Expression of ZKSCAN3 protein suppresses proliferation, migration, and invasion of pancreatic cancer through autophagy.

Elevated autophagy activity enhances the malignancy of pancreatic cancer (PaCa), and autophagy is recognized as a novel therapeutic target. Zinc finger protein with KRAB and SCAN domains 3 (ZKSCAN3) is a transcription factor that suppresses autophagy, but its association with PaCa is unknown. We analyzed the function of ZKSCAN3 in PaCa and investigated whether autophagy regulation through ZKSCAN3 could become a new therapeutic target for PaCa. Using reverse transcription-quantitative polymerase chain reaction and western blotting, we observed that ZKSCAN3 expression was upregulated in several PaCa cell lines compared with normal pancreatic ductal epithelial cells. Additionally, comparing ZKSCAN3 expression with the prognosis of PaCa patients using web databases, we found that higher ZKSCAN3 expression in PaCa was associated with extended overall survival. Knocking down ZKSCAN3 promoted the proliferation of PaCa cells. Moreover, following ZKSCAN3 knockdown, PaCa cells exhibited significantly enhanced migratory and invasive properties. Conversely, overexpression of ZKSCAN3 significantly suppressed the proliferation, migration and invasion of PaCa cells. Additionally, the knockdown of ZKSCAN3 increased the expression of LC3-II, a marker of autophagy, whereas ZKSCAN3 overexpression decreased LC3-II expression. In a xenograft mouse model, tumors formed by MIA PaCa-2 cells in which ZKSCAN3 was knocked down significantly increased in size compared with the control group. In conclusion, ZKSCAN3 expression was upregulated in several pancreatic cancer cells. Additionally, it was revealed that ZKSCAN3 is negatively correlated with the malignancy of PaCa through autophagy. These results suggest that autophagy regulation via ZKSCAN3 may be a new therapeutic target for PaCa.

The Natural Product Parthenolide Inhibits Both Angiogenesis and Invasiveness and Improves Gemcitabine Resistance by Suppressing Nuclear Factor κB Activation in Pancreatic Cancer Cell Lines.

We previously established pancreatic cancer (PaCa) cell lines resistant to gemcitabine and found that the activity of nuclear factor κB (NF-κB) was enhanced upon the acquisition of gemcitabine resistance. Parthenolide, the main active ingredient in feverfew, has been reported to exhibit antitumor activity by suppressing the NF-κB signaling pathway in several types of cancers. However, the antitumor effect of parthenolide on gemcitabine-resistant PaCa has not been elucidated. Here, we confirmed that parthenolide significantly inhibits the proliferation of both gemcitabine-resistant and normal PaCa cells at concentrations of 10 µM and higher, and that the NF-κB activity is significantly inhibited, even by 1 µM parthenolide. In Matrigel invasion assays and angiogenesis assays, the invasive and angiogenic potentials were higher in gemcitabine-resistant than normal PaCa cells and were inhibited by a low concentration of parthenolide. Furthermore, Western blotting showed suppressed MRP1 expression in gemcitabine-resistant PaCa treated with a low parthenolide concentration. In a colony formation assay, the addition of 1 µM parthenolide improved the sensitivity of gemcitabine-resistant PaCa cell lines to gemcitabine. These results suggest that parthenolide may be used as a novel therapeutic agent for the treatment of gemcitabine-resistant PaCa.

Simultaneous presentation and resection of esophageal cancer and metastasis to the pancreas: Α case report and literature review.

The frequency of metastasis to the pancreas is limited, and the frequency of metastasis of a squamous cell carcinoma of the esophagus is limited even further. The curative resection of this type of metastatic lesion has been reported for some patients; however, the survival benefit that can be attributed to these procedures has not yet been clearly determined. The patient examined in the present study was a 54-year-old man who was diagnosed with a lower thoracic esophageal cancer. Computed tomography revealed a 2-cm tumor at the tail of the pancreas. Since no other obvious distal metastases were observed, the patient underwent simultaneous surgical procedures, excising the esophageal squamous cell carcinoma and the pancreatic metastasis. A histopathological examination confirmed squamous cell carcinoma in both specimens. The patient has been free of disease for 9 months since the resection. A literature review of all relevant cases to date also demonstrated that the primary tumor site in all cases of patients with esophageal cancer presenting with metastasis to the pancreas was the lower thoracic esophagus. Complete simultaneous resections of esophageal squamous cell carcinoma and a solitary metastasis to the pancreas is beneficial and may produce favorable outcomes. However, due to the reduced number of corresponding reports, further studies are required for the confirmation of the benefits of surgery.

Upregulation of integrin­linked kinase enhances tumor progression in gemcitabine­resistant pancreatic cancer.

