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Dorothy Cimino Brown and Jennifer Reetz

Veterinary Clinical Investigations Center, Department of Clinical Studies, School of Veterinary Medicine and University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA 19104-6010, USA

Single Agent Polysaccharopeptide Delays Metastases and Improves Survival in Naturally Occurring Hemangiosarcoma
Evidence-Based Complementary and Alternative MedicineVolume 2012 (2012), Article ID 384301, 8 pagesdoi:10.1155/2012/384301

Introduction

As a Veterinarian, you are most assuredly aware of the 2008 World Health Organization's World Cancer Report, which suggests that the global cancer rate will increase by 20 million new diagnoses per year by 2020. As many of these will be in countries that lack traditional resources for more "standard treatments", alternative means of treatment are a viable and needed goal. It is also expected that improvements in the more traditional methods of treatment, such as radiation therapies, surgery and chemotherapy will improve, but the costs sometimes exceed what the patient (dog) owners are willing or able to pay. Again, an alternative treatment option will help in relieving this problem. Lastly, traditional treatment methods usually result in loss of appetite, depressed immune system, and other side effects, which also need to be considered when deciding on a regimen for one's dog.

While there are numerous products on the market that claim to be an alternative treatment for cancer, only I'm-Yunity ® has been clinically proven to aid in the prevention and treatment of canine cancer. I'm-Yunity ® is derived from the Coriolus Versicolor , or Yuzhi mushroom has a long history of providing immune enhancing properties. Over the past twenty years, there have been numerous studies of the supplement including University of California, San Francisco, New York Medical College, Shaghai Medical University and most recently at University of Pennsylvania, which was specifically for dogs, that have shown the benefits of I'm-Yunity ® in cancer treatment.


Study Design

This pilot study was a randomized, double-blind, and multidose study of I'm-Yunity in dogs with a histopathologic diagnosis of splenichemangiosarcoma. Dogs were recruited from a universitybased tertiary care veterinary academic teaching hospital. A computer generated randomization sequence with 3 potential treatment groups (I'm-Yunity 25, 50, or 100 mg/kg/day) was generated at an off -site pharmacy. The randomization scheme was stratified according to the presence or absence of metastatic disease documented at the time of diagnosis. The sequence was concealed so that no members of the research team were aware of the group to which a dog would be allocated as it was evaluated in the screening process. Once screening was completed and a dog was considered eligible for inclusion in the study, a unique study number was assigned in sequence. The study number and body weight of each dog were then provided to the pharmacy. Pharmacy personnel matched the study number with their randomization sequence, formulated the appropriate treatment, and packaged capsules for distribution by the investigators. Capsules were formulated to appear identical. Thus, all study personnel and the owners of the dogs were.

I'm-Yunity®

I'm-Yunity ® (brand name) is an extract of Coriolus versicolor mushroom commonly referred to as cloud mushroom, turkey tail, or Yunzhi mushroom in China. The mushroom's active ingredient, to which the product is standardized, is PSP, which is short for polysaccharopeptide or polysaccharide peptide (both names are used in the literature). It is important to mention brand name when stating PSP use in this study because various brands can have varying amounts of polysaccharides and peptides in what they claim is PSP. In the literature, it is commonly refereed to just as PSP; however, all PSP's may not be the same as it is considered a general term for a combination of polysaccharides and peptides together and potentially PSP could be isolated from another mushroom altogether [23, 24]. I'm-Yunity ® is Coriolus versicolor mushroom extract, specifically from the cov-1 strain. PSP in the form of I'm-Yunity ® is isolated from the mycelium of the mushroom and not the fruiting body as is the claim with other brands. It was supplied by Integrated Chinese Medicine Holdings, Ltd. (Hong Kong, China), as a mushroom product produced, using a proprietary fractionation scheme, from deep-layer cultivated mycelia of cov-1 according to good manufacturing practice (GMP) standards. The molar ratio of monosaccharides in polysaccharide moiety of I'm-Yunity ® PSP is glucose : galactose : mannose : xylose : arabinose=8.2 : 1.5 : 2.4 : 2.4 : 1.0. In I'm-Yunity ® PSP, soluble polysaccharide is 46%, and soluble protein is 31%. The amino acids in the protein portion are presented in Table 1 [25]. Quality control of I'm-Yunity involved determination of heavy metal contents, microorganism contamination, authentication ofelution properties on high pressure liquid chromatography, and supplementary bioactivity-guided assays, performed by laboratories at the manufacturing facilities and also independently by commercial testing centers.

Eligibility

Dogs were screened for enrollment from September 2008 through November 2009 following Institutional Animal Care and Use Committee approval by the University and written informed consent by the owners of the dogs. Inclusion criteria were histopathologic diagnosis of splenic hemangiosarcoma and life expectancy!4 weeks. Only dogs whose owners opted not to pursue chemotherapy following splenectomy were eligible for enrollment.

Evaluation of Response

Amino acid Content (%)
Aspartic acid 4.0
Threonine 2.3
Serine 3.2
Glutamic acid 5.8
Proline 1.0
Glycine 2.6
Alanine 2.6
Cysteine 0.9
Valine 1.8
Methionine 0.4
Isoleucine 2.2
Leucine 2.4
Tyrosine 1.5
Phenylalanine 1.5
Tryptophan 1.7
Lysine 2.3
Tyrosine 1.5
Phenylalanine 1.5
Tryptophan 1.7
Lysine 2.3
Histidine 0.7
Arginine 1.8

Table 1: Amino acids in the protein portion of I'm-Yunity PSP (polysaccharopeptide).

