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Immune Responses to Water-Soluble Ling Zhi Mushroom Ganoderma lucidum (W.Curt.:Fr.) P. Karst. Polysaccharides in Patients with Advanced Colorectal Cancer
Abstract
Preclinical studies have established that the polysaccharide fractions of Ganoderma lucidum have potent immunomodulating effects. A recent clinical study of healthy volunteers demonstrated that G. lucidum did not affect their immune functions. The present open-labeled study aimed to evaluate the effects of water-soluble G. lucidum polysaccharides (Ganopoly) in patients with advanced colorectal cancer. Forty-seven patients were enrolled and treated with Ganopoly at 5.4 g/day for 12 weeks. In 41 assessable cancer patients, treatment with Ganopoly tended to increase mitogenic reactivity to phytohemagglutinin; counts of CD3, CD4, CD8, and CD56; plasma concentrations of interleukin (IL)-2, IL-6, and interferon (IFN)-γ; and NK activity, but to decrease the plasma concentrations of IL-1 and tumor necrosis factor (TNF)-α. No statistical significance was observed when a comparison was conducted between baseline values and those after 12-week treatment with Ganopoly. The changes of IL-1 were correlated with those of IL-6, IFN-γ, CD3, CD4, CD8, and NK activity (p < 0.05), and IL-2 changes were correlated with those for IL-6, CD8, and NK activity. The results indicate that Ganopoly may have beneficial immunomodulating effects in patients with advanced colorectal cancer. Further studies are needed to explore the mode of action, efficacy, and safety of Ganopoly in cancer patients.
... A subsequent open-labeled study aimed to assess the effects of Ganopoly in advanced colorectal cancer patients. The findings suggest that Ganopoly may offer beneficial immunomodulatory effects for patients with advanced colorectal cancer (Huang, et al., 2005). A phase I/II clinical trial conducted at the Memorial Sloan-Kettering Cancer Center found that orally administered G. frondosa polysaccharides (GFPs) were able to boost the immune system of breast cancer patients (G. ...
... Another study was conducted on 47 patients with advanced colorectal cancer in which 5.4 g/day doses of Ganopoly was administered to patients for 12 weeks. Ganopoly was found to stimulate the immune response in the cancer patients [68]. ...
Mushrooms, the fruiting bodies of fungi, are known for a long time in different cultures around the world to possess medicinal properties and are used to treat various human diseases. Mushrooms that are parts of traditional medicine in Asia had been extensively studied and this has led to identification of their bioactive ingredients. North America, while home to one of the world’s largest and diverse ecological systems, has not subjected its natural resources especially its diverse array of mushroom species for bioprospecting purposes: Are mushrooms native to North America a good source for drug discovery? In this review, we compile all the published studies up to September 2020 on the bioprospecting of North American mushrooms. Out of the 79 species that have been investigated for medicinal properties, 48 species (60%) have bioactivities that have not been previously reported. For a mere 16 selected species, 17 new bioactive compounds (10 small molecules, six polysaccharides and one protein) have already been isolated. The results from our literature suggest that mushrooms native to North America are indeed a good source for drug discovery.
... Many studies have shown that mushroom polysaccharides and their derivatives enhance the ability of NK cells to recognize tumor cells as foreign and thereby enhance the effectiveness of host defense mechanisms. 15,16,[23][24][25][26][27][28][29] However, the influence of mushrooms' nucleic acids on immune system components during cancer prevention and treatment remain unknown. Slightly more is known about their direct impact on cancer cells. ...
Numerous studies indicate the crucial role of natural killer (NK) cells in the prevention of tumor growth and inhibition of their metastasis, which suggests the possibility of their use in cancer treatment. This therapeutic strategy required finding a selective NK cell stimulator that, upon administration, did not disturb organism homeostasis, unlike natural activators (interleukin-2 or interleukin-12). Because the majority of anticancer agents derived from Basidiomycetes are able to stimulate lymphocytes, we describe the influence of Boletus edulis RNA on a human NK cell line (NK92). Our studies showed that a B. edulis RNA fraction was not toxic against NK92 cells. Furthermore, the tested fraction significantly stimulated NK92 cell proliferation and their cytotoxicity against tumor cells. We demonstrate here, to our knowledge for the first time, that B. edulis RNA enhances NK cell activity and possesses immunomodulatory potential.
