北山 丈二

BACKGROUND AND PURPOSE: The peritoneal cavity constitutes a unique immune microenvironment that critically influences the pathobiology of peritoneal metastasis (PM). This study aimed to clarify the mechanisms by which local immune alterations affect the efficacy of intraperitoneal (IP) chemotherapy for PM from gastric cancer (GC). METHOD: Peritoneal lavage or ascitic fluid was obtained from 42 patients with GC and PM treated with IP paclitaxel (PTX) in combination with systemic oxaliplatin and oral S-1. Serial samples from 31 patients were analyzed after 1-3 cycles of chemotherapy. Immune cell subsets were evaluated using multicolor flow cytometry with monoclonal antibodies, and the functional properties of peritoneal eosinophils were assessed using gene expression profiling and cytotoxicity assays. RESULTS: IP chemotherapy was associated with decreased CD4(+) T cells and increased CD11b(+) myeloid cells. Notably, many patients, particularly those with negative cytology (CY0), exhibited striking recruitment of CD66b(+) CD16(-) CD193(+) Siglec-F(+) eosinophils into the peritoneal cavity. Eosinophil expansion was correlated with improved clinical outcomes. Post-treatment eosinophils displayed an activated, partially degranulated phenotype with elevated CD11b and CD63 expression and distinct messenger RNA signatures compared with circulating eosinophils. Peritoneal eosinophils demonstrated the ability to induce apoptosis in GC cells. CONCLUSION: IP PTX promotes the recruitment and activation of eosinophils with potent antitumor activity in the peritoneal cavity. Early post-treatment abdominal eosinophilia is a robust prognostic biomarker and may represent a promising therapeutic target to enhance the efficacy of IP chemotherapy in patients with PM from GC.

PURPOSE: There is limited awareness of work-related musculoskeletal disorders (MSDs) in Japan, despite the high ergonomic risks for surgeons. We conducted this study to investigate the prevalence, characteristics, and impact of MSDs on Japanese general surgeons. METHODS: An electronic survey of 136 general surgeons at a Japanese university hospital network used a modified Nordic Musculoskeletal Questionnaire to assess demographics, work factors, MSD symptoms, psychological distress, use of nonsteroidal anti-inflammatory drugs (NSAIDs), and their impact. RESULTS: Based on a 56.6% response rate, we found a high prevalence of chronic (37.7%) and acute (51.9%) MSDs. These disorders frequently impacted surgeons' work (30.0%) and daily life (39.0%), leading to time off (5.2%) and medical intervention (28.6%). Both MSD types correlated significantly with the use of NSAIDs and psychological distress. Notably, neck pain was strongly associated with the use of NSAIDs. The proportion of minimally invasive surgical procedures performed each week was associated significantly with acute, but not chronic, MSDs. CONCLUSIONS: MSDs are highly prevalent among Japanese surgeons, impacting their physical and psychological health. The high symptom prevalence and the strong association between neck pain and NSAID reliance underscore the urgent need for ergonomic interventions and preventive strategies in surgical practice to protect this essential workforce.

BACKGROUND: Perihilar cholangiocarcinoma with large hepatic resection is associated with high risk for morbidity and mortality. To improve outcomes, assessment of remnant liver function is crucial. METHODS: A total of 70 patients with perihilar cholangiocarcinoma were examined retrospectively. Liver function was evaluated <1 month preoperatively by hepatic clearance of remnant liver using 99mTc-galactosyl serum albumin (GAS) scintigraphy and computed tomography, and clinicopathological data and outcomes were analyzed in comparison GSA scintigraphy with liver function test based on computed tomography volumetry. RESULTS: There was no postoperative 90-day mortality, with 10 patients of posthepatectomy liver failure (PHLF) Grade A, 10 of Grade B, and 1 of Grade C. Area under the curve of receiver operating curve showed better prediction power for PHLF compared to remnant liver volume/body surface area or future liver remnant/body weight, especially in patients with incomplete change of liver function. In univariable analysis, <150 ml/min ml/min cutoff of hepatic clearance of remnant liver and >1750 ml intra-operative blood loss were significant risk factors for PHLF. In multivariable analysis, <150 ml/min cutoff was a significant risk factor for PHLF. The area under the curve of hepatic clearance of remnant liver indicated better predictivity in patients with incomplete change of liver function compared with complete change of liver function. CONCLUSIONS: The hepatic clearance of remnant liver may have predictive power in patients with incomplete changes in liver function compared to computed tomography-based methods. Preoperative measurement of hepatic clearance of remnant liver may assist in risk stratification for surgical management.

