Functional remodeling of intraperitoneal macrophages by oncolytic adenovirus restores anti-tumor immunity for peritoneal metastasis of gastric cancer.

Intraperitoneal tumor-associated macrophages (TAMs) are involved in evading anti-tumor immunity and promoting the peritoneal metastasis (PM) of gastric cancer (GC). Oncolytic viruses are known to induce the activation of host anti-tumor immunity in addition to tumor lysis. This study investigated whether a wild-type p53-loading telomerase-specific oncolytic adenovirus (OBP-702) could elicit the remodeling of intraperitoneal macrophages and enhance the efficacy of immune therapy. Increased numbers of CD163 TAMs and few CD8+ lymphocytes were immunohistochemically observed in clinical samples with PM, which suggested that TAMs were associated with the suppression of anti-tumor immunity. OBP-702 induced immunogenic cell death and upregulated PD-L1 expression in human and murine GC cell lines. Intraperitoneal administration of OBP-702 increased recruitment of CD8+ lymphocytes into the PM via the functional remodeling of intraperitoneal macrophages from TAM toward a pro-inflammatory phenotype, resulting in significantly suppressed tumor growth for the in vivo model. Furthermore, the combination of intraperitoneal OBP-702 with anti-programmed cell death-1 antibody enhanced anti-tumor immunity and prolonged the survival of mice bearing PM. Intraperitoneal immunotherapy using OBP-702 restores anti-tumor immunity via the remodeling of intraperitoneal macrophages in addition to direct tumor lysis and cooperates with immune checkpoint inhibitors to suppress PM in GC.

Modulation of p53 expression in cancer-associated fibroblasts prevents peritoneal metastasis of gastric cancer.

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are associated with the establishment and progression of peritoneal metastasis. This study investigated the efficacy of replicative oncolytic adenovirus-mediated p53 gene therapy (OBP-702) against CAFs and peritoneal metastasis of gastric cancer (GC). Higher CAF expression in the primary tumor was associated with poor prognosis of GC, and higher CAF expression was also observed with peritoneal metastasis in immunohistochemical analysis of clinical samples. And, we found transcriptional alteration of p53 in CAFs relative to normal gastric fibroblasts (NGFs). CAFs increased the secretion of cancer-promoting cytokines, including interleukin-6, and gained resistance to chemotherapy relative to NGFs. OBP-702 showed cytotoxicity to both GC cells and CAFs but not to NGFs. Overexpression of wild-type p53 by OBP-702 infection caused apoptosis and autophagy of CAFs and decreased the secretion of cancer-promoting cytokines by CAFs. Combination therapy using intraperitoneal administration of OBP-702 and paclitaxel synergistically inhibited the tumor growth of peritoneal metastases and decreased CAFs in peritoneal metastases. OBP-702, a replicative oncolytic adenovirus-mediated p53 gene therapy, offers a promising biological therapeutic strategy for peritoneal metastasis, modulating CAFs in addition to achieving tumor lysis.

Nutritional assessment and surgical outcomes in very elderly patients undergoing pancreaticoduodenectomy: a retrospective study.

PURPOSE: To evaluate and compare the nutritional factors and clinical outcomes of pancreaticoduodenectomy between elderly and non-elderly patients. METHODS: This retrospective study evaluated 122 consecutive patients who underwent pancreaticoduodenectomy from April 2008 to April 2020. Preoperative and postoperative nutritional factors (prognostic nutritional index), complication rates, and survival rates were compared between the elderly (≥ 80 years) and non-elderly (< 80 years) patient groups. Changes in nutrition markers were evaluated before surgery to 1 year after surgery. RESULTS: A total of 20 elderly patients (16.4%) and 102 non-elderly patients (83.6%) underwent pancreaticoduodenectomy. Elderly patients had a significantly lower preoperative prognostic nutritional index than did non-elderly patients. At 3 months postoperatively, elderly patients had a lower albumin level and prognostic nutritional index. The median length of hospital stay was significantly longer (39.9 vs. 27 days, P = 0.004), the rate of death due to other diseases was higher, and the overall survival rate was significantly lower (1-/3-/5 year overall survival rates: 78.1%/26.7%/13.3% vs. 87.1%/54.4%/46.7%; log-rank test, P = 0.003) in the elderly group than in the non-elderly group. CONCLUSIONS: The results suggest that careful patient selection and optimal perioperative care are necessary to determine whether pancreaticoduodenectomy is indicated for elderly patients.

