The encapsulated histopathological growth pattern (HGP) of colorectal liver metastases (CRLMs) has been reported as a favorable prognostic factor. However, its prognostic relevance in patients undergoing treatment for recurrence after liver resection remains unclear. This study aimed to evaluate the impact of encapsulated HGP on time to surgical failure (TSF) following liver resection, and to assess whether encapsulated HGP at initial resection is associated with outcomes after repeat resection for recurrence. We retrospectively analyzed 272 patients who underwent initial liver resection for CRLMs. HGPs were classified and their associations with postoperative outcomes were examined. 61 patients were classified as having encapsulated HGP. Patients with encapsulated HGP had significantly longer TSF after liver resection than those with non-encapsulated HGP (p < 0.01). Multivariate analysis identified encapsulated HGP as an independent factor for improved TSF (Hazard ratio: 0.35, p < 0.01). Recurrence occurred less frequently in encapsulated HGP than in non-encapsulated HGP (63.9

INTRODUCTION:The incidence of multiple primary malignancies has increased owing to advances in cancer screening and treatment. However, cases involving five distinct primary cancers remain extremely rare. Intraductal papillary mucinous neoplasms (IPMNs) are known to be associated with extrapancreatic malignancies. We report a very uncommon case of quintuple primary cancers, including noninvasive intraductal papillary mucinous carcinoma (IPMC), and discuss its clinical implications. CASE PRESENTATION:A 77-year-old man was referred for evaluation of pancreatic duct dilatation incidentally detected during staging for hypopharyngeal cancer. He had been diagnosed with hypopharyngeal squamous cell carcinoma and underwent radiotherapy. During this evaluation, a colonoscopy revealed sigmoid colon cancer, which was treated with a laparoscopic sigmoidectomy (pT2N0M0). Imaging revealed main pancreatic duct dilatation with a 15-mm enhancing mural nodule in the pancreatic head, meeting the criteria for high-risk stigmata of IPMN and prompting further pancreatic evaluation. Endoscopic ultrasonography demonstrated a 19 × 4 mm intraductal papillary lesion in the pancreatic head duct, consistent with an IPMN with high-risk stigmata. A pancreaticoduodenectomy was performed, and the pathology report confirmed noninvasive IPMC with negative margins and nodes (pTisN0M0). One year later, routine surveillance detected a solitary right middle-lobe lung nodule; thoracoscopic lobectomy confirmed squamous cell carcinoma (pT1aN0M0). At age 81, the patient was diagnosed with prostate cancer and began hormonal therapy. Histopathological diagnoses revealed five distinct malignancies without evidence of metastasis. The patient is currently alive and under surveillance without evidence of recurrence. CONCLUSIONS:Quintuple primary cancers including noninvasive IPMC are very uncommon. Patients with IPMN/IPMC may require risk-adapted and long-term follow-up for synchronous or metachronous malignancies.

INTRODUCTION:Portal vein embolization combined with hepatic vein embolization enhances future liver remnant hypertrophy in major hepatectomy. However, the optimal timing, simultaneous or sequential, remains undefined. This study evaluates the optimal timing of hepatic vein ligation (HVL) in combination with portal vein ligation (PVL) using a rat model. METHODS:PVL was performed for the middle and left lateral lobes, while HVL was applied to the hepatic vein of the left lateral lobe. Rats were allocated to the PVL only, PVL + HVL, or sham group. HVL was added at -3, 0, +3, +24, or +72 h relative to PVL, yielding seven groups. Nonligated liver volume was assessed at 7 d after PVL. Four representative groups were sacrificed at 1 d after PVL for histological evaluation and assessment of liver hypertrophy-related mediators. RESULTS:PVL + HVL (0 h) induced the most marked hypertrophy of nonligated lobes. In the sequential groups, early addition of HVL (+3 h) produced greater hypertrophy than later additions. Histologically, the PVL + HVL groups showed more severe injury, with the simultaneous group demonstrating the largest necrotic area. Hepatocyte growth factor expression in the ligated lobe was significantly higher in the PVL + HVL groups than the PVL only group, and serum hepatocyte growth factor at 7 d was significantly higher in the simultaneous group. Ki67 expression was highest in the simultaneous group at 1 and 7 d. CONCLUSIONS:Simultaneous HVL with PVL was the most effective strategy for promoting hypertrophy of nonligated lobes and enhancing regeneration-associated mediator expression.