Pancreatic cancer (PaCa) tends to be resistant to chemotherapy and is associated with a very poor prognosis. It has been previously reported by the authors that integrin­linked kinase (ILK) is a prognostic factor in PaCa. ILK expression was examined in a newly established gemcitabine (Gem)­resistant (Gem­R) PaCa cell line and it was demonstrated that ILK expression was upregulated compared with that in Gem­sensitive (Gem­S) cells. In the present study, the effects of increased ILK expression in Gem­R PaCa cells were evaluated and it was examined whether compound 22 (Cpd22), an ILK inhibitor, exerted antitumor effects not only in Gem­S cells but also in Gem­R cells. Reverse transcription­quantitative polymerase chain reaction and western blotting revealed that ILK expression was higher in Gem­R PaCa cells than in Gem­S PaCa cells. Cpd22 inhibited the growth of PaCa cells in a concentration­dependent manner. Cpd22 also inhibited the growth of Gem­R PaCa cells. The invasive and angiogenic potential of Gem­R PaCa cells was enhanced compared with that in Gem­S cells; however, ILK small interfering RNA and Cpd22 treatment suppressed this enhancement of invasive potential compared with that in Gem­S cells. The addition of Cpd22 to Gem also improved the sensitivity of Gem­R cell lines to Gem. Furthermore, enhanced Akt signaling was associated with increased malignancy in Gem­R cell lines. In conclusion, ILK was upregulated with resistance and may be involved in tumor angiogenesis, invasive potential, and chemotherapy resistance, which were all suppressed by Cpd22 treatment. Thus, Cpd22 may be a novel therapeutic agent for the treatment of PaCa.

Glissonean Pedicle Isolation Focusing on the Laennec's Capsule for Minimally Invasive Anatomical Liver Resection.

Background: Inflow control is one of the most important procedures during anatomical liver resection (ALR), and Glissonean pedicle isolation (GPI) is one of the most efficacious methods used in laparoscopic anatomical liver resection (LALR). Recognition of the Laennec's capsule covering the liver parenchyma is essential for safe and precise GPI. The purpose of this study was to verify identification of the Laennec's capsule, to confirm the validity of GPI in minimally invasive surgery, and to demonstrate the value of GPI focusing on the Laennec's capsule using a robotic system that has been developed in recent years. Methods: We used a cadaveric model to simulate the Glissonean pedicle and the surrounding liver parenchyma for pathologic verification of the layers. We performed 60 LALRs and 39 robotic anatomical liver resections (RALRs) using an extrahepatic Glissonean approach, from April 2020 to April 2023, and verified the layers of the specimens removed during LALR and RALR based on pathologic examination. In addition, the surgical outcomes of LALR and RALR were compared. Results: Histologic examination facilitated by Elastica van Gieson staining revealed the presence of Laennec's capsule covering the liver parenchyma in a cadaveric model. Similar findings were obtained following LALR and RALR, thus confirming that the gap between the Glissonean pedicle and the Laennec's capsule can be dissected without injury to the parenchyma. The mean GPI time was 32.9 and 27.2 min in LALR and RALR, respectively. The mean blood loss was 289.7 and 131.6 mL in LALR and RALR, respectively. There was no significant difference in the incidence of Clavien-Dindo grade ≥III complications between the two groups. Conclusions: Laennec's capsule is the most important anatomical landmark in performing a safe and successful extrahepatic GPI. Based on this concept, it is possible for LALR and RALR to develop GPI focusing on the Laennec's capsule. Furthermore, a robotic system has the potential to increase the safety and decrease the difficulty of this challenging procedure.

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.

Neuroendocrine carcinoma of the minor papilla with pancreas divisum: a case report and review of the literature.