Solitary Cardiac Metastasis of Hepatocellular Carcinoma.

Cardiac metastasis originating from hepatocellular carcinoma (HCC) is a rare condition with a poor prognosis. No therapeutic standards for cardiac metastasis originating from HCC have been established. At 19 months after a curative hepatectomy, a 64-year-old Japanese hepatitis B virus-positive male patient experienced solitary cardiac metastasis originating from HCC. The cardiac tumor was discovered in the right ventricle. The patient received three courses of radiotherapy and chemotherapy and survived > 3 years after the initial diagnosis of cardiac metastasis. His case demonstrates that radiotherapy combined with chemotherapy can be an effective treatment for cardiac metastasis.

The Late Phase/Early Phase Ratio of Pancreatic CT Values as a Novel Predictor of Pancreatic Fistula after Distal Pancreatectomy.

Post-operative pancreatic fistula (POPF) remains the most common complication after distal pancreatectomy (DP). In this retrospective study, we reviewed the data from patients who underwent DP between 2008 and 2019 in our institute to determine whether the late phase/early phase ratio (L/E ratio) by preoperative computed tomography (CT) scan in the pancreas could predict POPF occurrence after DP. We examined the relationship between preoperative or intraoperative factors and the occurrence of POPF after DP using statistical methods in 23 males and 21 females with a mean age of 73. The mean L/E ratio was significantly lower in the POPF group than the non-POPF group (p=0.035). The L/E ratio had moderate diagnostic accuracy, with a calculated optimal cutoff value of 0.77. In univariate analysis, a significant association was noted between POPF and stump thickness ≥ 16.9, body mass index ≥ 27.5, and L/E ratio ≤ 0.77. In the multivariate analysis, the L/E ratio (odds ratio, 5.96; p=0.036) was an independent risk factor for POPF. Our findings suggest that the pancreatic L/E ratio may predict the occurrence of POPF after DP. This measure may be useful in preoperative risk stratification, patient counseling, and perioperative patient management, improving clinical outcomes after DP.

Preoperative predictive factors of pancreatic fistula after pancreaticoduodenectomy: usefulness of the CONUT score.

PURPOSE: Postoperative pancreatic fistula (POPF) is the most important factor affecting morbidity and mortality after pancreaticoduodenectomy (PD). Patients with a high controlling nutritional status (CONUT) score, which is used to assess nutritional status, are expected to have high morbidity rates. This study aimed to determine the usefulness of the CONUT score. METHODS: Data from 97 consecutive cases of PD performed in the Department of Surgery of Iwakuni Clinical Center, from April 2008 to May 2018, were included. Preoperative patient data, including sex, age, and hypertension, and postoperative complication data were collected to analyze pancreatic fistula occurrence. RESULTS: Of the 97 patients, 2 9 patients (29.8%) were diagnosed with POPF ≥ B, with 26 cases (26.8%) classified as grade B and 3 (3.1%) as grade C. The mortality rate was 2.1% (2 of 97). In the univariate analysis, a significant association was observed between POPF and the following factors: body mass index (BMI) ≥ 22 kg/m2, high CONUT score, nonpancreatic carcinoma, and CT attenuation values. In multivariate analysis, BMI ≥ 22 kg/m2 (odds ratio [OR], 6.16; P < 0.001), high CONUT score (OR, 3.77; P = 0.009), nonpancreatic carcinoma (OR, 5.72; P = 0.009), and CT attenuation values (late/early ratio) in the pancreas (OR, 9.07; P = 0.006) were independent risk factors for POPF. CONCLUSION: Patients with a high CONUT score are at high risk of POPF. Further study correlating preoperative nutritional intervention with risk of POPF is necessary.

Preoperative C-Reactive Protein/Albumin Ratio as a Predictive Factor for Gallbladder Carcinoma.

