Microsoft word - hajto_jcru.docJournal of Cancer Research Updates, 2013, 2, 000-000 1
Case Reports of Cancer Patients with Hepatic Metastases Treated
by Standardized Plant Immunomodulatory Preparations
Tibor Hajto1,* and Angelika Kirsch2 1Department of Immunology and Biotechnology, University Pecs, Faculty of Medicine, Pecs, Hungary 2Private Praxis, Paradiesstr. 14, Binningen CH-4102, Switzerland Abstract: Background: Metastatic hepatocellular carcinoma often has a multifocal tumor pattern with markedly
depressed hepatic function. Hepatic resection in many cases results in no long-term benefit. After a chemotherapy
hepatic tumors rarely disappear completely and the duration of responses is short. In the last decades growing evidence
suggested that a disturbed balance in the innate system can also play a role in the poor prognosis of hepatic tumors.
Objectives: The aim of this article is to present and discuss several favorable clinical responses of patients with hepatic metastases who parallel to conventional oncologic therapy, were treated with immunologically effective and standardized plant extracts. Course of Therapy and Results: In accordance with the bell-shaped dose-response relationship of mistletoe lectins (MLs), the patients were treated with a fermented mistletoe extract (ME) preparation, standardized for the active sugar-binding lectin contents. Thus, an optimal dose between 0.5 and 1.0ng/kg MLs was given twice a week subcutaneously. In addition to ML therapy, a heteropolysaccharide rice bran preparation standardized for arabinoxylan (12-45mg/kg MGN-3/Biobran twice a week) and wheat germ extract (WGE) standardized for 2, 6-dimethoxy-p-benzoquinone (50- 80mg/kg Avemar four times a week) was also given. In these case reports the clinical progress of seven patients showed a complete or nearly complete remission of hepatic metastases. Conclusion: ML, MGN-3 and WGE seem to be potent candidates to be regarded as a supportive therapy to surgery, hormone treatment or chemotherapy for patients with hepatic metastases. These case reports require further clinical studies. Keywords: Hepatic metastasis, immunomodulation, mistletoe extract, mistletoe lectin, arabinoxylan, MGN-3, wheat
germ extract, benzoquinone.
article, several case reports of various tumor patients with hepatic metastases are presented who were The prognosis for patients with primary or treated with standardized plant immunomodulatory metastatic hepatocellular carcinoma is negatively preparations in combination with conventional correlated with jaundice, cirrhosis and metastases to oncologic therapy modalities. All patients received other organs. Median survival was mostly found to be mistletoe extracts (ME) standardized in term of very short (four to six months). Operative procedures, mistletoe lectins (ML) given in appropriate doses, which which generally entail lobectomy or segmentectomy, were shown to induce the most effective improvement are associated with considerably better survival rates in cancer-related disarray of the immune balance [9- . However, most patients with hepatocellular 12]. Parallel with ME therapy, two other standardized carcinoma are not surgical candidates because of a plant extracts with immunomodulatory effects were also multifocal tumor pattern or markedly depressed hepatic given: a heteropolysaccharide preparation from rice function, and hepatic resection in such cases results in bran standardized for arabinoxylan (BioBran/MGN-3) no long-term benefit. Consequently, these patients are and fermented wheat-germ extract standardized for its mostly treated with chemotherapy, which is sometimes 2, 6-dimethoxy-p-benzoquinone (2, 6-DMBQ) content able to induce reductions in the size of measurable (WGE / AvemarR). Since these immunomodulatory tumors. However, chemotherapy rarely causes the treatments in combination with oncologic therapies tumor to disappear completely, and the duration of resulted in more complete remission, their importance response is short. In the last decades special attention has been MATERIAL AND METHODS
