Clinical Nutrition 40 (2021) 3104e3113

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Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

Meta-analyses

Fungal beta-glucans as adjuvants for treating cancer patients e A

systematic review of clinical trials
Laiza Steimbach a, Ariela Victoria Borgmann a, Gabriella Giandotti Gomar a,
Lucas Ventura Hoffmann a, Renata Rutckeviski a, b, Diancarlos Pereira de Andrade b,
Fhernanda Ribeiro Smiderle a, b, *
a
Faculdades Pequeno Príncipe, CEP 80230-020, Curitiba, PR, Brazil
b
Instituto de Pesquisa Pel

e Pequeno Príncipe, CEP 80240-020, Curitiba, PR, Brazil

a r t i c l e i n f o s u m m a r y

Article history: Background & aims: Fungal b-glucans have been considered as biological response modifiers (BRMs)
Received 19 May 2020 promoting stimulation of immune system according to numerous scientific publications performed
Accepted 21 November 2020 in vitro and in vivo. Some clinical trials involving such compounds started to be published since 1980's.
This systematic review aimed to compile and compare clinical studies using these b-glucans as adjuvants
Keywords: on patients undergoing cancer treatment. Healthy subjects and b-glucans from other sources were
Fungal b-glucans
excluded.
Clinical trials
Methods: It was developed according to PRISMA-P guidelines (PROSPERO registered n.
Systematic review
Cancer treatment
CRD42020151539), using PICO criteria and the following databases: PubMed, Scielo and LILACS.
Results: We found 1018 articles and after removing duplicated records, select by title/abstract and full-
text, only 9 studies remained and 7 more were manually added, totalizing 16 trials involving 1650 pa-
tients, with arm sizes varying from 9 until 200 patients. The selected studies (published since 1992
e2018) included subjects with diagnosis of 9 types of cancer. The studies used different sources of b-
glucans, such as yeast (Saccharomyces cerevisiae), mushrooms (Lentinula edodes and Schizophyllum
commune) and non-described fungal sources.
Conclusions: It was observed that the administration of b-glucan is safe and well-tolerated. Most of the
trials pointed that concomitant administration of b-glucan with chemo or radiotherapy reduced the
immune depression caused by such treatments and/or accelerated the recovery of white blood cells
counts. However, some articles also commented that no statistical difference was encountered between
b-glucan treated vs. control groups, which gives a controversial conclusion about the b-glucan effects.
The great diversity among the methodology studies and insufficient information was an impeditive for
achieving profound statistical analysis, therefore a narrative report of the included studies was per-
formed indicating that further evidences are required to determine the efficacy of this adjuvant in the
cancer treatment.
© 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

1. Introduction

Cancer is the second leading cause of death globally, accounting

Abbreviations: LEM, Lentinula edodes mycelium extract; LNT, lentinan (b-glucan
from L. edodes); BTH1677, yeast-derived b-glucan from Biothera Pharmaceuticals;
SPG, b-glucan from Schyzophyllum commune mushroom; BRMs, biological response
modifiers; APCs, antigen-presenting cells; QOL, quality of life.
* Corresponding author. Instituto de Pesquisa Pele
Pequeno Príncipe, Avenida
Silva Jardim, 1632, Curitiba, PR, Brazil.
E-mail address: fhernandas@gmail.com (F.R. Smiderle).
for an estimated 9.6 million deaths, or one in six deaths, in 2018.
Lung, prostate, colorectal, stomach and liver cancer are the most
common types of cancer in men, while breast, colorectal, lung,
cervical and thyroid cancer are the most common among women
[1]. It has been reported that mushroom and other fungal b-glucans
may activate the host immune system and stimulate the production
of pro-inflammatory cytokines, increase frequency of immune cells
on blood, activate complement system and opsonization with