BACKGROUND/AIM: The C-reactive protein (CRP) to albumin ratio (CAR) is associated with outcomes in patients with sepsis. We aimed to evaluate the significance of preoperative CAR in therapeutic outcomes after gallbladder carcinoma (GBC) resection. PATIENTS AND METHODS: Fifty-three patients who underwent surgical resection for GBC between January 2008 and September 2019 were enrolled. We retrospectively investigated the relation between preoperative CAR and overall and disease-free survival. RESULTS: The optimal cut-off CAR was 0.07. Multivariate analysis showed that i) R1 or R2 resection (p=0.033), ii) advanced tumor stage (p=0.047), iii) CAR≥0.07 (p=0.011), and iv) postoperative complications (p=0.028) were significant independent predictors of overall survival; moreover, higher carbohydrate antigen levels (p=0.036) and R1 or R2 resection (p<0.001) were significant independent predictors of disease-free survival. CONCLUSION: Preoperative CAR may be a significant independent predictor of long-term outcomes after GBC resection.

Preoperative Nutritional Assessment Using the Controlling Nutritional Status Score to Predict Pancreatic Fistula After Pancreaticoduodenectomy.

Backgound: This study aimed to determine the usefulness of the Controlling Nutritional Status (CONUT) scorescore for predicting postoperative pancreatic fistula (POPF). PATIENTS AND METHODS: Data from 108 consecutive pancreaticoduodenectomy cases performed at the Surgery Department of Iwakuni Clinical Center, from April 2008 to May 2018, were included. Preoperative patient data and postoperative complication data were collected. RESULTS: Of the 108 patients (male=65; female=43; mean age=70 years), 41 (37.9%) had indication for pancreaticoduodenectomy due to pancreatic carcinoma. Grade B or higher POPF was diagnosed in 32 patients (29.6%). In the multivariate analysis, body mass index ≥22 kg/m2 [odds ratio (OR)=5.24; p=0.005], CONUT score ≥4 (OR=3.28; p=0.042), non-pancreatic carcinoma (OR=47.17; p=0.001), and a low computed tomographic contrast attenuation value (late/early ratio) (OR=4.39; p=0.029) were independent risk factors for POPF. CONCLUSION: Patients with high CONUT score are at high risk for POPF. Preoperative nutritional intervention such as immunonutrition might help reduce the POPF risk in these patients.

Adequacy evaluation of the annual colonoscopic surveillance and individual difference of disease phenotypes in Lynch syndrome.

BACKGROUND: Regular endoscopic surveillance for Lynch syndrome is reported to reduce colorectal cancer (CRC)-related mortality. However, the appropriate surveillance intervals are still unclear. We evaluated the adequacy of annual colonoscopy and investigated the differences in tumor occurrence rates between individual patients. METHODS: In total, 25 patients with Lynch syndrome who underwent colonoscopic surveillance between 2007 and 2016 at the Iwakuni Clinical Center were included. We retrospectively investigated the surveillance frequency and the clinical features associated with tumor development. RESULTS: Colonoscopic surveillance was performed every 397 days on average. A total of 101 tumors, including 8 intramucosal carcinomas and 15 carcinomas, were observed within the study period. Annual colonoscopy detected six malignancies, including a carcinoma requiring surgery. Tumor incidence was associated with tumor existence in the initial colonoscopies (P = 0.018). Patients with a tumor occurrence rate of 0.4 tumors per year during our observation period were significantly more likely to have malignancies detected during regular surveillance than patients who had a lower occurrence rate (P < 0.001). Malignancy occurrence rate was strongly associated with tumor occurrence rate (P < 0.001, R2 = 0.44). CONCLUSIONS: Annual colonoscopic surveillance for Lynch syndrome patients was effective in reducing the risk of CRC progression, but was insufficient to completely avoid surgery. Because the tumor occurrence rate differed substantially between individuals, more intensive surveillance was required for high-risk patients.

[A Case of Laparoscopic Distal Gastrectomy for Gastric Cancer with Common Hepatic Artery Anomaly].

