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 Expression of CD70 and POSTN in Cancer-Associated Fibroblasts Predicts Worse Survival of Colorectal Cancer Patients.

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide, with high morbidity and mortality rates. The evidence for the tumor-supporting capacities of cancer-associated fibroblasts (CAFs) that modulate cancer cell proliferation, invasion, metastasis, and tumor immunity, including in CRC, has been attracting attention. The present study examined the expression status of CD70 and POSTN in CRC and analyzed their association with clinicopathological features and clinical outcomes. In the present study, in total 15% (40/269) and 44% (119/269) of cases exhibited CD70 and POSTN expression on CAFs, respectively. Co-expression of CD70 and POSTN was detected in 8% (21/269) of patients. Fluorescent immunohistochemistry identified the co-expression of CD70 and POSTN with FAP and PDPN, respectively. ACTA2 was not co-expressed with CD70 or POSTN in CRC CAFs. CRC with CD70+/POSTN+ status in CAFs was significantly associated with distant organ metastasis (p = 0.0020) or incomplete resection status (p = 0.0011). CD70+/POSTN+ status tended to associate with advanced pT stage (p = 0.032) or peritoneal metastasis (p = 0.0059). Multivariate Cox hazards regression analysis identified CD70+/POSTN+ status in CAFs [hazard ratio (HR) = 3.78] as a potential independent risk factor. In vitro experiments revealed the activated phenotypes of colonic fibroblasts induced by CD70 and POSTN, while migration and invasion assays identified enhanced migration and invasion of CRC cells co-cultured with CD70- and POSTN-expressing colonic fibroblasts. On the basis of our observations, CD70 and POSTN immunohistochemistry can be used in the prognostication of CRC patients. CRC CAFs may be a promising target in the treatment of CRC patients.

Characterization of pleural mesothelioma by hierarchical clustering analyses using immune cells within tumor microenvironment.

INTRODUCTION: Over the past decade, classifications using immune cell infiltration have been applied to many types of tumors; however, mesotheliomas have been less frequently evaluated. METHODS: In this study, 60 well-characterized pleural mesotheliomas (PMs) were evaluated immunohistochemically for the characteristics of immune cells within tumor microenvironment (TME) using 10 immunohistochemical markers CD3, CD4, CD8, CD56, CD68, CD163, FOXP3, CD27, PD-1 and TIM-3. For further characterization of PMs, hierarchical clustering analyses using these 10 markers were performed. RESULTS: Among the immune cell markers, CD3 (P < 0.0001), CD4 (P = 0.0016), CD8 (P = 0.00094), CD163+ (P = 0.042) and FOXP3+ (P = 0.025) were significantly associated with unfavorable clinical outcome. Immune checkpoint receptor expressions on tumor-infiltrating lymphocytes such as PD-1 (P = 0.050), CD27 (P = 0.014) and TIM-3 (P = 0.0098) were also associated with unfavorable survival. Hierarchical clustering analyses identified three groups showing specific characteristics and significant associations with patient survival (P = 0.011): the highest number of immune cells (ICHigh); the lowest number of immune cells, especially CD8+ and CD163+ cells (ICLow); and intermediate number of immune cells (ICInt). ICHigh tumors showed significantly higher expression of PD-L1 (P = 0.00038). Cox proportional hazard model identified ICHigh [hazard ratio (HR) = 2.90] and ICInt (HR = 2.97) as potential risk factors compared with ICLow. Tumor CD47 (HR = 2.36), tumor CD70 (HR = 3.04) and tumor PD-L1 (HR = 3.21) expressions were also identified as potential risk factors for PM patients. CONCLUSION: Our findings indicate immune checkpoint and/or immune cell-targeting therapies against CD70-CD27 and/or CD47-SIRPA axes may be applied for PM patients in combination with PD-L1-PD-1 targeting therapies in accordance with their tumor immune microenvironment characteristics.

Robotic resection for splenic artery aneurysm associated with neurofibromatosis type 1: a case report.