... not double-blind or placebo con- trolled) evaluating water-soluble G. lucidum polysaccharides (Ganopoly â ) in patients with advanced colorectal cancer re- ported that treatment with Ganopoly â tended to increase mitogenic reactivity to phytohemagglutinin. Larger double- blind trials are required to validate this effect and further studies are needed to determine the mechanism of action, efficacy, and safety of the water-soluble G. lucidum polysac- charides in cancer patients ( Gao et al., 2005). A randomized, placebo-controlled, double-blind clinical trial in which pa- tients with colorectal cancer were supplemented with Agari- cus sylvaticus mushroom, orally, twice daily (30 mg/kg/day), for 6 months also suggested benefits in hematological and immunological parameters and reduced glycemic levels in patients with colorectal cancer (Fortes, Novaes, Recova, & Melo, 2009). ...
... Recent clinical studies suggested that subgroups of advanced-stage caner patients treated with Gl-PS 5.4 g/day orally for 12 weeks might be responsive, which resulted in immune-modulation, such as significant increase in NK activity, phytohemagglutinin response, counts of CD3 + , CD4 + , CD8 + , CD56 + cells, and plasma concentration of interleukin 2, 6 and interferon-␥, whereas plasma concentrations of interleukin 1 and tumor necrosis factor-␣ decreased. The results of the clinical studies were significantly variable (Gao et al., 2003;Huang et al., 2005), but our experiment results from mice were less fluctuant comparatively. So the number of patients enrolled need to be increased to evaluate clinical response and toxicity. ...
The present study was designed to determine in vivo efficacy of Ganoderma lucidum polysaccharides (Gl-PS) for enhancing the activity of immunological effector cells in immunosuppressed mice. Mice were injected intraperitoneally (i.p.) once daily with low-dose (2.5mg/kg), intermediate-dose (25mg/kg), and high-dose (250 mg/kg) of Gl-PS, respectively, for 7 consecutive days 24h after i.p. injection of a immunosuppressing anti-tumor agent cyclophosphamide (Cy, 300 mg/kg). In Cy-treated mice, compared to vehicle, low-dose Gl-PS accelerated recovery of bone marrow cells, red blood cells and white blood cells, as well as splenic natural killer cells and natural killer T cells, and enhanced T and B cell proliferation responses on day 8, cytotoxic T lymphocyte activity on day 5, as well as NK cell and lymphokine activated killer cell activity on days 7-9. Furthermore, it promoted phagocytosis and cytotoxicity of macrophages on day 12. The above beneficial effects induced by the low-dose Gl-PS treatment did not result in any side effects. These results demonstrate the efficacious effects of low-dose Gl-PS treatment for enhancing the activity of immunological effector cells in immunosuppressed mice, and may provide a basis for applying this herb as an efficacious adjacent immunopotentiating therapy against cancer chemotherapy-induced immunosuppression.
For millennia, edible mushrooms have been used as a common diet for mankind based on their nutritional importance and medicinal benefits. Edible mushrooms are a rich source of carbohydrates (sucrose, xylose, rhamnose, mannose, and fructose), amino acids (glutamic acid, aspartic acid, glutamate, methionine, and cysteine), proteins, fatty acids (linoleic acid, stearic acid, palmitic acid, adrenic acid, and nervonic acid), vitamins (folate, riboflavin, ascorbic acid niacin, thiamine, ergocalciferol, and cyanocobalamine) mineral contents (Ca, Mg, K, P, Na, Fe, Cu, Zn, Cd, and Mo) and phenolic compounds (gallic acid, caffeic acid, protocatechuic acid, p-coumaric acid, p-hydroxybenzoic acid and pyrogallol) that control and ameliorate multiple functions of the human body and participate for maintaining the good health by reducing the occurrence of several chronic diseases. Bioactive polysaccharides, peptides, polyphenols, and dietary fibers extracted from mushroom mycelia have health-promoting properties including a number of medicinal benefits such as anticancerous properties, antihypertensive activity, protection against DNA damage, cardiovascular effects, neurodegenerative disorders, and improvement in innate immunity. In developing countries, the utilization of mushrooms for therapeutic applications is being implemented as a boon for promoting human health and natural dietary supplements. Recently, different pharmaceutical companies and food industries have taken initial steps for patenting the medicinal value of edible mushrooms based on their antioxidant, anticancer, hypolipidemic, hypotensive, and immunomodulatory effects. The immense role of nutritional components and bioactive molecules of edible mushrooms in correlation with health problems has become a burning task in modern nutraceutical therapy. Hence, the present article deals with up-to-date knowledge of edible mushrooms as a nutritional adjuvant with emphasis on profound biological properties and potential mechanisms of action to prevent different health diseases.
