Cholangiocarcinomas(bile duct cancers) are a heterogeneous group of malignancies arising from the epithelial cells of the intrahepatic,perihilar and extrahepatic bile ducts.Patients diagnosed with cholangiocarcinoma must be evaluated by a multidisciplinary team and be treated with individualized management.First of all,it is very important to define the potential resectability of the tumor because surgery is the main therapeutic option for these patients.Overall,cholangiocarcinomas have a very poor prognosis.The 5 year survival rate is 5%-10%.In cases with a potentially curative surgery,5 year survival rates of 25%-30% are reported.Therefore,it is necessary to increase the cure rate from surgery,exploring the survival benefit of any adjuvant strategy.It is difficult to clarify the role of adjuvant treatment in localized and locally advanced cholangiocarcinomas.There are limited data and the role of adjuvant chemotherapy/chemoradiation in patients with resected biliary tract cancer is poorly defined.The most relevant studies in the adjuvant setting are one from Japan,the well known ESPAC-3 and BILCAP from the United Kingdom and a meta-analysis.We show the results of these trials.According to medical oncology guidelines,postoperative adjuvant therapy is widely recommended for all patients with intrahepatic or extrahepatic cholangiocarcinoma who have microscopically positive resection margins,as well as for those with a complete resection but node-positive disease.Clinical trials are ongoing.The locally advanced cholangiocarcinoma setting includes a heterogeneous mix of patients:(1) patients who have had surgery but with macroscopic residual disease;(2) patients with locally recurrent disease after potentially curative treatment;and(3) patients with locally unresectable disease at presentation.In these patients,surgery is not an option and chemoradiation therapy can prolong overall survival and provide control of symptoms due to local tumor effects.Nowadays,no neoadjuvant therapy can be considered a standard approa

为 cholangiocarcinoma 的化疗: 更改

Targeted nanomedicine for cancer therapeutics: Towards precision medicine overcoming drug resistance.

The extracellular matrix (ECM) is one of the major components of tumors that plays multiple crucial roles, including mechanical support, modulation of the microenvironment, and a source of signaling molecules. The quantity and cross-linking status of ECM components are major factors determining tissue stiffness. During tumorigenesis, the interplay between cancer cells and the tumor microenvironment (TME) often results in the stiffness of the ECM, leading to aberrant mechanotransduction and further malignant transformation. Therefore, a comprehensive understanding of ECM dysregulation in the TME would contribute to the discovery of promising therapeutic targets for cancer treatment. Herein, we summarized the knowledge concerning the following: (1) major ECM constituents and their functions in both normal and malignant conditions; (2) the interplay between cancer cells and the ECM in the TME; (3) key receptors for mechanotransduction and their alteration during carcinogenesis; and (4) the current therapeutic strategies targeting aberrant ECM for cancer treatment.

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Extracellular matrix and its therapeutic potential for cancer treatment

To flourish, cancers greatly depend on their surrounding tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in TME are critical for cancer occurrence and progression because of their versatile roles in extracellular matrix remodeling, maintenance of stemness, blood vessel formation, modulation of tumor metabolism, immune response, and promotion of cancer cell proliferation, migration, invasion, and therapeutic resistance. CAFs are highly heterogeneous stromal cells and their crosstalk with cancer cells is mediated by a complex and intricate signaling network consisting of transforming growth factor-beta, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin, mitogen-activated protein kinase, Wnt, Janus kinase/signal transducers and activators of transcription, epidermal growth factor receptor, Hippo, and nuclear factor kappa-light-chain-enhancer of activated B cells, etc., signaling pathways. These signals in CAFs exhibit their own special characteristics during the cancer progression and have the potential to be targeted for anticancer therapy. Therefore, a comprehensive understanding of these signaling cascades in interactions between cancer cells and CAFs is necessary to fully realize the pivotal roles of CAFs in cancers. Herein, in this review, we will summarize the enormous amounts of findings on the signals mediating crosstalk of CAFs with cancer cells and its related targets or trials. Further, we hypothesize three potential targeting strategies, including, namely, epithelial–mesenchymal common targets, sequential target perturbation, and crosstalk-directed signaling targets, paving the way for CAF-directed or host cell-directed antitumor therapy.

