Understanding Cholangiocarcinoma

compiled by John G. Connor, M.Ac., L.Ac., edited by Barbara Connor, M.Ac., L.Ac.

Table of Contents
Introduction
Research on Natural Compounds That May be Suppressive Against Cholangiocarcinoma Cell Lines
Biomarkers in Cholangiocarcinoma
Blood Markers in Cholangiocarcinoma
Conventional Treatment Options in Cholangiocarcinoma
References

Introduction
Cholangiocarcinoma is classified as either intrahepatic or extrahepatic, with the second-order bile ducts acting as the separation point. Classically, extrahepatic cholangiocarcinoma has been divided in perihilar and distal extrahepatic cholangiocarcinoma at the level of the cystic duct. (Diagram from Biechacz et al 2012)

Cholangiocarcinomas (CCAs) are tumors that develop along the biliary tract. Depending on their site of origin, they have different features and require specific treatments. Classification of CCAs into intrahepatic, perihilar, and distal subgroups has helped standardize the registration, treatment, and study of this malignancy. (Razumilava & Gores 2012)

Cholangiocarcinoma (CCA) is a tumor of the bile ducts that usually presents with biliary obstruction and has a poor prognosis. The treatment of CCA is challenging as the tumor is usually diagnosed late and the treatments are not very effective except when complete surgical resection is possible. In carefully selected patients, liver transplant can be a curative therapy. In the majority of cases, complete surgical resection is not possible and palliation is the mainstay of treatment. Stenting, using plastic or metallic stents, allows for biliary drainage. Photodynamic therapy plays a role in palliation and might play a role in adjuvant or neoadjuvant therapy. While radiation and chemotherapy can be beneficial, newer ablative techniques and targeted chemotherapies are promising. (Charbel & Al-Kawas 2012)

Clinically, intrahepatic cholangiocarcinoma can be assumed on the basis of its venous phase contrast enhancement on dynamic imaging in the absence of other, extrahepatic primary malignancies and cirrhosis. Tumor markers such as CA 19-9 can be used for additional evidence but are not sufficient for diagnosis. However, for a definitive diagnosis of intrahepatic cholangiocarcinoma, a histological diagnosis is required. Intrahepatic cholangiocarcinoma arising from ductules may present with mixed histological and imaging features of both HCC and cholangiocarcinoma. Patients with intrahepatic cholangiocarcinoma or mixed HCC/intrahepatic cholangiocarcinoma should not undergo liver transplantation because of the risk of suboptimal outcomes. (Biechacz et al 2012)

Cholangiocarcinomas are a diverse group of tumors that are presumed to originate from the biliary tract epithelium either within the liver or the biliary tract. These cancers are often difficult to diagnose, their pathogenesis is poorly understood, and their dismal prognosis has resulted in a nihilistic approach to their management. The two major clinical phenotypes are intrahepatic, mass-forming tumors and large ductal tumors. Among the ductal cancers, lesions at the liver hilum are most prevalent. The risk factors, clinical presentation, natural history and management of these two types of cholangiocarcinoma are distinct. (Patel & Medscape 2011)

Cholangiocarcinoma is a tumor that originates from the neoplastic transformation of the epithelial cells of the intrahepatic or extrahepatic bile ducts. This type of cancer is difficult to diagnose, extremely aggressive, and has very poor prognosis. It is also relatively resistant to chemotherapy and radiation therapy. Its pathogenesis is poorly understood, however it is known that the tumor microenvironment is a very important factor in the regulation of tumor angiogenesis, invasion, and metastasis. (Leyva-Illades et al 2012)

Chronic inflammation and cholangiocarcinoma seem to be intimately related. Cholangiocarcinoma cells are known to overproduce many inflammatory cytokines, however, IL-6 is the most studied to date. How tumor-associated macrophages (TAMs) are involved in cholangiocarcinoma development and progression is still unclear. (Leyva-Illades et al 2012)