Reishi owes an exceptional value in nutritional, cosmeceutical, and medical treatments; however, none of the studies has provided its future‐driven critical assessment. This study documents an up‐to‐date review (2015–2020, wherever applicable) and provide valuable insights (preclinical and clinical evidence‐based) with comprehensive and critical assessments. Various databases ‘Google scholar’, ‘Web of Science’, ‘ScienceDirect’, ‘PubMed’, ‘Springer Link’, books, theses, and library resources were used. The taxonomic chaos of G. lucidum and its related species was discussed in detail with solution‐oriented emphasis. Reishi contains polysaccharides (α/β‐D‐glucans), alkaloids, triterpenoids (ganoderic acids, ganoderenic acids, ganoderol, ganoderiol, lucidenic acids), sterols/ergosterol, proteins (LZ‐8, LZ‐9), nucleosides (adenosine, inosine, uridine), and nucleotides (guanine, adenine). Some active drugs are explored at an optimum level to make them potential drug candidates. The pharmacological potential was observed in diabetes, inflammation, epilepsy, neurodegeneration, cancer, anxiety, sedation, cardiac diseases, depression, hepatic diseases, and immune disorders; however, most of the studies are preclinical with a number of drawbacks. In particular, quality clinical data are intensely needed to support pharmacological activities for human use. The presence of numerous micro‐, macro, and trace elements imparts an essential nutritional and cosmeceutical value to Reishi, and various marketed products are available already, but the clinical studies regarding safety and efficacy, interactions with foods/drinks, chronic use, teratogenicity, mutagenicity, and genotoxicity are missing for Reishi. Reishi possesses many valuable pharmacological activities, and the number of patents and clinical trials is increasing for Reishi. Yet, a gap in research exists for Reishi, which is discussed in detail in the forthcoming sections.
Ethnopharmacological relevance
Immunomodulation has become a crucial modality for cancer treatment. Chinese Herbal Medicines (CHMs) are expected as adjuvant therapy for immunomodulation against cancer, but face the key challenge of poor scientific evidence. Changes of natural killer (NK) cells on numbers and/or cytotoxicity are a novel respect to evaluate the immunomodulation of CHMs.
Aim of the study
The purpose of this review is to investigate the immunomodulation of Chinese Herbal Medicines (CHMs) on NK cell populations for cancer therapy.
Materials and methods
A systematic review was conducted and outside mainstream electronic databases were screened for potential reference articles. This review tried to report and critically analyzed all the correlative studies, especially these clinical trials (3 CHM extracts and 11 CHM formulas).
Results
Evidence-based functions of CHMs against cancer could be summarized as: (1) enhancement of NK cells activity or relative percentage; (2) prevention of tumor growth and metastasis; (3) relief on side-effects or complications of therapeutic strategies (i.e. chemotherapy, radiotherapy and resection). Briefly, most of cellular studies and two thirds animal studies were based on the extract or components of single herbs, whilst most of clinical trials were keen on formula or prescription of CHMs. The main components of CHMs were demonstrated active on promoting the cytotoxicity of NK cells, including Angelica sinensis, Ganoderma lucidum, Panax ginseng, Radix Astragali, Lentinus edodes, etc.
Conclusions
This comprehensive review demonstrated NK cells activity was positively associated with quality of life but not survival benefit of cancer patients. Thus exploring the roles of NK cells in adjuvant therapy against cancer is confirmed to be beneficial to explore the underlying relationship between immunomodulation and quality of life.