https://doi.org/10.1016/j.clnu.2020.11.029
0261-5614/© 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
L. Steimbach, A.V. Borgmann, G.G. Gomar et al.
complement protein iC3b, and suppress tumor growth when
administered to murine tumor models with tumor-targeting
monoclonal antibodies [2e4]. Furthermore, it was observed that
co-administration of fungal b-glucans with conventional cancer
treatments may reduce the adverse effects commonly observed on
chemotherapy and radiotherapy [5,6]. Such studies were based on
Chinese folk medicine, that uses mushrooms for thousands of years
for treating cancer and other diseases, and many studies have
demonstrated their medicinal qualities, such as anti-tumor activity
by increasing host defense mechanisms, among other therapeutic
properties [7,8]. Lentinan, the most common b-glucan isolated
firstly from Shiitake mushrooms, is available in Japan since 1985 as
an adjuvant for stomach cancer therapy and it was also approved
for treating multiple types of cancer in China [7]. Although it has
been tested and approved in Asian countries for long years, fungal
b-glucans have no authorization for the commercial claim for me-
dicinal activity of any mushroom or other fungal-derived substance
in other countries. Only oral formulations were authorized by FDA
(US Food and Drug Administration), EFSA (European Food Safety
Authority) and ANVISA (Brazilian National Health Surveillance
Agency) as dietary supplements [9e11].
Fungal b-glucans are a class of polysaccharides composed by
glucose, however their chemical structure can vary significantly.
According to scientific community, they can be linear or branched,
present b-(1,3)- and/or b-(1,6)-linkages, and vary their branching
degree, chain length, molecular weight, solubility and tridimen-
sional conformation [12,13]. Based on previous studies, it was
observed that different degree of branching on b-(1,3)/(1,6)-glucans
may influence their antitumor activity in some experimental
models, indicating that their chemical structure is closely related to
the biological effect observed [14].
A plenty of researchers have showed that such compounds act
as biological response modifiers (BRMs) in vitro and in vivo, stim-
ulating the immune system and consequently helping on cancer
remission [15,16]. A study demonstrated that orally ingested b-
glucans are taken up in the proximal gut via intestinal epithelial
cells or M-cells in Peyer's patches, followed by recognition by
dendritic cells (DCs) and macrophages from GALT system [17]. The
binding of b-glucans to antigen-presenting cells (APCs) induces
these cells to migrate to bone marrow or to lymph nodes. On bone
marrow, b-glucan degradation products can bind to CR3 on neu-
trophils, resulting in their activation; while in lymph nodes, the
activated APCs stimulate effector lymphocytes by producing pro-
inflammatory cytokines [2].
There are numerous studies in vitro and in animal models con-
firming the therapeutic benefits of fungal b-glucans [2,7], and also
many scientific reports regarding the variety of b-glucan structures
that can be extracted from different mushrooms and yeast [13,18].
Some of these fungal b-glucans are already commercialized as di-
etary supplements (Imprime PGG; Glucan 300®; Sizofiran; Imu-
neks®) and have been tested on clinical trials. However, there is still
a lack of information comparing the effects of such products on
patients undergoing cancer treatment, as well as their dosage,
administration route and time of consumption. Therefore, this
systematic review aimed to compile the clinical trials using fungal
b-glucans as adjuvants on patients undergoing cancer treatment
and evaluate their safety (occurrence of adverse effects) and effi-
cacy (immune function improvement).
2. Methods
2.1. Study protocol
This systematic review was developed according to the PRISMA-
P guidelines [19] and the PROSPERO (International Prospective
3105
Clinical Nutrition 40 (2021) 3104e3113
Register of Systematic Reviews) registered number obtained is No.
CRD42020151539.
2.2. Eligibility criteria
Studies selected for the analysis met the following criteria: (i)
population: patients diagnosed with cancer, in a clinical trial
(randomized or not); (ii) intervention: concomitant administration
of fungal b-glucans as adjuvants in cancer treatment (no matter
which dose or route of administration); (iii) comparator: b-glucans
treated group versus control group or before/after b-glucans
treatment; (iv) outcomes: any indication to measure safety
(occurrence of adverse effects) and efficacy (immune function
improvement) observed on patients were eligible. Studies that
were excluded: healthy subjects receiving fungal b-glucans; pa-
tients diagnosed with any other disease different from cancer, even
if treated with fungal b-glucans; patients treated with glucans from
plants or chemically modified b-glucans; and articles published in
Japanese or Chinese.
2.3. Search strategy
Two investigators (FRS and LS) extensively searched three
electronic databases (PubMed, Scielo and LILACS), on 2019 July, 11th
and the search was updated in April, 2020. The search strategy was
specifically developed for each database, using mainly the MESH
term (“beta glucans”) AND (“clinical trial” OR “controlled trial”).
The detailed search strategy can be found in Table S1
(supplementary material). In the beginning, the search was not
limited by language, however after evaluating the articles by title/
abstract, we decided to exclude articles written in Japanese and
Chinese due to difficulty to assess their information. Review articles
were also used to find additional eligible studies and the articles