BACKGROUND: Neuroendocrine tumors of the minor papilla are very rare, and only 20 cases have been reported in the literature. Neuroendocrine carcinoma of the minor papilla with pancreas divisum has not been reported previously, making this the first reported case. Neuroendocrine tumors of the minor papilla have been reported in association with pancreas divisum in about 50% of cases reported in the literature. We herein present our case of neuroendocrine carcinoma of the minor papilla with pancreas divisum in a 75-year-old male with a systematic literature review of the previous 20 reports of neuroendocrine tumors of the minor papilla. CASE PRESENTATION: A 75-year-old Asian man was referred to our hospital for evaluation of dilation of the main pancreatic duct noted on abdominal ultrasonography. Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography showed a dilated dorsal pancreatic duct, which was not connected to the ventral pancreatic duct; however, it opened to the minor papilla, indicating pancreas divisum. The common bile duct had no communication with the pancreatic main duct and opened to the ampulla of Vater. A contrast-enhanced computed tomography scan showed a 12-mm hypervascular mass near the ampulla of Vater. Endoscopic ultrasonography showed a defined hypoechoic mass in the minor papilla with no invasion. The biopsies performed at the previous hospital found adenocarcinoma. The patient underwent a subtotal stomach-preserving pancreaticoduodenectomy. The pathological diagnosis was neuroendocrine carcinoma. At the 15-year follow-up visit, the patient was doing well with no evidence of tumor recurrence. CONCLUSION: In our case, because the tumor was discovered during a medical check-up relatively early in the course of disease, the patient was doing well at the 15-year follow-up visit, with no evidence of tumor recurrence. Diagnosing a tumor of the minor papilla is very difficult because of the relatively small size and submucosal location. Carcinoids and endocrine cell micronests in the minor papilla occur more frequently than generally thought. It is very important to include neuroendocrine tumors of the minor papilla in the differential diagnosis of patients with recurrent pancreatitis or pancreatitis of unknown cause, especially for patients with pancreas divisum.

Accurate intraoperative real-time blood flow assessment of the remnant stomach during robot-assisted distal pancreatectomy with celiac axis resection using indocyanine green fluorescence imaging and da Vinci Firefly technology.

INTRODUCTION: Ischemic gastropathy is one of the unique postoperative complications associated with distal pancreatectomy with celiac axis resection for locally advanced pancreatic cancer. Therefore, it is essential to evaluate blood flow to the stomach following a resection; however, no intraoperative procedures have been established to assess this issue. Herein we describe two cases in which intraoperative evaluation of real-time blood flow in the residual stomach was performed using indocyanine green fluorescence and da Vinci Firefly technology during a robot-assisted distal pancreatectomy with celiac axis resection. METHODS: Robot-assisted distal pancreatectomy with celiac axis resection was performed using a da Vinci Xi surgical system on two patients with locally advanced pancreatic cancer and suspected invasion of the celiac artery. Indocyanine green (ICG) (0.5 mg/kg) was injected intravenously after resection to evaluate real-time blood flow of the stomach using the da Vinci Firefly system. Blood flow of the stomach was evaluated 60 seconds after the intravenous injection of ICG. RESULTS: All cases were confirmed that there was sufficient blood flow in the residual stomach. Therefore, reconstruction of the left gastric artery was not performed, and the surgery was completed with preservation of the stomach. Good postoperative outcomes were achieved and there was no evidence of ischemic gastropathy or delayed gastric emptying in both cases. CONCLUSION: This method is very useful in determining whether or not to perform reconstruction of the left gastric artery and/or additional resection of the remnant stomach during a robot-assisted distal pancreatectomy with celiac axis resection.

A Giant Duodenal Leiomyoma Showing Increased Uptake on 18F-Fluorodeoxyglucose Positron Emission Tomography.

BACKGROUND: Although 18F-fluorodeoxyglucose positron emission tomography (FDG-PET/CT) is now widely used in their differential diagnosis, it is sometimes difficult to distinguish between benign and malignant diseases. CASE PRESENTATION: A 44-year-old woman was found to have abnormalities on health screening. Magnetic resonance imaging for detailed examination showed an intra-abdominal tumor measuring 12 cm in the major axis near the cranial end of the uterus. Upper gastrointestinal tract endoscopy showed a tumor with an ulcer in the third part of the duodenum, involving half the circumference. Heterogeneous uptake was observed within the tumor on FDG-PET/CT. Based on these findings, the patient underwent surgery for suspected primary malignant lymphoma of the duodenum or gastrointestinal stromal tumor. Laparotomy revealed a 12 cm tumor in the third part of the duodenum. Partial duodenectomy and end-to-end duodenojejunostomy were performed. Pathological findings showed a solid tumor growing from the muscle layer of the duodenum to outside the serous membrane; based on immunostaining, it was diagnosed as a leiomyoma. CONCLUSIONS: Duodenal leiomyomas are originally benign; to date, there have been no reports of uptake in duodenal leiomyomas on FDG-PET/CT; therefore, our case is rare. Leiomyomas should be considered in the differential diagnosis of duodenal neoplastic diseases.

A post operative complication of foramen of Winslow hernia with left to right herniation of the small intestine: An extremely rare case report.

