Senescent Fibroblasts Potentiate Peritoneal Metastasis of Diffuse-type Gastric Cancer Cells via IL-8-mediated Crosstalk.

BACKGROUND/AIM: Diffuse-type gastric cancer (DGC) often forms peritoneal metastases, leading to poor prognosis. However, the underlying mechanism of DGC-mediated peritoneal metastasis is poorly understood. DGC is characterized by desmoplastic stroma, in which heterogeneous cancer-associated fibroblasts (CAFs), including myofibroblastic CAFs (myCAFs) and senescent CAFs (sCAFs), play a crucial role during tumor progression. This study investigated the CAF subtypes induced by GC cells and the role of sCAFs in peritoneal metastasis of DGC cells. MATERIALS AND METHODS: Conditioned medium of human DGC cells (KATOIII, NUGC-4) and human intestinal-type GC (IGC) cells (MKN-7, N87) was used to induce CAFs. CAF subtypes were evaluated by analyzing the expression of α-smooth muscle actin (α-SMA), senescence-associated ß-galactosidase (SA-ß-gal), and p16 in human normal fibroblasts (GF, FEF-3). A cytokine array was used to explore the underlying mechanism of GC-induced CAF subtype development. The role of sCAFs in peritoneal metastasis of DGC cells was analyzed using a peritoneally metastatic DGC tumor model. The relationships between GC subtypes and CAF-related markers were evaluated using publicly available datasets. RESULTS: IGC cells significantly induced α-SMA+ myCAFs by secreting transforming growth factor-ß, whereas DGC cells induced SA-ß-gal+/p16+ sCAFs by secreting interleukin (IL)-8. sCAFs further secreted IL-8 to promote DGC cell migration. In vivo experiments demonstrated that co-inoculation of sCAFs significantly enhanced peritoneal metastasis of NUGC-4 cells, which was attenuated by administration of the IL-8 receptor antagonist navarixin. p16 and IL-8 expression was significantly associated with poor prognosis of DGC patients. CONCLUSION: sCAFs promote peritoneal metastasis of DGC via IL-8-mediated crosstalk.

Role of robotic surgery as an element of Enhanced Recovery After Surgery protocol in patients undergoing pancreatoduodenectomy.

BACKGROUND: Although the current trend in pancreatoduodenectomy (PD) has shifted from open surgery to minimally invasive surgery (MIS), evidence on the role of MIS as an element of Enhanced Recovery After Surgery (ERAS) in PD is limited. This study aimed to investigate the effect of robotic surgery using the ERAS protocol on the outcomes of patients undergoing PD. METHODS: This retrospective study included 252 patients who underwent open PD (OPD) or robotic PD (RPD) managed using the ERAS protocol between January 2017 and March 2023. Outcomes stratified by the surgical approach were compared. Multivariable analyses were performed to evaluate the effect of ERAS items, including robotic surgery, on outcomes after PD. RESULTS: Of 252 patients, 202 (80.2%) underwent OPD, and 50 (19.2%) underwent RPD. Multivariable analyses demonstrated that perioperative management center support (odds ratio [OR], 2.85; 95% CI, 1.14-7.72; P = .025), robotic surgery (OR, 6.40; 95% CI, 1.94-26.1; P = .002), early solid intake (OR, 2.84; 95% CI, 1.46-5.63; P = .002), and early drain removal (OR, 3.77; 95% CI, 2.04-7.06; P < .001) were significant ERAS items related to early discharge after PD. CONCLUSION: Our study demonstrated that employing the ERAS protocol for OPD and RPD is feasible and safe. Moreover, our results suggested the role of robotic surgery as an element of the ERAS protocol for PD. A combination of ERAS protocols and MIS may be safe and feasible for accelerating postoperative recovery after PD.

Robotic Pancreatoduodenectomy in Portal Annular Pancreas Using a Hanging Maneuver with Indocyanine Green Fluorescence Imaging.