focused on the role of the disturbed immune balance in the poor prognosis of metastatic tumors [2-8]. In this Mistletoe Extract (ME) and its Standardization with
Enzyme Linked Lectin Assay (ELLA)
*Address corresponding to this author at the Károly krt. 3/C, Budapest H-1075, IscadorR is a fermented aqueous mistletoe plant Hungary; Tel: +36-309 735 337; Fax: +36-1-2689999; E-mail: [email protected] extract manufactured and supplied by Weleda AG (CH- 1929-2260
2013 Lifescience Global
2 Journal of Cancer Research Updates, 2013 Vol. 2, No. 1
Hajto and Kirsch
4144 Arlesheim, Switzerland). The active (sugar- Application of Fermented Wheat-Germ Extract
binding) lectin content of commercially available (WGE / AvemarR)
mistletoe extracts was measured in the research laboratory of Pharmacochemical Department of WGE (trade name AvemarR) is a complex of Medical University Pécs. multiple, biologically active molecules obtained from fermented wheat-germ extract. Its biological effects are The determination of sugar binding mistletoe lectins related to 2-methoxy-p-benzoquinone (2-MBQ) and 2, (MLs) level in ME was carried out by an optimized 6-dimethoxy-p-benzoquinone (2, 6-DMBQ) in the form ELLA technique as published previously . Briefly, of glucoside. During the fermentation the quinones are the method is based on the binding of lectin to an released by the glucosidase enzyme of the yeast immobilized oligosaccharide ligand (asialofetuin) and fungus. The 1045 mg tablets are manufactured and subsequent binding of specific (polyclonal) antibody to supplied by Biopharma Kft, Kunfehértó, Hungary. WGE the bound lectin. The specific binding of rabbit is standardized for its 2, 6-DMBQ content (0.4 mg/g antibodies was quantitatively assessed using goat anti- concentration on dry matter basis). In presented cases rabbit peroxidase and the subsequent generation of a WGE was given per oral in doses between 50 and 80 colored product from the substrate phenylendiamine mg/kg/die four times a week (on the day of hydrochloride. Standard lectin was isolated from fresh immunotherapy and 24h thereafter). plants using affinity chromatography and then it was Eligibility Criteria of Patients with Hepatic
lyophilized as described previously . Metastases
Dose of Standardized ME Preparations
Inclusion criteria: 1. histological defined malignant Cellular responses of the innate immune system in tumor; 2. patients did not require nursing; 3. at begin of Balb/c mice and in healthy volunteers induced by ME observation they did not receive morphine derivates. were repeatedly investigated. Standardized ME Exclusion criteria: 1. no histological data; 2. Karnofsky exhibited a bell-shaped dose-response relationship and index is less than 60; 3. undesired side effects (such as 0.5- 1.0 ng/kg lectin doses were found to be most effective as it was always assessed previously using Ethics Committee
healthy volunteers. Since two and three therapy-free days were found to be necessary for an immunologicall Ethics committee proposed to observe and publish optimal effect, the subcutaneous ME injections were case reports of own patients treated by ME regularly given twice a week. Consequently, lectin standardized in terms of lectin activity. All patients have oriented doses of ME applied in the treatment of given an informed consent to process and publish their patients corresponded to this regimen. dates. These case reports may stimulate an interest for Doses of Standardized Rice Bran Extract other research groups according to the opinion of the
ethics committee. The second immunomodulator used in the combinative treatment of the presented patients is In Table 1 eight patients with hepatic metastases
BioBran/MGN-3 which is manufactured and supplied by are listed according to the period of observation. Daiwa Pharmaceutical Co, Ltd, Tokyo, Japan.