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Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer

Background: Identification of patients at risk for mortality early in the course of acute pancreatitis (AP) is an important step in improving outcome. Methods: Using Classification and Regression Tree (CART) analysis, a clinical scoring system was developed for prediction of in-hospital mortality in AP. The scoring system was derived on data collected from 17 992 cases of AP from 212 hospitals in 2000-2001. The new scoring system was validated on data collected from 18 256 AP cases from 177 hospitals in 2004-2005. The accuracy of the scoring system for prediction of mortality was measured by the area under the receiver operating characteristic curve (AUC). The performance of the new scoring system was further validated by comparing its predictive accuracy with that of Acute Physiology and Chronic Health Examination (APACHE) II. Results: CART analysis identified five variables for prediction of in-hospital mortality. One point is assigned for the presence of each of the following during the first 24 h: blood urea nitrogen (BUN) >25 mg/dl; impaired mental status; systemic inflammatory response syndrome (SIRS); age >60 years; or the presence of a pleural effusion (BISAP). Mortality ranged from >20% in the highest risk group to <1% in the lowest risk group. In the validation cohort, the BISAP AUC was 0.82 (95% Cl 0.79 to 0.84) versus APACHE II AUC of 0.83 (95% Cl 0.80 to 0.85). Conclusions: A new mortality-based prognostic scoring system for use in AP has been derived and validated. The BISAP is a simple and accurate method for the early identification of patients at increased risk for in-hospital mortality.

The early prediction of mortality in acute pancreatitis : a large population-based study. Commentary

Background

The bedside index of severity in acute pancreatitis (BISAP) is a new, convenient, prognostic multifactor scoring system. As there were no studies designed to validate this system according to the latest Atlanta classification in China and more data are needed before clinical application, we compared BISAP, the Acute Physiology and Chronic Health Evaluation (APACHE) II and Ranson scoring systems in predicting the severity, pancreatic necrosis and mortality of acute pancreatitis (AP) using the latest 2012 Atlanta classification in a tertiary care center in China.



Methods

The medical records of all patients with AP admitted to our hospitals between January 2010 and June 2013 were reviewed retrospectively. Severe AP was defined as the persistence of organ failure for more than 48 h. The capacity of the BISAP, APACHE II and Ranson's score system to predict severity, pancreatic necrosis and mortality was evaluated using linear-by-linear association. The predictive accuracy of the BISAP, APACHE II and Ranson's score was measured as the area under the receiver operating characteristic curve (AUC).



Results

Of 155 patients enrolled in the study, 16.7% were classified as having severe AP, and six (3.2%) died. There were statistically significant trends for increasing severity (P < 0.001), PNec (P < 0.001) and mortality (P < 0.001) with increasing BISAP. The AUC for severity predicted by BISAP was 0.793 (95% confidence interval [CI] 0.700–0.886), APACHE II 0.836 (95% CI 0.744–0.928) and by Ranson score was 0.903 (95% CI 0.814–0.992). The AUC for PNec predicted by BISAP was 0.834 (95% CI 0.739–0.929), APACHE II 0.801 (95% CI 0.691–0.910) and by Ranson score was 0.840 (95% CI 0.741–0.939). The AUC for mortality predicted by BISAP was 0.791 (95% CI 0.593–0.989), APACHE II 0.812 (95% CI 0.717–0.906) and by Ranson score was 0.904 (95% CI 0.829–0.979).



Conclusions

BISAP score may be a valuable source for risk stratification and prognostic prediction in Chinese patients with AP. A prospective and multicenter validation study is required to confirm our results and further our recognition of BISAP scores in AP.

Comparison of the BISAP scores for predicting the severity of acute pancreatitis in Chinese patients according to the latest Atlanta classification

Purpose: Adjuvant chemotherapy is one of the significant treatments for colon cancer in clinic. However, it does not achieve the desired therapeutic efficacy, largely due to chemotherapeutic resistance. Integrinβ6 (ITGB6) is expressed in malignant colonic epithelia, but not in normal epithelia, and is associated with the progression, metastasis, and chemotherapeutic resistance of colon cancer. Accordingly, it is necessary to design therapeutic approaches for efficient and targeted drug delivery into ITGB6-positive cancer cells to improve chemotherapeutic efficacy in colon cancer. Experimental Design: PEGylated liposomes were employed to design ITGB6-targeted immunoliposomes, which have ITGB6 monoclonal antibodies (mAbs) conjugated. We evaluated the ITGB6-targeted immunoliposomes internalization into colon cancer cells and examined 5-fluorouracil (5-FU)–induced cellular apoptosis produced by ITGB6-targeted immunoliposomes+5-FU. In addition, the biodistribution and antitumor efficiency of ITGB6-targeted immunoliposomes were observed in vivo . Results: ITGB6-targeted immunoliposomes enhanced cellular internalization in ITGB6-positive colon cancer cells compared with liposomes. Furthermore, the ITGB6-targeted immunoliposome internalization was dependent on the ITGB6 expression level on cellular surface. ITGB6-targeted immunoliposomes decreased the 5-FU IC 50 more than 90% in HT-29 and SW480β6 cells relative to liposomes. Moreover, when loaded with 5-FU, ITGB6-targeted immunoliposomes produced an approximately 1.5-fold higher 5-FU–induced cellular apoptosis rate than liposomes. In vivo , the therapeutic activity of ITGB6-targeted immunoliposomes+5-FU was significantly superior, resulting in 25% to 35% reduction of tumor weight compared with 5-FU or liposomes+5-FU. Conclusions: ITGB6-targeted immunoliposomes provide a highly efficient approach for targeted drug delivery in colon cancer and thus offer the potential of a novel and promising anticancer strategy for clinical therapy. Clin Cancer Res; 21(5); 1183–95. ©2014 AACR .