found were added manually.
2.4. Study selection
EndNote library (EndNote X9 30-days free trial, USA) was used
to select searched results and find duplicates. Afterwards, data was
exported to MS Excel and MS Word softwares (Microsoft Inc., USA)
to assessment of title and abstracts. Two investigators (LS, LVH)
independently performed the first selection and the full text of
eligible articles was evaluated by the same investigators according
to pre-defined inclusion criteria. Disagreements among the authors
were solved through discussion with a third author (FRS) in a
consensus meeting.
2.5. Data extraction and outcome measures
Two authors (AVB, GGG) independently extracted data from the
selected articles using MS Excel software (Microsoft Inc., USA) plus
the pdf files and any discrepancies were resolved by a third author
(RR). The following information was extracted from the results: first
author and year of publication; intervention (type and source of b-
glucan); b-glucan dose, administration route and frequency;
number of participants; control group; cancer diagnosis; cancer
treatment; study design; presence of adverse effects (anemia,
nausea, constipation, vomiting, diarrhea, mucositis, neutropenia,
leucopenia, thrombocytopenia); improvement of immune function
(proliferation and activation of immune cells, cytokines and che-
mokines production); study location; funding source; and conflict
of interest. All outcomes measures, qualitative or quantitative, were
recorded. Articles were eligible preferably by the study design
(interventional trials, randomized or not), presence of adverse
L. Steimbach, A.V. Borgmann, G.G. Gomar et al.
effects, and immune function improvement, according to PICOS
strategy developed for this review.
2.6. Quality and risk of bias assessment
The risk of bias among the included studies was assessed in
order to evaluate their quality. It was used the Cochrane Risk of Bias
tool and the domains assessed were: the random sequence gen-
eration, allocation concealment, blinding of participants and
personnel, blinding of outcomes, incomplete outcome data, and
selective reporting. Lastly, other sources of bias were detected by
the declaration of conflict of interest or any other problem in the
study design [20].
2.7. Assessment of data heterogeneity
Data extraction was used also to evaluate clinical and method-
ological heterogeneity such as intervention (type and source of b-
glucan) and b-glucan administration (dose, route and frequency), as
well as outcome measurements, to check for the possibility of
performing meta-analysis.
2.8. Statistical analysis
Statistical analyses were performed using software Review
Manager (v. 5.4) for heterogeneity test and meta-analysis. The fixed
effect model was employed. Mantel-Haenszel method was used for
the meta-analysis of Risk Ratio and the difference was significant
given p < 0.05. The software R (v. 4.0.2) was used to develop the risk
of bias evaluation. Heterogeneity was evaluated using Higgins
inconsistency analyses (I2) [21] and Cochrane's Q test. I2 describes
an estimative of the percentage of variability in results across a
study which is due to real differences and not due to chance. The
Cochrane's Q test relies on a Chi-square distribution, generating
probability.
3. Results
The great diversity among the methodology studies and insuf-
ficient information was an impeditive for achieving profound sta-
tistical analysis, therefore a narrative report of the included studies
was performed.
3.1. Systematic review and assessment of the studies
We found 1018 articles from the searched databases and after
removing duplicated records, 901 studies remained and were
selected by title/abstract (Fig. 1). The elected studies (19) passed
through full-text assessment and 10 articles were excluded (details
are described in Table 2 of supplementary material). Finally, 9
studies remained and 7 more were added after identification via
other sources, totalizing 16 trials involving 1650 patients, with arm
sizes varying from 9 until 200 patients (Table 1). The selected
studies were published since 1992 until 2018 and included subjects
with diagnosis of advanced non-small cell lung cancer (NSCLC) and
head and neck squamous cell carcinoma (HNSCC); cervical;
ovarian; breast; prostate; gastric; gastrointestinal and colorectal
cancers. The studies involved patients that were submitted to
surgical removal of tumor, chemotherapeutical, hormone or
radiotherapy treatments associated with administration of fungal
b-glucans. The studies used different sources of b-glucans, such as
yeast (Saccharomyces cerevisiae), mushrooms (Lentinula edodes and
Schizophyllum commune) and non-described sources. Furthermore,
the way of preparation of such b-glucans seemed to be different,
however the detailed information was not presented in the studies,
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Clinical Nutrition 40 (2021) 3104e3113
and on the other side, some authors used food supplement b-glu-
cans commercially available (Imuneks®, Glucan 300®). Among the
selected trials, it was also observed great variability of dosage, route
of administration and period of intervention with b-glucans. More
details about each study can be observed on Table 1. Among the 16
trials, only 4 reported that a protocol was registered in a clinical
trial registry: two of them were registered on ClinicalTrials.gov
(Engel-Riedel et al., 2018: NCT00874107; Thomas et al., 2017:
NCT00874848) [3,4], one was registered on IRCT (Ostadrahimi et al.,
2014: IR201212172017N10) [5], and another was registered on
UMIN (Yoshino et al., 2016: ID 000000574) [22].
3.2. Qualitative efficacy analysis