BioBran/MGN-3 is composed of denaturated Case 1
hemicellulose, which is obtained by rice bran
hemicellulose reacting with multiple carbohydrate-
In a 72-year-old patient, tumor extirpation of a hydrolyzing enzymes from shiitake mushrooms. malignant melanoma (IA SSM Clark level II, pT1 N0 BioBran/MGN-3 is standardized for its main chemical M0, Breslow 0.375 mm) from the right upper arm was component: arabinoxylan with a xylose (in its main carried out in 1992, and because of a second nodular chain) and with an arabinose polymer (in its side melanoma (IIA, pT3 pN0 pM0) on the right shoulder a chain). To the presented patients BioBran/MGN-3 was second surgery was performed in 1999. In August given per oral in doses between 12 and 45mg/kg twice 2001three axillary lymph nodes (right) were removed. a week parallel to the optimized, lectin-oriented ME At the same time in segments 4/5 a solitary hepatic metastasis was detected. From October 2001 the Case Reports of Cancer Patients with Hepatic Metastases Treated
Journal of Cancer Research Updates, 2013 Vol. 2, No. 1 3
Table 1: Brief Summary of Eight Case Reports of Various Patients with Hepatic Metastases
Multiple Retrop. L+B+W Avastin Abbreviations: L = 0.5-1.0ng/kg mistletoe lectin given in standardized mistletoe extract twice a week; B = 12-45 mg/kg MGN-3/Biobran standardized for
arabinoxylan (twice a week); W = 50-80 mg/kg wheat germ extract standardized for 2, 6-dimethoxy-p-benzoquinone (four times a week); LN = lymph nodes;
FOLFOX = Oxaliplatin + Leukovorin+ 5-Fluoruracil; FOLFIRI = Leukovorin+ 5-Fluoruracil. CR=complete remission; PR= partial remission; NC= no change.
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 In the now 47-year-old patient the first diagnosis of metastasis and normal liver functions were regularly breast cancer (cT4b cN3 M1) with multiple hepatic observed. The patient quality of life has been excellent. 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 In a 59-year-old patient nine years after a breast (Letrozol). At the same time she was regularly treated cancer operation (left) an extensive local recurrence of with lectin-standardized ME. After a partial remission of a multifocal, invasive ductal carcinoma was removed hepatic metastases an ablation of the breast was by surgery in November 2011. At the same time carried out in October 2009. Following the operation multiple hepatic metastases in the right lobe of the liver the patient was given an irradiation with 54 GY. with extents up to 35 mm were detected Thereafter the patient received only a hormone therapy sonographically. In November 2011 lectin-oriented ME together with lectin-standardized ME, and in June 2010 therapy was started together with MGN-3/Biobran and a complete remission of the hepatic metastases was WGE. Parallel to this immunomodulatory treatment an established in PET/CT. In June 2011 the hepatic anti-estragen therapy (20 mg Femara/die) was also metastases were renewed in PET/CT but only in a given. In January 2012 PET/CT and sonography could small degree. In April 2012 the patient was given a not find any hepatic metastases. Liver functions were TARE-therapy (superselective radioactive ray also normal. Further control investigations in June 2012 treatment in segment 4a/b and segments 1 and 2). In and in November 2012 have pointed to complete May 2012 another nearly complete remission was again found accompanied by excellent quality of life.
4 Journal of Cancer Research Updates, 2013 Vol. 2, No. 1
Hajto and Kirsch
The patient has been able to work 100% in her job and 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 In the now 66-year-old patient an ovary carcinoma the same time an immunomodulatory treatment with (pT3c pN1 M0) was removed by surgery in August lectin-standardized ME, MGN-3/Biobran and WGE was 2005. Following the operation the patient was given six started. In April 2012 a considerable remission of the cycles Taxotere and Carboplatin. In November 2007 hepatic metastases (only three small metastases) were multiple hepatic metastases were detected in PET/CT. detected in CT (Figure 1). The liver functions have
From November 2007 until April 2010 lectin- been normalized. From January 2012 until July 2012 standardized ME therapy together with chemotherapy the tumor markers decreased: carcinoembryonic (Caelix and Gemzar, later Xeloda and Uromitexan) was antigen (CEA) from 36.1 to 2.95 ng/ml and the tissue given. In the course of 30 months no progression of her polypeptide antigen (TPA) from 232 to 56.3 U/l (Figure disease was observed. 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
Because the now 49-year-old patient had ductal established. (The metastases were not measurable in mammary carcinoma [T2 N1 (3/17) Mx], a tumorectomy CT). So far the quality of life has been excellent; the in January 2010, and subsequently a hormone patient has been able to work 100%. treatment (Femara) and chemotherapy (six cycles epirubicin and docetaxel) were carried out. In April 2011 multiple hepatic metastases were detected in In the now 63-year-old patient, a tumorectomy and PET/CT. In December 2011 seven liver metastases a revision of regional lymph node metastases were Figure 1: Computed tomography (CT) scans of hepatic metastases in a patient (case 5) who had a partial remission after three
months and a complete remission after 8 months. She was treated with low doses of Xeloda (1500 - 2500 mg/die) combined
with ME/ML, MGN-3/Biobran and WGE.