Tumor metastasis is a major cause of the lethality present in this disorder and the spread of tumor cells generally occurs through lymphatic vasculature. In the lymph nodes, a higher incidence of tumor foci is found which leads to an unfavorable prognostic factor in most cancers. Previously, it was thought that the spread of tumor cells via the lymphatic system was a passive process where detached tumor cells would enter pre-existing lymphatic vessels in the tumor area. We now know that new lymphatic vessels are formed in the tumor microenvironment and that this correlates with lymphatic metastasis. Lymphangiogenesis is regulated by growth factors similar to those that control angiogenesis. VEGF-C and VEGF-D are secreted from the tumors and in turn activate VEGFR-3, which is expressed on lymphatic endothelium. VEGFR-3 activation induces the proliferation of lymphatic endothelial cells in vitroand the formation of new lymphatic vessels in vivo. Additional lymphangiogenic factors include VEGF-A, fibroblast growth factor-2, angiopoietin-2, and platelet-derived growth factor-BB. (Leyva-Illades et al 2012) 

Since the factors mentioned above have overlapping angiogenic and lymphangiogenic activities, agents that block angiogenesis may also block lymphangiogenesis. Inhibitors that block VEGF-C/VEGF-D/VEGFR3 signaling could potentially block lymphangiogenesis in addition to angiogenesis, leading to blockage of lymphogenous metastatic spread. Supporting this, it has been shown that blocking the interaction between VEGF-D and its receptors with a monoclonal neutralizing antibody resulted in the inhibition of angiogenesis, lymphangiogenesis, and metastatic spread through the lymphatics in a murine tumor model. (Leyva-Illades et al 2012)

Individual studies estimate that as many as 69% of US cancer patients employ some type of complementary and alternative medicine, 76% of patients in a study of Midwestern cancer patients and 95% of radiation oncology patients in another study.  (Wargovich et al 2010)

There is an ever growing interest in treatment with natural compounds as an adjuvant cancer therapy along with conventional cancer therapy. (Virk-Baker et al 2010) For example the combination of a natural VEGF inhibitor along with lower doses of a pharmacological agent may prove helpful in reducing the unwanted side effects of chemotherapy. (Wargovich et al 2010)

Recent evidence shows that pharmaconutrients may act against proliferation, angiogenesis and metastasis in different types of human cancer. (Granci et al 2010)

Research on Natural Compounds That May be Suppressive Against Cholangiocarcinoma Cell Lines
Artemisinin – Cytotoxic activity of artemisinin and derivatives in the presence and absence of holo-transferrin and expression of genes involved in resistance of cancer cells Super Mario were investigated in human cholangiocarcinoma (CL-6) and hepatocarcinoma (Hep-G2) cell lines in vitro. Dihydroartemisinin exhibited the most potent cytotoxic activity against both cell lines and holo-transferrin caused different patterns of expression of resistance-associated genes. (Chaijaroenkul et al 2011)

Atractylodes – The ethanolic extract of AL (Atractylodes lancea thung. DC) was shown to possess the most potent anti-CCA activity similar to 5-FU with regards to the reduction of tumor mass, prolongation of survival time, and inhibition of lung metastasis. All dose levels significantly reduced tumor size (by 97.3%), prolonged survival time (by 208.5%), and inhibited lung metastasis (by 95% of total lung mass) compared with the untreated control. To the best of our knowledge, the present study is the first study that demonstrated the anticancer activity of AL. Interestingly, AL extract exhibited prominent inhibitory effect on lung metastasis. Metastasis is one of the major problems in the treatment of several cancer types. In severe stage CCA, metastatic tumors in the lungs are CCA cancers which developed in the lung tissues by spreading from the liver origin through the bloodstream or lymphatic system to the lungs. (Plengsuriyakam et al 2012)

Berberine – Together, this study for the first time identified berberine as a chemotherapeutic agent against human cholangiocarcinoma cells QBC939 cells in vitro. Further in vivo studies are required to determine whether berberine could be an effective chemotherapeutic agent for the management of cholangiocarcinoma. (He et al 2012)