As fungal b-glucans are considered biological response modi-
fiers (BRMs), commonly used in oriental countries as folk treatment
of cancer, and a plenty of studies in vitro and in vivo have demon-
strated their potential to stimulate the immune system [2,17], we
decided to evaluate the efficacy of adjuvant administration of this
supplement by observing its effect on immune function such as:
influence on immune cells (increase, reduction or activation of
white blood cells and antigen presenting cells) as well as on the
production of important mediators such as cytokines and chemo-
kines (e.g. TNF-a, IFN-g; IL-12; IL-4; IL-6).
Among the 16 selected studies, 4 of them evaluated other effi-
cacy parameters instead of the immunological ones (e.g. quality of
life, overall survival, overall response rate, time-to-treatment fail-
ure). While most of the 12 remaining trials concluded in general
that concomitant administration of b-glucan with chemotherapy or
radiotherapy reduced the immune depression caused by such
treatments and/or accelerated the recovery of white blood cells
counts or of the patient. Two reports observed that the results were
no conclusive [23,24] because of insufficient data or low number of
patients and one article concluded that b-glucan helped to recover
from chemotherapy immune depression, however the authors
observed no statistical differences between b-glucan and control
groups [25]. Due to great variability of the parameters and mea-
surements evaluated among the studies, meta-analysis was not
possible to be performed with the data available and we decided to
list the own authors conclusions as described in Table 2.
3.3. Qualitative and meta-analysis of safety outcomes
The safety outcomes were assessed by observing the presence of
adverse effects, such as anemia, nausea, constipation, vomiting,
diarrhea, mucositis, neutropenia, leucopenia, thrombocytopenia,
among others [26]. However, this symptoms are generally reported
by the patients who receives conventional cancer treatments as
chemotherapy or radiotherapy, which was the case of all selected
trials. Therefore, it was took in consideration if the b-glucan adju-
vant could influence somehow the adverse events commonly
described by patients receiving cancer treatments.
After a qualitative analysis of the studies, it was observed that, in
general, the administration of b-glucan concomitantly with other
cancer treatments is safe, well-tolerated or promote only mild side
effects that disappear after the intervention, totalizing 8 of 16 trials
(Table 3). Four studies [5,6,24,27] reported that the b-glucan
intervention reduced or prevented the side effects caused by cancer
treatment, although one of them observed no statistic difference
between control and b-glucan groups [5].
The great variability of parameters observed on the studies and
insufficient information was an impeditive to include most of the
trials on a quantitative evaluation. Therefore we selected some
trials that reported anemia, nausea, vomiting, diarrhea, mucositis/
stomatitis, neutropenia, thrombocytopenia and leukopenia for both
L. Steimbach, A.V. Borgmann, G.G. Gomar et al.
Fig. 1. Study flow diagram.
groups (b-glucan treated and control), to verify the possibility of
performing meta-analysis. After analyzing each symptom, nausea
showed p ¼ 0.05, while the other symptoms showed higher p-
values (Fig. 2). Only 3 recent studies were included in this analysis,
therefore the conclusions obtained should be extrapolated with
caution due to the low number of studies. Unexpectedly, the results
demonstrated that patients who received intervention with b-
glucan plus cancer treatment presented a tendency to have more
nausea than patients who did not receive b-glucan. The I2 value was
equivalent to 0%, indicating low heterogeneity among that three
trials.
3.4. Risk of bias assessment
Considering the quality and risk of bias, overall, the 16 studies
presented an unclear or high risk of bias (Fig. S1, supplementary
material). This result mainly occurred due to the selection, perfor-
mance and detection bias. Regarding the selection bias, 5 studies
described random sequence generation [5,25,27e29], while only
one presented allocation concealment [25]. Concerning to perfor-
mance bias, the majority of studies were open-label except by three
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Clinical Nutrition 40 (2021) 3104e3113
that were reported as double-blinded [5,28,29]. Thirteen trials
were considered as high risk of bias for blinding of outcome
assessment while three [5,28,29] provided insufficient information
about this domain. The attrition and reporting bias were the only
domains with low risk for majority of trials, except for Ina et al.,
2011 [30] which did not provide clear information. Finally, 6 trials
[4,22,24,31e33] were funded by industry, while 8 studies were not
clear about financing support [5,6,23,25,27,30,34,35].
4. Discussion
Despite of the great number of scientific publications about the
effects of fungal b-glucans on the immune system cells and their
health benefits, this systematic review seems to be the first report
to assess the clinical trials that studied fungal b-glucans as adjuvant
in cancer treatments. Some systematic reviews were published
reporting the effect of b-glucans on reducing blood cholesterol and
glucose levels [36,37], which is a common effect of fibers such as b-
glucans; and a detailed systematic review was recently published
about the efficacy and safety of oral and inhalation of commercial
beta-glucan products [38].
L. Steimbach, A.V. Borgmann, G.G. Gomar et al. Clinical Nutrition 40 (2021) 3104e3113