Case Reports of Cancer Patients with Hepatic Metastases Treated
Journal of Cancer Research Updates, 2013 Vol. 2, No. 1 5
Figure 2: A. Carcinoembryonic antigen (CEA) values of patients (case 5) with hepatic metastases prior to therapy and during a
treatment with low doses of Xeloda (1500 - 2500 mg/die) combined with ME/ML, MGN-3/Biobran and WGE. (Reference values:
B. Tissue polypeptide antigen (TPA)values of patients (case 5) with hepatic metastases prior to therapy and during a treatment
with low doses of Xeloda (1500 - 2500 mg/die) combined with ME/ML, MGN-3/Biobran and WGE. (Reference values: 0-75).
carried out in November 2010 because of metastatic the immunomodulatory treatment was broken off and colon carcinoma [Dukes C, T3 N1 (3/5) M1]. In the the patient died after a rapid progression in September 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- Because of a metastatic sigmoid carcinoma [pT4 Fluoruracil) with Avastin and Irinotecan. In July 2011 a pN1 (13/35) M1] a hemicolectomy was carried out in progression of hepatic and lymph node metastases June 2004 in a now 54-year-old patient. Following the was observed in PET/CT. From August 2011 an operation six cycles FOLFOX (Oxaliplatin + immunomodulatory treatment with lectin-standardized Leukovorin+ 5-Fluoruracil) were given, and in ME, MGN-3/Biobran and WGE was given. As further December 2004 a liver segment resection was carried oncotherapy only Avastin was parallelly applied. In out. From August 2004 lectin-standardized ME therapy October 2011 no hepatic and no more lymph node was applied. Until her death in July 2008 no recurrence metastases were established in CT. In November 2011 6 Journal of Cancer Research Updates, 2013 Vol. 2, No. 1
Hajto and Kirsch
Figure 3: A. Gamma-glutamyltranspeptidase (gamma-GT) values of patients (case 5) with hepatic metastases prior to therapy
and during a treatment with low doses of Xeloda (1500 - 2500 mg/die) combined with ME/ML, MGN-3/Biobran and WGE.
(Reference values: 7-35 U/l.)
B. Alkaline phosphatase values of patients (case 5) with hepatic metastases prior to therapy and during a treatment with low
doses of Xeloda (1500 - 2500 mg/die) combined with ME/ML, MGN-3/Biobran and WGE. (Reference values: 98-280 U/l.)
