Abstract Background: Peptide receptor radionuclide therapy (PRRT) is an internal radiotherapy for somatostatin receptor (SSTR)-positive neuroendocrine tumor (NET). The tumor microenvironment, particularly cytotoxic T lymphocyte (CTL), is a key determinant of tumor behavior, treatment response, and prognosis, but NET typically shows a “cold” immune microenvironment with sparse immune-cell infiltration, which may contribute to the limited efficacy of ICI-based therapies. External beam radiotherapy can activate systemic antitumor immunity and occasionally induce abscopal effects, in which irradiation of a primary lesion leads to shrinkage of both irradiated and distant metastatic sites; however, the influence of PRRT on systemic immunity has scarcely been studied. We hypothesized that PRRT modulates systemic immunity in NET patients and investigated changes in circulating cytokines. Methods: We analyzed changes in serum cytokine levels in NET patients treated with PRRT at Yokohama City University. Twelve paired serum samples from 9 patients were collected before and after PRRT and analyzed with a 36-plex cytokine array. Results: Of the 9 patients, 7 were undergoing their first PRRT course and 2 a second course (retreatment after a prior four-administration PRRT course that had achieved at least partial response with ≥1.5 year of disease control). Primary sites were pancreas (n=6), rectum (n=1), lung (n=1), and thymus (n=1), and target lesions were in the liver (n=7), bone (n=2), primary site (n=1), lymph node (n=1), and peritoneum (n=1). Twelve serum pairs comprised 10 pre- and post-individual PRRT administrations and 2 pre- and post-full-course pairs. Of the 36 examined cytokines, only 12 were detectable. Among these, CD154 showed more than 2-fold changes in 7 pairs, with 6 showing downregulation and 1 showing upregulation after PRRT. IL-1ra was also upregulated in 3 pairs. Conclusion: We found that PRRT is associated with systemic changes in circulating cytokines in NET patients, notably modulation of CD154 and IL-1ra. These data suggest that PRRT may influence host antitumor immunity; larger studies are required to elucidate the mechanisms and clinical significance of these immune changes. Citation Format: Eriko Katsuta, Takuto Nobuhiro, Masaru Takeuchi, Satoshi Matsui, Asano Daisuke, Ishikawa Yoshiya, Hiroki Ueda, Keiichi Akahoshi, Noritoshi Kobayashi, Yasushi Ichikawa, Daisuke Ban. Peripheral immune signatures associated with peptide receptor radionuclide therapy in neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7754.

BACKGROUND:For anatomically resectable pancreatic cancer, a "biological borderline resectable" concept based on carbohydrate antigen 19-9 (CA19-9) elevation or suspected nodal metastasis is proposed; however, preoperative nodal staging remains imprecise. We evaluated whether embryologic tumor location combined with CA19-9 can stratify biological risk of resectable pancreatic head cancer (RPHC). METHODS:We retrospectively analyzed 78 patients who underwent pancreaticoduodenectomy for RPHC between January 2010 and June 2024. Embryologic tumor location was determined from preoperative imaging and categorized as ventral or dorsal pancreas. The optimal pretreatment CA19-9 cutoff for overall survival was determined using maximally selected rank statistics. Associations between embryologic tumor location, CA19-9, and survival outcomes were examined, and predictors of recurrence were identified using Cox proportional hazards models. RESULTS:An optimal CA19-9 cutoff of 150 U/mL was identified. Dorsal tumors were associated with shorter recurrence-free survival (RFS) (p = 0.004) and overall survival (OS) (p = 0.048), while CA19-9 levels > 150 U/mL were associated with worse RFS (p = 0.015) and OS (p < 0.001). On multivariate analysis, dorsal location (hazard ratio [HR] 2.30, p = 0.035) and CA19-9 levels > 150 U/mL (HR 1.93, p = 0.024) remained independent predictors of recurrence, whereas clinical nodal status was not (HR 1.91, p = 0.149). A three-tier classification combining tumor location and CA19-9 stratified patients by RFS (p = 0.001) and OS (p < 0.001), with dorsal/high-CA19-9 tumors showing the poorest outcomes. CONCLUSIONS:Integrating embryologic tumor location with CA19-9 levels may refine risk stratification in RPHC and help guide treatment strategies.

BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) with peritoneal dissemination is highly refractory to chemotherapy and immunotherapy, leading to poor prognosis. We aimed to develop an innovative therapeutic approach for advanced PDAC. METHODS:We performed comprehensive analyses of 498 bulk and 99 single-cell RNA-sequencing datasets. We established a syngeneic mouse model for subcutaneous and intraperitoneal metastatic tumours using mouse KrasG12D; Trp53R172H PDAC cells. A multimodal immunotherapy with mRNA-induced cytokines (MIMIC), that is, oxaliplatin, anti-PD-1 and anti-CTLA-4 antibodies, and intratumoural administration of mRNA therapeutics encoding interferon-α and interleukin-12, was evaluated in this preclinical model. FINDINGS:The aggressive PDAC subtype exhibited a paucity of dendritic cells (DCs) and T cells, causing an immunosuppressive tumour microenvironment. The syngeneic mouse model recapitulated this immunological phenotype with resistance to conventional systemic therapies. The MIMIC therapy not only significantly reduced the local tumour burden but also elicited a robust abscopal effect, suppressing distant peritoneal metastases and prolonging survival (P < 0.001). The omission of any single agent from the MIMIC regimen substantially abrogated the therapeutic efficacy. Flow cytometry and immunohistochemical analyses revealed that the MIMIC treatment enhanced immunogenic cell death, increased peripheral CD44+ CD62L- effector memory T cells, induced intratumoural infiltration of CD11c+ DCs and CD8+ T cells, and expanded TCR repertoire diversity. INTERPRETATION:Combining cytokine mRNA immunotherapy with cytotoxic killing and immune checkpoint blockade can reactivate antitumour immunity, offering a promising strategy for treating advanced PDAC. FUNDING:This work was supported by Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), Japan Agency for Medical Research and Development (AMED), and the Princess Takamatsu Cancer Research Fund.

INTRODUCTION:Metastatic tumors to the pancreas account for approximately 2% of all pancreatic malignancies, and pancreatic metastasis from distal cholangiocarcinoma is extremely rare. Differentiating pancreatic metastasis of cholangiocarcinoma from primary pancreatic cancer is often difficult, as both typically present as adenocarcinoma with similar immunohistochemical features. CASE PRESENTATION:A 65-year-old man underwent subtotal stomach-preserving pancreatoduodenectomy (SSPPD) for distal cholangiocarcinoma. He was diagnosed with pT3N0M0, Stage IIB according to the UICC TNM classification, 8th edition. Seven years after surgery, a routine blood test revealed an elevated serum carbohydrate antigen 19-9 level. Abdominal MRI and CT demonstrated 2 small masses, each approximately 10 mm in diameter, in the remnant pancreas without evidence of distant metastasis. Both lesions were diagnosed as adenocarcinoma by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), suggesting either pancreatic metastases from distal cholangiocarcinoma or primary pancreatic cancer in the remnant pancreas. Completion total pancreatectomy with splenectomy was therefore performed. Histopathological examination showed that both lesions in the remnant pancreatic tail were morphologically similar to the initial cholangiocarcinoma. However, the possibility of primary pancreatic cancer could not be completely excluded. Comprehensive genomic profiling (CGP) of the initial cholangiocarcinoma and the remnant pancreatic tumor revealed a shared TP53 H214R alteration, supporting the diagnosis of pancreatic metastases from distal cholangiocarcinoma. In addition, CGP identified BRCA1 loss and an FGFR3 alteration in the remnant pancreatic tumor as potentially actionable findings, although their therapeutic relevance in cholangiocarcinoma remains uncertain. CONCLUSIONS:We report a rare case of multiple pancreatic metastases occurring 7 years after resection of distal cholangiocarcinoma. Evaluation of genetic alterations provided supportive evidence to aid in distinguishing metastatic disease from primary pancreatic cancer in the remnant pancreas. In addition, these findings also suggested potentially relevant therapeutic targets.