Table 1
Qualitative analysis of selected study.

Author, year Type of cancer Treatment arm Control arm Follow-up

period

Engel-Riedel et al., Advanced NSCLC - Same as in control arm plus BTH1677 (glucan) - i.v. bevacizumab, 15 mg/kg (day 1) 3 weeks
2018 [3] - i.v.; 4 mg/kg; weekly; - i.v. carboplatin of 6 mg/mL and i.v. paclitaxel
- 59 patients 200 mg/m2 (day 2)
- 30 patients
Hazama et al., 2009 Colorectal cancer - chemotherapy regimens plus Lentinan (LNT) - different chemotherapy regimens such as 5- 12 weeks
[40] - oral; 15 mg of LNT once daily; for 12 weeks fluorouracil (5-FU); tegafur and uracil (UFT);
- 80 patients tegafur, gimeracil and oteracil potassium (S-
1); doxifluoridine (50 -DFUR); levofolinate
(LV); irinotecan (CPT-11); gemcitabine
(GEM); or cisplatin (CDDP)
- 64 patients
Ina et al., 2011 [30] Gastric cancer - Same as in control arm plus Lentinan - chemotherapy used included S-1 alone, S-1/ 2 weeks
- i.v.; 2 mg/body of LNT for 30 min; every 2 or 3 paclitaxel, S-1/cisplatin, and paclitaxel with
weeks S-1 plus cisplatin (PSC triple therapy).
- 31 patients - twice daily based on the patient's body
surface area (BSA)
- 37 patients
Inoue et al., 1993 Ovarian cancer PAC regimen plus sizofiran (SPG) - i.v. PAC regimen (cisplatin: 60 mg/mm2; 1e3 months
[25] - i.m.; 40 mg, weekly. adriamycin: 30 mg/mm2 and intervals up to
- 46 patients cyclophosphamide: 500mg/body); every 2 years
week.
- 18 patients
Karaca et al., 2014 Colorectal cancer Chemotherapy plus pure preparation of b-glucan - Chemotherapy; FOLFOX-4 (oxaliplatin, 5- 1 year
[41] - oral; 50 mg/day, for 1 week fluorouracil, and folinic acid)
- 31 patients - 31 patients
Mantovani et al., Advance - Same as in control arm plus Schizophyllan (SPG) - chemotherapy 4 months
1997 [23] HNSCC - i.m.; 40 mg, weekly; for 4 months 1) cisplatin 100 mg/m2 i.v. (day 1), 5-FU
- 13 patients 1000 mg/m2 i.v. continuous infusion (days 1
e5); 2) cisplatin 80 mg/m2 i.v. (day 1), 5-FU
600 mg/m2 i.v. over 4 h (days 2e5), vinorelbine
20 mg/m2 i.v. (days 2 and 8)
- 9 patients
Miyazaki et al., Cervical - Same as in control arm plus Sizofiran - radiotherapy 2 years
1995 [34] carcinoma - i.m.; 20e40 mg/week, for 2 years - adjuvant chemotherapy with 5-FU (200
- 159 patients e300 mg/day) was also randomly performed
in 60 patients treated with radiotherapy for 1
year.
- 153 patients
Nagashima et al., Breast cancer - FEC75 chemotherapy (5-fluorouracil 500 mg/m2; No control arm 6 weeks
2013 [6] cyclophosphamide, 500 mg/m2; epirubicin,
75 mg/m2), every 21 days for 2 courses
- Lentinula edodes mycelia extract (LEM)
- oral; 1800 mg/day, during the 2nd course (3
weeks)
- 10 patients
Noda et al., 1992 Cervical cancer - Radiotherapy as in control arm plus sizofiran - radiotherapy 40 Gy or more from Sept, 1987
[27] (SPG) - 92 patients until March,
- i.m., 40 mg once and 20 mg twice, a week 1989
- 200 patients
Okuno et al., 2011 Gastrointestinal - Chemotherapy (5-fluorouracil, irinotecan, UFT® No control arm 8 weeks
[24] cancer (uracil and tegafur), levofolinate, mitomycin or
taxol), for 2 courses of 4 weeks
- Lentinula edodes mycelia extract (LEM)
- oral; 1800 mg/day, during the 2nd course (4
weeks)
- 8 patients
Ostadrahimi et al., Breast cancer - Same as in control arm plus 1e3, 1e6, D-beta - 4 chemotherapy courses 21 days
2014 [5] glucan (Imuneks®, Turkey) - 15 patients
- oral; two 10 mg capsules; daily, for 21 days
(interval of 2 courses)
- 15 patients
Richter et al., 2016 Breast, Prostate - Cancer patients 2e6 months after the end of - Cancer patients 2e6 months after the end of 60 days
[35] or chirurgical, chemotherapeutical or radiation chirurgical, chemotherapeutical or radiation
Gastrointestinal therapy plus Glucan #300®. therapy plus placebo capsules
Cancer - oral; 200 mg/d or 100 mg/d (authors do not - 10 patients
clarify); for 60 days.
 26 patients
Suzuki et al., 2013 Breast cancer - Hormone therapy (4 weeks) followed by Lentinula - No control arm 12 weeks
[42] edodes mycelia extract (LEM)
- oral; 1800mg/daily, for 8 weeks.
- 20 patients

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L. Steimbach, A.V. Borgmann, G.G. Gomar et al. Clinical Nutrition 40 (2021) 3104e3113

Table 1 (continued )

Author, year Type of cancer Treatment arm Control arm Follow-up

period

Thomas et al., 2017 Advanced NSCLC - Same as in control arm plus BTH1677 (glucan) - cetuximab on day 1 (initial i.v. loading dose of 5 years
[4] - i.v.; 4 mg/kg; once a week during 3 week cycles 400 mg/m2 over 120 min and subsequent i.v.
- 59 patients doses at 250 mg/m2 over 60 min); and i.v.
paclitaxel on day 2 (200 mg/m2 over 3 h).
Carboplatin and paclitaxel administration
continued for at least four cycles.
- 29 patients
Yenidogan et al., Breast cancer - Patients after Modified Radical Mastectomy plus - Patients after Modified Radical Mastectomy 10 days
2014 [29] b-Glucan (source not clarified by the authors) plus placebo
- intervention via not informed; 10 mg b-glucan - 61 patients
twice a day; for 10 days.
- 49 patients
Yoshino et al., 2016 Gastric cancer - Same as in control arm plus Lentinan (LNT) - Chemotherapy, orally S-1 for 4-weeks 48 months
[22] - i.v.; 2 mg/body; every week; for undetermined - 146 patients
period
- 149 patients

NSCLC: non-small cell lung cancer; HNSCC: head and neck squamous cell carcinoma; i.v.: intravenous; i.m.: intramuscular.

