Girdin regulates both migration and angiogenesis in pancreatic cancer cell lines.

Girdin, an actin­binding protein, is reportedly involved in the invasion and angiogenesis of various cancers. It has been suggested that the flavonoid Scutellarin (SCU) inhibits Girdin signaling. In the present study, the function and therapeutic applications of Girdin in pancreatic cancer (PaCa) were investigated. Immunohistochemical staining of Girdin in resected PaCa specimens from the Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science showed that high Girdin expression was associated with poor overall survival and relapse­free survival, as well as with T factor, indicating invasion into the surrounding tissues. On the other hand, Girdin was highly expressed in almost all PaCa cell lines, and the migration ability of Girdin­knockdown cell lines was decreased even under epidermal growth factor (EGF) stimulation. In addition, SCU suppressed PaCa cell migration by inhibiting the phosphorylation of Girdin. The expression and production of vascular endothelial growth factor A (VEGF­A) was significantly decreased in Girdin­knockdown cell lines. Furthermore, in Matrigel tube formation assays performed using culture supernatant, the lumen­forming ability of vascular endothelial cells was also decreased in Girdin­knockdown cell lines. However, SCU treatment did not significantly alter the expression or production of VEGF­A. These results suggested that Girdin is involved in EGF signaling­mediated migration of PaCa cells, that SCU inhibits PaCa invasion by suppressing Girdin activity, and that Girdin is also involved in angiogenesis via an activation pathway different from the action site of SCU. Girdin may be a prognostic biomarker, and the development of a novel molecular­targeted drugs for Girdin may improve the prognosis of PaCa in the future.

[A Case of Surgical Resection of Advanced Gallbladder Cancer with Adult Annular Pancreas].

An-81-year-old man presented to another doctor complaining of epigastric pain. He was referred to us after the laboratory data revealed a high serum CEA and abdominal ultrasonography showed the space occupying lesion in the left liver. Abdominal CT revealed advanced gallbladder cancer infiltrating the liver and colon and found annular pancreas surrounding the descending portion of duodenum. We chose partial hepatectomy(S4a+S5), extrahepatic bile duct resection with hepaticojejunostomy and partial colectomy. Pathological diagnosis of the tumor was pT3N1M0, gallbladder cancer. The patient was discharged on the 21 days after operation. The frequency of malignant tumors in adult annular pancreas are not revealed. But some cases present with adult annular pancreas complicating the biliary tract tumor. We experienced a case of advanced gallbladder cancer with adult annular pancreas and report our case and review the pertinent literature.

Enhanced CXCL12/CXCR4 signaling increases tumor progression in radiation­resistant pancreatic cancer.

Pancreatic cancer (PaCa) exhibits one of the poorest prognoses among all gastrointestinal cancers due to the rapid development of treatment resistance, which renders chemotherapy and radiotherapy no longer effective. However, the mechanisms through which PaCa becomes resistant to radiotherapy are unknown. Here, we established radiation­resistant PaCa cell lines to investigate the factors involved in radiation resistance. The role of the C­X­C motif chemokine ligand 12 (CXCL12)/C­X­C chemokine receptor type 4 (CXCR4) axis in radiation resistance in PaCa and the effects of a CXCR4 antagonist on radiation­resistant PaCa cell lines were investigated. As confirmed by immunofluorescence staining, reverse transcription quantitative polymerase chain reaction, and western blotting, the expression of CXCR4 was higher in radiation­resistant PaCa cell lines than that noted in normal PaCa cell lines. The invasion ability of radiation­resistant PaCa cell lines was greater than that of normal cell lines and was enhanced by CXCL12 treatment and coculture with fibroblasts; this enhanced invasion ability was suppressed by the CXCR4 antagonist AMD070. Irradiation after treatment with the CXCR4 antagonist suppressed the colonization of radiation­resistant PaCa cell lines. In conclusion, the CXCL12/CXCR4 axis may be involved in the radiation resistance of PaCa. These findings may facilitate the development of novel treatments for PaCa.

10Z­Hymenialdisine inhibits angiogenesis by suppressing NF­κB activation in pancreatic cancer cell lines.