INTRODUCTION: A foramen of Winslow hernia (FWH) is a type of internal hernias. Generally, the contents of the hernia pass through the foramen of Winslow from right to left. The case presented in this report is very unusual, as the small intestine in the hernia passed through the foramen from left to right. PRESENTATION OF CASE: A 67-year-old woman developed a sudden abdominal pain 15 days after laparoscopic subtotal colectomy. Abdominal contrast-enhanced computed tomography (CT) examination revealed a FWH, and an emergency surgery was scheduled. The small intestine was found to be herniating from the cavity of the omental bursa through the foramen of Winslow, to the right side of the hepatoduodenal ligament, and was incarcerated. The incarcerated intestine was reduced, and the necrotic part of the intestine was resected. In addition, the foramen of Winslow and the cavity of omental bursa were closed to prevent relapse. CONCLUSION: To our knowledge, here we report the first FWH of which the contents of the hernia are herniated from left to right, in literature. Whether the Foramen should be closed or not requires discussion, however, we conclude that the foramen should be closed when possible, acknowledging previous reports and the present case.

Technique of totally robotic delta-shaped anastomosis in distal gastrectomy.

BACKGROUND: We aimed to clarify the utility of delta-shaped anastomosis (Delta), an intracorporeal Billroth-I anastomosis-based reconstruction technique used after laparoscopy-assisted distal gastrectomy (LADG), in robot-assisted distal gastrectomy (RADG). METHODS: RADG was performed in patients with clinical Stage I gastric cancer, and reconstruction was performed using Delta. The Delta procedure was the same as that performed after LADG, and the operator practiced the procedure in simulated settings with surgical assistants before the operation. After gastrectomy, the scope and robotic first arm were reinserted from separate ports on the right side of the patient. Then, a port on the left side of the abdomen was used as the assistant port from which a stapler was inserted, with the robotic arm in a coaxial mode. The surgical assistant performed functional end-to-end anastomosis of the remnant stomach and duodenal stump using a powered stapler. RESULTS: The mean anastomotic time in four patients who underwent Delta after RADG was 16.5 min. All patients were discharged on the post-operative day 7 without any post-operative complications or need for readmission. CONCLUSIONS: Pre-operative simulation, changes in ports for insertion of the scope and robotic first arm, continuation of the coaxial operation, and use of a powered stapler made Delta applicable for RADG. Delta can be considered as a useful reconstruction method.

Primary mesenteric neuroendocrine tumor that changed its internal composition from cystic to solid: a case report.

Mesenteric neuroendocrine tumors are usually metastases originating from the small intestine; however, primary mesenteric cases are rare. We present an interesting case of a mesenteric neuroendocrine tumor that changed its internal composition from cystic to solid. A 72-year-old male visited our hospital because of epigastralgia 4 years earlier. A 25-mm tumor was recognized around the terminal duodenum on computed tomography and magnetic resonance imaging, and was diagnosed as a cystic lesion. Over the following 2 years, the tumor grew to 40 mm and its internal composition changed from cystic to solid. The lesion showed positive findings on fluorodeoxyglucose positron emission tomography. Upon laparotomy, a solid tumor was detected in the mesentery of the jejunum near the ligament of Treitz. The tumor was extracted without intestinal resection and was diagnosed as a low-grade neuroendocrine tumor after histopathological and immunohistochemical examination. One year has passed since the operation, and there has been no recurrence.

Technique of Roux-en-Y reconstruction using overlap method after laparoscopic total gastrectomy for gastric cancer: 100 consecutively successful cases.

BACKGROUND: We have established a standard procedure for Roux-en-Y (RY) reconstruction in laparoscopic total gastrectomy (LTG) using esophagojejunostomy by the overlap method (OL). We report on our RY reconstruction technique and special approaches, and evaluate the usefulness of our reconstruction method based on the surgical results of 100 patients we have experienced to date. METHODS: We performed LTG in 100 patients with gastric cancer. After total gastrectomy using five ports, the resected stomach was extracted through a small laparotomy. Through that, we performed sacrifice of the jejunum, Y limb anastomosis, creation of the lifted jejunum. As the OL, a side-to-side anastomosis of the lifted jejunum to the esophageal stump was laparoscopically performed using a linear stapler in an isoperistaltic direction, and the entry hole was closed with full-thickness suturing. The lifted jejunum was fixed with suture to the duodenal stump at a location where the esophagojejunostomy site was made linear, and the duodenal stump was buried. The mesenteric gap was laparoscopically closed with suture. RESULTS: The median operative time in 100 patients undergoing LTG was 385 min, the median blood loss was 65 mL, and the median time required for the OL was 32 min. The mean hospitalization period was 10 days, and postoperative complications included bleeding requiring reoperation in one patient; other complications such as pancreatic fistula in five patients (5 %) were treated conservatively. No complication associated with anastomosis occurred. CONCLUSION: In RY reconstruction using the OL, there were no complications associated with the anastomosis site in 100 consecutive patients, such as anastomotic leak or stenosis, indicating that it is a very useful and safe reconstruction method.