Several studies have shown that mushroom polysaccharides enhance the ability of natural killer (NK) cells to recognize cancer cells as foreign and thereby enhance the effectiveness of host immune defence mechanisms. Nevertheless, the use of NK cells in cancer treatment requires finding selective stimulators of their cytotoxicity without disturbing organism homeostasis. Our studies revealed that Cantharellus cibarius polysaccharides present in the CC2a fraction, mainly composed of an O-2 and O-3 branched (1→6)-linked mannan, not only beneficially influenced the viability and proliferation of the human natural killer cells NK92 but also enhanced their anticancer properties against the human lung and colon cancer cells A549 and LS180, and at the same time did not affect the human lung and colon epithelial cells NL20 and CCD841 CoN. Furthermore, the CC2a fraction used alone was also nontoxic to the normal epithelium, while it inhibited the viability of these cancer cells. Nevertheless, the therapeutic potential of NK92 cells was greatly enhanced after coincubation with these polysaccharides and the observed effect was dependent on the CC2a concentrations. The beneficial effect of CC2a on NK92 cells was associated with stimulation of p38 and Erk expression as well as induction of the transcription factor CREB. The discovered beneficial impact of the CC2a fraction on NK92 cells suggested the therapeutic use of the investigated compound especially as an adjuvant. Furthermore, taking into account the abundance of these water soluble mannans in C. cibarius, the results also suggest that an increase in the intake of C. cibarius may promote innate immunity response against cancer through the enhancement of NK cell activity.
This chapter examines some of the recent evidence-based scientific information about the contribution of phytotherapeutics for effective cancer management with particular emphasis on results of human clinical trials. It discusses the clinical evidence of effectiveness of phytotherapeutics mainly in relation to the anticancer mechanisms through natural killer (NK) cell enhancement. NK cells play an important role in anticancer immunomodulation. Two commonly used phytotherapeutics, the medicinal mushrooms Lentinula edodes mycelia and Ganoderma lucidum, have been found to elicit their anticancer functions by regulating NK cells. If effects on both NK numbers and toxicity are taken into account, the recommended phytotherapy strategies appear to be Hochu-ekki-to, Shenqi Fuzheng Injection (SFI), and Aidi Injection. The chapter highlights the importance of careful documentation of the clinical effects for both overall survival and quality of life, in relation to potential mechanisms of action for further evidence-based use of selected cancer phytotherapeutics.
Ganoderma lucidum is a natural medicine that is widely used and recommended by Asian physicians and naturopaths for its supporting effects on immune system. Laboratory research and a handful of preclinical trials have suggested that G. lucidum carries promising anticancer and immunomodulatory properties. The popularity of taking G. lucidum as an alternative medicine has been increasing in cancer patients. However, there is no systematic review that has been conducted to evaluate the actual benefits of G. lucidum in cancer treatment.
To evaluate the clinical effects of G. lucidum on long-term survival, tumour response, host immune functions and quality of life in cancer patients, as well as adverse events associated with its use.
The authors ran an extensive set of databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, NIH, AMED, CBM, CNKI, CMCC and VIP Information/Chinese Scientific Journals Database was searched for randomised controlled trials (RCTs) in October 2011. Other strategies used were scanning the references of articles retrieved, handsearching of the International Journal of Medicinal Mushrooms and contact with herbal medicine experts and manufacturers of G. lucidum.
To be eligible for being included in this review, studies had to be RCTs comparing the efficacy of G. lucidum medications to active or placebo control in patients with cancer that had been diagnosed by pathology. All types and stages of cancer were eligible for inclusion. Trials were not restricted on the basis of language.
Five RCTs met the inclusion criteria and were included in this review. Two independent review authors were assigned to assess the methodological quality of individual trials. Common primary outcomes were tumour response evaluated according to the World Health Organization (WHO) criteria, immune function parameters such as natural killer (NK)-cell activity and T-lymphocyte co-receptor subsets, and quality of life measured by the Karnofsky scale score. No trial had recorded long-term survival rates. Associated adverse events were reported in one study. A meta-analysis was performed to pool available data from the primary trials. Results were gauged using relative risks (RR) and standard mean differences (SMD) for dichotomous and continuous data respectively, with a 95% confidence interval (CI).