BACKGROUND: Neurofibromatosis type 1 is an autosomal-dominant disease characterized by café-au-lait spots and neurofibromas, as well as various other symptoms in the bones, eyes, and nervous system. Due to its connection with vascular fragility, neurofibromatosis type 1 has been reported to be associated with vascular lesions, such as aneurysms. However, there have been few reports of abdominal visceral aneurysms associated with neurofibromatosis type 1. Furthermore, there have been no reports of robotic treatment of aneurysms associated with neurofibromatosis type 1. In this report, we describe the case of a patient with neurofibromatosis type 1 with a splenic artery aneurysm who was successfully treated with robotic surgery. CASE PRESENTATION: This report describes a 41-year-old Asian woman with a history of neurofibromatosis type 1 who was referred to our hospital for evaluation of a 28 mm splenic artery aneurysm observed on abdominal ultrasound. The aneurysm was in the splenic hilum, and transcatheter arterial embolization was attempted; however, this was difficult due to the tortuosity of the splenic artery. Thus, we suggested minimally invasive robotic surgery for treatment and resection of the splenic artery aneurysm with preservation of the spleen. The postoperative course was uneventful, and the patient was discharged on the eighth day after surgery. At 1 year of follow-up, the patient was doing well, with no evidence of recurrence. CONCLUSION: We encountered a rare case of splenic artery aneurysm in a patient with neurofibromatosis type 1 who was successfully treated with robotic surgery. There is no consensus on treatment modalities for neurofibromatosis-related aneurysms, and endovascular treatment is considered safe and effective; however, surgery remains an important treatment modality. Especially in patients with stable hemodynamic status, robotic surgery may be considered as definitive treatment. To our knowledge, this is the first successfully treated case of a splenic artery aneurysm in a patient with neurofibromatosis type 1.

Suctionable Gauze Ball Operated by the Console Surgeon Overcomes Wet Scenes during Robotic Rectal Surgery.

Although robotic rectal resections are now widely performed, there are few robotic suction tools that can be easily used by console surgeons. It can therefore be difficult to maintain a clear visual field in the pelvis when there is effusion and bleeding from either a highly advanced cancer or from preoperative cancer treatment. In this report, we introduce our unique surgical technique that uses a soft catheter with a small gauze ball attached, inserted through the assistant port. This simple and inexpensive "instrument" can be used by the console surgeon as a retractor as well as a reliable suction device to secure their view of the operative field in the pelvis. This technique can be used in a narrow surgical field and does not rely on an assistant surgeon, making it potentially applicable to all types of surgery.

Robotic distal gastrectomy plus spleen-preserving distal pancreatectomy: optimal resection for simultaneous gastric cancer and intraductal papillary mucinous neoplasm of the pancreatic body.

BACKGROUND: Organ-preserving surgery has recently gained increasing attention. However, performing the surgery for duplicated gastric and distal pancreatic tumors is difficult because of procedural complexity and concerns of remnant gastric necrosis. We present the first case of simultaneous robotic distal gastrectomy plus spleen-preserving distal pancreatectomy in a patient with overlapping gastric cancer and intraductal papillary mucinous neoplasm. CASE PRESENTATION: A 78-year-old man was diagnosed with gastric cancer in the middle stomach and intraductal papillary mucinous neoplasm of the pancreatic body. Radical cure surgery was performed using the da Vinci Xi robotic system. Conventional distal gastrectomy was initially completed using near-infrared ray guidance when transecting the stomach. After dividing the pancreas, the parenchyma of the distal pancreas was detached from the splenic artery and vein; multiple branches from these splenic vessels were dissected. Indocyanine green imaging confirmed sufficient blood flow in the splenic vessels and perfusion of the remnant stomach. Ultimately, gastrointestinal reconstruction was performed, and the postoperative course was uneventful. CONCLUSIONS: The robotic distal gastrectomy plus spleen-preserving distal pancreatectomy procedure was safely performed. Compared to the total gastrectomy plus distal pancreatectomy with splenectomy procedure, this technique may improve the quality of dietary life, reduce weight loss, and prevent complications associated with splenectomy.

[A Case of Transverse Colon Cancer with Gastrointestinal Amyloidosis Prevented from Anastomotic Leakage by Multidimensional Approach].

