the pure and partial (90.0% vs. 100.0%; P=0.200) types, but rates were significantly higher in the R0 resection group compared with those in the R1 resection group (100.0% vs. 50.0%; P=0.025). In conclusion, these results suggest that it is important for CLC patients to achieve curative resection, and CLC may have a good prognosis regardless of the proportion of CLC components in a single tumor.

[Two Cases of Portal Vein Stent Placement for Portal Vein Stenosis Due to Recurrence of Pancreatic Cancer].

We report 2 cases of portal vein stent placement for malignant portal stenosis due to recurrence of pancreatic cancer with symptoms of portal hypertension. Case 1: The patient was a 68-year-old female. Five years ago, a mass was found around the aorta on a computerized tomography(CT)scan taken after a residual pancreatectomy for pancreatic cancer. It was diagnosed as lymph node recurrence and S-1 therapy was started. As further tumor enlargement led to portal vein compression, venostasis around the ascending jejunum, anemia, and black stools, a portal vein stent was placed. The portal vein blood flow was improved, the collateral vessels disappeared, and the patient no longer experienced anemia or black stool. Case 2: A 75-year-old female patient underwent a subtotal gastric-sparing pancreaticoduodenectomy and combined resection of the portal vein for pancreas head cancer. On a postoperative CT scan taken 6 months later, a mass compressing the portal vein appeared, which was diagnosed as a local recurrence. As thrombocytopenia was observed, a portal vein stent was placed before starting chemotherapy. The portal vein blood flow and the platelet count improved. Portal vein stenting is an effective procedure for malignant portal stenosis, improving portal blood flow and clinical symptoms.

Morphology of the Dorsal Pancreatic Artery and Its Oncological Significance in Pancreatic Cancer.

OBJECTIVES: Although the dorsal pancreatic artery (DPA) is an important artery that supplies the pancreas, its morphology has not been sufficiently studied. We investigated the morphology of the DPA and the progression of pancreatic cancer along this vessel. MATERIALS AND METHODS: Overall, 142 patients with pancreatic cancer who underwent surgical resection at Kanazawa University Hospital between 2004 and 2015 were enrolled. We examined the morphology of the DPA using preoperative computed tomography and cancer progression along the DPA using resected specimens. We investigated the anatomical structures surrounding the DPA through cadaveric examination. RESULTS: The analysis of computed tomography images revealed the presence of the DPA in 141 patients. In typical cases, the DPA divides into a head and a body branch. Histopathological examination revealed cancer progression along the DPA in 32 patients. Cancer progression along the DPA was identified as a factor associated with a poor prognosis in pancreatic head or body cancer. Cadaveric examination showed the presence of abundant nerve and lymphatic tissues along the DPA. CONCLUSIONS: It is important to remove the soft tissue surrounding the DPA during surgery for pancreatic head or body cancer because it may serve as an important route for cancer progression.

Cilostazol improves the prognosis after hepatectomy in rats with sinusoidal obstruction syndrome.

BACKGROUND AND AIM: Safe radical hepatectomy is important for patients with colorectal liver metastases complicated by sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy. This study aimed to investigate the impact of preoperative administration of cilostazol (CZ), an oral selective phosphodiesterase III inhibitor, on hepatectomy in rat SOS model. MATERIAL AND METHODS: Rats were divided into NL (normal liver), SOS (monocrotaline [MCT]-treated), and SOS + CZ (MCT + CZ-treated) groups. MCT or CZ was administered orally, and a 30% partial hepatectomy was performed 48 h after MCT administration. Postoperative survival rates were evaluated (n = 9, for each). Other rats were sacrificed on postoperative days (POD) 1 and 3 and evaluated histologically, immunohistochemically, biochemically, and using transmission electron microscopy (TEM), focusing particularly on SOS findings, liver damage, and liver sinusoidal endothelial cell (LSEC) injury. RESULTS: The cumulative 10-day postoperative survival rate was significantly higher in the SOS + CZ group than in the SOS group (88.9% vs 33.3%, P = 0.001). Total SOS scores were significantly lower in the SOS + CZ group than in the SOS group on both POD 1 and 3. Serum biochemistry and immunohistochemistry showed that CZ reduced liver damage after hepatectomy. TEM revealed that LSECs were significantly preserved morphologically in the SOS + CZ group than in the SOS group on POD 1 (86.1 ± 8.2% vs 63.8 ± 9.3%, P = 0.003). CONCLUSION: Preoperative CZ administration reduced liver injury by protecting LSECs and improved the prognosis after hepatectomy in rats with SOS.