BACKGROUND: Sufficient knowledge and surgical management of portal annular pancreas (PAP) are essential for pancreatic surgery. As PAP is a relatively rare pancreatic anomaly, few studies have described surgical techniques for patients with PAP undergoing robotic pancreatoduodenectomy (RPD). PATIENTS AND METHODS: An 82-year-old female patient who underwent RPD presented with distal cholangiocarcinoma and type III PAP (the fusion of the uncinate process with the anteportal main pancreatic duct). After the Kocher maneuver and stomach transection, the pancreas was transected into the neck of the anteportal portion. The retroportal portion was dissected, encircled with hanging tape, and compressed. Blood supply from the mesenteric vessels was confirmed using indocyanine green (ICG) fluorescence imaging. Subsequently, the retroportal portion was stapled. CONCLUSIONS: This study demonstrates a unique surgical technique for type III PAP using the hanging maneuver with ICG fluorescence imaging. Surgeons should decide on the surgical strategy on the basis of the fusion and ductal anatomy of the pancreas.

p53-armed oncolytic adenovirus induces autophagy and apoptosis in KRAS and BRAF-mutant colorectal cancer cells.

Colorectal cancer (CRC) cells harboring KRAS or BRAF mutations show a more-malignant phenotype than cells with wild-type KRAS and BRAF. KRAS/BRAF-wild-type CRCs are sensitive to epidermal growth factor receptor (EGFR)-targeting agents, whereas KRAS/BRAF-mutant CRCs are resistant due to constitutive activation of the EGFR-downstream KRAS/BRAF signaling pathway. Novel therapeutic strategies to treat KRAS/BRAF mutant CRC cells are thus needed. We recently demonstrated that the telomerase-specific replication-competent oncolytic adenoviruses OBP-301 and p53-armed OBP-702 exhibit therapeutic potential against KRAS-mutant human pancreatic cancer cells. In this study, we evaluated the therapeutic potential of OBP-301 and OBP-702 against human CRC cells with differing KRAS/BRAF status. Human CRC cells with wild-type KRAS/BRAF (SW48, Colo320DM, CACO-2), mutant KRAS (DLD-1, SW620, HCT116), and mutant BRAF (RKO, HT29, COLO205) were used in this study. The antitumor effect of OBP-301 and OBP-702 against CRC cells was analyzed using the XTT assay. Virus-mediated modulation of apoptosis, autophagy, and the EGFR-MEK-ERK and AKT-mTOR signaling pathways was analyzed by Western blotting. Wild-type and KRAS-mutant CRC cells were sensitive to OBP-301 and OBP-702, whereas BRAF-mutant CRC cells were sensitive to OBP-702 but resistant to OBP-301. Western blot analysis demonstrated that OBP-301 induced autophagy and that OBP-702 induced autophagy and apoptosis in human CRC cells. In BRAF-mutant CRC cells, OBP-301 and OBP-702 suppressed the expression of EGFR, MEK, ERK, and AKT proteins, whereas mTOR expression was suppressed only by OBP-702. Our results suggest that p53-armed oncolytic virotherapy is a viable therapeutic option for treating KRAS/BRAF-mutant CRC cells via induction of autophagy and apoptosis.

Oncolytic virus-mediated reducing of myeloid-derived suppressor cells enhances the efficacy of PD-L1 blockade in gemcitabine-resistant pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is often refractory to treatment with gemcitabine (GEM) and immune checkpoint inhibitors including anti-programmed cell death ligand 1 (PD-L1) antibody. However, the precise relationship between GEM-resistant PDAC and development of an immunosuppressive tumor microenvironment (TME) remains unclear. In this study, we investigated the immunosuppressive TME in parental and GEM-resistant PDAC tumors and assessed the therapeutic potential of combination therapy with the telomerase-specific replication-competent oncolytic adenovirus OBP-702, which induces tumor suppressor p53 protein and PD-L1 blockade against GEM-resistant PDAC tumors. Mouse PDAC cells (PAN02) and human PDAC cells (MIA PaCa-2, BxPC-3) were used to establish GEM-resistant PDAC lines. PD-L1 expression and the immunosuppressive TME were analyzed using parental and GEM-resistant PDAC cells. A cytokine array was used to investigate the underlying mechanism of immunosuppressive TME induction by GEM-resistant PAN02 cells. The GEM-resistant PAN02 tumor model was used to evaluate the antitumor effect of combination therapy with OBP-702 and PD-L1 blockade. GEM-resistant PDAC cells exhibited higher PD-L1 expression and produced higher granulocyte-macrophage colony-stimulating factor (GM-CSF) levels compared with parental cells, inducing an immunosuppressive TME and the accumulation of myeloid-derived suppressor cells (MDSCs). OBP-702 significantly inhibited GEM-resistant PAN02 tumor growth by suppressing GM-CSF-mediated MDSC accumulation. Moreover, combination treatment with OBP-702 significantly enhanced the antitumor efficacy of PD-L1 blockade against GEM-resistant PAN02 tumors. The present results suggest that combination therapy involving OBP-702 and PD-L1 blockade is a promising antitumor strategy for treating GEM-resistant PDAC with GM-CSF-induced immunosuppressive TME formation.