BACKGROUND: The effectiveness of intraperitoneal chemotherapy using paclitaxel (i.p.-PTX) in pancreatic ductal adenocarcinoma (PDAC) patients with peritoneal dissemination remains elusive. The aim of this study is to investigate the clinical outcome of patients treated with i.p.-PTX combined with systemic chemotherapy compared with current standard chemotherapy including gemcitabine plus nab-paclitaxel and FOLFIRINOX. METHODS: Data of patients with peritoneal dissemination was retrospectively collected and analyzed (i.p.-PTX, n = 83; control, n = 86). Inverse probability of treatment-weighted analyses (IPTW) was used to balance baseline characteristics between two groups. Survival curves were estimated using Kaplan-Meier method, and the differences were compared using the log-rank test. RESULTS: No significant differences were noted in overall survival (14.9 vs. 15.5 months, p = 0.481) and progression free survival (9.5 vs. 9.1 months, p = 0.267) between i.p.-PTX and the control groups. Nevertheless, i.p.-PTX (9.9 months) significantly prolonged the median progression-free survival (PFS) time compared with the control (8.6 months), among the matched patients using IPTW (hazard ratio 0.666, p = 0.041). Moreover, subgroup analysis among the patients whose primary tumor were evaluated either as resectable or borderline resectable disease revealed significantly better overall survival in the i.p.-PTX group compared with the control group (21.3 vs. 14.7 months, hazard ratio; 0.532, p = 0.033). Conversion surgery was more frequently performed in the i.p.-PTX group than the control group (24% vs. 4%, p = 0.006). CONCLUSION: The i.p. PTX regimen prolonged PFS but not overall survival, and subgroup analysis suggested the possibility of survival benefit in patients with occult peritoneal dissemination whose primary tumor was classified as resectable/borderline resectable disease.

Introduction: Peritoneal metastasis (PM) is the most common site of recurrence following curative resection for advanced gastric cancer (GC). Along with disease progression, it can lead to complications such as intestinal obstruction, hydronephrosis, obstructive jaundice, and ascites, significantly impairing the patient’s quality of life. Therefore, peritoneal metastasis is considered a critical target for treatment. In general, these patients are treated with systemic chemotherapy; however, the therapeutic effect is often limited due to the anticancer agents’ poor penetration into the peritoneal cavity. We aim to identify factors associated with the best overall survival (OS) in GC patients with peritoneal metastasis. Methods: Patients with advanced GC who were diagnosed as having macroscopic PM or positive peritoneal cytology by staging laparoscopy were enrolled. We introduced intraperitoneal Paclitaxel (IP-PTX) combined with S-1 plus oxaliplatin (SOX). Gastrectomy with lymph node dissection was performed as conversion surgery when the PM showed an excellent response. Results: Ninety-six patients received IP-PTX + SOX, with a median of 16 courses. The 1- and 5-year OS rates were 70.2% and 24.5%, respectively, with a mean survival time (MST) of 20.0 months. No chemotherapy-related mortality was observed. Conversion surgery was performed in 44 patients (45.8%), with a 1-year OS rate of 100%. Conclusions: Combination chemotherapy using the IP-PTX + SOX regimen is highly effective and is recommended as induction chemotherapy for patients with PM from GC. Conversion gastrectomy should be considered following an excellent response, particularly in patients with peritoneal cancer index (PCI) scores below 20.

BACKGROUND: The aim of this study was to elucidate the association of pancreatic fluid cytology with intrapancreatic recurrence of intraductal papillary mucinous neoplasms (IPMNs). MATERIALS AND METHODS: A total of 68 patients with IPMN who underwent pancreatectomy and obtained cytologic analysis of pancreatic fluid at Jichi Medical University Hospital were included in this study. Computed tomography scan and magnetic resonance cholangiopancreatography were performed preoperatively. Endoscopic retrograde cholangiopancreatography was used to obtain pancreatic fluid. The association of recurrence with variables was determined by logistic regression multivariate analysis. RESULTS: Class V cytology was found in 7/68 patients preoperatively. Metachronous intrapancreatic recurrences occurred in 6/68 patients, including one branched type, main pancreatic duct type in two and mixed pancreatic duct type in three. Four of seven patients with class V cytology developed intra-pancreatic recurrences as a new lesion. Class V cytology was significantly associated with intrapancreatic recurrence, compared to those with class IV or lower cytology. In univariate analysis, patients with pathological findings with high-grade dysplasia or adenocarcinoma (P = 0.0392, odds ratio (OR) 10.2, 95 % confidence interval (CI) 1.12-93.6) and class V pancreatic fluid cytology (P = 0.0005, OR 38.7, 95 % CI 4.94-302) were significant risk factors. In multivariate analysis, class V pancreatic fluid cytology was significantly associated with developing intrapancreatic recurrence (P = 0.0149, OR 22.7, 95 % CI 1.83-279). CONCLUSION: Preoperative class V pancreatic fluid cytology is associated with intra-pancreatic recurrence after resection of IPMN.

