INTRODUCTION 

The prognosis for patients with primary or metastatic hepatocellular carcinoma is negatively correlated with jaundice, cirrhosis and metastases to other organs. Median survival was mostly found to be very short (four to six months). Operative procedures, which generally entail lobectomy or segmentectomy, are associated with considerably better survival rates [1]. However, most patients with hepatocellular carcinoma are not surgical candidates because of a multifocal tumor pattern or markedly depressed hepatic function, and hepatic resection in such cases results in no long-term benefit. Consequently, these patients are mostly treated with chemotherapy, which is sometimes able to induce reductions in the size of measurable tumors. However, chemotherapy rarely causes the tumor to disappear completely, and the duration of response is short. In the last decades special attention has been focused on the role of the disturbed immune balance in the poor prognosis of metastatic tumors [2-8]. In this *Address correspondence to this author at the Károly krt. 3/C, Budapest H1075, Hungary; Tel: +36-309 735 337; Fax: +36-1-2689999; E-mail: drhajtot@t-online.hu article, several case reports of various tumor patients with hepatic metastases are presented who were treated with standardized plant immunomodulatory preparations in combination with conventional oncologic therapy modalities..

 All patients received mistletoe extracts (ME) standardized in term of mistletoe lectins (ML) given in appropriate doses, which were shown to induce the most effective improvement in cancer-related disarray of the immune balance [9- 12]. Parallel with ME therapy, two other standardized plant extracts with immunomodulatory effects were also given: a heteropolysaccharide preparation from rice bran standardized for arabinoxylan (BioBran/MGN-3) and fermented wheat-germ extract standardized for its 2, 6-dimethoxy-p-benzoquinone (2, 6-DMBQ) content (WGE / FWGE ). Since these immunomodulatory treatments in combination with oncologic therapies resulted in more complete remission, their importance is discussed. MATERIAL AND METHODS Mistletoe Extract (ME) and its Standardization with Enzyme Linked Lectin Assay (ELLA) IscadorR is a fermented aqueous mistletoe plant extract manufactured and supplied by Weleda AG (CH-4144 Arlesheim, Switzerland). The active (sugarbinding) lectin content of commercially available mistletoe extracts was measured in the research laboratory of Pharmacochemical Department of Medical University Pécs. The determination of sugar binding mistletoe lectins (MLs) level in ME was carried out by an optimized ELLA technique as published previously [13].

 Briefly, the method is based on the binding of lectin to an immobilized oligosaccharide ligand (asialofetuin) and subsequent binding of specific (polyclonal) antibody to the bound lectin. The specific binding of rabbit antibodies was quantitatively assessed using goat antirabbit peroxidase and the subsequent generation of a colored product from the substrate phenylendiamine hydrochloride. Standard lectin was isolated from fresh plants using affinity chromatography and then it was lyophilized as described previously [13]. Dose of Standardized ME Preparations Cellular responses of the innate immune system in Balb/c mice and in healthy volunteers induced by ME were repeatedly investigated. Standardized ME exhibited a bell-shaped dose-response relationship and 0.5- 1.0 ng/kg lectin doses were found to be most effective as it was always assessed previously using healthy volunteers. Since two and three therapy-free days were found to be necessary for an immunologicall optimal effect, the subcutaneous ME injections were regularly given twice a week. Consequently, lectin oriented doses of ME applied in the treatment of patients corresponded to this regimen. Doses of Standardized Rice Bran Extract (BioBran/MGN-3) The second immunomodulator used in the combinative treatment of the presented patients is BioBran/MGN-3 which is manufactured and supplied by Daiwa Pharmaceutical Co, Ltd, Tokyo, Japan. BioBran/MGN-3 is composed of denaturated hemicellulose, which is obtained by rice bran hemicellulose reacting with multiple carbohydratehydrolyzing enzymes from shiitake mushrooms.