Background:Surgical resection for neuroendocrine liver metastasis (NELM) is the key to long survival; however, the indications remain unclear due to the high recurrence rate. We aimed to identify candidates who would benefit from surgical resection for NELM. Methods:Patients with NELM treated at our institution from January 2005 to December 2020 were included. Neuroendocrine carcinoma (NEC) was excluded. Risk factors for overall survival (OS) and recurrence-free survival (RFS) were analyzed. The cut-off value for the number of NELM predicting poor RFS was determined by minimum p-value approach. Results:Of the total 126 patients, 67 patients underwent liver resection. The median follow-up time from the date of initial diagnosis of NELM was 4.3 years. Surgical resection and NET-G1/2 were associated with good OS in multivariate analysis (p < 0.001). In patients underwent R0/1 resection (n = 44), NET-G3 [HR: 3.1 (95% CI 1.4-7.2)] and the number of NELM [HR: 1.1 (95% CI 1.0-1.1)] were associated with poor RFS in multivariate analysis. The optimal cut-off value for the number of NELM was calculated as 8. The median RFS for patients with 8 or more liver metastases or NET-G3 was 3.9 months, which was extremely short compared to patients with NET-G1/2 (13.8 months) and to those who had fewer than 8 liver metastases (19.1 months). Conclusion:This study suggests that fewer than 8 liver metastases and NET-G1/2 are indications for surgical resection in patients with NELM considering the RFS. Surgical resection for patients with 8 or more liver metastases or NET-G3 needs deliberate selection.

INTRODUCTION:Symptom control is sometimes as important as tumor burden control in patients with functional neuroendocrine tumors (NETs). The selective arterial calcium injection (SACI) test is widely used to localize functional NETs, particularly insulinomas and gastrinomas; however, its utility in adrenocorticotropic hormone (ACTH)-producing tumors (ACTHomas) remains unclear. We present a case of a pancreatic head ACTHoma with synchronous liver metastases in which the SACI test with venous sampling ("hormonal mapping") enabled a safe, staged curative resection. CASE PRESENTATION:A 42-year-old woman presented with features of Cushing's syndrome, including edema and weight gain. CT revealed a pancreatic head tumor with multiple liver metastases. Liver biopsy confirmed the diagnosis of NET, suggesting an ACTHoma. Hormonal mapping demonstrated that liver metastases, rather than the pancreatic tumor, were the predominant sources of ACTH secretion. To achieve hormonal control, we prioritized laparoscopic liver resection, followed by laparoscopic pancreatoduodenectomy three months later after confirming the absence of new metastatic lesions. At 21 months postoperatively, the patient remains recurrence-free. CONCLUSIONS:Hormonal mapping was effective in identifying hormone-producing lesions and guiding surgical strategies for ACTHomas with liver metastases.

Pancreatoduodenectomy (PD) is a highly invasive surgery that raises concerns about postoperative loss of independence (LOI), a critical outcome defined as a decline in activities of daily living (ADL). LOI reflects a significant shift in functional status, often requiring additional care such as rehabilitation or home-based healthcare. While reducing complications and mortality is prioritized, maintaining a preoperative lifestyle remains underexplored. Therefore, this study aimed to elucidate the risk factors of LOI after PD. We retrospectively analyzed 215 patients underwent PD between August 2017 and April 2024. Patients were classified into young (< 65 years) and elderly groups (≥ 65 years). Using univariate and multivariate analyses, we assessed risk factors of LOI after PD. There was no incidence of LOI in the young group, whereas 22 patients (16.7

