Loss of Skeletal Muscle Mass During Neoadjuvant Chemotherapy for Pancreatic Cancer Is Related to the Continuation of S-1 Adjuvant Chemotherapy After Pancreatectomy.

BACKGROUND/AIM: Although perioperative chemotherapy has improved patient survival, sarcopenia may occur during chemotherapy owing to decreased food intake and physical strength. However, reports on the occurrence of sarcopenia and changes in body composition in patients with pancreatic cancer during neoadjuvant chemotherapy are scarce. This study aimed to determine the effect of changes in skeletal muscle mass during neoadjuvant chemotherapy on the S-1 adjuvant chemotherapy clinical course in patients who underwent perioperative chemotherapy and surgical resection. PATIENTS AND METHODS: We retrospectively enrolled 159 patients with pancreatic cancer who underwent neoadjuvant chemotherapy and surgical resection, followed by S-1 adjuvant chemotherapy. We evaluated changes in skeletal muscle mass during neoadjuvant chemotherapy using abdominal computed tomography and the SliceOmatic software. The association between the rate of change in skeletal muscle mass index (Δ%SMI) during neoadjuvant chemotherapy and the continuation of S-1 adjuvant chemotherapy was investigated. RESULTS: Eighty-eight (55.3%) patients lost skeletal muscle mass (Δ%SMI <0) during neoadjuvant chemotherapy with a significantly low S-1 adjuvant completion rate (p=0.02). Δ%SMI <0 was an independent risk factor for the continuation of S-1 adjuvant chemotherapy (hazard ratio=1.924, 95% confidence interval=1.002-3.695, p=0.049). Moreover, the lower the Δ%SMI, the lower the S-1 continuation rate (p=0.022). CONCLUSION: Loss of skeletal muscle mass during neoadjuvant chemotherapy for pancreatic cancer affected the continuation of S-1 adjuvant chemotherapy after pancreatic resection. Therefore, ameliorating loss of skeletal muscle mass during neoadjuvant chemotherapy should be carefully considered to improve the continuation rate of adjuvant chemotherapy and the survival of patients with pancreatic cancer.

Small extracellular vesicles carrying reovirus, tumor antigens, interferon-ß, and damage-associated molecular patterns for efficient tumor treatment.

Small extracellular vesicles (SEV) have attracted much attention both as mediators of intercellular communication and as drug delivery systems. In addition, recent studies have shown that SEV containing virus components and virus particles are released from virus-infected cells. Oncolytic viruses, which efficiently kill tumor cells by tumor cell-specific replication, have been actively studied as novel anticancer agents in clinical and preclinical studies. However, it remains to be fully elucidated whether SEV released from oncolytic virus-infected cells are involved in the antitumor effects of oncolytic viruses. In this study, we examined the tumor cell killing efficiencies and innate immune responses following treatment with SEV released from oncolytic reovirus-infected tumor cells in vitro and in vivo. Reovirus-infected B16 cells secreted SEV associated with or containing reovirus particles (Reo-SEV) with a diameter of approximately 130 nm and a zeta potential of -17 mV, although death of reovirus-infected B16 cells was not observed. The secreted Reo-SEV also contained interferon (IFN)-ß, tumor antigens, and damage-associated molecular patterns (DAMPs), including heat shock proteins (HSPs). Reo-SEV were secreted from the tumor tissues of reovirus-injected mice. Inhibition of the SEV secretion pathway using GW4869, which is a neutral sphingomyelinase inhibitor, resulted in significant reduction in the infectious titers of reovirus in the culture supernatants, suggesting that the cells released progeny virus via the SEV secretion pathway. Reo-SEV more efficiently killed mouse tumor cells and induced innate immune responses in mouse bone marrow-derived dendritic cells than reovirus. Reovirus and Reo-SEV mediated efficient and comparable levels of growth suppression of B16 subcutaneous tumors and induction of tumor infiltration of CD8+ T cells following intravenous administration. These results indicate that Reo-SEV are a promising oncolytic agent and that SEV are an effective delivery vehicle for oncolytic virus.

Synthesis of a novel adapter lipid using Fc-region mediated antibody modification for post-insert preparation of transferrin receptor targeted messenger RNA-loaded lipid nanoparticles.

Lipid nanoparticles (LNPs) are promising delivery systems with the ability to deliver small interfering RNA (siRNA) and messenger RNA (mRNA) in diseased tissues and intracellular sites of action. However, delivery to non-hepatic tissues via systemic administration remains challenging. Antibody modification of LNPs is a hopeful approach for improving their selectivity to target tissues. The conventional method of antibody modification via thiol-maleimide linkage is concerned with reduced recognition efficiency of the disease-related target molecules owing to variations in antibody orientation on the surface of the LNPs. In this study, we developed a novel adapter lipopeptide for antibody modification of LNPs via the Fc-region. Here, we selected RI7-217, an anti-transferrin receptor antibody, as the ligand. Through optimization of spacer peptides, we found a FcBP-EKGG-lipid exhibits high water-dispersibility for post-insertion method to LNPs. We prepared RI7-217-modified LNPs by modifying LNPs with FcBP-EKGG-lipids and mixing the antibodies. We found that the luciferase protein expression of RI7-217-modified LNPs was significantly enhanced in an antibody-specific manner against transferrin receptor-expressing U-87 MG cells. This information would be valuable in the development of antibody-modified LNPs for cell-selective targeting.