Curcumin – In search for a suitable chemopreventive agents, we investigated the effect of curcumin, a traditional anti-inflammatory agent derived from turmeric (Curcuma longa), on Cholangiocarcinoma (CCA) development in an animal model. Curcumin suppressed the expression of proteins related to cell survival (bcl-2 and bcl-xL), proliferation (cyclin D1 and c-myc), tumor invasion (MMP-9 and ICAM-1) and angiogenesis (VEGF), and microvessel density. Induction of apoptotic events as indicated by caspase activation and PARP cleavage was also noted. Our results suggest that curcumin exhibits an anticarcinogenic وكذالك اكشن رائع potential via suppression of various events involved in multiple steps of carcinogenesis, which is accounted for by its ability to suppress proinflammatory pathways. (Prakobwong et al 2011) 

DIM 
(3,3′-diindolylmethane) – These results support AKT and FLIP as potential molecular targets and DIM as a potent compound for cholangiocarcinoma intervention. (Chen et al 2006)

Emodin – Our findings strongly suggest that increased inhibition of the antiapoptotic kinase Akt activation produced by the emodin/celecoxib combination treatment plays a key role in the mechanism by which this drug combination acts to enhance cell growth suppression and apoptosis in cultured C611B ChC (cholangiocarcinoma) cells and WBneu cells. (Lai et al 2003) 

GABA (gamma-aminobutyric acid) – decreases biliary cancer proliferation and reduces the metastatic potential ofcholangiocarcinoma. GABA may represent a therapeutic agent for patients affected by malignancies of the biliary tract. (Fava et al 2005)

Ginger – Significant anti-CCA activity of rhizome extract of ZO (Zingiber officinale) was also observed in the xenograft mouse model. High dose ZO significantly reduced tumor volume (by 35.8%), and all dose levels significantly prolonged survival time (by 161.5%) compared with the control group. Inhibition of lung metastasis by about half was seen at high dose. Furthermore, the extract possessed anti-inflammatory at all dose levels. The anticancer properties of ZO have been attributed to the presence of certain pungent vallinoids, viz. [6]-gingerol and [6]-paradol, as well as some other constituents like shogaols and zingerone. (Plengsuriyakam et al 2012)

Omega-3 PUFAs -These findings suggest that ω3-PUFAs (polyunsaturated fatty acids) block cholangiocarcinoma cell growth at least in part through inhibition of Wnt/β-catenin and COX-2 signaling pathways. Thus, utilization of ω3-PUFAs may represent an effective and safe therapeutic approach for the chemoprevention and treatment of human cholangiocarcinoma. (Lim et al 2008)

Resveratrol, caffeic acid, tannic acid, and green tea polyphenols – Another strategy to improve the treatment options of cholangiocarcinoma is to increase the sensitivity of cholangiocarcinoma to common chemotherapeutic agents. A large body of research has focused on plant-derived polyphenols, such as resveratrol, caffeic acid, tannic acid, and green tea polyphenols, as therapeutic and chemopreventive agents. Research indicates that these polyphenols may have antioxidant characteristics with potential health benefits including reducing the risk of cancer. Caffeic acid, a polyphenol extracted from the propolis of honeybee hives, exerts antiproliferative effects on cholangiocarcinoma and other tumor types in vitro and in vivo by inhibiting the nuclear factor-κB pathway. Furthermore, high concentrations of resveratrol have been shown to be antiproliferative in a cholangiocarcinoma cell line as well as in other tumor types through a number of different mechanisms including increased cyclooxygenase 2 expression, facilitation of death receptor complex formation, or cell cycle arrest. (Francis et al 2010) 

Resveratrol – The observed cytotoxic effect of resveratrol on the human cholangiocarcinoma SK-ChA-1 cell line cultured two- and three-dimensionally suggests to further analyse its chemotherapic/chemopreventive possibilities for this kind of cancer. (Roncoroni et al 2008) 

Biomarkers in Cholangiocarcinoma
Targeting PDGFR-β sensitizes CCA cells to apoptotic stimuli and appears to be therapeutic in vivo. (Fingas et al 2012)
The serum level of PDGFA in CCA patients was significantly higher than those of healthy control by 1.4-fold (P = 0.014). The present results suggest that PDGFA and PDGFRA may be used for CCA (cholangiocarcinoma) prognosis and/or as diagnostic candidate markers. (Boonjaraspinyo et al 2012)