Advanced hepatic fibrosis is a major risk factor for cirrhosis and hepatocellular carcinoma (HCC), and it is required to identify a key mediator involved in intratumoral fibrosis and HCC development. Transcriptomic analysis of 372 HCC samples using publicly available datasets revealed that SPP1 was significantly upregulated in fibrotic HCC tissues and associated with unfavorable outcomes. Immunohistochemical analysis of 103 HCC tissues and single-cell RNA sequencing (scRNA-seq) analysis of 228,564 live cells identified SPP1 overexpression in HCC cells, which strongly correlated with intratumoral fibrosis. In xenograft models, HCC cells with SPP1 overexpression (SPP1-OE) exhibited enhanced fibrosis and tumor growth. Coculture assay demonstrated that SPP1-OE cells stimulated hepatic stellate cells (HSCs), and gene set enrichment analysis and differential gene expression analysis elucidated the activation of the Hedgehog signaling pathway and upregulation of GLI1 in HSCs. Cell-cell interaction prediction analysis using scRNA-seq data suggested that SPP1-CD44 signaling transduction might contribute to HSC activation. Pharmacological inhibition of GLI1 with the SMO inhibitor vismodegib suppressed HSC activation in vitro and reduced fibrosis and tumor growth in vivo. These findings indicate that SPP1 promotes intratumoral fibrosis and HCC progression through the SPP1-CD44-GLI1 axis, highlighting its potential as a prognostic biomarker and therapeutic target. Inhibition of SPP1-CD44-Hedgehog signaling may provide a promising strategy to mitigate fibrosis and improve HCC patient outcomes.

BACKGROUND & AIMS:Insulinomas are rare pancreatic neuroendocrine neoplasms (pan-NENs) characterized by inappropriate insulin secretion. Despite advances in imaging techniques, the reliable identification of insulin-secreting lesions remains challenging. In addition, medical treatment options are limited and have seen little development in recent years, highlighting the unmet need for improved diagnostic tools and therapeutic strategies. This study aimed to identify the molecular mechanisms underlying insulin hypersecretion in insulinomas. METHODS:We established a biobank of human insulinoma surgical specimens and matched organoids. Comprehensive transcriptomic analyses-including bulk RNA sequencing, single-cell RNA sequencing, quantitative polymerase chain reaction, and immunohistochemistry-were conducted to identify genes enriched in insulin-secreting components. Functional validation was performed using MIN6 cells, a xenograft mouse model, and long-term cultured human insulinoma organoids. RESULTS:We identified dedicator of cytokinesis 10 (DOCK10) as a gene selectively overexpressed in insulin-secreting components of insulinomas. DOCK10 knockdown impaired glucose-stimulated insulin secretion in both mouse insulinoma cells and patient-derived organoids. Inhibition of the downstream effector Cdc42 with ML141 reduced insulin hypersecretion and improved survival in a MIN6 xenograft mouse model. These findings uncover a previously unrecognized role of the DOCK10-Cdc42 axis in regulating insulin secretion in insulinoma. CONCLUSIONS:This study suggests that DOCK10 may serve as a diagnostic marker for insulin-secreting lesions and a potential therapeutic target in insulinoma. It provides mechanistic insights that may inform future strategies for precision diagnostics and treatment of functional pancreatic neuroendocrine tumors.

Background: Systemic therapy is a standard treatment option for pancreatic neuroendocrine neoplasms (Pan-NENs) with unresectable or metastatic disease. Streptozocin (STZ)-based chemotherapy is considered a standard treatment option for tumors with a high Ki-67 index or for cases refractory to molecular targeted agents. More recently, the combination of capecitabine and temozolomide (CAPTEM) therapy has emerged as a new treatment option. Objectives: This study aimed to compare the efficacy, safety, and clinical outcomes between the STZ-based regimen and CAPTEM therapy in patients with unresectable or metastatic Pan-NENs. Design: This was a single-center retrospective study of histologically confirmed Pan-neuroendocrine tumor (NET) patients treated with either STZ-based regimens or CAPTEM between November 2015 and June 2024. Methods: We compared efficacy, safety, and clinical outcomes between the two regimens. Tumor responses were assessed using Response Evaluation Criteria in Solid Tumors version 1.1, and adverse events were graded according to Common Terminology Criteria for Adverse Events version 5.0. The study was conducted in compliance with the STROBE guidelines. Results: Of the 371 patients diagnosed with Pan-NENs, 47 received STZ-based regimen and 21 received CAPTEM therapy. In the NET-G1/G2 patients, the STZ group showed a significantly higher tumor shrinkage rate compared to CAPTEM therapy. Although no significant differences were observed in progression-free survival (PFS) or overall survival between the two groups, subgroup analysis showed that the median PFS in the STZ group was significantly longer than that in the CAPTEM group in NET G1/G2 patients. Renal dysfunction was the main adverse event in the STZ regimen group, while gastrointestinal symptoms were common in the CAPTEM therapy group; however, both were manageable. Conclusion: Both STZ-based regimen and CAPTEM therapy are safe and effective treatment options for advanced Pan-NENs. STZ-based regimen was more beneficial in NET-G1/G2 patients, suggesting Ki-67 index and tumor grade may serve as indicators for treatment selection. Further prospective studies are warranted to validate these findings.