Clinical impacts of positive intraepithelial neoplasia at pancreatic transection margin in pancreatic cancer surgery.

BACKGROUND/OBJECTIVES: The outcomes of patients with intraepithelial neoplasia at the pancreatic transection margin after pancreatic cancer surgery remain unclear. We evaluated the clinical impact of pancreatic transection margin status. METHODS: This retrospective observational study included 171 patients who underwent surgery for pancreatic ductal adenocarcinoma between January 2008 and December 2019. Patients were classified into three groups: negative pancreatic transection margin (group N), positive low-grade (group L), and positive high-grade (group H) intraepithelial neoplasia. The clinicopathological findings and prognoses were analyzed for each group. RESULTS: There were 140, 14, and 9 patients in groups N, L, and H, respectively. The median age was significantly higher in group H (p = 0.035). There were no significant differences in male ratio, preoperative chemotherapy administration rate, pretreatment tumor markers, operative procedure, operative time, or blood loss. Overall survival and recurrence-free survival were not significantly different; however, the cumulative risk of recurrence in the remnant pancreas was significantly higher in group H (p = 0.018). CONCLUSIONS: Intraepithelial neoplasia at the pancreatic transection margin did not affect overall/recurrence-free survival. As patients with high-grade intraepithelial neoplasia at the pancreatic transection margin have an increased risk of recurrence in the remnant pancreas, careful postoperative follow-up is required.

Assaying ADAMTS13 Activity as a Potential Prognostic Biomarker for Sinusoidal Obstruction Syndrome in Mice.

Sinusoidal obstruction syndrome (SOS) is a serious liver disorder that occurs after liver transplantation, hematopoietic stem cell transplantation, and the administration of anticancer drugs. Since SOS is a life-threatening condition that can progress to liver failure, early detection and prompt treatment are required for the survival of patients with this condition. In this study, female CD1 mice were divided into treatment and control groups after the induction of an SOS model using monocrotaline (MCT, 270 mg/kg body weight intraperitoneally). The mice were analyzed at 0, 12, 24, and 48 h after MCT administration, and blood and liver samples were collected for assays and histopathology tests. SOS was observed in the livers 12 h after MCT injection. In addition, immunohistochemical findings demonstrated CD42b-positive platelet aggregations, positive signals for von Willebrand factor (VWF), and a disintegrin-like metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) in the MCT-exposed liver sinusoid. Although ADAMTS13's plasma concentrations peaked at 12 h, its enzyme activity continuously decreased by 75% at 48 h and, inversely and proportionally, concentrations in the VWF-A2 domain, in which the cleavage site of ADAMTS13 is located, increased after MCT injection. These findings suggest that the plasma concentration and activity of ADAMTS13 could be useful biomarkers for early detection and therapeutic intervention in patients with SOS.