The patient was a 68-year-old woman who was on hemodialysis due to systemic amyloidosis and nephrotic syndrome. Biopsy revealed amyloid deposition in the stomach, duodenum, and colon. A transverse colon tumor was found on a follow- up CT after the aortic dissection surgery. We performed lower gastrointestinal endoscopy and contrast-enhanced CT and diagnosed transverse colon cancer with gastric wall infiltration(cStage Ⅲc). We considered that transverse colon resection was oncologically sufficient. However, due to concurrent gastrointestinal amyloidosis, which increased the risk of anastomotic leakage we performed laparoscopic extended right hemicolectomy to avoid colon-colon anastomosis with partial gastrectomy. Additionally intraoperative indocyanine green(ICG)fluorescence imaging showed that the fluorescence signal in the small intestinal wall was satisfactory, while it was weak in the colon wall. As a result, we suspected of impaired blood flow of colon wall due to an amyloidosis, so we additionally created a loop ileostomy. It is said that gastrointestinal amyloidosis raises the risk of anastomotic leakage. A case of transverse colon cancer complicated by gastrointestinal amyloidosis in which we successfully prevented anastomotic leakage through a multidimensional evaluation and approach is reported, along with a literature review.

Association between the antiadhesion membrane and small bowel obstruction after open gastrectomy: A supplemental analysis of the randomized controlled JCOG1001 trial.

Aim: Postoperative small bowel obstruction (SBO) is one of the major complications that is mainly caused by postoperative adhesion. Recently, the antiadhesion membrane has become popular for postoperative SBO prevention. However, its efficacy is yet to be confirmed in the gastric cancer surgery field. Here, we conducted the supplemental analysis of the randomized controlled trial JCOG1001 to investigate the efficacy of the antiadhesion membrane on SBO prevention in patients with open gastrectomy for gastric cancer. Methods: Of the 1204 patients enrolled in JCOG1001, 1200 patients were included. The development of SBO of Grade ≥ IIIa according to the Clavien-Dindo classification was recorded. Univariable and multivariable analyses were performed using the Fine and Gray model to determine the risk factors for SBO. Results: Fifty-one patients developed SBO (median follow-up duration: 5.6 years). Total gastrectomy, combined resection, and blood loss significantly increased the risk for SBO development in the univariable analysis. Large amount of blood loss was independently associated with SBO development in the multivariable analysis (hazard ratio [HR], 3.089; 95% confidence interval [CI], 1.562-6.109, p = 0.0012). Antiadhesion membrane did not reduce the risk for SBO (HR, 1.299; 95% CI 0.683-2.470; p = 0.4246). In the patients belonging to subgroup analyses who received distal and total gastrectomy, the antiadhesion membrane was not associated with the incidence of SBO. Conclusions: Antiadhesion membrane did not decrease SBO occurrence rate after open gastrectomy. Therefore, the use of antiadhesion membrane would not be effective for preventing SBO in gastric cancer surgery.

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.

"Role-sharing surgery": a new surgical education system that gives beginner surgeons more chances to operate while ensuring the surgical quality of robotic surgery.

It has been pointed out that robotic surgery is more time-consuming than laparoscopic surgery, and a major challenge for the future is educating young surgeons while maintaining the surgical quality. To solve these problems, we report a role-sharing surgery (RSS) approach in which the surgery is divided into several areas and timetabled, with roles shared by several operators. We performed RSS for 19 standard colorectal cancer surgeries. The surgery was completed within + 28 min of the scheduled operation time, and a beginner robotic surgeon (BRS) was able to perform approximately 66% of the total surgery. There were no statistically significant differences in the short-term outcomes between the RSS and conventional surgery groups. Based on these findings, RSS has the potential to be the best practice for educating BRSs in robotic surgery, the use of which is expected to increase steadily in the future.

Safety and short-term outcomes of robotic-assisted transabdominal preperitoneal repair for inguinal hernia in pioneering hospitals in Japan: A nationwide retrospective cohort study.

INTRODUCTION: We aimed to evaluate the safety and short-term outcomes of robotic-assisted transabdominal preperitoneal repair for inguinal hernia in 12 pioneering hospitals in Japan. METHODS: Clinical data of patients who underwent robotic-assisted transabdominal preperitoneal repair between September 1, 2016, and December 31, 2021 were collected. Primary outcome measures were intra-operative adverse events and post-operative complications, whereas secondary outcomes were surgical outcomes, including chronic pain, recurrence, and learning curve. RESULTS: In total, 307 patients were included. One case of inferior epigastric arterial injury was reported; no cases of bowel or bladder injury were reported. Thirty-five seromas were observed, including four (1.3%) cases that required aspiration. The median operative time of a unilateral case was 108 minutes (interquartile range: 89.8-125.5), and post-operative pain was rated 1 (interquartile range: 0-2) on the numerical rating scale. In complicated cases, such as recurrent inguinal hernias and robotic-assisted radical prostatectomy-associated hernias, dissection and suture were safely achieved, and no complications were observed, except for non-symptomatic seroma. All patients underwent robotic procedures, and there was no chronic post-operative inguinal pain, although one case of hernia recurrence was reported. Regarding the learning curve, plateau performance was achieved after 7-10 cases in terms of operative time (P < .001). CONCLUSION: Robotic-assisted transabdominal preperitoneal repair can be safely introduced in Japan. Regardless of the involvement of many surgeons, the mastery of robotic techniques was achieved relatively quickly. The advantage of robotic technology such as wristed instruments may expand the application of minimally invasive hernia repair for complicated cases.