 BioBran/MGN-3 is standardized for its main chemical component: arabinoxylan with a xylose (in its main chain) and with an arabinose polymer (in its side chain). To the presented patients BioBran/MGN-3 was given per oral in doses between 12 and 45mg/kg twice a week parallel to the optimized, lectin-oriented ME therapy. Application of Fermented Wheat-Germ Extract (WGE / FWGE ) WGE (trade name FWGE ) is a complex of multiple, biologically active molecules obtained from fermented wheat-germ extract. Its biological effects are related to 2-methoxy-p-benzoquinone (2-MBQ) and 2, 6-dimethoxy-p-benzoquinone (2, 6-DMBQ) in the form of glucoside. During the fermentation the quinones are released by the glucosidase enzyme of the yeast fungus. The 1045 mg tablets are manufactured and supplied by Biopharma Kft, Kunfehértó, Hungary. WGE is standardized for its 2, 6-DMBQ content (0.4 mg/g concentration on dry matter basis). In presented cases WGE was given per oral in doses between 50 and 80 mg/kg/die four times a week (on the day of immunotherapy and 24h thereafter). Eligibility Criteria of Patients with Hepatic Metastases Inclusion criteria: 1. histological defined malignant tumor; 2. patients did not require nursing; 3. at begin of observation they did not receive morphine derivates. Exclusion criteria: 1. no histological data; 2. Karnofsky index is less than 60;

 3. undesired side effects (such as allergy). Ethics Committee Ethics committee proposed to observe and publish case reports of own patients treated by ME standardized in terms of lectin activity. All patients have given an informed consent to process and publish their dates. These case reports may stimulate an interest for other research groups according to the opinion of the ethics committee. RESULTS In Table 1 eight patients with hepatic metastases are listed according to the period of observation. Case 1 In a 72-year-old patient, tumor extirpation of a malignant melanoma (IA SSM Clark level II, pT1 N0 M0, Breslow 0.375 mm) from the right upper arm was carried out in 1992, and because of a second nodular melanoma (IIA, pT3 pN0 pM0) on the right shoulder a second surgery was performed in 1999. In August 2001three axillary lymph nodes (right) were removed. At the same time in segments 4/5 a solitary hepatic metastasis was detected. From October 2001 the patient was given lectin-standardized ME therapy. In June 2002 a complete remission of liver metastasis was established. Until 2012 no recurrence of the liver metastasis and normal liver functions were regularly observed. The patient quality of life has been excellent. Case 2 In a 59-year-old patient nine years after a breast cancer operation (left) an extensive local recurrence of a multifocal, invasive ductal carcinoma was removed by surgery in November 2011. At the same time multiple hepatic metastases in the right lobe of the liver with extents up to 35 mm were detected sonographically. In November 2011 lectin-oriented ME therapy was started together with MGN-3/Biobran and WGE.

 Parallel to this immunomodulatory treatment an anti-estragen therapy (20 mg Femara/die) was also given. In January 2012 PET/CT and sonography could not find any hepatic metastases. Liver functions were also normal. Further control investigations in June 2012 and in November 2012 have pointed to complete remission. Case 3 In the now 47-year-old patient the first diagnosis of breast cancer (cT4b cN3 M1) with multiple hepatic metastases (in segment 4a/b) took place in March 2009. From April 2009 until September 2009 the patient was given six cycles Epirubicin and Cyclophosphamide together with hormone therapy (Letrozol). At the same time she was regularly treated with lectin-standardized ME. After a partial remission of hepatic metastases an ablation of the breast was carried out in October 2009. Following the operation the patient was given an irradiation with 54 GY. Thereafter the patient received only a hormone therapy together with lectin-standardized ME, and in June 2010 a complete remission of the hepatic metastases was established in PET/CT. In June 2011 the hepatic metastases were renewed in PET/CT but only in a small degree. In April 2012 the patient was given a TARE-therapy (superselective radioactive ray treatment in segment 4a/b and segments 1 and 2). In May 2012 another nearly complete remission was again found accompanied by excellent quality of life.in her family. Case 4 In the now 66-year-old patient an ovary carcinoma (pT3c pN1 M0) was removed by surgery in August 2005. 