Hemophagocytic Lymphohistiocytosis With Elevated Cytokines Related to Macrophage Activation After Liver Transplantation for Autoimmune Hepatitis: A Case Report.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but lethal complication of liver transplantation (LT). HLH is characterized by pathologic macrophage activation with hypercytokinemia, excessive inflammation, and tissue destruction, resulting in progressive organ dysfunction. HLH is also known as macrophage activation syndrome (MAS) when complicated by rheumatic or autoinflammatory diseases. Measuring several serum cytokines could be helpful in diagnosing HLH and MAS. Cytokines related to macrophage activation: neopterin, interleukin-18 (IL-18), and soluble tumor necrosis factor receptors (sTNF-R) I and II have not been assessed in patients with HLH complicated by LT. In this case, these cytokines were evaluated in the perioperative period of LT. The patient was a 24-year-old woman who underwent living-donor LT for acute worsening of autoimmune hepatitis. On postoperative day 12, the patient was diagnosed with HLH on the basis of the criteria. Plasma exchange, steroid pulse therapy, intravenous immunoglobulin and granulocyte-colony stimulating factor effectively inhibited progression to lethal HLH. When HLH occurred after LT, cytokine analysis showed that neopterin, IL-18, sTNFR-I, and II were elevated: cytokine storm. Of note, cytokine analysis on hospital admission also revealed elevated cytokine levels. Particularly, IL-18 levels were markedly elevated, suggesting that activation of the innate immune system was involved. These results revealed that a cytokine storm and macrophage activation developed before LT. Based on these findings, cytokine analysis related to macrophage activation may be useful for diagnosing and predicting HLH and MAS in patients with LT.

Case report: therapeutic monitoring of vancomycin in an acute liver failure patient with anuria under high-flow continuous hemodiafiltration.

BACKGROUND: High-flow continuous hemodiafiltration (HF-CHDF) combines diffusive and convective solute removal and is employed for artificial liver adjuvant therapy. However, there is no report on dosage planning of vancomycin (VCM) in patients with acute liver failure under HF-CHDF. CASE PRESENTATION: A 20-year-old woman (154 cm tall, weighing 50 kg) was transferred to the intensive care unit (ICU) with acute liver failure associated with autoimmune liver disease. On the following day, HF-CHDF was started due to elevated plasma ammonia concentration. On ICU day 8, VCM was started for suspected pneumonia and meningitis (30 mg/kg loading dose, then 20 mg/kg every 12 hrs). However, on ICU day 10, VCM blood concentration was under the limit of detection (< 3.0 µg/mL) and the patient developed anuria. The VCM dose was increased to 20 mg/kg every 6 hrs. Calculation with a one-compartment model using the HF-CHDF blood flow rate as a surrogate for VCM clearance, together with hematocrit and protein binding ratio, predicted a trough VCM blood concentration of 15 µg/mL. The observed concentration was about 12 µg/mL. The difference may represent non-HF-CHDF clearance. Finally, living donor liver transplantation was performed. CONCLUSION: We report an acute liver failure patient with anuria under HF-CHDF in whom VCM administration failed to produce an effective blood concentration, likely due to HF-CHDF-enhanced clearance. VCM dosage adjustment proved successful, and was confirmed by calculation using a one-compartment model.

Early progression of a pancreatic metastasis of synovial sarcoma after pancreatectomy.

BACKGROUND: Synovial sarcoma is a malignant tumor that constitutes up to 10% of all soft-tissue sarcomas. The most frequent metastatic sites of synovial sarcoma are the lungs, lymph nodes, and bone, whereas pancreatic metastasis is extremely rare. Here, we report a case of pancreatic metastasis of synovial sarcoma. CASE PRESENTATION: Nine years before presentation, a 31-year-old woman underwent extensive resection of the primary tumor after chemotherapy for left upper extremity synovial sarcoma. Six months before presentation, interscapulothoracic amputation was performed for an enlarged mass in the left upper extremity; the patient was treated with pazopanib. Three months before presentation, chest computed tomography showed multiple lung metastases; during subsequent follow-up, abdominal computed tomography revealed a pancreatic metastasis of synovial sarcoma. The doubling time of the pancreatic tumor was 14 days, and it grew rapidly. Furthermore, treatment-resistant pancreatitis symptoms were detected; thus, we performed distal pancreatectomy and administered one course of a 70% dose of trabectedin. However, the patient died of rapid progression of lung metastasis and respiratory failure within 2 months after surgery. CONCLUSIONS: Pancreatectomy may be carefully performed in cases of isolated pancreatic metastasis. However, the presence of other distant extrapancreatic metastases (e.g., uncontrolled lung metastases) may rule out pancreatectomy treatment.