Oncolytic virus-mediated p53 overexpression promotes immunogenic cell death and efficacy of PD-1 blockade in pancreatic cancer.

Immune checkpoint inhibitors, including anti-programmed cell death 1 (PD-1) antibody, provide improved clinical outcome in certain cancers. However, pancreatic ductal adenocarcinoma (PDAC) is refractory to PD-1 blockade therapy due to poor immune response. Oncolytic virotherapy is a novel approach for inducing immunogenic cell death (ICD). We demonstrated the therapeutic potential of p53-expressing telomerase-specific oncolytic adenovirus OBP-702 to induce ICD and anti-tumor immune responses in human PDAC cells with different p53 status (Capan-2, PK-59, PK-45H, Capan-1, MIA PaCa-2, BxPC-3) and murine PDAC cells (PAN02). OBP-702 significantly enhanced ICD with secretion of extracellular adenosine triphosphate and high-mobility group box protein B1 by inducing p53-mediated apoptosis and autophagy. OBP-702 significantly promoted the tumor infiltration of CD8+ T cells and the anti-tumor efficacy of PD-1 blockade in a subcutaneous PAN02 syngeneic tumor model. Our results suggest that oncolytic adenovirus-mediated p53 overexpression augments ICD and the efficacy of PD-1 blockade therapy against cold PDAC tumors. Further in vivo experiments would be warranted to evaluate the survival benefit of tumor-bearing mice in combination therapy with OBP-702 and PD-1 blockade.

Open abdominal management for perforative peritonitis with septic shock: a retrospective analysis on usefulness of a standardized treatment protocol.

BACKGROUND: Damage control surgery (DCS) with open abdominal management (OAM) has been increasingly expanded to include critically ill non-trauma patients. However, there is limited data regarding the usefulness of this protocol for the treatment of severe perforative peritonitis (PP), especially with septic shock (SS). Here, we retrospectively evaluated the usefulness of our OAM protocol for PP with SS. METHODS: We retrospectively reviewed patients with from June 2015 to September 2018. The proposed protocol was composed of the following steps: (1) rapid control of contamination; (2) temporary abdominal closure; (3) repeated washout of the abdominal cavity; and (4) delayed definitive surgery. For temporary abdominal closure, a negative pressure wound therapy device was used. The end points were the morbidity and 30-day mortality rates. Logistic backward regression was performed to identify factors associated with complications. RESULTS: The mortality rate was 4% (1/25) and the overall morbidity rate of surviving patients was 58.3% (14/24). The mean duration of the first DCS was 67.36 ± 22.83 min. The median durations of ventilation and intensive care unit stay were 5 and 7 days, respectively. Although not significant, morbidity might be associated with age, diabetes mellitus, initial operative time, and OAM duration. CONCLUSIONS: A standardized protocol for OAM may improve the outcomes of patients with SS due to PP. This damage control approach can be applied for the treatment of severe abdominal sepsis.

Novel laparoscopic methods for inguinal hernia post pelvic fracture: A case report.

INTRODUCTION: Pelvic fractures can occur in minor injuries, such as falls, in the elderly. Extensive adhesion of preperitoneal space is common after pelvic fracture surgery; hence, surgical interventions for inguinal hernia may be challenging. We treated a case of inguinal hernia after pelvic fracture surgery, using novel laparoscopic methods: iliopubic tract repair (IPTR) and modified intraperitoneal onlay mesh (mIPOM) approach. PRESENTATION OF CASE: This is the case of an elderly male with pelvic fracture. Open reduction and internal fixation were performed. Eighteen months after the procedure, a right inguinal bulge appeared, swelling increased, and he opted for surgery. We chose laparoscopic surgery to determine the status of the hernia and anatomy around the pelvis. He was diagnosed with an indirect inguinal hernia, and the inner inguinal ring was widely open. We chose the mIPOM approach and IPTR. He was discharged on day 3 post-operation. He developed a seroma after surgery, which disappeared after a month. Six months post-operation, no recurrence or neurologic pain observed. DISCUSSION: The transabdominal preperitoneal approach (TAPP) was initiated at first; however, the adhesion inside the inferior epigastric vessels was very strong, challenging to break into the preperitoneal space. We switched to the mIPOM method because the peritoneum was fragile and difficult to suture. Additionally, the internal ring was widely opened; hence, we proceeded with IPTR on confirmation that no tension on the abdominal wall was applied. CONCLUSIONS: Laparoscopic surgery is useful in flexibility of surgical options, such as TAPP, IPTR, IPOM, in addition to hybrid conversion.