In conclusion, our results showed high prevalence of activation of mTOR pathway in ICC (intrahepatic cholangiocarcinoma) tumors, suggesting that a high proportion of ICC patients might benefit from mTOR pathway targeted therapies. In addition, p-4EBP1 phosphorylation at Thr 70 could be a useful prognostic biomarker for ICC patients. (Wang et al 2012)

microRNA-21 expression is up-regulated in human cholangiocarcinoma and PTEN, PDCD4 are direct effectors of microRNA-21. Loss of microRNA-21 function led to a significant increase of PTEN and PDCD4 protein levels in QBC939 cells. (Liu et al 2012)

Mutations in p53 were detected in 22 of 36 cholangiocarcinoma patients (61.1%). Xiaofant et al 2012)
The reduced expression of E-cadherin and β-catenin and EGFR over expression in patients with cholangiocarcinoma seems to be correlated with tumor differentiation and tumor progression than tumor invasion and tumor proliferation. (Gu & Choi 2012)

The tumor epithelium was defined by deregulation of the HER2 network and frequent overexpression of EGFR, the hepatocyte growth factor receptor (MET), pRPS6, and Ki67, whereas stroma was enriched in inflammatory cytokines. Lapatinib, an inhibitor of HER2 and EGFR, was more effective in inhibiting growth ofcholangiocarcinoma cell lines than trastuzumab. (Anderson et al 2012)

uPA (urokinase plasminogen activator) expression correlates with lymphatic invasion and metastasis in vivo and is required for CCA (cholangiocarcinoma) cell invasion in vitro, suggesting its potential as a therapeutic target. (Thummarati et al 2012)

The prevalence of K-ras mutations in a considerably large cohort of ICC (intrahepatic cholangiocarcinoma) was 22%. K-ras mutation is strongly associated with perineural invasion phenotypically. K-ras mutation is an independent prognostic factor of ICC after hepatectomy. (Chen et al 2012)

The stimulation of TNF-α enhances migration behavior and showed significantly induced expression of Snail in CCA cell lines. (Techasen et al 2012)

Patients with extrahepatic CC with low E-cadherin expression had a significantly lower survival rate than patients with high E-cadherin expression (P=0.0059). Patients with decreasing E-cadherin and increasing N-cadherin expression had a significantly lower survival rate than patients with increasing E-cadherin and decreasing N-cadherin expression (P=0.017). (Araki et al 2011)

NF-kappaB-Snail-E-cadherin signal is a potential target for antimetastatic therapeutics in cholangiocarcinoma. (Zhang et al 2011)

The expressions of cleaved poly ADP-ribose polymerase (PARP), Bcl-2, Survivin, and Cyclin B1 were detected by Western blot analysis in human cholangiocarcinoma (CCA) cells. (Zhang et al 2012)

Fascin is an actin-binding protein involved in the cell motility. Fascin expression was an unfavorable prognostic factor for patients with intrahepatic CC (cholangiocarcinoma). In vitro studies showed that TNF-alpha could induce the overexpression of fascin and MMP-9 in two CC cell lines. A knockdown study of fascin by siRNA showed that TNF-alpha induced the overproduction of fascin, which in turn upregulated MMP9 expression. Overexpression of fascin may have an important function in the progression of CC, and fascin expression might be involved in the signaling pathway in TNF-alpha-dependent production of MMP9 in CC. (Onodeera et al 2009)

COX-2 protein is constitutively detectable in liver tissue macrophages. Inflammatory mononuclear phagocytes contribute to the increase of COX-2 gene expression in acute and chronic liver damage induced by different toxins and in the CC (cholangiocarcinoma) microenvironment. (Wojcik et al 2012)