BACKGROUND: Patients with advanced gastric cancer (GC) with peritoneal involvement have a dismal prognosis. Recent clinical trials have shown that anti-Claudin18.2 (CLDN18.2) antibody (zolbetuximab) enhances survival in patients with GC expressing high levels of CLDN18.2. However, the effectiveness of the zolbetuximab in patients with peritoneal metastases (PMs) remains unclear. In this study, we aimed to evaluate the expression of CLDN18.2 in disseminated lesions to assess the clinical utility of zolbetuximab in the treatment of GC with PM. METHODS: In 42 patients diagnosed with stage IV GC with PM, biopsy samples from the primary tumors and peritoneal metastatic nodules were collected and immunostained using the specific antibody (43-14A, Ventana). The expression of CLDN18.2 was comparatively evaluated based on staining intensity and the proportion of positive cells. RESULTS: Positive immunoreactivity of CLDN18.2 was observed in 37 (88%) of the primary tumors. Specifically, CLDN18.2 positivity was identified in 26 (62%) or 12 (29%) patients based on moderate to strong membrane staining in at least 40% or 75% of tumor cells, respectively. In comparison, the staining intensity in tumor cells was consistently reduced in PM across all patients. CLDN18.2 expression was absent in PM of 29 (69%) patients, while 3 (7.1%) cases were determined to be CLDN18.2-positive based on a cutoff value of 40% for high staining. This trend was particularly pronounced in cases with undifferentiated type and human epidermal growth factor receptor 2 (HER-2) negative primary tumors. CONCLUSIONS: Although CLDN18.2 expression in PM mirrored that in primary lesions, the levels were generally reduced. When zolbetuximab is used for GC patients with peritoneal involvement, it is preferable to assess the expression of CLDN18.2 in the disseminated lesions.

BACKGROUND: This study aimed to elucidate the clinical impact of osteopenia on the recurrence of colon cancer liver metastases. METHODS: Patients with colon cancer liver metastases (N = 186) undergoing hepatectomy at Jichi Medical University Hospital between March 2006 and March 2020 were examined retrospectively. Computed tomography (CT) scans on the 11th vertebra within 3 months of surgery assessed bone mineral density (BMD). Age-adjusted BMD determined osteopenia presence. Kaplan-Meier method with a log-rank test estimated survival. Factors associated with survival were assessed using Cox's proportional hazards model after adjustment for confounders. RESULTS: Patients with osteopenia had shorter overall (p = 0.0001; 5-year overall survival, 51.8% vs 81.8%) and recurrence-free survival (p = 0.0008, 5-year recurrence-free survival: 26.3% vs 51.5%) than BMD-normal patients. In multivariable analysis, the risk factor for overall survival was osteopenia (Hazard ratio (HR) 3.79, 95% confidence interval (CI) 2.09-6.87, p = 0.001). Risk factors for recurrence were chemotherapy (HR 1.92, 95%CI 1.12-3.30, p = 0.002), tumor number (HR 1.51, 95%CI 1.02-2.27, p = 0.04), and osteopenia (HR 2.18, 95%CI 1.46-3.24 p = 0.001). Patients with osteopenia are more likely to develop lung metastases, and BMD-value reduction associated with KRAS mutation. CONCLUSION: Osteopenia may have prognostic significance in patients with liver metastases colorectal cancer.

INTRODUCTION: Neoadjuvant gemcitabine plus S-1 (GS) therapy for resectable pancreatic cancer has been shown to prolong overall survival significantly compared with upfront surgery. Herein, we report two opposite cases of patients with resectable pancreatic cancer who underwent distal pancreatectomy after neoadjuvant GS therapy. CASE PRESENTATION: In Case 1, a 49-year-old female with a 12 mm tumor in the pancreatic body (cT1N0M0, cStage IA, union for international cancer control [UICC] 8th edition) underwent two courses of neoadjuvant GS therapy followed by an open distal pancreatectomy. Pathological examination revealed no residual cancer and the patient was diagnosed with a pathological complete response (pCR) without recurrence 31 months after surgery. However, in Case 2, a 74-year-old male with a 12 mm tumor in the pancreatic body (cT1N0M0, cStage IA, UICC 8th edition) also underwent two courses of neoadjuvant GS therapy, and then a laparoscopic distal pancreatectomy was performed. Pathological examination showed invasive pancreatic ductal adenocarcinoma with a 20 mm tumor. The tumor exhibited invasion into the lumen of the splenic vein and retroperitoneal tissue (ypT1N0M0, ypStage IA, UICC 8th edition). Adjuvant chemotherapy with S-1 was started, but 4 months postoperatively, a significant rise in serum CA19-9 levels was observed with multiple hepatic metastases and portal venous tumor thrombus. Gemcitabine plus nab-paclitaxel (GnP) therapy was started, however, the tumor progressed rapidly. The patient died 6 months after surgery. CONCLUSIONS: Neoadjuvant GS therapy is potentially expected to have a significant therapeutic effect as the pCR. Nevertheless, even after surgical resection, some patients still exhibit extremely poor prognosis. Therefore, it is necessary to clarify their clinical characteristics.