Intraluminal Apple as a Rare Cause of Small Bowel Obstruction.

Small bowel obstruction due to ingested foreign bodies is rare in adults. A 48-year-old male visited our hospital with abdominal pain and vomiting. Computed tomography revealed intestinal obstruction by a 3 × 4 cm apple-shaped foreign body. Emergency surgery was performed to clear the obstruction which, upon inspection, was caused by a sexual toy made of rubber. Flexible rubber products that are ingested should be carefully followed after they pass thorough the pylorus. For obstructions related to sexual behavior, the patient's sense of shame often delays the process of seeking medical attention, thereby making preoperative diagnosis difficult.

[Damage Control Surgery for Perforation of Colon Cancer].

Perforation due to colon cancer maycause peritonitis and septic shock. In these cases, we maynot be able to rescue the patients in spite of emergencysurgical intervention; in these conditions, owing to limitations of operation time, it is difficult for us to assess the state or extent of the disease and to perform an ideal oncological surgerywith dissection of lymph nodes. To overcome these limitations, we introduce the concept of "damage control surgery" developed in the trauma region to treat perforations of colon cancer. There are 3 steps: first, the perforated intestine is resected and the peritoneal cavityis lavaged to control contamination. Open abdominal management is used as a temporaryabdominal closure; second, sepsis is treated in the ICU; and third, based on the treatment strategydecided upon after consulting a colorectal surgeon and the patient's family, a colostomy, anastomosis, and extra dissection of lymph node are performed before abdominal closure. We report the fatal case of a 92-year-old woman who had developed severe shock to indicate the significance of this strategy.

Enhanced TLR-MYD88 signaling stimulates autoinflammation in SH3BP2 cherubism mice and defines the etiology of cherubism.

Cherubism is caused by mutations in SH3BP2. Studies of cherubism mice showed that tumor necrosis factor α (TNF-α)-dependent autoinflammation is a major cause of the disorder but failed to explain why human cherubism lesions are restricted to jaws and regress after puberty. We demonstrate that the inflammation in cherubism mice is MYD88 dependent and is rescued in the absence of TLR2 and TLR4. However, germ-free cherubism mice also develop inflammation. Mutant macrophages are hyperresponsive to PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns) that activate Toll-like receptors (TLRs), resulting in TNF-α overproduction. Phosphorylation of SH3BP2 at Y183 is critical for the TNF-α production. Finally, SYK depletion in macrophages prevents the inflammation. These data suggest that the presence of a large amount of TLR ligands, presumably oral bacteria and DAMPs during jawbone remodeling, may cause the jaw-specific development of human cherubism lesions. Reduced levels of DAMPs after stabilization of jaw remodeling may contribute to the age-dependent regression.

[A case of a patient who underwent resection of the remnant pancreatic cancer following a distal pancreatectomy for invasive ductal carcinoma].

Herein, we report the case of a patient who underwent resection of the remnant pancreas for pancreatic cancer following a distal pancreatectomy for invasive ductal carcinoma. An 81-year-old woman underwent a distal pancreatectomy. The tumor was found to be pancreatic cancer. The tumor was histologically diagnosed as a poorly differentiated tubular adenocarcinoma (Stage I). An abdominal computed tomography (CT) performed 17 months later revealed a 13 mm tumor in the remnant pancreatic head. A remnant pancreatectomy was performed. The histological diagnosis was a moderately differentiated tubular adenocarcinoma (StageIII). Remnant pancreatic cancer is rare following a pancreatectomy for invasive ductal carcinoma. The course of remnant pancreatic cancer can be followed with imaging. Long-term follow-up of patients who have undergone a pancreatectomyis, therefore, essential.