Successful second conversion surgery after trastuzumab deruxtecan for recurrent HER2-positive gastric cancer.

A 65-year-old woman with HER2-positive gastric cancer with multiple liver metastases underwent first conversion surgery of gastrectomy with D2 lymph nodes dissection and three liver metastases after combination therapy with capecitabine, cisplatin, and trastuzumab. Two years later, she experienced multiple liver metastases that were refractory to combination therapy with paclitaxel albumin-bound nanoparticles and ramucirumab. She participated in the DESTINY-Gastric01 trial and received tri-weekly trastuzumab deruxtecan as third-line treatment for 26 cycles. The recurrent lesions markedly shrank, and this effect continued for 19 months. We then performed partial hepatectomy for the one remaining lesion. No adjuvant chemotherapy was given, and she remains alive without recurrence 18 months after the second conversion surgery. Trastuzumab deruxtecan may generate a notable tumor response and subsequent conversion surgery could be a treatment option for HER2-positive stage IV gastric cancer.

Thrombopoietin accumulation in hepatocytes induces a decrease in its serum levels in a sinusoidal obstruction syndrome model.

Sinusoidal obstruction syndrome (SOS) is a type of fatal hepatic injury, which predominantly occurs following exposure to drugs, such as oxaliplatin, or bone marrow transplantation. Extravasated platelet aggregation (EPA) plays an important role in the development of SOS in rat and mouse models. Furthermore, platelets invading the space of Disse adhere to hepatocytes and are phagocytized in patients with SOS. Aging platelets and platelets in patients with sepsis are phagocytized by hepatocytes through Ashwell­Morell receptors, and thrombopoietin (TPO) is produced by the JAK2­STAT3 signaling pathway. The purpose of the present study was to examine the significance of TPO as a biomarker of SOS. SOS was induced in Crl:CD1(ICR) female mice by intraperitoneal administration of monocrotaline (MCT). TPO levels were measured in the serum and liver tissue. Pathological and immunohistochemical studies of the liver were performed to analyze the expression levels of TPO. TPO mRNA expression levels were measured using reverse transcription­quantitative PCR. In the SOS model, the platelet counts in peripheral blood samples were significantly decreased at 24 and 48 h after MCT treatment as compared with that at 0 h. In addition, a pathological change in hepatic zone 3 was observed in the SOS model group. Furthermore, the protein levels of TPO in liver tissue were significantly increased in the SOS model group compared with those in the control group, which was confirmed by immunohistochemistry. By contrast, serum TPO protein levels were significantly decreased in the SOS model group compared with those in the control group. These results indicated that EPA may induce sinusoidal endothelial fenestration in a mouse model of SOS, preventing TPO from translocating into the blood. In conclusion, serum TPO levels may be reduced in a mouse model of SOS owing to the accumulation in hepatocytes, suggesting that TPO could be a useful biomarker of SOS.

Verification of Resectability Status for Pancreatic Cancer: Radiological and Pathological Analysis of Patients Undergoing Pancreatoduodenectomy With Combined Resection of the Superior Mesenteric Artery.