BACKGROUND: Globally, prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing, and there is an urgent need to develop innovative therapies that promote liver regeneration following hepatectomy for this disease. Surgical excision is a key therapeutic approach with curative potential for liver tumors. However, hepatic steatosis can lead to delayed liver regeneration and higher post-operative complication risk. Mesenchymal stem cells-conditioned medium (MSC-CM) is considered a rich source of paracrine factors that can repair tissues and restore function of damaged organs. Meanwhile, hydrogels have been widely recognized to load MSC secretome and achieve sustained release. This study aimed to evaluate the therapeutic effect of hydrogel-encapsulated MSC-CM on liver regeneration following partial hepatectomy (PHx) in a rodent model of diet-induced hepatic steatosis. METHODS: Male Lewis rats were fed with a methionine and choline-deficient diet. After 3 weeks of feeding, PHx was performed and rats were randomly allocated into two groups that received hydrogel-encapsulated MSC-CM or vehicle via the intra-mesenteric space of the superior mesenteric vein (SMV). RESULTS: The regeneration of the remnant liver at 30 and 168 h after PHx was significantly accelerated, and the expressions of proliferating cell nuclear antigen were significantly enhanced in the MSC-CM group. MSC-CM treatment significantly increased hepatic ATP and β-hydroxybutyrate content at 168 h after PHx, indicating that MSC-CM fosters regeneration not only in volume but also in functionality. The number of each TUNEL- and cleaved caspase-3 positive nuclei in hepatocytes at 9 h after PHx were significantly decreased in the MSC-CM group, suggesting that MSC-CM suppressed apoptosis. MSC-CM increased serum immunoregulatory cytokine interleukin-10 and interleukin-13 at 30 h after PHx. Additionally, mitotic figures and cyclin D1 expression decreased and hepatocyte size increased in the MSC-CM group, implying that this mode of regeneration was mainly through cell hypertrophy rather than cell division. CONCLUSIONS: MSC-CM represents a novel therapeutic approach for patients with MASLD requiring PHx.

This study explores a novel therapeutic approach for peritoneal metastasis (PM) using AAV-mediated delivery of tumor suppressor microRNA-29b (miR-29b) to peritoneal mesothelial cells (PMC). AAV serotypes 2 and DJ demonstrate high transduction efficiency for human and murine PMC, respectively. In vitro analysis indicates that AAV vectors encoding miR-29b precursor successfully elevate miR-29b expression in PMC and their secreted small extracellular vesicle (sEV), thereby inhibiting mesothelial mesenchymal transition and reducing subsequent attachment of tumor cells. A single intraperitoneal (IP) administration of AAV-DJ-miR-29b demonstrates robust and sustained transgene expression, suppressing peritoneal fibrosis and inhibiting the development of PM from gastric and pancreatic cancers. Additionally, AAV-DJ-miR-29b enhances the efficacy of IP chemotherapy using paclitaxel, restraining the growth of established PM. While conventional gene therapy for cancer encounters challenges targeting tumor cells directly but delivering miRNA to the tumor stroma offers a straightforward and efficient means of altering the microenvironment, leading to substantial inhibition of tumor growth. AAV-mediated miR-29b delivery to peritoneum via IP route presents a simple, minimally invasive, and promising therapeutic strategy for refractory PM.