The results observed after compiling all the assessed reports,
let us conclude there are a plenty of in vitro and in vivo evi-
dences, which did not advance for clinical tests; moreover most
of the available trials are heterogeneous concerning clinical trial
methodology and the measured parameters. Besides that, the
studies present small sample sizes (majority of groups con-
taining less than 60 participants). The variability observed on
the studies includes mainly: (i) type and preparation of b-glu-
cans; (ii) b-glucan dose and via of administration; (iii) period of
intervention and follow-up of patients; (iv) evaluation of im-
mune parameters; (v) study design; and (vi) cancer stages. All
this variability associated with small sample sizes contributed
for weakening the evidences and preclude proper statistical
analyses.

Table 2
Qualitative analysis of immune function.

Study Conclusions

Engel-Riedel et al., 2018 Not reported

[3]
Hazama et al., 2009 [40]
Ina et al., 2011 [30]
Inoue et al., 1993 [25]
Karaca et al., 2014 [41]
Mantovani et al., 1997
[23]
Miyazaki et al., 1995
[34]
Nagashima et al., 2013
[6]
Noda et al., 1992 [27]
Okuno et al., 2011 [24]
Ostadrahimi et al., 2014
[5]
Richter et al., 2016 [35]
Suzuki et al., 2013 [42]
Thomas et al., 2017 [4]
Yenidogan et al., 2014
[29]
Yoshino et al., 2016 [22]
Not reported
“Our data on S-1-based chemotherapy showed that the addition of lentinan to chemotherapy prolonged the survival of advanced gastric
cancer patients along with immunological activation, compared to chemotherapy alone."
“The number of white blood cells and lymphocytes decreased from the initial counts due to the chemotherapy in both the SPG and control
groups. No differences were found between the two groups after each chemotherapy (data not shown)."
“Leucocytes were counted before chemotherapy and after 3 courses of chemotherapy. In the group that received oral b-glucan the decrease
in leucocyte counts after chemotherapy was limited, whereas in the group that received chemotherapy alone leucocyte counts decreased
significantly."
“In conclusion, it was not possible to demonstrate a significant immunostimulating activity of SPG on the basis of the clinical and
immunological parameters evaluated in the present study."
“Our study showed that the percentages of activated CD8þ T cells out of the total CD8þ T-cell subsets were significantly increased in both
the sizofiran and control groups by radiotherapy, and that sizofiran accelerated a recovery in this immunologic parameter after
radiotherapy."
“ … 1 week following the second course of chemotherapy with concomitant use of LEM, no decreases were observed in white blood cells,
neutrophils, or hemoglobin; and subsequently all hematological parameters showed recovery at 3 weeks following treatment."
“During the present study, we observed the prevention of a decrease in the lymphocyte count during six weeks of radiotherapy and a
recovery, one month after the completion of radiotherapy, in the SPG group, while lymphocyte counts were decrease after the initiation of
radiotherapy in the control and SPG groups."
“IFN-g production by CD4þ, CD8þ T and CD56þ NK/NKT cells tended to be increased by LEM in this study."
“However, limited data were available from this study and further investigations are necessary."
“The results of this study showed that Beta glucan consumption in breast cancer patients undergoing chemotherapy increased serum level of
IL-12 in intervention group and change in serum level of IL-4 in Beta glucan group comparison with the placebo group was significant after
21 days. Our results also showed white blood cells counts decreased after 21 days of the intervention, however in Beta glucan group, white
blood cells lower decreased in comparison to control group. These findings suggest that Beta glucan usage can be useful as a nutrition
adjuvant therapy in combination cancer treatments."
“Our results showed an increase [of NK cells] … in the glucan-supplemented group (p < 0.0001). In the placebo group, the numbers of NK
cells remained the same with some small decrease … "
“Our clinical study confirmed that it is possible to influence the quality of cellular immunity by glucan supplementation. We conclude that
glucan treatment has positive effects on immunoregulatory activities, particularly on adaptive immunity."
“In summary, oral L.E.M. ingestion is safe and can be effective in improving the QOL and immune function in breast cancer patients receiving
hormone therapy. Nevertheless, this implication needs to be confirmed in further larger-scale studies."
Not reported
“In this study, we showed that b-glucan significantly reduced drainage between days 2 and 8. Drain removal days were significantly earlier.
TNF-a and IL-6 levels on postoperative days 1 and 2 were significantly lower in b-glucan administrated patients."
“In conclusion, the present study showed no efficacy of LNT administration combined with S-1 treatment in patients with unresectable or
recurrent gastric cancer."

LEM: Lentinula edodes mycelium (preparation of b-glucan); QOL: Quality of life; SPG: sizofiran (b-glucan from Schizophyllum commune).

