Prognostic factors based on histological categorization of desmoplastic reactions in pancreatic cancer.

BACKGROUND/PURPOSE: In colorectal cancer, the morphological categorization of fibrotic cancer stroma in the invasive frontal zone of the primary tumor is well reflected in the prognosis. Conversely, the histological characteristics of pancreatic cancer (PC) reveal fibrotic hyperplasia of stroma known as desmoplasia; however, its characterization is unknown. Therefore, this study aimed to evaluate the prognostic factors according to the histological categorization of desmoplastic reactions in PC. METHODS: We retrospectively enrolled 167 patients who underwent curative resection for PC. The desmoplastic pattern was histologically classified as mature, intermediate, or immature. Clinicopathological features were evaluated, and disease-free and overall survival (OS) were analyzed in the three groups. Prognostic factors were assessed using univariate and multivariate analyses. RESULTS: In total, 19 mature, 87 intermediate, and 61 immature desmoplastic patterns were evaluated. Jaundice decompression, white blood cell count, and platelet/lymphocyte ratio were significantly different among the groups. The mature group had a better disease-free survival (DFS) prognosis than the other two groups; however, OS did not differ between the groups. Desmoplastic patterns showed significant differences between the three groups for DFS. CONCLUSIONS: Desmoplastic patterns are a prognostic factor of DFS for PC, with mature desmoplastic reactions associated with good prognosis. Thus, they may aid in individualized therapeutic approaches in patients with PC.

Extracellular Vesicles Are Important Mediators That Regulate Tumor Lymph Node Metastasis via the Immune System.

Extracellular vesicles (EVs) are particles with a lipid bilayer structure, and they are secreted by various cells in the body. EVs interact with and modulate the biological functions of recipient cells by transporting their cargoes, such as nucleic acids and proteins. EVs influence various biological phenomena, including disease progression. They also participate in tumor progression by stimulating a variety of signaling pathways and regulating immune system activation. EVs induce immune tolerance by suppressing CD8+ T-cell activation or polarizing macrophages toward the M2 phenotype, which results in tumor cell proliferation, migration, invasion, and metastasis. Moreover, immune checkpoint molecules are also expressed on the surface of EVs that are secreted by tumors that express these molecules, allowing tumor cells to not only evade immune cell attack but also acquire resistance to immune checkpoint inhibitors. During tumor metastasis, EVs contribute to microenvironmental changes in distant organs before metastatic lesions appear; thus, EVs establish a premetastatic niche. In particular, lymph nodes are adjacent organs that are connected to tumor lesions via lymph vessels, so that tumor cells metastasize to draining lymph nodes at first, such as sentinel lymph nodes. When EVs influence the microenvironment of lymph nodes, which are secondary lymphoid tissues, the immune response against tumor cells is weakened; subsequently, tumor cells spread throughout the body. In this review, we will discuss the association between EVs and tumor progression via the immune system as well as the clinical application of EVs as biomarkers and therapeutic agents.

Neuroendocrine carcinoma of the common bile duct associated with congenital bile duct dilatation: a case report.

BACKGROUND: Cholangiocarcinoma is frequently observed in patients with congenital bile duct dilatation (CBDD). Most cholangiocarcinomas are adenocarcinomas. Other types, especially neuroendocrine carcinomas (NECs), are rare. To the best of our knowledge, this is the third reported case of an NEC of the common bile duct associated with CBDD and the first to receive adjuvant chemotherapy for advanced disease. CASE PRESENTATION: A 29-year-old woman presented with upper abdominal pain. Preoperative imaging indicated marked dilatation of the common bile duct and a tumor in the middle portion of the common bile duct. She was suspected of having distal cholangiocarcinoma associated with CBDD and underwent pylorus-preserving pancreaticoduodenectomy. Pathological and immunohistological findings led to a final diagnosis of large-cell NEC (pT3aN1M0 pStageIIB). The postoperative course was uneventful, and she was administered cisplatin and irinotecan every 4 weeks (four cycles) as adjuvant chemotherapy. She has remained recurrence-free for 16 months. CONCLUSIONS: NEC might be a differential diagnosis in cases of cholangial tumor associated with congenital bile duct dilatation. This presentation is rare and valuable, and to establish better treatment for NEC, further reports are necessary.

Precise anatomical resection based on structures of nerve and fibrous tissue around the superior mesenteric artery for mesopancreas dissection in pancreaticoduodenectomy for pancreatic cancer.