The methodological quality of primary studies was generally unsatisfying and the results were reported inadequately in many aspects. Additional information was not available from primary trialists. The meta-analysis results showed that patients who had been given G. lucidum alongside with chemo/radiotherapy were more likely to respond positively compared to chemo/radiotherapy alone (RR 1.50; 95% CI 0.90 to 2.51, P = 0.02). G. lucidum treatment alone did not demonstrate the same regression rate as that seen in combined therapy. The results for host immune function indicators suggested that G. lucidum simultaneously increases the percentage of CD3, CD4 and CD8 by 3.91% (95% CI 1.92% to 5.90%, P < 0.01), 3.05% (95% CI 1.00% to 5.11%, P < 0.01) and 2.02% (95% CI 0.21% to 3.84%, P = 0.03), respectively. In addition, leukocyte, NK-cell activity and CD4/CD8 ratio were marginally elevated. Four studies showed that patients in the G. lucidum group had relatively improved quality of life in comparison to controls. One study recorded minimal side effects, including nausea and insomnia. No significant haematological or hepatological toxicity was reported.
Our review did not find sufficient evidence to justify the use of G. lucidum as a first-line treatment for cancer. It remains uncertain whether G. lucidum helps prolong long-term cancer survival. However, G. lucidum could be administered as an alternative adjunct to conventional treatment in consideration of its potential of enhancing tumour response and stimulating host immunity. G. lucidum was generally well tolerated by most participants with only a scattered number of minor adverse events. No major toxicity was observed across the studies. Although there were few reports of harmful effect of G. lucidum, the use of its extract should be judicious, especially after thorough consideration of cost-benefit and patient preference. Future studies should put emphasis on the improvement in methodological quality and further clinical research on the effect of G. lucidum on cancer long-term survival are needed. An update to this review will be performed every two years.
AIM: To study the effects of polysaccharides isolated from mycelium of Ganoderma lucidum (MGLP1 and MGLP2) on HL-60 cell apoptosis. METHODS: The in vitro effect of MGLP1 and MGLP2 on the proliferation of HL-60 cells were evaluated by MTT assay. DNA gel electrophoresis and flow-cytometric analysis were used to determine the apoptotic cells. RESULTS: MGLP1 did not show inhibition of HL-60 cell proliferation in vitro. When the concentrations of MGLP2 were at higher doses (187.5 ∼ 750 μg·ml-1), it slightly inhibited HL-60 proliferation. Furthermore, MGLP1 and MGLP2 showed no effect on inducing HL-60 apoptosis even at a high dose of 600 μg·ml-1. However, the conditioned medium from MGLP1 and MGLP2 activated splenocytes (MGLP1-S-CM, MGLP2-S-CM) markedly induced HL-60 apoptosis. DNA gel electrophoresis showed obvious DNA "ladder". Flow-cytometric analysis revealed that few 8.0% ± 0.4% apoptotic cells were seen in the control cultures, while MGLP1-S-CM and MGLP2-S-CM treatment resulted in significant increase in the apoptotic population in the HL-60 28.1% ± 0.3%, MGLP1-S-CM; 32.4% ± 0.9%, MGLP2-S-CM). CONCLUSION: MGLP1 and MGLP2 showed no obvious effect on HL-60 cell proliferation and inducing HL-60 apoptosis in vitro, whereas MGLP1-S-CM and MGLP2-S-CM markedly induced HL-60 apoptosis.
Acutiaporberine is a novel ether-linked bisalkaloid isolated from the traditional Chinese medicinal herb Thalictrum acutifolium (Hand.-Mazz.) Boivin (TAB). The present study demonstrates for the first time, by means of nuclear staining, DNA agarose gel electrophoresis, and flow cytometry, that acutiaporberine induces apoptosis in PLA-801 cells, a cultured human non-small cell lung cancer (NSCLC) cell line. An immunohistochemical assay and western immunoblot analysis showed down-regulation of the bcl-2 gene and up-regulation of the bax and c-myc genes in the acutiaporberine-treated cells. The observations also indicate that acutiaporberine induces apoptosis of PLA-801 cells in a concentration- and time-dependent manner. These results suggest that acutiaporberine may be a potential, natural apoptosis-inducing agent for NSCLC.
The need for dextran fractions with a narrow molecular-weight distribution for clinical use is well known. The definition of such material has significantly improved by the use of gel permeation chromatography (GPC) techniques. However, an internationally accepted standard method of analysis giving accurate and reproducible results in different laboratories has yet to be defined. This paper reviews the GPC packings that can be or have been used for determining the molecular weight distribution of dextran polymers. The application of GPC to the determination of the molecular weight of dextrans on TSK PW type columns is described and its accuracy and reproducibility are discussed. This material appears to meet the criteria required for a standard method.