A 67-year-old woman with upper abdominal pain was referred to our hospital. Upper gastrointestinal endoscopy revealed a type 3 gastric cancer at the greater curvature of the angular notch. Abdominal CT helped detect the primary tumor. Multi-detector-row computed tomography(MDCT)and 3D-CT angiography revealed a vascular anomaly in which the left gastric and splenic arteries formed the common trunk. The common hepatic and superior mesenteric arteries formed the common trunk. We performed a laparoscopic distal gastrectomy with D2 lymph node dissection. During suprapancreatic lymph node dissection, the surface of the portal vein was difficult to expose toward the left side because the portal vein joined the splenic and superior mesenteric veins on the caudal side. Therefore, the No. 8a lymph nodes were dissected along the anterior hepatic plexus. In cases of common hepatic artery anomaly, identifying the anterior hepatic plexus is useful for the dissection of the suprapancreatic lymph nodes.

[A Case of Surgery for Transversal Colon Cancer with Intestinal Malrotation -Visualizing Method of Blood Flow in the Fluorescence Navigation Period].

BACKGROUND: Anastomotic blood flow evaluation using the fluorescence method with indocyanine green(ICG)is expected to decrease the risk of anastomotic leakage in colorectal cancer surgery. The fluorescence method is considered to be also useful for assessing arterial divergence patterns in patients with special anatomical features. We report a case of transverse colon cancer with intestinal malrotation treated with laparoscopic surgery using the ICG fluorescence method. CASE: A 62- year-old woman who was diagnosed as having transverse colon cancer with intestinal malrotation underwent a laparoscopic transverse colon resection with D3 lymph node dissection. We identified the ileocolic artery and middle colic artery (MCA)after the ICG injection and the severed MCA during lymphadenectomy. We made a final diagnosis of pT2N0M0, pStage Ⅰ. CONCLUSION: The fluorescence method was useful for assessing the arterial divergence pattern in a patient with a special anatomical feature. However, the ICG fluorescence method had some problems, including visualizing blood flow for only a short time and poorly transmitting the dye through thick fat.

Safety of Surgical Treatment for Elderly Patients with Gallbladder Carcinoma.

Gallbladder carcinoma (GBC) is a common malignancy with a poor prognosis. With the average life expectancy increasing globally, the incidence of GBC is predicted to increase as well. We investigated the safety and feasibility of surgical treatment for elderly patients with GBC. We retrospectively compared clinical pathological data and treatment outcomes in 45 consecutive GBC patients (23 patients ≥ 75 years [elderly group] and 22 patients < 75 years [younger group]) who underwent curative resection at the Iwakuni Center from January 2008 to December 2017. The proportion of preoperative comorbidities and anticoagulant use was significantly higher in the elderly group. The American Society of Anesthesiologists score was higher in the elderly versus the younger group, and the elderly group had significantly shorter operation times. Reduced activities of daily living was more common in the elderly versus younger group. The percentage of radical resection and overall 3-year survival (66.6% younger vs. 64.4% elderly) were similar between the groups. Controlling Nutritional Status (CONUT) score ≥ 3 and R0 resection were identified as prognostic factors for overall survival rate among all patients. After careful patient selection.

Pancreatic Ductal Adenocarcinoma in Remnant Pancreas after Pancreaticoduodenectomy for Acinar Cell Carcinoma: A Case Report.

We report a case of a pancreatic ductal adenocarcinoma (PDAC) in the remnant pancreas of a 78-year-old man after pancreaticoduodenectomy for acinar cell carcinoma, a relatively rare pancreatic neoplasm. After diagnosis of pancreatic carcinoma, subtotal stomach-preserving pancreaticoduodenectomy was performed. The pathological diagnosis was acinar cell carcinoma of the pancreas (disease stage IA, pT1, pN0, M0), without regional lymph node invasion. Cancer antigen 19-9 levels gradually increased during the 22 months after surgery, and computed tomography showed two solid tumors, 1.1 and 2.1 cm in diameter, at the site of the remnant pancreas. Endoscopic ultrasound fine-needle aspiration revealed pancreatic ductal adenocarcinoma. The tumor cells were not immunoreactive for trypsin. Both tumors were diagnosed as PDAC of the remnant pancreas. The patient declined curative resection, and chemoradiotherapy was started as alternative treatment. The patient died 28 months after surgery. Because this is an extremely rare case, additional cases and studies are needed in order to clarify its pathogenesis.