OBJECTIVES: Resectability status is considered an important indicator for progression of pancreatic cancer. We verified the superior mesenteric artery (SMA) factors of resectability status by radiological and pathological analysis in patients who underwent pancreatoduodenectomy with combined resection of the SMA. METHODS: We enrolled 22 patients who underwent pancreatoduodenectomy with combined resection of the SMA. Patients were divided into 3 groups according to the contact angle between the tumor and the SMA in preoperative computed tomography images (no contact, R-sma; contact within 180 degrees, BR-sma; contact more than 180 degrees, UR-sma). We pathologically evaluated cancer progression toward the SMA. RESULTS: There were 3 patients with R-sma, 12 with BR-sma, and 7 with UR-sma. The median distance (mm) between the cancer and the SMA was 7.0 with R-sma, 1.0 with BR-sma, and 0 with UR-sma (P = 0.0003). Invasion to the superior mesenteric nerve plexus was positive in none with R-sma, 11 with BR-sma, and 7 with UR-sma (P < 0.0001). Invasion to the SMA was positive in none with R-sma and BR-sma, and 7 with UR-sma (P < 0.0001). CONCLUSIONS: Superior mesenteric artery factors of resectability status are reliable indicator for cancer progression toward the SMA.

Analysis of perioperative glucose metabolism using an artificial pancreas.

Hyperglycemia associated with insulin resistance is common in surgical patients with and without diabetes and is associated with poor surgical outcomes. Several studies have recently shown that a closed-loop blood glucose monitoring system in the form of an artificial pancreas is safe and effective for surgical patients. In this study, we analyzed the risk factors for insulin resistance in patients using an artificial pancreas. We investigated 109 patients who underwent surgical management by an artificial pancreas for 24 hours from the start of surgery during either major hepatectomy (MH), defined as resection of more than two liver segments, or pancreaticoduodenectomy (PD). The target glucose range was from 80 to 110 mg/dL using an artificial pancreas. We analyzed the risk factors for and predictors of a high insulin dose, including sarcopenia markers, according to the median 24-hour total insulin infusion. The median total insulin dose and glycemic control rate (GCR), which is the rate of achieving the target blood glucose range, per 24 hours were 78.0 IU and 30.4% in the MH group and 82.6 IU and 23.5% in the PD group, respectively. The muscle volume was the only independent factor in the high-dose subgroup, and the GCR was significantly lower in the high-dose subgroup despite a high insulin dose in both the MH and PD groups. The results of this study suggest that preoperative sarcopenia is closely associated with insulin resistance in the perioperative period. Clinicians must effectively manage sarcopenia, which may result in improved perioperative glycemic control and reduced postoperative complications.

[Four Cases of Surgical Treatment for Radiation Enteritis].

Although radiation therapy for pelvic cancer leads to improved outcomes, it may cause radiation enteritis. Radiation enteritis is classified as early and late reaction. Late reaction indicate progressive and irreversible changes caused by ischemic changes of the intestinal mucosa. Severe cases require a surgical treatment, which is challenging because of severe adhesions and a high risk of suture failure. In addition, the postoperative course may be unfavorable in some cases. We performed surgery for 4 radiation enteritis cases; however, the postoperative course was unfavorable in 2 cases because of impaired absorption and ileus of the remaining short bowel. These patients could not eat adequately after discharge; therefore, we needed to explain and make them understand the benefits and disadvantages of radiation therapy.

Comparison of prognostic impact of anatomic location of the pancreas on postoperative pancreatic fistula in laparoscopic and open gastrectomy.

BACKGROUND: Postoperative pancreatic fistula (POPF) is a serious complication after gastric cancer surgery. The current study aimed to investigate the significance of the anatomic location of the pancreas as a predictor for POPF in both laparoscopic gastrectomy (LG) and open gastrectomy (OG). METHODS: In total, 233 patients with gastric cancer were assessed retrospectively. We measured the maximum vertical (P-L height; PLH) and horizontal length (P-L depth; PLD) between the upper border of pancreas and the root of left gastric artery on a preoperative CT in the sagittal direction. The maximum length of the vertical line between the surface of the pancreas and the aorta (P-A length), previously reported as prognostic factor of POPF, was also measured. We investigated the correlations between these parameters and the incidence of POPF in LG and OG groups. RESULTS: Among the patients in this study, 118 underwent OG and 115 underwent LG. In LG, the median PLH and P-A length in patients with POPF were significantly longer compared with those without POPF (p = 0.026, 0.034, respectively), but not in OG. There was no significant difference in the median PLD between the patients with or without POPF in both LG and OG. The multivariate analysis demonstrated that PLH (odds ratio [OR] 4.19, 95% confidence interval [CI] 1.57-11.3, P = 0.004) and P-A length (OR 4.06, 95%CI 1.05-15.7, P = 0.042] were independent factors for predicting POPF in LG. However, intraoperative blood loss (OR 2.55, 95%CI 1.05-6.18, P = 0.038) was extracted as an independent factor in OG. The median amylase level in the drained fluid (D-Amy) were significantly higher in patients with high PLH(≥12.4 mm) or high P-A length (≥45 mm) compared with those with low PLH or low P-A length in LG. However, there were no differences in the D-Amy levels by PLH or P-A length in OG patients. CONCLUSIONS: The anatomic location of the pancreas is a specific and independent predictor of POPF in LG but not in OG. PLH is a simple parameter that can evaluate the anatomic position of the pancreas, and it may be useful for preventing POPF after LG.