Detection and quantification of bacterial endotoxin in plasma by the Limulus amebocyte lysate test (or other assays for endotoxins) is hindered by the presence of inhibitors. Treatment of plasma to overcome inhibitory activities is required before plasma can be successfully assayed for endotoxin. We have conducted an investigation comparing the three most commonly used procedures (dilution-heating, trifluoroacetic acid oxidation, and chloroform extraction) for treatment of plasma before its assay for endotoxin with the chromogenic Limulus test. Initially, conditions were optimized for treatment of plasma by each of these methods. Subsequently, a direct comparison of the three plasma treatment procedures was performed with plasma spiked with known concentrations of endotoxin. The optimized dilution-heating procedure resulted in the most sensitive detection of endotoxin, with sensitivity approximately 10 times greater than the optimized trifluoroacetic acid oxidation procedure and approximately 100 times greater than treatment of plasma by chloroform extraction. Maximal detection of low concentrations of endotoxin by the chromogenic Limulus test was obtained by dilution of plasma fourfold with 0.15 mol/L NaCl followed by heating at 60 degrees C for 30 minutes. This procedure was simple, rapid, and did not involve addition of any reagents to plasma that could potentially add contaminating endotoxin.
We have previously reported that soluble aminated beta-1,3-D-glucan (AG), a potent immunomodulator, specifically inhibited binding and internalization of AG-coated microbeads (GDM) in mouse peritoneal macrophages. The present study was undertaken to determine parameters of AG binding to macrophages. For this purpose, AG was conjugated with tyraminyl cellobiose (TC), which can be radioiodinated. With this method the immunomodulator was labelled with a very high specific radioactivity, allowing sensitive measurements of binding. Maximal binding capacity was 0.33 micrograms [125I]TC-AG/10(6) cells. Binding was inhibited by TC-AG and AG, but not by mannose and mannan, showing that the receptor different from the mannose receptor was involved. Binding was reversible, with an initial association rate of 120 cpm/min, and a much faster initial dissociation rate of 680 cpm/min. Bound [125I]TC-AG was internalized. These findings suggest that both AG and GDM are bound and internalized via the same beta-glucan receptor in mouse peritoneal macrophages.
The sequencing of the human genome is likely to speed the discovery of factors involved in cancer pathogenesis and lead to an age of individually tailored anti-cancer drugs. But does the ability to obtain an abundance of genetic information mean that we necessarily know how to use it?
Patients with metastatic melanoma often have defects in the percentage and function of peripheral blood NK cells, which are involved in the non-specific innate antitumor immune response, and T cells, which participate in the specific acquired antitumor immune response. The aim of this study was to investigate in more detail not only the percentage but also the activation status and function of NK and T cells in patients with metastatic melanoma prior to therapy.
The percentage of peripheral blood CD56+ NK cells, CD3+ T cells and their CD4+ and CD8+ subsets, as well as the expression of the activation antigens CD69, CD38 and HLA-DR were analyzed by flow cytometry. The functional capacity of NK cells was evaluated by the 51-chromium release cytotoxicity assay, while the proliferative activity of T cells was estimated by the lymphocyte transformation test to mitogen phytohemagglutinin.
The results obtained in this study have revealed a new aspect of NK and T cell dysfunction that is not, as commonly reported, associated with a decrease in their percentage. Moreover, a significant number of the investigated patients had a higher percentage of NK cells that did not lead to improved NK cell cytotoxicity as a result of the detected defect in the NK cell perforin-mediated cytotoxic mechanism of tumor cell lysis. The impaired proliferative response of T cells was associated with a decreased expression of the activation antigen HLA-DR.
The novel finding in this study of melanoma patients with metastatic disease is the impaired perforin-dependent NK cell cytotoxic mechanism, which was recently shown to be primarily responsible for preventing metastasis. Another interesting finding was the generally hyporeactive status of T cells, possibly resulting from persistent antigenic stimulation. The observed dysfunction of NK and T cells in patients with metastatic melanoma prior to therapy point to the need to supplement chemotherapy with appropriate immunotherapeutic agents in order to overcome the immunosuppression associated with advanced malignancy.