3109
L. Steimbach, A.V. Borgmann, G.G. Gomar et al.
Table 3
Qualitative analysis of adverse events associated to cancer treatment and/or b-glucan supplementation.
Author, year AE Treated arm
Engel-Riedel et al., 2018 The same as in Control arm plus stomatitis,
[3] chills, hemoglobin decreased,
polyneuropathy, dyspnea,
Hazama et al., 2009 [40] Diarrhea, rash, constipation
Ina et al., 2011 [30] The same as in Control arm
Inoue et al., 1993 [25] The same as in Control arm
Karaca et al., 2014 [41] Leukopenia, diarrhea and oral mucositis
Mantovani et al., 1997 No adverse events
[23]
Miyazaki et al., 1995 Not mentioned
[34]
Nagashima et al., 2013 Hematotoxicity, nausea and vomiting after
[6] the first course of chemotherapy without b-
glucan (LEM);
No adverse effects after the second course
of chemotherapy with concomitant b-
glucan (LEM)
Noda et al., 1992 [27] Side effects observed in 11 of 211 patients.
Symptoms observed on the injection site:
redness, swelling and pain. Nausea,
vomiting, drug eruption and rash, increase
in GOT:GPT value.
Okuno et al., 2011 [24] First course of chemotherapy (without
LEM): nausea and abdominal pain
Second course of chemotherapy (with
LEM): no adverse events were observed
Ostadrahimi et al., 2014 Not clearly mentioned
[5]
Richter et al., 2016 [35] Not mentioned
Suzuki et al., 2013 [42] No serious adverse events
Thomas et al., 2017 [4] Neutropenia, leucopenia, anemia,
thrombocytopenia, nausea, diarrhea,
constipation, vomiting, abdominal pain,
stomatitis, fatigue, mucosal inflammation,
chest pain, chills, pyrexia, edema
peripheral, astenia, chest discomfort,
hypersensitivity, nasopharyngitis,
paronychia, decreased apetite,
hypokalaemia, hypomagnesemia, myalgia,
pain in extremity, bone pain, arthralgia,
back pain, tumor pain, polyneuropathy,
paresthesia, dizziness, headache, dysgeusia,
insomnia, cough, dyspnea, dysphonia,
epistaxis, pleural effusion, oropharyngeal
pain, rash, alopecia, dermatitis, pruritus,
skin fissures, dry skin
Yenidogan et al., 2014 Not mentioned
[29]
AE in Control arm
Neutropenia, leukopenia, nausea,
constipation, vomiting, upper
abdominal pain, pyrexia,
thrombocytopenia, hypertension
Neutropenia, pruritus, nausea,
vomiting, thrombocytopenia,
leucopenia, malaise, diarrhea.
Neutropenia, grade 3 Febril
neutropenia, mucositis
Leukopenia, lymphocytopenia
The same as in Treated arm plus
neutropenia, and thrombocytopenia
Not mentioned
Not mentioned
No control arm
Not mentioned
No control arm
Not clearly mentioned
Not mentioned
No control arm
The same as in Treated arm plus withe
blood cell count decreased and
peripheral sensory neuropathy
Not mentioned
3110
Clinical Nutrition 40 (2021) 3104e3113
Conclusion
“AEs reported in these categories, … occurred at
an incidence at least 5% higher in the BTH1677
arm than in the Control arm."
“Four adverse events (5%) that were or were
suspected to have been related to SDL
(Superfine dispersed lentinan) were observed
within the period of SDL treatment” “These
events were grade 2 and disappeared or
remitted within the study period."
“In this preliminary study, there were
essentially no differences in the incidence and
degree of adverse effects between patients who
did and those who did not receive lentinan"
“No side effects ascribable to the SPG
administration were observed in the SPG
group."
“There were no b-glucan-induced side effects."
“Treatment with SPG was proven safe and was
well-tolerated in all patients: no patient
complained of any subjective or objective signs/
symptoms, no adverse events were registered
and no abnormal values of laboratory
parameters were registered during the study."
No information about adverse effects was
encountered.
“These findings indicate that LEM can reduce
the adverse effects of FEC75 therapy, including
hematotoxicity as well as nausea and vomiting,
and help maintain the QOL of the patients."
“None of these (side effects) was serious."
“In summary, ingestion of LEM decreased
adverse events in a preliminary study."
The authors mentioned that white blood cells
count decreased less in the beta-glucan group
than in control group, however there was no
statistic difference.
“Our clinical study confirmed that it is possible
to influence the quality of cellular immunity by
glucan supplementation."
“In this study, no subjects had any serious
adverse events. Therefore, at least in breast
cancer patients receiving hormone therapy, the
oral ingestion of L.E.M. is likely to be safe."
“In terms of safety, BTH1677 combination
therapy was well tolerated among patients … "
“Overall, most AEs were mild or moderate in
severity. Only skin fissures occurred at a 10%
greater incidence in the BTH1677 arm than in
the Control arm (18.6% vs 6.9%)."
L. Steimbach, A.V. Borgmann, G.G. Gomar et al.
Table 3 (continued )
Author, year AE Treated arm
Yoshino et al., 2016 [22] Leucopenia, neutropenia, anemia,
thrombocytopenia, anorexia, nausea,
vomiting, diarrhea, fatigue, stomatitis,
pigmentation, rash lacrimation, hand-foot
syndrome, creatinine elevation and
hyponatremia
AE: Adverse events; LNT: lentinan; LEM: Lentinula edodes mycelium.
Fig. 2. Safety outcomes comparing nausea observed on b-glucan group vs. control group.
The type of b-glucans and way of preparation may significantly
influence their effect on the patient and it is an information that is
poorly described by all authors. Depending on the source (yeast or
different species of mushrooms), there is a class of b-glucans with
different chemical structures among each other, which should be
taken into account on the clinical tests, specially because the
recognition of these BRMs are made by cell membrane receptors
that are strictly specific. Furthermore, the way of extracting/pro-
ducing these compounds may modify their intermolecular in-
teractions and consequently their tridimensional structures [13].