We report 2 cases of primary hepatic perivascular epithelioid cell tumor(PEComa), treated with laparoscopic partial liver resection. Case 1: A 44-year-old woman who presented with abdominal pain. Abdominal dynamic contrast-enhanced computed tomography(Dy-CT)revealed a low-enhancing liver tumor in both the arterial and venous phases. She underwent laparoscopic partial liver resection of segment 5 for diagnostic and therapeutic purposes. Histopathological examination confirmed the diagnosis of PEComa. Case 2: A 40-year-old woman was found to have a hepatic tumor was during an annual health checkup. Dy-CT demonstrated arterial-phase enhancement of the tumor with early visualization of the hepatic vein adjacent to the tumor. The tumor was preoperatively diagnosed as hepatocellular carcinoma, and laparoscopic partial liver resection of segment 3 was performed. Histopathological examination confirmed the diagnosis of PEComa. Preoperative diagnosis of hepatic PEComa remains challenging due to its rarity. However, early visualization of draining hepatic veins during the arterial-phase may aid in its diagnosis. Surgical resection is generally recommended, as PEComa may exhibit malignant potential in rare cases.

BACKGROUND:Although perioperative chemotherapy has recently been advocated for patients with biliary tract cancer (BTC) undergoing resection, little is known about its risks and efficacy in those who also require preoperative portal vein embolization (PVE) to secure residual liver capacity. This study aimed to examine liver hypertrophy and perioperative outcomes in patients with BTC treated with preoperative chemotherapy and PVE. METHODS:A total of 186 patients who underwent PVE for BTC in our institution were retrospectively analyzed. Patients were divided into two groups: those who received gemcitabine and cisplatin chemotherapy after PVE (P+C group, n=57) and those who did not (P group, n=129). Propensity score matching was performed to reduce bias. Liver hypertrophy, liver function, and perioperative outcomes were compared. We also examined the frequency of chemotherapy-related adverse events. RESULTS:After matching, the degree of liver hypertrophy and the kinetic growth rates after PVE were similar between the two groups. Liver enzyme changes and indocyanine green test results also showed no significant differences. The resection rates were 88.4% in the P group and 61.4% in the P+C group. Postoperative complication rates among the resected cases were comparable between the groups. Moreover, no increase in chemotherapy-related adverse events was observed when chemotherapy was administered concurrently with PVE. CONCLUSION:Perioperative gemcitabine and cisplatin chemotherapy in patients with BTC did not significantly suppress PVE-induced liver hypertrophy or impair liver function. It did not impact on postoperative complications or chemotherapy-related adverse events.