BACKGROUND: The aim of the present study was to investigate the feasibility of resection based on the nerve and fibrous tissue (NFT) structures around the superior mesenteric artery (SMA) for resectable pancreatic adenocarcinoma (R-PDAC) patients. METHODS: NFTs around the SMA were classified into four "intensive NTFs area" with spreading the NFTs around the SMA and three SMA nerve plexus regions without branching nerves according to autopsy findings. Complete dissection of four "intensive NTFs areas" was performed by pre-exposing three SMA nerve plexus regions without branching nerves as "dissection-guiding points" with SMA nerve plexus preservation (NFT-based resection). Among 157 R-PDAC patients undergoing pancreaticoduodenectomy, surgical outcomes of 78 patients with NFT-based resection were compared with 59 patients with half-SMA nerve plexus dissection and 20 patients without NFTs dissection. RESULTS: In the NFT-based resection group, 76.5% had tumor involvement and metastasis in each intensive NTFs area. Operative time, blood loss, and postoperative diarrhea rate were significantly lower in NFT-based resection than in half-SMA nerve plexus group (321 vs 390 min; P < .01, 228 vs 550 mL; P < .01, 5.1% vs 15.3%; P = .04, respectively). R0 rate and median overall survival significantly improved in NFT-based resection than in non-NFT dissection group (93.6% vs 65.0%; P < .01, 49.6 vs 23.6 months, P = .01). CONCLUSION: NFT-based resection may become a novel method for R-PDAC patients.

Indocyanine green clearance of remnant liver (ICG-Krem) predicts postoperative subclinical hepatic insufficiency after resection of colorectal liver metastasis: theoretical validation for safe expansion of Makuuchi's criteria.

BACKGROUND: Multidisciplinary treatment for colorectal liver metastases (CLMs) often includes major hepatectomy for preoperative chemotherapy-related hepatic injury, although the safety limit for resection extent is unclear. We investigated this parameter using the estimated indocyanine green clearance rate (ICG-K) of liver remnants, focusing on postoperative subclinical hepatic insufficiency (PHI). METHODS: Altogether, 225 patients who underwent resection of CLMs were studied. The predictive power of estimated ICG-K of liver remnant (ICG-Krem) for subclinical PHI (peak bilirubin ≥3 mg/dL or refractory ascites) was compared with those of other potential predictors. The suggested safety limit of ICG-Krem ≥0.05 was also assessed. RESULTS: Receiver-operating curve analysis revealed that ICG-Krem [area under the curve (AUC) 0.752, cutoff 0.102] was the best predictor of subclinical PHI (AUC range for others was 0.632-0.668). Makuuchi's criteria corresponded to ICG-Krem 0.10. Subclinical PHI incidence was significantly elevated at ICG-Krem <0.10 (26% vs 8%, p = 0.002), while potentially fatal PHI (peak bilirubin >7 mg/dL) was not observed until down to ICG-Krem of 0.05. CONCLUSIONS: ICG-Krem sensitively predicts subclinical PHI. Liver failure-related death could be avoided so long as ICG-Krem remains at ≥0.05. However, patients with ICG-Krem 0.05-0.10 are at high risk of subclinical PHI and require intensive care postoperatively.

Conversion surgery after extensive chemotherapy for stage IV mixed adenoneuroendocrine carcinoma (MANEC) of the gallbladder: clinical implications from the patterns of response and recurrence.

A 53-year-old woman who was diagnosed as having advanced gallbladder cancer (T3N1M1, Stage IVB) showed a dramatic response to chemotherapy using gemcitabine + cisplatin and surgery with curative intent was attempted. Histopathological examination revealed residual tumor limited to the perimuscular connective tissue of the gallbladder (T2bN0M0, Stage IIB) and a mixture of poorly differentiated adenocarcinoma and neuroendocrine carcinoma (NEC) components was confirmed. At 6 months after the surgery, a small peritoneal nodule was detected and chemotherapy was resumed with gemcitabine, cisplatin, and S-1. However, the recurrent lesion showed no response at all and gradually formed a mass with the liver and kidney. Considering the difficulty of intensive chemotherapy and the relatively indolent progression of the disease at 15 months after the recurrence was first detected, repeat resection was performed. Histopathology of the resected lesions revealed only a NEC components. Although surgical intervention may be effective in selected cases, given that the NEC component is often associated with progression and recurrence of the disease, the chemotherapy regimen would need to include drugs for the NEC component in cases where the histopathological diagnosis of MANEC has been established.

Expanded Makuuchi's criteria using estimated indocyanine green clearance rate of future liver remnant as a safety limit for maximum extent of liver resection.