COX-2 – Consistent with the strong association between bile duct chronic inflammation and cholangiocarcinoma,recent studies have documented an important role of cyclooxygenase-2 (COX-2)–derived prostaglandin E2 (PGE2), a potent lipid inflammatory mediator, in cholangiocarcinogenesis. For example, increased COX-2 expression has been documented in cholangiocarcinoma cells and precancerous bile duct lesions but not in normal bile duct epithelial cells (BEC; refs. 7– 9). Overexpression of COX-2 in cultured human cholangiocarcinoma cells enhances PGE2 production and promotes tumor growth, whereas depletion of COX-2 attenuates growth. Treatment of cholangiocarcinoma cells with exogenous PGE2 increases tumor cell growth and prevents apoptosis. Consistent with these findings, selective COX-2 inhibitors prevent cholangiocarcinoma cell growth and invasion, in vitro and in nude mice, although their effect may be mediated through COX-2–dependent and -independent mechanisms. (Lim et al 2008)

These findings suggested that HDAC1 positive expression was a potential new prognostic indicator of IHCC (intrahepatic cholangiocarcinoma), and a possible promising molecular target through the regulation of HIF-1α. (Morine et al 2012)

In this study we identified elevation in CD14+CD16+, a minor blood monocyte subpopulation incholangiocarcinoma (CCA) patients, compared to normal and biliary disease patient specimens. These data indicate that the CD14+CD16+ monocytes from CCA patients with pro-tumorigenic characteristics may associate with rapid tumour progression and poor patient outcome. (Subimerb et al 2010)

Serum values of MMP7 and CA19-9 appear to be useful biomarkers for differentiating cholangiocarcinoma from benign biliary tract obstructive diseases. (Leelawat et al 2010)

MMP-9 and MMP- 14 were present in metaplasia, dysplasia carcinoma sequence in all of the bile tract tumors, suggesting that MMPs play an important role in carcinogenesis. The higher expression of the MMPs with neural invasion suggests the significant role of those tumors in the invasion activity.(Kirimlioglkuk eet al 2009)
We conclude that P-cadherin and CD24 are expressed in carcinomas of the biliary tract with high frequency and at an early stage of carcinogenesis. Therefore, they may be useful markers for early detection and as targets for therapy of cholangiocarcinoma. (Riener et al 2010)

The sensitivity of cells to CD40 activation was similar in magnitude in both primary and malignant cells and wasSTAT-3 and AP-1 dependent in both cholangiocytes cell lines. (Humphreys et al 2010)

Inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway by the PI3K inhibitor, LY294002, markedly suppressed HGF-stimulated invasion of both CCA (cholangiocarcinoma) cell lines, and inhibition of the ERK pathway by U0126 suppressed HGF-induced invasion of the KKU-M213 cell line but had a moderate effect on HuCCA-1 cells. (Menakongka & Suthiphongchai 2010)

Human intrahepatic cholangiocarcinomas express receptors for estrogens and IGF-1, which cooperate in the modulation of cell growth and apoptosis. By interacting at both receptor and postreceptor levels, 17β-estradiolmarkedly potentiates the proliferating effect of insulin-like growth factor 1 (IGF-1) on isolated rat cholangiocytes. Modulation of ER and IGF-1R could represent a strategy for the management of cholangiocarcinoma. (Alvaro et al 2006)

In cholangiocarcinoma cells, IL-6 overexpression resulted in the altered promoter methylation of a number of genes including the epidermal growth factor receptor (EGFR). EGFR promoter methylation was decreased and gene and protein expression were increased by IL-6, suggesting that the epigenetic regulation of gene expression by the inflated IL-6 expression seen in cholangiocarcinoma can contribute to tumor progression by altering the expression of growth regulatory pathways, such as those involving EGFR, caspase 8, and survivin in a manner that promotes survival and growth of the tumor cell. (Francis et al 2010) 

Immunohistochemical studies have shown that the overexpression of NGF-β (nerve growth factor beta) and VEGF-C occurred in ~57.1 and 46.4% of cholangiocarcinoma samples, respectively. A number of human cholangiocarcinoma cell lines and samples express VEGF-A and VEGF receptors (VEGFRs) and the angiogenic factors angiopoietin-1, -2, and thrombospondin-1. Also, estrogens modulate cholangiocarcinoma growth. (Francis et al 2010)
Other studies have shown that intrahepatic and extrahepatic cholangiocarcinoma samples overexpress EGFR and VEGF. The studies have also shown that 1) EGFR expression is associated with cholangiocarcinoma progression and 2) VEGF expression regulates metastasis in cholangiocarcinoma. (Francis et al 2010)