Non-invasive intraductal oncocytic papillary neoplasm forming a protruding lesion toward the duodenum from the accessory papilla: a case report.

BACKGROUND: Intraductal oncocytic papillary neoplasm (IOPN), previously classified as a subtype of intraductal papillary mucinous neoplasm (IPMN), has been described as an independent disease by the WHO since 2019. IOPN is a rare tumor, with few reported cases. Herein, we report a case of resected non-invasive IOPN that formed a lesion protruding toward the duodenum from the accessory papilla. CASE PRESENTATION: An 80-year-old woman was referred to our hospital because of a giant mass in the pancreatic head detected on abdominal contrast-enhanced computed tomography (CT) performed for a close examination of a mass in the right breast. CT revealed a 90-mm-sized tumor with a mixture of solid and cystic components, with contrast enhancement in the pancreatic head, and a dilated main pancreatic duct. Esophagogastroduodenoscopy revealed a semi-circumferential papillary tumor protruding toward the duodenal lumen, which did not protrude from the papilla of Vater. Transpapillary biopsy led to a preoperative diagnosis of IPMN with an associated invasive carcinoma. As there were no distant metastasis, open subtotal stomach-preserving pancreaticoduodenectomy was performed. Analysis of the surgical specimen and histopathological examination revealed that the tumor was an IOPN that protruded toward the duodenal mucosa from the accessory papilla while replacing the duodenal mucosa with no obvious stromal invasion. CONCLUSION: IOPN is a rare and poorly recognized tumor with few reported cases. There have been no reports describing IOPN forming a protruding lesion toward the duodenum from the accessory papilla. Therefore, further accumulation of cases such as this one is important to advance the study of IOPN.

Clinical Impact of Preoperative Neutrophil-to-Lymphocyte Ratio in Surgical Patients With Pancreatic Cancer.

BACKGROUND/AIM: The prognosis of patients with pancreatic cancer remains poor, despite recent advances in surgical techniques, perioperative care, neoadjuvant and adjuvant chemotherapy. This study aimed to investigate the preoperative neutrophil-to-lymphocyte ratio (NLR) as a prognostic factor and determine the optimal cutoff value in surgical patients with pancreatic cancer. PATIENTS AND METHODS: We retrospectively enrolled 461 patients with pancreatic cancer who underwent resection between January 2013 and December 2022 in the Department of Gastrointestinal Surgery at Kanagawa Cancer Center. The association between continuous or categorical variables and NLR was analyzed using the Mann-Whitney U-test and Fisher's exact test. Overall survival (OS) and relapse-free survival (RFS) rates were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed using Cox proportional-hazard regression models. RESULTS: The optimal cutoff value for the preoperative NLR was 3.2. The NLR≥3.2 was associated with a large tumor size (p=0.005), poor histological differentiation (p=0.002), and less adjuvant chemotherapy (p=0.048). The NLR≥3.2 had an important influence on the decreased OS (21.6 vs. 25.8 months), and RFS (10.3 vs. 14.3 months). In univariate and multivariate analyses, the preoperative NLR was an independent prognostic factor for OS (p=0.022) and RFS (p=0.002). CONCLUSION: Preoperative NLR (cutoff value: 3.2) within two weeks before surgery is a prognostic factor for OS and RFS in surgical patients with pancreatic cancer. This study could help establish evidence on the immune system's impact and a unified treatment strategy pre-surgery, potentially improving the prognosis for patients with pancreatic cancer.

Induction of liver-resident memory T cells and protection at liver-stage malaria by mRNA-containing lipid nanoparticles.

Recent studies have suggested that CD8+ liver-resident memory T (TRM) cells are crucial in the protection against liver-stage malaria. We used liver-directed mRNA-containing lipid nanoparticles (mRNA-LNPs) to induce liver TRM cells in a murine model. Single-dose intravenous injections of ovalbumin mRNA-LNPs effectively induced antigen-specific cytotoxic T lymphocytes in a dose-dependent manner in the liver on day 7. TRM cells (CD8+ CD44hi CD62Llo CD69+ KLRG1-) were induced 5 weeks after immunization. To examine the protective efficacy, mice were intramuscularly immunized with two doses of circumsporozoite protein mRNA-LNPs at 3-week intervals and challenged with sporozoites of Plasmodium berghei ANKA. Sterile immunity was observed in some of the mice, and the other mice showed a delay in blood-stage development when compared with the control mice. mRNA-LNPs therefore induce memory CD8+ T cells that can protect against sporozoites during liver-stage malaria and may provide a basis for vaccines against the disease.

Incidence and Risk of Venous Thromboembolism in Patients With Resectable Pancreatic Cancer Receiving Neoadjuvant Chemotherapy.