INTRODUCTION:Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy with limited responsiveness to chemotherapy. RAD51, a key component of homologous recombination repair, has been implicated in tumor progression and therapeutic resistance in several cancers; however, its clinical and biological role in ICC is unclear. METHODS:RAD51 expression was evaluated by immunohistochemistry in 96 patients having upfront surgery for ICC. Clinicopathological correlations and survival outcomes were analyzed. Functional studies were conducted in the ICC cell lines, HuCCT1 and TKKK, using small interfering RNA-mediated RAD51 knockdown and RAD51 inhibitor IBR2. RESULTS:High nuclear RAD51 expression was detected in 60 cases (62.5%). Patients with high RAD51 expression exhibited larger tumor sizes and more frequent lymph node metastases than those with low RAD51 expression. Kaplan-Meier analysis revealed that high RAD51 expression was significantly associated with worse disease-free survival and overall survival. Multivariate analysis confirmed RAD51 as an independent prognostic factor of poor survival. In vitro, RAD51 knockdown reduced ICC cell proliferation without affecting migration or invasion. IBR2-mediated pharmacological inhibition of RAD51 reduced cell proliferation with induced G2-phase arrest. Cisplatin treatment increased RAD51 messenger RNA expression and enhanced nuclear RAD51 foci colocalizing with γH2AX, indicating compensatory homologous recombination repair activation in response to DNA damage. Even low doses of IBR2 promoted cisplatin-induced cytotoxicity, increased lactate dehydrogenase release, and augmented apoptosis. CONCLUSIONS:RAD51 expression predicts poor prognosis after surgery for patients with ICC and functionally promotes ICC cell survival. Therapeutic targeting of RAD51 may enhance the antitumor efficacy of cisplatin and represents a promising strategy to improve prognosis.

INTRODUCTION:Percutaneous endoscopic gastrostomy (PEG) is commonly performed for enteral nutrition in patients with various diseases. However, there are few reports on abdominal surgeries for patients after PEG, and the tips for these procedures have not been established. Specifically, in laparoscopic surgeries of the upper abdomen, a gastrostomy can interfere with the surgical field. In addition, perioperative management of concomitant diseases that require PEG placement, including neuromuscular disorders, is required. CASE PRESENTATION:A 64-year-old man with a PEG due to malnutrition from myotonic dystrophy was diagnosed with acute cholangitis and choledocholithiasis. After lithotomy during endoscopic retrograde cholangiopancreatography, the patient was scheduled for laparoscopic cholecystectomy for the cholelithiasis. Although the patient had myotonic dystrophy and limited respiratory function, his general condition was deemed acceptable for surgery. Given the potential risk of gastrostomy injury and the need to ensure sufficient working space, the location of the gastrostomy tube was preoperatively confirmed via a computed tomography scan, and precautions were taken to prevent injuries caused by port insertion, forceps manipulation, and pneumoperitoneum during the procedure. Ultimately, the gastrostomy did not interfere with manipulation around the gallbladder, and the surgery was completed without any complications. To manage myotonic dystrophy, general intravenous anesthesia with propofol was administered, with minimal use of muscle relaxants during surgery. Postoperatively, the patient was managed with high nasal flow to reduce respiratory workload, epidural anesthesia to prevent respiratory depression due to pain, and early initiation of aggressive physical therapy. The patient was discharged on postoperative day 4 without complications. CONCLUSIONS:Using appropriate surgical strategies, laparoscopic cholecystectomy may be safely performed for patients with myotonic dystrophy after PEG.

Drug therapy for hepatocellular carcinoma has made remarkable progress in recent years, and surgical resection of tumors that respond well to drug therapy has been performed in some cases. We report a case of hepatocellular carcinoma with hepatopulmonary metastases that was successfully treated with atezolizumab plus bevacizumab and surgically resected. The patient was a 56-year-old man who underwent a posterior segmentectomy and was diagnosed with hepatocellular carcinoma. Three months after the surgery, CT revealed multiple liver and lung metastases. Fifteen courses of atezolizumab and bevacizumab were administered. Drug therapy was effective, and most metastases disappeared; however, the liver metastasis remained in segment 8/4, and partial resection of the liver was performed. Recurrence was observed in liver segment 2 after 1 year and 2 months, and partial resection of the liver was performed. The patient is currently alive and recurrence-free 3 months after the surgery. With progress in drug therapy, multimodal treatment for unresectable hepatocellular carcinoma is expected to improve the prognosis.