Some authors have mentioned that even the tridimensional
conformation of such molecules are responsible for presence or
absence of biological effects, suggesting that b-glucans in triple
helical conformation are more effective than single helical ones
[39].
Among the selected studies, we observed that 7 trials tested oral
administration of b-glucans, while 4 trials used intravenous (i.v.)
and 4 other studies administered b-glucans by intramuscular in-
jection. Previous reports have demonstrated that b-glucans are
non-digestible fibers and can be directly absorbed in the proximal
gut via intestinal epithelial cells or M-cells in Peyer's patches, fol-
lowed by recognition by antigen-presenting cells (APCs) from GALT
system [17]. The binding of APCs to b-glucans induces these cells to
migrate to bone marrow or to lymph nodes and activate neutro-
phils and lymphocytes, respectively [2]. Taking all this information
into account, it seems that oral or i.v. administration are more
appropriate for the desired activation of immune system. By our
observation, only 1 article registered side effects related to
administration via [27], however no inference could be made from
the other studies relating administration via with efficacy or side
effects. The greatest variability of the studies was related to the
dose and period of administration. b-Glucan doses given to the
patients fluctuated from 2 mg/body/week until 1800 mg/body/day
during 8 weeks. There were trials studying the effect of 7e10 days
with b-glucans intervention, while others evaluated the adjuvant
ingestion for 2e24 months, making it impossible to reach a clear
conclusion about which is the most effective period of b-glucans
Clinical Nutrition 40 (2021) 3104e3113
AE in Control arm Conclusion
The same as in Treated Arm plus febrile “The incidences of haematologic and non-
neutropenia haematologic adverse events were similiar in
both groups.” “The proportions of patients who
terminated treatment because of intolerable
adverse events were similar: 13,1% in the S-1
group and 19,9% in the s-1 plus LNT group."
ingestion. Moreover, cancer stages and different types of cancer
could not be compared and may also influence the prognosis of
patients receiving b-glucans.
The three studies evaluated on meta-analysis were recently
published and despite of their low heterogeneity (I2 ¼ 0%), they
presented unclear and high risk of bias in 5 of the 7 evaluated
domains. Different from what is expected based on scientific liter-
ature, that the b-glucan administration may reduce immune
depression and also the side effects of chemotherapy, our meta-
analysis results showed a tendency to increase nausea (p ¼ 0.05)
in patients who received chemotherapy plus b-glucan. However,
the conclusions obtained should be extrapolated with caution due
to the low number of studies. Selection, performance and detection
bias showed the higher risk for majority of studies indicating poor
quality of the trials. Furthermore, we included industry financing
support as other risk of bias, and observed that at least 6 of the trials
were financed by b-glucans producers, which could lead to dubious
interpretations.
Unfortunately, we could not assess information of Chinese and
Japanese publications due to language incompatibility and also
restrict access to their scientific journals. Although the language
and culture of oriental countries should be preserved as any other
cultural heritage, in science, the chosen language should be uni-
versal with the aim of enabling researchers to assess all scientific
information and contribute to the whole community.
5. Conclusion
This systematic review carefully evaluated all the English writ-
ten trials available with the aim of compiling important informa-
tion about the interesting biological effects that seems to be related
to fungal b-glucans, as exemplified on cells and animal studies, as
well as by the folk usage of b-glucan in traditional oriental medi-
cine. The compilation of data included 16 trials involving 1650
patients, with arm sizes varying from 9 until 200 patients, however
the majority of studies involved small groups, which weakened the
results and statistical analysis. Qualitative evaluation summed by
3111
L. Steimbach, A.V. Borgmann, G.G. Gomar et al.
authors conclusion of each trial showed that fungal b-glucan
administration concomitant to standard cancer treatments reduced
the side effects of chemo and radiotherapy and helped with the
patient recovery. However, some of the studies did not observe
statistical differences between b-glucan treated vs. control groups
and further evidences are required to reach to such conclusions.
Moreover, the meta-analysis of most studied side effects did not
show statistical difference between both groups; and surprisingly,
b-glucan treated patients reported a tendency to present more
nausea than patients who received only chemotherapy. It is
important to mention that due to the low number of studies, this
result should be extrapolated with caution. We expect that this
compilation serves as guidance for the next clinical trials with the
aim of unifying scientific knowledge about a possible adjuvant in
the cancer treatment.
Funding
Part of this study was supported by Coordenaça ~o de Aperfei-
çoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance
Code 001.
Author's contribution
Study design: LS, FRS; Data search, extraction and analysis: LS,
AVB, GGG, LVH, RR, FRS; Drafting the manuscript: LS, AVB, GGG,
LVH, RR, DPA, FRS; Statistical analysis: DPA; Final approval of the
manuscript to be submitted: LS, AVB, GGG, LVH, RR, DPA, FRS.
Conflict of interest
All the authors declared no conflict of interest.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.clnu.2020.11.029.
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