SOCS-3 epigenetic silencing is responsible for sustained IL-6/STAT-3 signaling and enhanced Mcl-1 expression in cholangiocarcinoma. (Isomoto et al 2007)
 
Blood Markers in Cholangiocarcinoma
From 1998 to 2008, we obtained preoperative CA19-9 and CEA serum levels in 136 patients with hilar cholangiocarcinoma. We correlated tumor stage, resectability rate and survival with preoperative CA 19-9 and CEA serum levels. CA19-9 and CEA serum levels are associated with the tumor stage. If preoperatively obtained CA19-9 and CEA serum levels are highly elevated patients have an even worse survival and the frequency of irresectability is significantly higher. (Juntermanns et al 2010)

CRP (C-reactive protein) level at the time of diagnosis is a novel indicator for the prognosis of patients withperihilar cholangiocarcinoma. (Gerhardt et al 2006)

Conventional Treatment Options in Cholangiocarcinoma
The biliary tract carcinomas rank fifth in incidence among all gastrointestinal tumours. This group of tumours includes both cholangiocarcinoma and gallbladder carcinoma. Although surgery represents the main therapeutic option for these patients, both radiotherapy and chemotherapy could be used in a multidisciplinary approach. Several studies are currently available on the use of chemotherapy, including 5-fluorouracil, mitomycin C, methotrexate, doxorubicin and cisplatin or newer anticancer molecules, such as gemcitabine, capecitabine, oxaliplatin and irinotecan. However, the small sample size of most of these studies prevents generalization. (Romiti et al 2012)

Gemcitabine is frequently used in the treatment of patients with solid tumors. Gemcitabine is taken up into the cell via human nucleoside transporters (hNTs) and is intracellularly phosphorylated by deoxycytidine kinase (dCK) to its monophosphate and subsequently into its main active triphosphate metabolite 2′,2′-difluorodeoxycytidine triphosphate (dFdCTP), which is incorporated into DNA and inhibits DNA synthesis. In addition, gemcitabine is extensively deaminated to 2′,2′-difluorodeoxyuridine, which is largely excreted into the urine. High expression levels of human equilibrative nucleoside transporter type 1 were associated with a significantly longer overall survival duration after gemcitabine treatment in patients with pancreatic cancer. (Veltkamp et al 2008)

Gemcitabine inhibits ribonucleotide reductase, thereby decreasing the deoxynucleotide pool available for DNA synthessis and causing DNA strand termination and apoptosis. (Zhang et al 2011)

Cholangiocarcinoma is an infrequent malignancy, often unresectable at the time of diagnosis. Liver transplantation may offer a chance for cure, but results in the past have been disappointing, prompting transplant centres to adopt multimodal treatment protocols and extreme patient selection. Acceptable survival rates can be achieved by transplantation for hilar cholangiocarcinoma with lymph node metastases as the only exclusion criterion. We recommend staging laparotomy with lymphadenectomy along the common hepatic artery prior to liver transplantation. (Schule eet al 2012)

Cholangiocarcinoma is relatively resistant to most currently approved chemotherapeutic agents, and as such these treatment options, although perhaps extending the prognosis for a few months, are largely ineffectual in curing this disease. Recently a number of experimental treatment options have come to the forefront. The most promising of these appears to be a multiple kinase inhibitor, sorafenib. This has been approved for use as a chemotherapeutic agent for renal cancer. Recently, sorafenib was shown to display significant tumor suppression in a rodent model of cholangiocarcinoma and is currently undergoing phase II trials. (Francis et al 2010)

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    One Response to Understanding Cholangiocarcinoma

    1. Thank you for this information. It is very reader friendly and extremely helpful to someone like myself who is trying to find out what I can do to help myself, being faced with advanced cholangiocarcinoma.

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