IntroductionComprehensive genomic profiling (CGP) is increasingly being integrated into standard clinical practice as a strategy to guide subsequent treatment decisions by identifying novel therapeutic options based on tumor-specific mutations. However, its clinical utility in neuroendocrine neoplasms (NENs) remains to be determined. We conducted a cross-sectional analysis of genomic alterations, including tumor mutational burden (TMB) and microsatellite instability (MSI), in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), comparing neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs).ResultsCGP was performed on 50 patients with advanced GEP-NENs between August 2017 and October 2023. Of these, 38 were diagnosed with NETs and 12 with NECs. Primary tumor sites included the pancreas (n = 24), gastrointestinal tract (n = 25), and one case of unknown origin. In our study, CGP analysis comparing NETs and NECs documented different genetic profiles. In addition, median TMB was significantly higher in NECs (5.0 vs. 1.9 mutations/megabase; p = 0.0101). High TMB was identified in 4 of 12 NECs (33.3%) and in only 1 of 38 NETs (2.6%) (p = 0.0093). NECs also harbored a significantly greater number of mutations per case than NETs (5.5 vs. 2.0; p = 0.0014). Actionable mutations were identified in 18 of 50 patients, and 7 patients received mutation-guided therapy: 2 with NETs and 5 with NECs. The frequency of treatment initiation based on CGP findings was significantly higher in patients with NECs (p = 0.0059).ConclusionsNECs are genetically distinct from NETs, with a higher prevalence of actionable mutations and greater therapeutic relevance of CGP findings. These results suggest that CGP may be particularly valuable in NECs, where therapeutic options are limited, supporting its proactive implementation in this subgroup.

INTRODUCTION:While para-aortic lymph node recurrence may occur after curative resection for pancreatic ductal adenocarcinoma (PDAC), it is rarely seen as a late recurrence and is usually treated with systemic chemotherapy. In contrast, recurrence of pancreatic neuroendocrine neoplasms (Pan-NENs) can occur more than a decade after surgery and may be amenable to surgical resection. Although immunohistochemical techniques have significantly enhanced the diagnostic distinction between PDAC and Pan-NEN, challenges remain, particularly in older cases. CASE PRESENTATION:A 77-year-old man underwent distal pancreatectomy for pancreatic body cancer 11 years prior, initially diagnosed as PDAC based on glandular morphology, and received adjuvant S-1 chemotherapy. Surveillance ended after 5 years without recurrence. Eleven years after surgery, imaging performed during evaluation for elevated prostate-specific antigen revealed a 16-mm para-aortic lymph node enlargement. CT-guided biopsy showed neuroendocrine morphology with chromogranin A and synaptophysin positivity, consistent with neuroendocrine tumor (NET). Retrospective histological review of the original surgical specimen revealed previously unrecognized NET-G2 components (Ki-67, 5.0%). Surgical resection of the para-aortic and mesenteric lymph nodes was performed, and pathology confirmed NET-G2 metastases (Ki-67, 6.7%). The patient recovered uneventfully and remains recurrence-free at 7 months postoperatively under active surveillance. CONCLUSIONS:This case highlights the importance of tissue diagnosis when late-onset recurrence is observed in patients with a prior diagnosis of PDAC. It also underscores the potential for extremely delayed recurrence in Pan-NENs and the importance of long-term surveillance. For patients presenting with isolated distant recurrence long after initial treatment for PDAC, biopsy and pathological re-evaluation should be considered to ensure appropriate therapeutic decision-making.