of hepatic metastases was observed in spite of a retroperitoneal lymph node metastases from May 2011 surgical operation because of an adnex metastasis in until January 2012 eleven cycles FOLFOX (Oxaliplatin January 2007. The patient died following new lymph + Leukovorin+ 5-Fluoruracil) were given. From May node and lung metastases. 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 In the now 56-year-old patient a colon carcinoma the lymph node metastases showed a nearly complete [pT4 N1 (4/13) M1] was removed by surgery in July remission with a good quality of life. Because of 2009. Two months later (in September 2009) a financial problems in April 2012 the patient stopped the resection of hepatic metastases was carried out. immunomodulatory treatment. Following the surgical operation seven cycles FOLFIRI (Leukovorin+ 5-Fluoruracil) and Avastin parallel with DISCUSSION
lectin-standardized ME therapy were given. In May 2011 no hepatic metastases were detected in PET/CT. These case reports suggest that standardized plant Because of enlarged mediastinal, abdominal and immunomodulators (ML-oriented ME, arabinoxylan- Case Reports of Cancer Patients with Hepatic Metastases Treated
Journal of Cancer Research Updates, 2013 Vol. 2, No. 1 7
standardized MGN-3/Biobran and 2, 6-dimethoxy-p- report 7 prior to the surgical resection lectin- benzoquinone-standardized WGE) can be helpful in the standardized ME therapy had been given for 5 months. oncologic treatment of hepatic metastases. The Further clinical observations did not reveal a combination of these plant immunomodulators with recurrence of hepatic metastases and the patient died conventional oncologic treatments can render possible on account of other metastases five years later. complete remissions which are rarely attainable by Therefore the question is arises, whether various oncologic therapies only. As mentioned, the patients metastases can react to this immunomodulatory with hepatic metastases after chemotherapy can rarely treatment in different degrees? In spite of the fact that reach a greater reduction than 50%, and the responses various tumor cells can exhibit different sensitivity to immune responses, a great tumor burden is always less susceptible for therapeutic influence. In case The first case report (Table 1) represents a
report 8 the patient received pre-operative complete remission of a liver metastasis after a lectin- chemotherapy with lectin-standardized ME preparation standardized ME therapy given only. Until now the for six months. After a postoperative chemotherapy patient has had no recurrence of the tumor with best ME, MGN-3 and WGE were regularly given and 31 quality of life after an observation for 12 years. On the months after the liver operation no recurrence of base of this good clinical progress further patients with hepatic metastases was observed. The last two case hepatic metastases were specially worked up. The liver reports support the hypothesis that preoperative and metastases of case 2 and 3 showed a remission after a postoperative treatments with these standardized combined therapy of hormones (anti-estrogens) and immunomodulators may improve the prognosis of immunomodulators. As is well known, anti-estrogens patients following a liver metastasis operation. In all are able to inhibit the proliferation of mammary cancer presented cases the quality of life was beneficially cells and therefore it can be speculated that the effect of anti-tumor immune cells on tumor progression is enhanced by this hormone therapy. Similarly to anti- Growing evidence support that the effector cells of estrogens, cytostatic drugs with antiproliferative effects the innate immune system are committed in two seem to be helpful for anti-tumor immunological directions: M1 macrophages and CD1a+ dentritic cells mechanisms. Case report 4 can support this (DC1) generate IL-12, pro-inflammatory cytokines and hypothesis since the progression of liver metastases activate cytotoxic effector cells (such as natural killer under high doses of chemotherapy only was stopped /NK/ and natural killer T /NKT/ cells) which are potent following its combination with lectin-standardized ME inhibitors of tumor growth. However, they are defective therapy, but no remission was attained. Case report 5 in tumor patients. Available information suggests that shows an important and rapid remission of hepatic tumor-associated macrophages belong to a prototypic metastases (Figure 1) treated with low doses of mono-