Clinical features and diagnostic imaging of cholangiolocellular carcinoma compared with other primary liver cancers: a surgical perspective.

BACKGROUND AND OBJECTIVES: Although cholangiolocellular carcinoma is considered a combined hepatocellular and cholangiocarcinoma, we feel that this classification is not appropriate. Therefore, we compared the diagnostic imaging findings, surgical prognosis, and pathological features of cholangiolocellular carcinoma with those of other combined hepatocellular and cholangiocarcinoma subtypes, hepatocellular carcinoma, and cholangiocarcinoma. METHODS: The study patients included 7 with classical type combined hepatocellular and cholangiocarcinoma; 8 with stem cell feature, intermediate type combined hepatocellular and cholangiocarcinoma; 13 with cholangiolocellular carcinoma; 58 with cholangiocarcinoma; and 359 with hepatocellular carcinoma. All patients underwent hepatectomy or living-related donor liver transplantation from 2001 to 2014. RESULTS: cholangiolocellular carcinoma could be distinguished from hepatocellular carcinom, other combined hepatocellular and cholangiocarcinoma subtypes, and cholangiocarcinoma by the presence of intratumoral Glisson's pedicle, hepatic vein penetration, and tumor-staining pattern on angiography-assisted CT. Cholangiolocellular carcinoma was associated with a significantly lower SUV-max than that of cholangiocarcinoma on FDG-PET. Hepatocellular carcinoma, classical type, and cholangiolocellular carcinoma had significantly better prognoses than stem cell feature, intermediate type and cholangiocarcinoma. A cholangiocarcinoma component was detected in cholangiolocellular carcinoma that progressed to the hepatic hilum, and the cholangiocarcinoma component was found in perineural invasion and lymph node metastases. CONCLUSIONS: From the viewpoint of surgeon, cholangiolocellular carcinoma should be classified as a good-prognosis subtype of biliary tract carcinoma because of its tendency to differentiate into cholangiocarcinoma during its progression, and its distinctive imaging and few recurrence rates different from other combined hepatocellular and cholangiocarcinoma subtypes.

Extravasated platelet aggregation contributes to tumor progression via the accumulation of myeloid-derived suppressor cells in gastric cancer with peritoneal metastasis.

Extravasated platelet aggregation (EPA) serves an important role in the cancer microenvironment during cancer progression, and has been demonstrated to interact with tumor cells in several types of cancer. EPA induces epithelial-mesenchymal transition (EMT) via transforming growth factor-ß, and also recruits immunosuppressive cells, including regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs). However, the role of EPA in gastric cancer with peritoneal metastasis remains unknown. The present study analyzed the association between EPA and prognosis in patients with gastric cancer with peritoneal metastasis. The present study evaluated 62 patients diagnosed with advanced gastric cancer with peritoneal metastasis between 2001 and 2016. EPA, EMT, Treg cells and MDSCs in peritoneal metastatic lesions were detected by immunohistochemical evaluation of CD42b, SNAIL, FOXP3 and CD33, respectively. CD42b expression was observed in 56.5% (35/62) of peritoneal metastatic lesions. CD42b expression in peritoneal metastatic lesions was associated with poor overall survival compared with lower frequencies (hazard ratio, 2.03; 95% confidence interval, 1.12-3.69; P=0.018). SNAIL, FOXP3 and CD33 expression were not associated with overall survival, but CD33 expression was markedly higher in CD42b-positive patients (P=0.022). These results indicated that EPA affects immunosuppression by recruiting MDSCs in the tumor microenvironment via the secretion of soluble factors, resulting in tumor progression. EPA may be a novel therapeutic target for gastric cancer with peritoneal metastasis.