Middle-segment preserving pancreatectomy (MSPP) serves as an alternative to total pancreatectomy (TP) for preserving the pancreatic body in multifocal pancreatic neoplasms. Despite the potential benefits of TP, the detailed short- and long-term prognoses remain unclear. We evaluated the feasibility of MSPP by comparing the perioperative outcomes and postoperative endocrine and exocrine functions with those of TP. The study included 10 TP and 7 MSPP patients. Patients with pancreatic ductal adenocarcinoma and invasive intraductal papillary mucinous carcinoma were excluded. MSPP was associated with a high incidence (57.1

BACKGROUND:Postoperative pancreatic fistula (POPF) continues to be the most common complication after distal pancreatectomy (DP). Recent advancements in surgical techniques have established minimally invasive distal pancreatectomy (MIDP) as the standard treatment for various conditions, including pancreatic cancer. However, MIDP has not demonstrated a clear advantage over open DP in terms of POPF rates, indicating the need for additional strategies to prevent POPF in MIDP. This trial (WRAP study) aims to evaluate the efficacy of wrapping the pancreatic stump with polyglycolic acid (PGA) mesh and fibrin glue in preventing clinically relevant (CR-) POPF following MIDP. METHODS:This multicenter, randomized controlled trial will include patients scheduled for laparoscopic or robotic DP for tumors in the pancreatic body and/or tail. Eligible participants will be centrally randomized into either the control group (Group A) or the intervention group (Group B), where the pancreatic stump will be reinforced by PGA mesh and fibrin glue. In both groups, pancreatic transection will be performed using a bioabsorbable reinforcement-attached stapler. A total of 172 patients will be enrolled across 14 high-volume centers in Japan. The primary endpoint is the incidence of CR-POPF (International Study Group of Pancreatic Surgery grade B/C). DISCUSSION:The WRAP study will determine whether the reinforcement of the pancreatic stump with PGA mesh and fibrin glue, a technique whose utility has been previously debated, could become the best practice in the era of MIDP, thereby enhancing its safety. TRIAL REGISTRATION:This trial was registered with the Japan Registry of Clinical Trials on June 15, 2024 (jRCTs032240120).

Objective: To clarify the short and long-term postoperative outcomes and surgical indications for patients accompanied by hepatocellular carcinoma with tumor thrombus (TT) in the inferior vena cava (IVC) or right atrium (RA). Background: These patients are known to have an extremely poor prognosis; however, the postoperative outcomes have not been fully verified because of the rarity of this disease. Methods: We contacted 211 specialized centers in Japan and collected data on liver resection for hepatocellular carcinoma with TT in the IVC or RA from centers with experience performing surgery for such patients. The patient characteristics, operative procedures, and surgical outcomes were then analyzed. Results: A total of 119 patients from 23 institutions were enrolled; 49 patients had TT in the IVC below the diaphragm (type I), 42 had TT in the IVC above the diaphragm (type II), and 28 had TT entering the RA (type III). The severity and frequency of postoperative complications did not differ among the 3 groups. There was one surgery-related death in the type III group. The median survival times were 2.47 years in the type I group, 1.77 years in the type II group, and 1.02 years in the type III group. Multivariate analysis identified an indocyanine green retention rate at 15 minutes >15% and ≥3 tumors as prognostic factors affecting survival, whereas the use of cardiopulmonary bypass and ≥3 tumors were risk factors for recurrence. Conclusions: As the postoperative prognosis of patients with type I or type II disease and of patients with no risk factors is relatively good, surgery should be considered for these patient populations.