10Z­Hymenialdisine is a natural product derived from the marine sponge Axinella carteri. 10Z­Hymenialdisine has anti­inflammatory effects exerted through NF­κB; however, it is unclear whether 10Z­Hymenialdisine has anti­angiogenic effects in cancer cells. In the present study, both the anti­angiogenic and antimetastatic effects of this compound in pancreatic cancer were investigated. It was initially confirmed that 10Z­Hymenialdisine significantly inhibited the proliferation of pancreatic cancer cells. Next, using both reverse transcription­quantitative PCR and ELISA, it was demonstrated that 10Z­Hymenialdisine significantly suppressed the expression of VEGF and IL­8 mRNAs and proteins in pancreatic cancer. Immunohistochemical analysis revealed that 10Z­Hymenialdisine inhibited NF­κB activity in pancreatic cancer cell lines. It was also identified that 10Z­Hymenialdisine inhibited tube formation in EA.hy926 cells. In vivo, 10Z­Hymenialdisine significantly inhibited the growth of BxPC­3 pancreatic cancer cells that were subcutaneously injected into model mice. In conclusion, the present study demonstrated that 10Z­Hymenialdisine exerted anti­angiogenic effects by suppressing NF­κB activity and angiogenic factors, such as VEGF and IL­8, in pancreatic cancer cell lines. 10Z­Hymenialdisine has potential applications as a novel therapeutic agent for the treatment of pancreatic cancer.

Escin inhibits angiogenesis by suppressing interleukin­8 and vascular endothelial growth factor production by blocking nuclear factor­κB activation in pancreatic cancer cell lines.

Pancreatic cancer (PaCa) is one of the most aggressive types of cancer. Thus, the development of new and more effective therapies is urgently required. Escin, a pentacyclic triterpenoid from the horse chestnut, has been reported to exhibit antitumor potential by reducing cell proliferation and blocking the nuclear factor­κB (NF­κB) signaling pathway in several types of cancer. Our previous study reported that NF­κB enhanced the secretion of interleukin (IL)­8 and vascular endothelial growth factor (VEGF), thereby inducing angiogenesis in PaCa cell lines. In the present study, it was examined whether escin inhibited angiogenesis by blocking NF­κB activation in PaCa. It was initially confirmed that escin, at concentrations >10 µM, significantly inhibited the proliferation of several PaCa cell lines. Next, using immunocytochemical staining, it was found that escin inhibited the nuclear translocation of NF­κB. Furthermore, ELISA confirmed that NF­κB activity in the escin­treated PaCa cells was significantly inhibited and reverse transcription­quantitative PCR showed that the mRNA expression levels of tumor necrosis factor­α­induced IL­8 and VEGF were significantly suppressed following escin treatment in the PaCa cell lines. ELISA also showed that escin decreased the secretion of IL­8 and VEGF from the PaCa cells. Furthermore, tube formation in immortalized human endothelial cells was inhibited following incubation with the supernatants from escin­treated PaCa cells. These results indicated that escin inhibited angiogenesis by reducing the secretion of IL­8 and VEGF by blocking NF­κB activity in PaCa. In conclusion, escin could be used as a novel molecular therapy for PaCa.

A hybrid approach for chronic pancreatitis: combination of laparoscopic assisted distal pancreatectomy and open Frey procedure.

BACKGROUND: The treatment of chronic pancreatitis requires a surgical approach in patients who are refractory to medical therapy. During surgical treatment, ductal decompression is required, but a pancreatectomy is necessary for some patients, such as those with severe stenosis of the pancreatic duct. Indeed, suboptimal procedures lead to recurrent pancreatitis. We used a laparoscopic hybrid approach for patients with severe stenosis of the pancreatic duct. In this report, we present the feasibility and outcomes of our approach. METHODS: We selected a laparoscopic approach for the distal pancreatectomy, which is relatively safe and the effect of reducing the length of the wound is substantial. We selected an open approach for the Frey procedure because complete ductal compression has a high risk for injury to the vessels posterior to the pancreas. We recorded the operative outcomes, postoperative complications, and recurrence of pancreatitis. RESULTS: We performed the laparoscopic hybrid approach on 3patients between January and December 2018. There were no major intraoperative complications (Clavien-Dindo classification IIIa or more) and the postoperative course was uneventful in all patients. There were no recurrences of pancreatitis and no postoperative pain in all patients in > 2 years of follow-up. CONCLUSION: Our hybrid method with a focus on complete ductal compression with safety and minimal invasiveness might be the optimal approach for the surgical treatment of chronic pancreatitis that requires a pancreatectomy with the Frey procedure.