51-year-old man underwent pancreatoduodenectomy(PD)for pancreatic head cancer, followed by 6 months of adjuvant chemotherapy with S-1. At 20 months postoperatively, 3 pulmonary metastases were detected. S-1 chemotherapy was administered for 16 months and no new lesions or disease progression was observed. Based on the sustained response, the patient was diagnosed with oligometastatic pancreatic cancer and staged bilateral pulmonary resections were conducted. Histopathological analysis confirmed that all the nodules were lung metastases from pancreatic cancer. At 24 months after pulmonary resection, the patient remains alive without evidence of recurrence. Currently, there are no standardized criteria for the indication or timing of surgical resection in patients with isolated pulmonary metastases from pancreatic cancer. Additionally, the definition of oligometastatic disease in pancreatic cancer remains unclear. This case suggests that pulmonary resection can lead to long-term survival in selected patients with lung metastases from pancreatic cancer. Chemotherapy for lung metastases may help identify optimal candidates for pulmonary resection.

For malignant biliary obstruction with surgically altered anatomy, endoscopic intervention is generally the first-line approach for palliative treatment. However, in cases with surgically altered anatomy, gastrointestinal stenosis, or difficulty in biliary cannulation, a percutaneous transhepatic approach may be required. In this study, we retrospectively analyzed 9 patients who underwent percutaneous transhepatic biliary stent at our institution between 2021 and 2024, focusing on the reasons for selecting this approach and the clinical outcomes. In addition to technical difficulties, logistical factors such as delays in endoscopic preparation also influenced the selection of this method. No major complications were observed, and the procedure was performed safely. Although advances in endoscopic techniques are expected to reduce the need for percutaneous interventions, this approach remains essential in selected cases, and maintaining the skillset for this technique continues to be a clinical challenge.

Anaplastic carcinoma of the pancreas (ACP) is a rare disease with rapid growth. Therefore, the significance of surgery for ACP remains unknown. The present study aimed to elucidate the oncological outcome following surgical resection for ACP and investigated pathological features associated with prognosis. In the present study, 12 patients who underwent surgical resection for ACP at Chiba University Hospital (Chiba, Japan) were retrospectively analyzed. Among the 12 patients, 7 had anaplastic undifferentiated carcinoma, 1 had sarcomatoid undifferentiated carcinoma, 2 had carcinosarcoma and 2 had undifferentiated carcinoma with osteoclast-like giant cells (OCGC). A total of 7 cases exhibited early recurrence within 6 months postoperatively, and the median overall survival (OS) time of the patients with curative resection was 15.0 months, which was shorter than that of patients with pancreatic ductal adenocarcinoma. The median OS time of patients with pT3 was significantly shorter than that of those with pT1 or pT2 (2.2 vs. 24.5 months; P<0.01). pT3 tumors frequently exhibited a high Ki-67 proliferative index with tumor necrosis and intratumoral hemorrhage. These cases exhibited high serum inflammatory marker levels, including white blood cells, C-reactive protein and neutrophil-to-lymphocyte ratio. On the other hand, 4 patients survived for ≥2 years without recurrence after surgery. These patients included 2 cases with undifferentiated carcinoma with OCGC and 2 pT1 cases with undifferentiated carcinoma who did not exhibit tumor necrosis or intratumoral hemorrhage. The present study demonstrated that a number of ACP cases exhibited early recurrence with poor survival, whereas limited cases experienced long-term survival. The tumor subtype and pathological features, such as tumor diameter, tumor necrosis and intratumoral hemorrhage, may be associated with the postoperative prognosis of patients with ACP.