O6-methylguanine-DNA methyltransferase (MGMT) has been linked with alkylating agent resistance and tumor growth suppression. However, its role remains undetermined in pancreatic neuroendocrine tumors (Pan-NET). The MGMT expression was examined by immunohistochemistry in 142 patients to evaluate MGMT immunoreactivity and clinicopathological factors. We analyzed the relationship between MGMT expression and treatment efficacy in 19 patients who received STZ-based regimens. In 142 Pan-NET, 97 cases (68.3%) were judged as MGMT-positive and 45 cases (31.6%) as negative. MGMT negativity was significantly more common in NET-G2 (62.5%) than in NET-G1 (11.2%, p < 0.001). MGMT-negative cases were associated significantly with larger tumor size (p < 0.01), higher Ki-67 index (p < 0.01), higher mitotic index (p < 0.05), and more frequent liver metastasis (p < 0.05). Of the 19 cases treated with STZ, 6 cases were determined as SD and 4 cases as PD in MGMT-positive patients (N = 10), while 5 cases were determined as PR and 4 cases as SD in MGMT-negative patients (N = 9). Progression-free survival in MGMT-negative cases was significantly better than in MGMT-positive cases (p < 0.05). MGMT expression was lower in NET-G2 than in NET-G1, and STZ-based regimens improved the therapeutic outcomes of MGMT-negative Pan-NET. These findings indicate that NET-G2 may represent a better therapeutic target for STZ treatment.

The invasiveness of pancreatic cancer and its resistance to anticancer drugs define its malignant potential, and are considered to affect the peritumoral microenvironment. Cancer cells with resistance to gemcitabine exposed to external signals induced by anticancer drugs may enhance their malignant transformation. Ribonucleotide reductase large subunit M1 (RRM1), an enzyme in the DNA synthesis pathway, is upregulated during gemcitabine resistance, and its expression is associated with worse prognosis for pancreatic cancer. However, the biological function of RRM1 is unclear. In the present study, it was demonstrated that histone acetylation is involved in the regulatory mechanism related to the acquisition of gemcitabine resistance and subsequent RRM1 upregulation. The current in vitro study indicated that RRM1 expression is critical for the migratory and invasive potential of pancreatic cancer cells. Furthermore, a comprehensive RNA sequencing analysis showed that activated RRM1 induced marked changes in the expression levels of extracellular matrix-related genes, including N-cadherin, tenascin-C and COL11A. RRM1 activation also promoted extracellular matrix remodeling and mesenchymal features, which enhanced the migratory invasiveness and malignant potential of pancreatic cancer cells. The present results demonstrated that RRM1 has a critical role in the biological gene program that regulates the extracellular matrix, which promotes the aggressive malignant phenotype of pancreatic cancer.

OBJECTIVE:To clarify the short and long-term postoperative outcomes and surgical indications for patients accompanied by hepatocellular carcinoma with tumor thrombus (TT) in the inferior vena cava (IVC) or right atrium (RA).BACKGROUND:These patients are known to have an extremely poor prognosis; however, the postoperative outcomes have not been fully verified because of the rarity of this disease.METHODS:We contacted 211 specialized centers in Japan and collected data on liver resection for hepatocellular carcinoma with TT in the IVC or RA from centers with experience performing surgery for such patients. The patient characteristics, operative procedures, and surgical outcomes were then analyzed.RESULTS:A total of 119 patients from 23 institutions were enrolled; 49 patients had TT in the IVC below the diaphragm (type I), 42 had TT in the IVC above the diaphragm (type II), and 28 had TT entering the RA (type III). The severity and frequency of postoperative complications did not differ among the 3 groups. There was one surgery-related death in the type III group. The median survival times were 2.47 years in the type I group, 1.77 years in the type II group, and 1.02 years in the type III group. Multivariate analysis identified an indocyanine green retention rate at 15 minutes >15% and ≥3 tumors as prognostic factors affecting survival, whereas the use of cardiopulmonary bypass and ≥3 tumors were risk factors for recurrence.CONCLUSIONS:As the postoperative prognosis of patients with type I or type II disease and of patients with no risk factors is relatively good, surgery should be considered for these patient populations.