[A Case of Solitary Liver Metastasis from Renal Cell Carcinoma That Was Difficult to Distinguish from Hepatocellular Carcinoma and Underwent Laparoscopic Resection].

We experienced a case of solitary liver tumor that developed after renal cancer surgery. Before the surgery, the tumor was suspected to be hepatocellular carcinoma and was subsequently diagnosed as renal cancer liver metastasis. An 81-year-old man underwent retroperitoneal laparoscopic nephrectomy for left renal cancer in January 2017. After that, the cancer had not recurred, but a follow-up CT examination 1 year after the operation revealed a 42 mm-sized tumor in the liver S6. Liver biopsy was performed for diagnosis, but in histopathological findings, the diagnosis was difficult to make. Eventually, the preoperative final diagnosis was hepatocellular carcinoma. Laparoscopic partial hepatectomy was performed in June 2018, and in the histopathological findings of the resected specimen, the final diagnosis was the liver metastasis from renal cancer. Generally, the prognosis of renal cancer with liver metastasis is poor, but if complete resection is possible, it is recommended in the Clinical Practical Guideline for Renal Cancer. In recent years, the number of minimally invasive laparoscopic surgeries for hepatectomy has increased, and its safety has also improved. Therefore, resection is diagnostic treatment for cases where, like this case, preoperative diagnosis for solitary liver tumor is difficult. Laparoscopic hepatectomy could be one of the effective treatment strategies.

Epithelial cyst arising in an intrapancreatic accessory spleen: a case report of robotic surgery and review of minimally invasive treatment.

BACKGROUND: An epithelial cyst in an intrapancreatic accessory spleen (ECIPAS) is rare. We report a case of ECIPAS that was treated with robot-assisted distal pancreatectomy with splenectomy. CASE PRESENTATION: The case was a 59-year-old woman who was referred to our hospital after a pancreatic tail tumor was found on computed tomography prior to surgery for small bowel obstruction at another hospital. A cystic lesion in the pancreatic tail was discovered and evaluated by magnetic resonance imaging and endoscopic ultrasonography. Based on clinical and radiological features, mucinous cystic neoplasm was included in the differential diagnosis. The patient underwent robot-assisted distal pancreatectomy with splenectomy. The postoperative course was uneventful. Pathological evaluation revealed a 20-mm ECIPAS in the pancreatic tail. CONCLUSIONS: If a pancreatic tail tumor is present, ECIPAS should be included in the differential diagnosis. However, preoperative diagnosis is difficult, and a definitive diagnosis is often not obtained until after surgery. Surgery should be minimally invasive. Laparoscopic distal pancreatectomy has become a standard surgical procedure because it is minimally invasive. Robot-assisted surgery is not only minimally invasive, but also advantageous, because it has a stereoscopic magnifying effect and allows the forceps to move smoothly. Robot-assisted distal pancreatectomy may be a good option, when performing surgery for a pancreatic tail tumor.

[A Case of Unresectable Hilar Cholangiocarcinoma Resected Curatively Through Effective Response to Neoadjuvant Chemotherapy].