BACKGROUND: Recent advances in liver surgery have dramatically improved the safety of hepatectomy for hepatocellular carcinoma (HCC). The aim of this study was to compare outcomes for patients fulfilling an extended criteria vs. those fulfilling the conventional criteria based on the bilirubin and indocyanine green (ICG) clearance (Makuuchi's criteria). METHODS: The short term outcomes of patients undergoing hepatectomy for HCC and who fulfilled the expanded criteria (ICG clearance of future remnant liver [ICG-Krem] ≥ 0.05 estimated using 3-D volumetry) were retrospectively reviewed and were compared between those fulfilling the conventional criteria. Postoperative hepatic insufficiency (PHI) was defined as peak total bilirubin >7 mg/dL. RESULTS: A total of 323 patients undergoing resection of whom 269 (83%) met conventional criteria (In-M) and 54 (17%) extended criteria (Ex-M). The overall morbidity rates were not significantly different. The incidence of PHI was 0.37% in In-M and 3.7% in Ex-M (P = 0.074), with no liver-related deaths. When the ICG-Krem ≥ 0.05 criterion was included, major hepatectomy was performed in 24 patients (41%) in Ex-M with no significant increase in major morbidity (13%), PHI(3.3%), or liver-related death (0%) compared with minor hepatectomy (n = 30) in Ex-M(10%, 4% and 0%, respectively). CONCLUSIONS: Objective criteria using ICG clearance rate and 3-D volumetry may offer opportunities for safe surgical resection in selected patients exceeding the conventional criteria.

Combined hepatocellular-cholangiocarcinoma with angiosarcomatoid change: A case report with immunohistochemical study.

Sarcomatoid combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare condition, with only 16 cases reported to date; however, there have been no reports of hepatic sarcomatoid carcinoma with angiosarcomatous features. Here, we report a rare case of cHCC-CCA with angiosarcomatoid changes in a 77-year-old man. The tumor was biphasic with malignant epithelial and mesenchymal components. Histologically, the epithelial component was concordant with classical type cHCC-CCA. The mesenchymal component included angiosarcomatoid cells growing in a vasoformative structure and undifferentiated spindle cells. Immunohistochemical analyses showed that angiosarcomatoid cells were positive for CD31, factor VIII-related antigen, and other angiosarcoma markers. Characteristically diffuse and strong expression of p53 protein was observed in the nuclei of angiosarcomatoid cells but not in carcinoma cells, suggesting that TP53 gene mutations commonly occur in these cells. Transitional zones were observed between HCC and spindle cells and between HCC and angiosarcomatoid cells. A small portion of undifferentiated spindle cells expressed pan-cytokeratin. These findings suggested that this extremely rare tumor developed from dedifferentiation or metaplastic changes of cHCC-CCA.

Platelet-Albumin Score as a Sensitive Measure for Surgical Risk Prediction and Survival Outcomes of Patients with Hepatocellular Carcinoma.

BACKGROUND: Given that patients with hepatocellular carcinoma (HCC) usually suffer from dual diseases (i.e., HCC and underlying liver disease), a complete survival estimation model is difficult to establish because both the oncological stage and the underlying liver function affect the survival outcome. METHODS: A new surgical risk model for estimating the survival of patients undergoing resection for HCC was created using a cohort treated between 1995 and 2013 (training set, n = 889), and its efficacy was then validated using a cohort treated between 2014 and 2017 (validation set, n = 310). RESULTS: The following statistical model was developed based on the results of multivariate analysis: albumin-platelet (PAL) score = - 0.777 × albumin (g/dL) - 0.575 × log10 (platelet count [104/µL]) (cut-off value, - 3.77 and - 3.04 for grading). A time-dependent receiver-operating curve analysis revealed that the area under the curve for 3-year survival was 0.644 in the training set and 0.666 in the validation set. The incidences of postoperative morbidity were 14.0% for PAL grade 1, 18.7% for PAL grade 2, and 26.1% for PAL grade 3 (P = 0.039), while the incidences of refractory ascites were 2.2, 7.1, and 12.5% (P = 0.005), respectively, in the training set. The reproducibility of these results was confirmed in the validation set with morbidity rates of 13.5, 23.3, and 40.7% (P = 0.003), respectively, and the incidences of refractory ascites were 0.7, 10.7, and 22.2% (P < 0.0001), respectively. CONCLUSIONS: The PAL score can be used as a grading system for the stratification of survival outcomes and surgical risks of patients undergoing HCC resection.