Characterization of colorectal cancer by hierarchical clustering analyses of five immune cell markers.

The present study analyzed the expression of five independent immunohistochemical markers, CD4, CD8, CD66b, CD68, and CD163, on immune cells within the colorectal cancer (CRC) tumor microenvironment (TME). Using hierarchical clustering, patients were successfully classified according to significant associations with clinicopathological features and/or survival. Patients with mismatch repair-proficient (pMMR) CRC were categorized into four groups with survival differences (p = 0.0084): CD4Low , CD4High , MΦHigh , and CD8Low . MΦHigh tumors showed significantly higher expression of CD47 (p < 0.0001), a phagocytosis checkpoint molecule. These tumors contained significantly greater numbers of PD-1+ (p < 0.0001), TIM-3+ (p < 0.0001), and SIRPA+ (p < 0.0001) immune cells. Notably, 10% of the patients with pMMR CRC expressed PD-L1 (CD274) on tumor cells with significantly worse survival (p = 0.00064). The Cox proportional hazards model identified MΦ High (hazard ratio [HR] = 2.02, 95%, p = 0.032), CD8Low (HR = 2.45, p = 0.011), and tumor PD-L1 expression (HR = 2.74, p = 0.0061) as potential risk factors. PD-L1-PD-1 and/or CD47-SIRPA axes targeting immune checkpoint therapies might be considered for patients with pMMR CRC according to their tumor cells and tumor immune microenvironment characteristics.

Laparoscopic pancreas-preserving duodenectomy: Minimally invasive surgery for superficial nonampullary duodenal epithelial tumors.

No consensus exists regarding the optimal treatment for superficial nonampullary duodenal epithelial tumors. Herein, we describe a laparoscopic pancreas-preserving duodenectomy for the treatment of a 30-mm adenoma located in the third portion of the duodenum. The adenoma was located on the pancreatic side, further hindering safe endoscopic resection. Via laparoscopy, the jejunum was transected first. After releasing the third portion of the duodenum from the retroperitoneal space, the jejunum was pulled to the right side of the superior mesenteric artery and separated from the pancreas. Under endoscopic guidance, the duodenum was then transected and duodenojejunostomy performed intracorporeally. Laparoscopic pancreas-preserving duodenectomy can be considered minimally invasive, achieving tumor radicality while preserving organs and causing minimal destruction to the abdominal wall. In conclusion, although technically demanding, laparoscopic pancreas-preserving duodenectomy is a valuable treatment option for superficial nonampullary duodenal epithelial tumors.

Remnant gastritis in gastric cancer patients causes loss of muscle mass 6 months after gastrectomy: a retrospective cohort study of Helicobacter pylori infection.

PURPOSE: In this study, we assessed the relationship between remnant gastritis and muscle mass loss and then investigated the potential relationship between Helicobacter pylori (HP) infection and remnant gastritis and muscle loss. METHODS: We reviewed the medical records of 463 patients who underwent distal gastrectomy between January 2017 and March 2020. Of these patients, 100 with pStage I after laparoscopic surgery were included in this analysis. RESULTS: A multivariate analysis showed that the total Residue, Gastritis, Bile (RGB) classification score, which indicates the degree of gastritis, was significantly associated with the rate of change (rate of decrease) in the psoas muscle area (PMA) during the first 6 months after surgery (p = 0.014). Propensity score matching was performed according to HP infection, and the rate of change in the PMA and the degree of remnant gastritis in 56 patients were compared. Neither was significantly associated with HP infection. CONCLUSIONS: Remnant gastritis did contribute to psoas muscle mass loss during the initial 6 months after gastrectomy, and HP infection was not significantly associated with either remnant gastritis or psoas muscle mass loss. Nevertheless, the potential for HP eradication to prevent muscle loss and improve the survival prognosis for gastrectomy patients merits further research.