M2 population . M2 generates IL-4 and IL-10 which chemotherapy (Xeloda) and with standardized plant facilitate the generation of Th2 cells and inhibit Th1 immunomodulators (lectin-standardized ME, MGN- cells . M2 macrophages affect inflammation, promote 3/Biobran and WGE). These observations suggest the cell proliferation by producing growth factors and hypothesis that under certain circumstances these products of the arginase pathway, as well as promoting immunomodulatory treatments combined with low angiogenesis and tissue repair . doses of chemotherapy may be more effective than their combination with high doses of cytostatic drugs. Tumor patients can have up to 40% more M2 Case report 6 shows that a combination of Avastin peripheral monocytes than healthy individuals who (VEGFR inhibitor) with these standardized plant have only 10% M2 monocytes . Natural killer T immunomodulators can also induce a complete (NKT) cells can also have a similar opposing effect. In remission. In case report 6 it can be presumed that cancer, NKT-1 cells are protective by producing IFN- after a clinical success stopping these gamma to activate M1 and DC1 dendritic cells which immunomodulatory treatments is not advisable since produce IL-12, NKT-2 cells primarily inhibiting tumor after a complete remission the patient did not continue immunity  and these findings indicate an impaired the immune therapy and she died following a rapid balance of the innate immune system in cancer progression after one year. Case reports 7 and 8 represent patients whose Consequently, learning to manipulate this balance hepatic metastases were removed by surgery. In case along the regulatory axis may be critical to devising 8 Journal of Cancer Research Updates, 2013 Vol. 2, No. 1
Hajto and Kirsch
successful immune therapies against cancer in terms of safety and toxicity of ME, available studies advanced stages of the disease . For ML a highly indicate that mistletoe therapy is well tolerated, and specific receptor, the CD75 ganglioside was described serious adverse events were not reported. Only a local [14-15], which was found in the PRR on several reaction (erythema at the injection site after 8-10h) was effector cells of the innate immune system . The observed in a percentage between 0.9 and 43 . existence of this PRR receptor may explain the MGN-3 has also been judged to be a highly safe food selective binding capacity of neutrophils and as it was verified by conducting acute oral toxicity, monocytes to ML since this lectin can act as a mutagenicity, subacute toxicity, and antigenicity studies Pathogen Associated Molecular Patterns (PAMP) . WGE has been put on the market as a non-toxic similar to certain lectin-like receptors of dietary supplement. Toxicological studies with high microorganisms [13; 16]. This selective binding can does of WGE (3 g/kg) did not show any deviation from explain why ML was found to enhance the IL-12/NK- the controls . mediated cellular immune responses improving the tumor-related disturbance in the balance of innate CONCLUSIONS
immune system . Using standardized plant extracts, ML and Similar to ME modulation, modified arabinoxylan arabinoxylan (which in previous studies have been from rice bran was also found to stimulate the type-1 shown to bind pattern recognition receptors on cellular cells in the innate immune system, such as human NK components of the innate immune system improving cell activity in vivo and in vitro  and phagocytic the tumor-induced derangement of the natural immune function by macrophages . Its simulteneous balance) in combination with WGE may be helpful in administration with lectin oriented ME therapy renders the oncologic treatment of eight patients with hepatic possible an additive effect. Standardized wheat germ extracts contain 2, 6- The aim of these case reports is to attract attention, DMBQ in 0.4 mg/g concentration on dry matter basis and it is also clear that further clinical investigations are . The original perception originated more than 50 years ago by Albert Szent-Györgyi (discovery of DISCLOSURE STATEMENT
vitamin C goes back also to him) . In vitro and in vivo experiments with WGE revealed to a significant The authors declare that there is no competing or antimetastatic effect [20-22]. The combination of WGE other conflicting interest in relation to this paper. The with NK stimulatory substances, such as ML and sponsor had no influence on the design or conduct of arabinoxylan is promising since WGE induces a the study, interpretation of data or approval of the downregulation of major histocompatibility complex (MHC) class I proteins . It is well known that decreased MHC I expression reduce the effect of killing REFERENCES
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Annexe l 06-10-18.pdf
ANNEXE L AU CODE SPORTIF INTERNATIONAL / APPENDIX L TO THE INTERNATIONAL SPORTING CODE CHAPITRE I - LICENCES INTERNATIONALES FIA POUR PILOTES CHAPTER I - FIA INTERNATIONAL DRIVERS' LICENCES Degrés de licences pour courses sur circuits Grades of licences for circuit racing Qualiﬁ cation et conditions de délivrance pour les