Following the operation the patient was given six cycles Taxotere and Carboplatin. In November 2007 multiple hepatic metastases were detected in PET/CT. From November 2007 until April 2010 lectinstandardized ME therapy together with chemotherapy (Caelix and Gemzar, later Xeloda and Uromitexan) was given. In the course of 30 months no progression of her disease was observed. Case 5 Because the now 49-year-old patient had ductal mammary carcinoma [T2 N1 (3/17) Mx], a tumorectomy in January 2010, and subsequently a hormone treatment (Femara) and chemotherapy (six cycles epirubicin and docetaxel) were carried out. In April 2011 multiple hepatic metastases were detected in PET/CT. In December 2011 seven liver metastases were removed by surgery. Six weeks later a considerable progression of hepatic metastases was established in PET/CT. Because of the bad liver functions only a mono-chemotherapy with reduced dose (2500 later 1500 mg Xeloda /day) was given. In the same time an immunomodulatory treatment with lectin-standardized ME, MGN-3/Biobran and WGE was started. In April 2012 a considerable remission of the hepatic metastases (only three small metastases) were detected in CT (Figure 1). The liver functions have been normalized. From January 2012 until July 2012 the tumor markers decreased: carcinoembryonic antigen (CEA) from 36.1 to 2.95 ng/ml and the tissue polypeptide antigen (TPA) from 232 to 56.3 U/l (Figure 2).

 A rapid improvement of liver functions was summarized in Figure 3. In August 2012 a nearly complete remission of the hepatic metastases could be established. (The metastases were not measurable in CT). So far the quality of life has been excellent; the patient has been able to work 100%. Case 6 In the now 63-year-old patient, a tumorectomy and a revision of regional lymph node metastases were carried out in November 2010 because of metastatic colon carcinoma [Dukes C, T3 N1 (3/5) M1]. In the same time multiple hepatic, retroperitoneal and mesenteric lymph node metastases were established in PET/CT. From December 2010 until July 2011 the patient was given 12 cycles FOLFIRI (Leukovorin+ 5- Fluoruracil) with Avastin and Irinotecan. In July 2011 a progression of hepatic and lymph node metastases was observed in PET/CT. From August 2011 an immunomodulatory treatment with lectin-standardized ME, MGN-3/Biobran and WGE was given. As further oncotherapy only Avastin was parallelly applied. In October 2011 no hepatic and no more lymph node metastases were established in CT. In November 2011 the immunomodulatory treatment was broken off and the patient died after a rapid progression in September 2012.

 Case 7 Because of a metastatic sigmoid carcinoma [pT4 pN1 (13/35) M1] a hemicolectomy was carried out in June 2004 in a now 54-year-old patient. Following the operation six cycles FOLFOX (Oxaliplatin + Leukovorin+ 5-Fluoruracil) were given, and in December 2004 a liver segment resection was carried out. From August 2004 lectin-standardized ME therapy was applied. Until her death in July 2008 no recurrence of hepatic metastases was observed in spite of a surgical operation because of an adnex metastasis in January 2007. The patient died following new lymph node and lung metastases. Case 8 In the now 56-year-old patient a colon carcinoma [pT4 N1 (4/13) M1] was removed by surgery in July 2009. Two months later (in September 2009) a resection of hepatic metastases was carried out. Following the surgical operation seven cycles FOLFIRI (Leukovorin+ 5-Fluoruracil) and Avastin parallel with lectin-standardized ME therapy were given. In May 2011 no hepatic metastases were detected in PET/CT. Because of enlarged mediastinal, abdominal and retroperitoneal lymph node metastases from May 2011 until January 2012 eleven cycles FOLFOX (Oxaliplatin + Leukovorin+ 5-Fluoruracil) were given. From May 2011 the lectin-standardized ME therapy was combined with MGN-3/Biobran and WGE. CT investigations in October 2011, in January 2012 and in March 2012 could not detect hepatic metastases and the lymph node metastases showed a nearly complete remission with a good quality of life. Because of financial problems in April 2012 the patient stopped the immunomodulatory treatment.