BACKGROUND/AIM: Pancreatic cancer has the highest risk of venous thromboembolism (VTE). Additionally, chemotherapy for cancer patients increases the risk of developing VTE. Due to recent advances in neoadjuvant chemotherapy (NAC) regimens, more patients with resectable pancreatic cancer will receive NAC. However, the incidence, risk, and predictors of developing VTE in these patients have not been fully evaluated. PATIENTS AND METHODS: We retrospectively evaluated the incidence, risk, and predictors of VTE among 67 consecutive patients with resectable pancreatic cancer who received neoadjuvant combination therapy with gemcitabine+S-1 (NAC-GS) followed by surgery and 45 patients with resectable pancreatic cancer who underwent upfront surgery (Up-S). RESULTS: The incidence of VTE in the NAC-GS and Up-S groups was 10.4% and 6.6%, respectively. Preoperative D-dimer levels were significantly higher in the NAC-GS group, and D-dimer levels were significantly increased during NAC-GS. Preoperative D-dimer level was the only predictor for VTE in patients with resectable pancreatic cancer who received NAC-GS. CONCLUSION: There is an increased risk of developing VTE during NAC. Screening with D-dimer and taking appropriate measures to suppress critical VTE is essential to provide NAC to patients with resectable pancreatic cancer.

Effect of Cholesterol Content of Lipid Composition in mRNA-LNPs on the Protein Expression in the Injected Site and Liver After Local Administration in Mice.

Delivery of messenger RNA (mRNA) using lipid nanoparticles (LNPs) is expected to be applied to various diseases following the successful clinical use of the mRNA COVID-19 vaccines. This study aimed to evaluate the effect of the cholesterol molar percentage of mRNA-LNPs on protein expression in hepatocellular carcinoma-derived cells and in the liver after intramuscular or subcutaneous administration of mRNA-LNPs in mice. For mRNA-LNPs with cholesterol molar percentages reduced to 10 mol% and 20 mol%, we formulated neutral charge particles with a diameter of approximately 100 nm and polydispersity index (PDI) <0.25. After the intramuscular or subcutaneous administration of mRNA-LNPs with different cholesterol molar percentages in mice, protein expression in the liver decreased as the cholesterol molar percentage in mRNA-LNPs decreased from 40 mol% to 20 mol% and 10 mol%, suggesting that reducing the cholesterol molar percentage in mRNA-LNPs decreases protein expression in the liver. Furthermore, in HepG2 cells, protein expression decreased as cholesterol in mRNA-LNPs was reduced by 40 mol%, 20 mol%, and 10 mol%. These results suggest that the downregulated expression of mRNA-LNPs with low cholesterol content in the liver involves degradation in systemic circulating blood and decreased protein expression after hepatocyte distribution.

[A Case of Local Recurrence of Esophageal Cancer after Chemoradiation Therapy Successfully Treated with Nivolumab].

We report a case of a patient with locally recurrent esophageal cancer after chemoradiation therapy(CRT)who responded to nivolumab. The patient was an 86-year-old man with advanced esophageal cancer. Upper gastrointestinal endoscopy (EGD)revealed a type 2 lesion in the middle thoracic esophagus, and biopsy revealed squamous cell carcinoma(SCC). Contrast- enhanced CT showed invasion of the left main bronchi. The patient was diagnosed as Stage Ⅳa advanced esophageal cancer, and was treated with 5-FU plus cisplatin chemotherapy, and 60 Gy of radiation therapy. The tumor disappeared by CT and EGD, and the patient was followed up for observation. The patient experienced a feeling of tightness again, and EGD revealed an ulcerative lesion in the middle thoracic esophagus, and a biopsy detected SCC. Because of the early recurrence after CRT, the patient was judged to be resistant to 5-FU plus cisplatin chemotherapy, and 8 courses of nivolumab were administered as second-line treatment. Follow-up EGD confirmed disappearance of ulcerative lesions, and no tumors have been observed to date.

[Indications and Outcomes of Laparoscopic Endoscopic Cooperative Surgery(LECS)for Gastric Gastrointestinal Stromal Tumor].

Laparoscopic and endoscopic cooperative surgery(LECS)for gastric gastrointestinal stromal tumor(GIST)has become a popular surgery with both curability and functional preservation. In this study, we examined the outcomes of 14 patients who underwent classical LECS or CLEAN-NET in our hospital. Until March 2022, classical LECS was performed in patients with intraluminal growth tumors or tumors close to the gastroesophageal junction. After April 2022, classical LECS was performed in patients with intraluminal growth tumors without ulceration, and CLEAN-NET was performed in patients with ulceration or intramural growth tumors. There were 10 males and 4 females with a median age of 80.5 years. Intraluminal growth tumor were 8 patients, close to the gastroesophageal junction tumor were 3, and intramural growth tumor were 4, respectively. Five of these patients had tumors with ulceration. Classical LECS was performed in 10 patients and CLEAN-NET in 4 patients, and the median operative time was 165.5 minutes. All patients underwent R0 resection, and no postoperative complications or recurrences were observed. LECS was performed safely, and it is important to select the surgical procedure according to the tumor site and growth type.