OBJECTIVE:Colorectal liver metastases (CRLMs) with replacement growth pattern (rHGP) are associated with a poor prognosis; however, the underlying mechanisms driving rHGP remain poorly understood. This study investigated the effect of the TWEAK/Fn14 axis in CRLMs on tumor progression to explore the pathology of CRLMs with rHGP. METHOD:In total, 129 patients with CRLMs who underwent curative resection were investigated. RESULTS:Patients with rHGP had significantly poor overall survival after surgery than those with other growth patterns. CRLMs with rHGP exhibited epithelial-mesenchymal transition (EMT) activation and a distinct immune microenvironment. We focused on TWEAK/Fn14 axis to clarify the mechanism by which the tumor microenvironment affects tumor progression in CRLMs with rHGP. TWEAK was expressed in the tumor microenvironment, accompanied by the infiltration of Th17 cells and M2 macrophages, whereas Fn14 was expressed in cancer cells within CRLMs. High TWEAK/high Fn14 expression in CRLMs was more frequently observed in CRLMs with rHGP and was associated with a worse prognosis. This was accompanied by high grade of tumor budding and poorly differentiated clusters in CRLMs, and increased risk of extrahepatic metastases. In vitro, recombinant TWEAK (100 ng/mL) induced phosphorylation of IκB and NFκB (p65) and also enhanced cell migration, invasion, and EMT maker expression in colorectal cancer cells. Cell migration and invasion enhanced by recombinant TWEAK were suppressed by an Fn14 antagonist (ITEM-4: 200 ng/mL). DISCUSSION:This study clarified that the TWEAK/Fn14 axis in CRLMs promotes invasiveness and metastatic potential, leading to poor prognosis. It may be crucial in the adverse survival outcomes of CRLMs with rHGP.

Background Leucine-rich alpha 2-glycoprotein (LRG) has been identified as a disease activity marker that reflects pathology of inflammatory diseases including inflammatory bowel disease (IBD). Whereas LRG was reported to modulate transforming growth factor beta-1 (TGF-beta) signaling, the role of LRG in inflammatory diseases has not been fully clarified. Here we investigated the role of LRG in IBD.Methods First, we investigated the difference of pathologies between wild-type (WT) mice and LRG-deficient (LRG-/-) mice in dextran sodium sulfate (DSS)-induced experimental colitis. Next, we analyzed the role of LRG in colonic inflammation by using in vitro assay.Results Prompt LRG upregulation was detected on the colonic epithelial cells on day 1 post 3% DSS treatment. Body weight loss after DSS treatment was significantly less severe in LRG-/- mice than in WT mice. Histological examination disclosed that leukocyte infiltration in colonic tissue was attenuated in LRG-/- mice compared with WT mice on day 3. Interestingly, the expression of endoglin, one of adhesion molecules in vascular endothelial cells, was markedly elevated in WT mice on day 1 post-DSS treatment, but was not in LRG-/- mice. Anti-TGF-beta antibody treatment in mice with DSS colitis revealed that TGF-beta is critical for endoglin upregulation in endothelial cells. Importantly, recombinant LRG when added to the culture media enhanced TGF-beta 1-induced endoglin expression in endothelial cells and increased adherence of monocytes to endothelial cells.Conclusions Our data suggest that LRG accelerates the progression of colonic inflammation at least in part by enhancing leukocyte trafficking through the upregulation of TGF-beta 1-induced endoglin expression in vascular endothelial cells. We investigated the role of leucine-rich alpha 2-glycoprotein (LRG) in IBD. Our data suggest that LRG accelerates the progression of colonic inflammation at least in part by enhancing leukocyte trafficking through the upregulation of TGF-beta 1-induced endoglin expression in vascular endothelial cells.