Despite advances in systemic chemotherapy, patients with gastric cancer (GC) and peritoneal metastases (PMs) continue to have poor prognoses. Intraperitoneal (IP) administration of Paclitaxel (PTX) combined with systemic chemotherapy shows promise in treating PMs from GC. However, methods of drug administration need to be optimized to maximize efficacy. In this study, we utilized a mouse model with PMs derived from a human GC cell line, administering PTX either IP or intravenously (IV), and Carboplatin (CBDCA) IV 0, 1, and 4 days after PTX administration. The PMs were resected 30 min later, and concentrations of PTX and CBDCA in resected tumors were measured using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Results indicated that PTX concentrations were higher with IP administration than with IV administration, with significant differences observed on days 0 and 1. CBDCA concentrations 4 days post-IP PTX administration were higher than with simultaneous IV PTX administration. These findings suggest that IP PTX administration enhances CBDCA concentration in peritoneal tumors. Therefore, sequential IV administration of anti-cancer drugs appears more effective than simultaneous administration with IP PTX, a strategy that may improve prognoses for patients with PMs.

Abstract Background Osteopenia reflects frailty and has been shown to be associated with outcomes in cancer patients. This study was undertaken to examine whether osteopenia is an independent prognostic factor in patients with esophageal cancer after resection. Methods A total of 214 patients who underwent surgery for esophageal cancer were analyzed retrospectively. Bone mineral density (BMD) of the 11th thoracic vertebra was measured by computed tomography scan, and patients classified into osteopenia and normal BMD groups with BMD &lt;160 Hounsfield units as the cutoff. Clinicopathological data and prognosis were analyzed. Results The 5‐year survival rate was 55.4% for the osteopenia group and 74.7% for the normal BMD group with a significantly worse prognosis in the osteopenia group (p = 0.0080). In multivariable analysis, osteopenia was a significant independent risk factor associated with overall survival (hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.27–3.34, and p = 0.0151) along with R1/2 resection (HR 3.02, 95% CI 1.71–5.18, and p = 0.0002). Conclusion In patients with esophageal cancer undergoing resection, osteopenia may be a surrogate marker for frailty and an independent predictor of prognosis.

Background: Osteopenia is a well-known risk factor for survival in patients with hepatocellular carcinoma; however, it is unclear whether osteopenia can apply to both genders and how osteopenia is associated with cancer progression. The aim of this study was to elucidate whether osteopenia predicts reduced survival in regression models in both genders and whether osteopenia is associated with the pathological factors associated with reduced survival. Methods: This study included 188 consecutive patients who underwent hepatectomy. Bone mineral density was assessed using computed tomography (CT) scan images taken within 3 months before surgery. Non-contrast CT scan images at the level of the 11th thoracic vertebra were used. The cutoff value of osteopenia was calculated using a threshold value of 160 Hounsfield units. Overall survival (OS) curves and recurrence-free survival (RFS) were constructed using the Kaplan–Meier method, as was a log-rank test for survival. The hazard ratio and 95% confidence interval for overall survival were calculated using Cox’s proportional hazard model. Results: In the regression analysis, age predicted bone mineral density. The association in females was greater than that in males. The OS and RFS of osteopenia patients were shorter than those for non-osteopenia patients. According to univariate and multivariate analyses, osteopenia was an independent risk factor for OS and RFS. The sole pathological factor associated with osteopenia was microvascular portal vein invasion. Conclusion: Models suggest that osteopenia may predict decreased OS and RFS in patients undergoing resection of hepatocellular carcinoma due to the mechanisms mediated via microvascular portal vein invasion.

Abstract The vagus nerve is the only pathway for transmitting parasympathetic signals between the brain and thoracoabdominal organs, thereby exhibiting anti-inflammatory functions through the cholinergic anti-inflammatory pathway. Despite often being resected during lymph node dissection in upper gastrointestinal cancer surgery, the impact of vagotomy on postoperative outcomes in gastric cancer patients remains unclear. Sub-diaphragmatic vagotomy was performed on C57BL/6 mice. Three weeks later, syngeneic murine gastric cancer cell line YTN16P was injected into the peritoneal cavity, and the number of peritoneal metastases (PM) on the mesentery and omentum compared with control mice. The phenotypes of immune cells in peritoneal lavage and omental milky spots one day after tumor inoculation were analyzed using flow cytometry and immunohistochemistry. Intraperitoneal transfer of 3 × 10⁵ YTN16P significantly increased the number of metastatic nodules on the mesentery in the vagotomy group compared to the control group. The omental metastasis grade was also significantly higher in the vagotomy group. Phenotypic analysis of immune cells in peritoneal lavage did not reveal significant differences after vagotomy. However, vagotomized mice exhibited a notable increase in milky spot area, with a higher presence of cytokeratin(+) tumor cells, F4/80(+) macrophages, and CD3(+) T cells. Vagus nerve signaling appears to regulate the immune response dynamics within milky spots against disseminated tumor cells and inhibits the development of PM. Preserving the vagus nerve may offer advantages in advanced gastric cancer surgery to reduce peritoneal recurrence.