https://clincancerres.aacrjournals.org/content/clincanres/21/5/1183.full.pdf

Integrinβ6-Targeted Immunoliposomes Mediate Tumor-Specific Drug Delivery and Enhance Therapeutic Efficacy in Colon Carcinoma

Tumor microenvironment (TME) is the cellular environment in which tumor exists, and it contributes to tumor formation and progression. The TME is composed of tumor cells, stromal cells, cytokines, and chemotactic factors of which fibroblasts are the main cellular components. In our present study, we found that colorectal cancer (CRC) cells expressing integrin αvβ6 clearly could induce morphological changes in inactive fibroblasts and increased the expression of activated fibroblast markers such as α-smooth muscle actin (α-SMA) and fibroblast-activating protein (FAP). Those activated fibroblasts in the TME are called cancer-associated fibroblasts (CAFs). In order to investigate the mechanism by which CRC cells expressing integrin αvβ6 activated CAFs, a series of assays have been carried out in the follow-up. We found that CRC cells could secrete inactive transforming growth factor β (TGF-β); however, integrin αvβ6 activated TGF-β, which subsequently activated fibroblasts. This process was disrupted by knockdown of integrin αvβ6. In contrast, activated fibroblasts could promote CRC cell invasion. In particular, the strengthening effect on expression of integrin αvβ6 in colon cancer cells was obvious. Additionally, we found that CAFs could secrete stromal cell-derived factor-1 (SDF-1) and promote CRC cell metastasis in distant organs via the SDF-1/C–X–C chemokine receptor type 4 (CXCR4) axis. Taken together, we assumed that CRC cells and CAFs activated one another and worked together to promote cancer progression, with integrin αvβ6 playing a role in the bi-directional regulation of these cells. Hence, integrin αvβ6 may serve as a therapeutic target for the future CRC treatment.

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Integrin αvβ6 plays a bi-directional regulation role between colon cancer cells and cancer-associated fibroblasts.

Cholangiocarcinoma is a devastating malignancy that is notoriously difficult to diagnose and is associated with a high mortality. Despite extensive efforts to improve the diagnosis and treatment of this neoplasm, limited progress has been made. Integrin β6 is a subtype of integrin that is expressed exclusively on the surfaces of epithelial cells and is associated with a variety of tumors. In the present study, we investigated the expression and roles of integrin β6 in cholangiocarcinoma. β6 upregulation in cholangiocarcinoma was correlated with lymph node metastasis and distant metastasis. Moreover, integrin β6 was identified as a biomarker for the diagnosis of cholangiocarcinoma and an indicator of lymph node metastasis. Integrin β6 significantly promoted the proliferation, migration and invasion of cholangiocarcinoma cells. Furthermore, integrin β6 increased Rac1-GTPase, resulting in the upregulation of metalloproteinase-9 (MMP9) and F-actin polymerization. Taken together, our results indicate that integrin β6 promotes tumor invasiveness in a Rac1-dependent manner and is a potential biomarker for tumor metastasis. Integrin β6 may help to improve the diagnostic accuracy, and targeting β6 may be a novel strategy for the treatment of cholangiocarcinoma.

/pdf/integrin-b6-serves-as-an-immunohistochemical-marker-for-4uf3ks9naw.pdf

Ruliang Fang

Papers

Comparison of the BISAP scores for predicting the severity of acute pancreatitis in Chinese patients according to the latest Atlanta classification

Integrinβ6-Targeted Immunoliposomes Mediate Tumor-Specific Drug Delivery and Enhance Therapeutic Efficacy in Colon Carcinoma

Integrin αvβ6 plays a bi-directional regulation role between colon cancer cells and cancer-associated fibroblasts.

Integrin β6 serves as an immunohistochemical marker for lymph node metastasis and promotes cell invasiveness in cholangiocarcinoma.