527 Background: Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic duct and bile duct anatomically merge outside the duodenal wall, and is associated with a high rate of biliary cancer. It has been reported that TP53 and KRAS mutations are found not only in the cancerous area but also in the noncancerous area. However, there is no report of precise mapping of genetic mutations throughout the gallbladder and bile ducts. Methods: Ninety-seven patients (including 31 patients with biliary cancer) who underwent cholecystectomy and cholangiectomy for PBM between 1990 and 2023 at our hospital and affiliated hospitals were included in the study, and consent forms were obtained from 36 patients. The panel targeting 60 genes frequently identified in biliary tract cancer was created in-house and deep sequenced to compare with clinicopathological features. To date, we have analyzed 4 patients with biliary tract cancer and 5 patients without it (with prophylactic resection). The same analysis was also performed on cancerous and noncancerous parts of patients of gallbladder cancer and cholangiocarcinoma without confluence abnormalities for comparison. Results: A total of 33 Samples (7 cancerous parts and 26 noncancerous parts) were examined for biliary tract cancer. We found a variety of functional gene abnormalities, including driver mutations such as TP53, ARID2, and BRCA2, in 9 non-cancerous areas including hyperplasia and normal bile duct mucosa. Some of these mutations were not shared with cancerous areas. On the other hand, in 46 samples from 5 patients who did not develop gallbladder cancer (prophylactic resection), Driver mutations were found in only 3 sites. Pathological findings of dysplasia/hyperplasia in these prophylactic resections were observed in 28 of the 46 sections. In addition, Driver mutations were rarely observed in noncancerous areas in patients with normal gallbladder or cholangiocarcinoma. Conclusions: Unlike conventional biliary tract cancers, the patients with PBM showed a great variety of genetic abnormalities in both cancerous and noncancerous areas. On the other hand, in patients of prophylactic resection without cancer, driver mutations were almost completely absent despite the presence of mucosal changes. We believe that these findings can develop better strategy for biliary cancers with PBM.

A 50-year-old male with a pancreatic tail tumor underwent distal pancreatectomy. At 14 and 27 months after the primary surgery, metachronous liver metastases were identified and partial hepatectomies were performed for each. Pathologic findings of the primary pancreatic tumor were heterogeneous, but they essentially categorized into two components based on their cytologic features: (i) clear cell component and (ii) epithelioid cell component. The metastatic hepatic tumor was entirely composed of the epithelioid cell component. SMARCB1 expression was lost by immunohistochemistry and heterozygous deletion of SMARCB1 was identified by fluorescence in situ hybridization for both the primary and metastatic tumors. Targeted DNA sequencing of a metastatic hepatic tumor sample was performed and SMARCB1 loss was identified. Based on the morphologic, immunohistochemical, and molecular analyzes, the present case was difficult to classify into any of the existing entities. SMARCB1 deficiency might play a key role in the tumorigenesis.

BACKGROUND:Hepatectomy is recommended for colorectal liver metastases and repeat resection of recurrent lesions is an effective treatment for patients with recurrence. However, treatment outcomes are unclear in patients with aggressive tumor behavior. SUBJECTS:Initial hepatectomy for colorectal liver metastases was performed on 180 patients between 2010 and 2021, and recurrence, treatment outcomes, and prognostic factors were analyzed. RESULTS:Of the 180 patients, 124 developed recurrences, and repeat resection was performed in 58. Of these, 34 patients had liver metastasis alone, 12 had lung metastasis alone, and 2 had simultaneous liver and lung recurrence. The median overall survival(OS)and 5-year survival were significantly longer in the resectable group(70 months and 64.4%, respectively)than in the unresectable group (54 months and 35.3%, respectively). The presence of 3 or more recurrent lesions was an independent risk factor for unresectability. The time to surgical failure(TSF)was significantly shorter in patients with 3 or more recurrent lesions, suggesting that an increased number of recurrent lesions is an indicator of poor prognosis. CONCLUSION:The number of recurrent lesions post-initial hepatectomy is a risk factor for poor OS and TSF. Patients with 3 or more recurrent lesions have a higher risk of becoming unresectable early, necessitating combined resection and chemotherapy.

Although some clinical trials have demonstrated the benefits of neoadjuvant therapy for resectable pancreatic ductal adenocarcinoma (PDAC), its optimal candidate has not been clarified. This study aimed to detect predictive prognostic factors for resectable PDAC patients who underwent upfront surgery and identify patient cohorts with long-term survival without neoadjuvant therapy. A total of 232 patients with resectable PDAC who underwent upfront surgery between January 2008 and December 2019 were evaluated. The median overall survival (OS) time and 5-year OS rate of resectable PDAC with upfront surgery was 31.5 months and 33.3