Severe esophageal stricture after perforation and necrotizing esophagitis: unusual presentation of a duodenal gastrinoma.

Gastrinomas are pancreatic or duodenal endocrine tumors that secrete excess gastrin, which causes gastroesophageal reflux disease, peptic ulcers, and chronic diarrhea. Due to the rarity of the disease, nonspecific symptoms, and the outstanding effect of proton pump inhibitors, diagnosing gastrinomas is difficult. Here, we present the case of a 58-year-old woman who had a duodenal gastrinoma that caused rare but critical events, including esophageal perforation, necrotizing esophagitis, and severe esophageal stricture. She presented with a non-malignant severe lower esophageal stricture, which was resistant to endoscopic dilatation. During esophagectomy, a duodenal mass was excised and diagnosed as gastrinoma. This was considered the main cause of all events. Gastrinomas are rarely encountered in clinical practice, but early diagnosis is necessary to avoid serious conditions. Therefore, whenever we encounter a patient with gastroesophageal reflux disease requiring long-term treatment or is refractory, we must not forget to screen for gastrinomas.

Eosinophil may be a predictor of immune-related adverse events induced by different immune checkpoint inhibitor types: A retrospective multidisciplinary study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can cause severe immune-related adverse events (irAEs). However, biomarkers for irAEs common to different types of ICIs and cancers have not been reported. This study examined whether eosinophils can be used as a predictor of irAEs. METHODS: Six hundred fourteen patients with cancer (esophageal, gastric, head and neck, lung, melanoma, renal cell, urothelial, and other cancer) received anti-PD-1, anti-PD-L1, or anti-CTLA-4 plus anti-PD-1 therapy. The patients were divided into two groups depending on whether they experienced irAEs (irAE group) or not (non-irAE group). Eosinophils were examined before the two-course treatment. RESULTS: Patients in the irAE group who received anti-PD-1 or anti-CTLA-4 plus anti-PD-1 therapy had higher eosinophils before the two-course treatment than those in the non-irAE group (p < 0.05). The eosinophils in the anti-PD-L1 therapy group tended to increase in the irAE group. Furthermore, eosinophils in gastric, head and neck, lung, melanoma, renal, and urothelial cancers were significantly higher in the irAE group than in the non-irAE group (p < 0.05). The optimal cutoff value for eosinophils against irAEs was 3.0% (area under the curve = 0.668). In multivariate analyses, eosinophils of ≥3.0% were an independent factor for irAEs (odds ratio: 2.57, 95% CI: 1.79-3.67). CONCLUSION: An increased eosinophil before the two-course treatment may be a predictor of irAEs in various cancers treated with different ICIs.

A case of laparoscopic sigmoidectomy using thermography for colonic blood flow assessment.

BACKGROUND: Indocyanine green (ICG) fluorescence imaging is widely used in gastrointestinal surgery and is considered useful for reducing anastomotic leakage; however, because ICG remains in the tissue for a certain amount of time, we occasionally must re-evaluate colonic blood flow over a short time period during surgery. Herein, we verify the usefulness of thermography (TG) for evaluating colonic blood flow in a patient who underwent a laparoscopic sigmoidectomy for sigmoid colon cancer. CASE PRESENTATION: The patient is 43-year-old man who underwent laparoscopic resection of the sigmoid colon for colon cancer. After vascular treatment of the colonic mesentery, ICG/TG identified the boundary between ischemic and non-ischemic colon tissues. An additional 2 cm of colonic mesentery was resected because of the presence of a diverticulum noted at the intended site of oral anastomosis when attaching the anvil head. After additional vascular treatment of the colonic mesentery and administration of ICG, fluorescence was observed in the colon; however, TG identified the zone of the temperature transition on the surface of the colonic mesentery, even after additional colonic mesentery resection in the same region as previously observed. This zone was used as the cut-off line. There were no complications, such as anastomotic leakage, after the surgery. CONCLUSION: Although accumulation of similar cases is necessary, TG has the potential for use as an auxiliary diagnostic tool in clinical practice. TG can depict the presence or absence of blood flow based on surface temperature without the use of imaging agents, and is inexpensive and easy to perform.

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.

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.

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.