Pretreatment with a Phosphodiesterase-3 Inhibitor, Milrinone, Reduces Hepatic Ischemia-Reperfusion Injury, Minimizing Pericentral Zone-Based Liver and Small Intestinal Injury in Rats.

BACKGROUND Severe pericentral zone (zone 3)-based liver injury (LI) may become intractable, with allograft dysfunction after liver transplantation. The phosphodiesterase-3 inhibitor, milrinone, has been reported to attenuate hepatic ischemia-reperfusion injury (IRI). This study clarified how hepatic IRI involved zone 3-based LI, in which zone milrinone was effective, and whether milrinone could improve small intestinal injury (SII) with hepatic IRI. MATERIAL AND METHODS Rats were divided into sham, ischemia-reperfusion (IR), or IR+milrinone groups (n=13 per group). Milrinone was administered intraportally via intrasplenic injection, and whole hepatic ischemia was induced for 30 min. Five hours after reperfusion, serum chemistry and histopathological findings were compared. Expression of CD34 for the detection of altered sinusoidal endothelium as sinusoidal capillarization and cleaved caspase-3 as an apoptosis marker were analyzed via immunohistochemistry. Survival rates were examined after 45 min of whole hepatic ischemia. RESULTS Serum aspartate aminotransferase and direct bilirubin levels were significantly decreased in the IR+milrinone group compared with those of the IR group. The degree of LI, sinusoidal capillarization and apoptosis at zone 3 in the IR group was significantly increased compared with those at the periportal zone (zone 1). These findings at zone 3 in the IR group were improved in the IR+milrinone group. SII with villus congestion and apoptosis in the IR group was significantly attenuated in the IR+milrinone group. The 7-day survival rate was significantly elevated in the IR+milrinone group as compared with that of the IR group. CONCLUSIONS A hepatic IRI model caused zone 3-based LI and SII, which were attenuated by intraportal administration of milrinone.

Interactions Between Neutrophils and Platelets in the Progression of Acute Pancreatitis.

OBJECTIVE: Severe acute pancreatitis is a serious disease, but its detailed mechanism has not yet been elucidated. We aimed to clarify the interaction between neutrophils and platelets in the pathogenesis of acute pancreatitis. METHODS: We induced acute pancreatitis in rats by injection of sodium taurocholate into the biliopancreatic duct and killed them over time. We observed the histological changes in pancreatic tissue with special attention to the dynamics of neutrophils and platelets. We also measured the concentrations of neutrophil- and platelet-derived factors in pancreatic tissue and blood samples. RESULTS: Neutrophils and platelets in the pancreatic tissue showed a similar pattern of migration. They initially spread in the interlobular connective tissue and finally into the lobules. The concentration of myeloperoxidase gradually increased in the inflamed pancreas until 24 hours and the concentration of thromboxane B2, plasminogen activator inhibitor 1, and CD41 also increased with time. Finally, the concentration of serum myeloperoxidase, citrullinated histone H3, and high-mobility group box 1 increased over time. CONCLUSIONS: The interaction between neutrophils and platelets in pancreatic tissue plays an important role in the mechanism of advancing severity in acute pancreatitis. Circulating damage-associated molecular patterns induced by excessive local inflammation may lead to other organ injuries.