A 60's man came to our hospital for jaundice. Contrast-enhanced CT showed irregular thickening of the hilar bile duct, and the lymph nodes(LN)were swollen from the hilar to the abdominal aorta. These LNs showed similar findings in endoscopic ultrasonography(EUS), and fine needle aspiration cytology(FNA)was performed on the enlarged No.13LN to diagnose LN metastasis of hilar cholangiocarcinoma. Since the peri-aortic LN was also markedly enlarged, it was considered to be metastasis, and was diagnosed as unresectable hilar cholangiocarcinoma with distant LN metastasis. When gemcitabine/cisplatin therapy(GC therapy)was started, tumor markers normalized and LN decreased in 4 months. We performed GC therapy for a total of 12 cycles and did not re-exacerbate. Cholangioscopy revealed that bile duct stenosis at the hilar portion had improved. We have determined that curative resection is possible and performed surgery. We confirmed that No.16b1LN was negative by pathological diagnosis during surgery and performed left hepatic caudate lobectomy, extrahepatic cholangectomy, and biliary reconstruction. Diagnosis was pT2aN1(n8a)M0, fStage ⅢB, and pR0. After surgery, adjuvant chemotherapy with S-1 was continued.

[A Case Report of Lymph Node Metastasis of Hepatocellular Carcinoma Resected by Laparoscopic Surgery].

The case presented is a 72-year-old male with no history of hepatitis B or C. Dynamic CT revealed a 2 cm mass in the liver (S8), with arterial phase hyperenhancement and delayed phase washout. The patient underwent an open S8 subsegmentectomy. The mass was pathologically diagnosed as well-to-moderately differentiated hepatocellular carcinoma(T2N0M0, Stage Ⅱ). At 2 years 10 months postoperatively, MRI showed a 4 cm mass in contact with the pancreatic head, inferior vena cava, and duodenum. The mass had moderate FDG uptake on PET scan, and early phase hyperenhancement and delayed phase washout on dynamic CT. We performed laparoscopic mass resection, suspecting lymph node metastasis of the hepatocellular carcinoma, which was confirmed by the pathological diagnosis. The patient has survived for 1 year without recurrence. Lymph node metastasis of hepatocellular carcinoma is rare. It is unclear whether surgical resection is feasible in such cases. Here, we report a case of lymph node metastasis of hepatocellular carcinoma resected by laparoscopic surgery.

[A Case of Gallbladder Cancer with Para-Aortic Lymph Node Metastasis Successfully Treated by Gemcitabine plus Cisplatin Combination Chemotherapy and Conversion Surgery].

The case is a 59-year-old woman. A medical examination revealed a high CA19-9, she visited a nearby hospital. Abdominal echo showed thickening of the gallbladder wall, and she was referred to our hospital for further examination. EUS-FNA was performed and a biopsy of #12 lymph node revealed undifferentiated cancer, which was diagnosed as gallbladder cancer. FDG-PET showed accumulation of FDG in the gallbladder lumen and swollen lymph nodes around the aorta. Therefore, the cancer was considered unresectable and chemotherapy was performed. FDG-PET was re-examined after 4 courses of gemcitabine plus cisplatin combination chemotherapy. As a result, the lymph node swelling contracted, the accumulation of FDG disappeared, and surgery was scheduled. Extended cholecystectomy and extrahepatic bile duct resection were performed. She was discharged 22 days after the surgery without complications. Histopathological examination showed fibrotic tissue at the gallbladder and lymph nodes, but no residual tumor cells. There are no recurrences 11 months after surgery. Although the prognosis of gallbladder cancer with para-aortic lymph node metastasis is generally poor, it is suggested that conversion surgery with multimodality treatment including preoperative chemotherapy may be a useful therapeutic strategy.

Acquisition of gemcitabine resistance enhances angiogenesis via upregulation of IL­8 production in pancreatic cancer.

Gemcitabine (Gem) is widely used as chemotherapy for pancreatic cancer (PaCa), but its effect is not fully satisfactory. One of the reasons for this is the acquisition of Gem resistance (Gem­R). To elucidate the mechanism of Gem­R, two Gem­R PaCa cell lines were established from AsPC­1 and MIA PaCa­2 cells. It was demonstrated that expression of interleukin­8 (IL­8) mRNA was significantly upregulated in Gem­R PaCa cells by cDNA microarray and RT­qPCR analyses. Increased IL­8 secretion by Gem­R cells was confirmed by cytokine array and enzyme­linked immunosorbent assay. Moreover, we found that co­culture with Gem­R PaCa cells significantly enhanced tube formation of human umbilical vein endothelial cells, and treatment with an anti­CXCR2 (main receptor for IL­8) antibody significantly prevented this effect. We previously reported that a chemokine network centered on the IL­8/CXCR2 axis plays an important role in PaCa angiogenesis, and suppression of this axis has an antitumor effect. Since acquisition of Gem­R increased IL­8 production and consequently increased tumor angiogenesis, the IL­8/CXCR2 axis may be a potential novel therapeutic target for PaCa after acquiring Gem­R.

[A Case with Long Survival after Total Remnant Pancreatectomy for Recurrence of Pancreatic Body Cancer].

A 56-year-old man underwent distal pancreatectomy due to pancreatic body carcinoma in 2009, at the age of 46. There had been no sign of metastasis and recurrence until levels of tumor markers began to increase in January 2014. PET scan, CT scan, and other examinations showed a possible carcinoma in the pancreas head. The patient underwent total remnant pancreatectomy. The tumor was located in the uncinate process of the pancreas with infiltration of the portal vein. The pathological diagnosis of the tumor was moderately differentiated adenocarcinoma. The ductal lumen structure was relatively maintained and the cytoplasm was comparatively clear. Since its pathological findings were similar to those observed in 2009, the tumor appeared to be a recurrence of the tumor resected at that time. The patient had received postoperative chemotherapy and remains alive in 2019 without recurrence. While there is evidence that surgical resection for the recurrence of other cancers such as colon cancer may improve patient survival, it remains unclear if surgical resection of recurrence in the remnant pancreas after pancreatectomy of pancreatic cancer is feasible. We report a case with long survival after surgical resection of a pancreatic carcinoma recurrence in the remnant pancreas.

[A Case of Conversion Surgery for an Initially Locally Advanced Unresectable Pancreatic Cancer after S-1 Chemotherapy].

We report a case of conversion surgery for a locally advanced unresectable(UR-LA)pancreatic cancer that was radically resected after S-1 therapy. A 65-year-old man visited a referral physician because of fatigue and liver dysfunction. A CT scan revealed a mass in the pancreatic uncinate process that was suspected to be superior mesenteric artery(SMA)infiltration and was diagnosed as UR-LA pancreatic cancer. GEM nab-PTX therapy was initiated but was discontinued after 2 courses because of adverse events. The treatment was switched to S-1 monochemotherapy. After that, the tumor did not progress for around 1.5 years, and the patient was referred to our hospital for surgical treatment. As the contact between the tumor and the SMA was considered to be less than half-round, we made a diagnosis of borderline resectable(BR-A)pancreatic cancer. Subsequently, we performed a pancreaticoduodenectomy with partial resection of the portal vein and achieved R0 resection. The patient received adjuvant chemotherapy with S-1 and showed no signs of recurrence for 10 months after surgery.

[A Methotrexate-Associated Malignant Lymphoma with Laparoscopic Resection of the Pericardium].

We report a case of a malignant lymphoma that was treated with laparoscopic resection of the pericardium. A 43-year-old woman was diagnosed with asymptomatic extrahepatic nodule by medical examination. CT, MRI, and PET-CT examination indicated a solitary fibrous tumor(SFT). Therefore, we performed laparoscopic resection for definitive diagnosis and treatment. The tumor was located in the upper abdominal wall and adhered to the liver; hence, we additionally performed partial resection of the liver. Thereafter, we dissected the tumor from the abdominal wall alongwith a part of the diaphragm. Because intraoperative pathological examination revealed more malignancy than was preoperatively expected, we also resected a part of the pericardium. The laparoscopic approach to the pericardium can be performed safely because of its magnification effect, which is an advantage of laparoscopic surgery.

Bilaterally existing sternoclavicularis anticus muscles.

A 92-year-old Japanese woman was found to have the sternoclavicularis anticus muscles existing bilaterally during the course of educational dissection at Nagoya City University Medical School. It was confirmed that these muscles received the nerve supply from small branches of the lateral pectoral nerves from the brachial plexus. Herein is documented the precise gross anatomical findings with some morphometric measurements. Moreover, the morphology of this muscle is discussed in relation to previously described variations of the pectoral sheet of muscles.