All dogs were evaluated at baseline to ensure that they were stable in their general condition. Hematological and biochemical tests (complete blood count, electrolytes, liver and renal function), 3-view digital thoracic radiographs, and contrast enhanced harmonic abdominal ultrasound [26] for baseline assessment of abdominal metastatic disease (liver, omentum, mesentery) were performed. All diagnostics were repeated at monthly follow-up visits. Reports, digital images, and video recordings of the baseline studies were compared to each monthly follow-up study. Based on this comparison, the board certified radiologist made the determination of progression of metastatic disease. Time to progression was defined as the number of days from the baseline assessment to the first evaluation day in which progression was documented by the radiologist based on contrast enhanced harmonic abdominal ultrasound.

25 mg/kg/day 50 mg/kg/day 75 mg/kg/day
Breed 1 mixed 4 pure 2 mixed 3 pure 2 mixed 3 pure
Age (years) 9.0 ± 1.9 9.6 ± 2.7 8.6 ± 1.1
Weight (kg) 34.0 ± 7.0 28.2 ± 4.8 30.0 ± 12.8
Sex 1 female 4 male 2 female 3 male 1 female 4 male
Metastatic disease present at enrollment 2 No 3 Yes 2 No 3 Yes 2 No 3 Yes
Time from diagnosis to study enrollment (days) 16 ± 9 23 ± 10 20 ± 8

Table 2: Baseline characteristics of 15 dogs diagnosed with splenic hemangiosarcoma randomized to one of three doses of I'm-Yunity®.

Statistical Analysis

Descriptive statistics were calculated. Continuous data were expressed as mean and SD, unless not normally distributed, in which case median values and ranges were reported. Categorical data were expressed as frequencies. Because of the non-normality of the data, the Kruskal Wallis test was used to evaluate the changes that occurred in complete blood count and serum biochemistry parameters within each dose group and between dose groups over time. The Mann Whitney test was used to compare the median days to progression of abdominal metastases between the high-(100 mg/kg/day) and low-(25 mg/kg/day) dose groups. Median survival times were determined by the use of the Kaplan-Meier product limit method and log rank analysis was used to compare survival curves amongst dose groups. P < 0. 05 was considered statistically significant and all analyses were performed using STATA 11.

abdominal-metastases

Figure 1: Days to progression of abdominal metastases for 15 dogs diagnosed with splenic hemangiosarcoma randomized to one of three doses of I'm-Yunity (5 dogs in each dose group). * Denotes a statistically significant difference in median days to progression of abdominal metastases between groups (30 versus 112 days).

Results

The baseline characteristics of 15 dogs with splenic hemangiosarcoma enrolled in the study were equally distributed amongst the three treatment groups (25 mg/kg/day 50 mg/kg/day, or 100 mg/kg/day) via randomization and are presented in Table 2. In a double-blind (investigator and owner) manner, all dogs received capsules containing PSP daily from baseline assessment until death. One dog, in the 25 mg/kg/day dose group, developed hypercalcemia secondary to a parathyroid adenoma eight months after enrolling in the study. This dog was maintained on I'm- Yunity throughout treatment for the adenoma and was followed with all evaluations according to protocol until death. No unexpected comorbidities developed in any of the other dogs. There was no significant variability in any complete blood count or serum biochemistry parameter in any dose group or between dose groups through the course of the study.

Table 3 - Median and range blood chemistry values for 15 dogs with hemangiosarcoma treated with 25, 50, or 100mg/kg/day I'm-Yunity® - and Median and range complete blood count values for 15 dogs with hemangiosarcoma treated with 25, 50, or 100mg/kg/day I'm-Yunity.

High-Dose PSP Delayed the Progression of Metastases

The median time to development or progression of abdominal metastases was significantly delayed in dogs receiving 100 mg/kg/day I'm-Yunity (112 days; range 30 to 308 days) compared to dogs receiving 25 mg/kg/day (30 days; range 16 to 126 days; P=0. 046). Dogs receiving 50 mg/kg/day I'm-Yunity had median 35 days to progression of metastases (range 23 to 331 days), which was not significantly different than the 25 or 100 mg/kg/day groups ( Figure 1). 3.2. Median Survival Time Increased as Dose of PSP Increased and High Dose PSP Provided the Longest Median Survival Times Reported to Date. The Kaplan Meier survival curves for the three dose groups are presented in ( Figure 2). While there was no statistically significant diff erence in the survival curves amongst the 3 dose groups, the two highest dose groups had median survival times longer than the longest median survival time reported in the literature to date, which is 86 days, as compared to 117 days in dogs receiving 50 mg/kg/day I'm-Yunity and 199 days in dogs receiving 100 mg/kg/day.

Conclusions

The objective of this clinical study was to collect pilot data on the potential effect of I'm-Yunity ® progression of abdominal metastases and mortality associated with cancer in dogs. This study was generated to collect outcome data so that definitive proof-of-concept study could be appropriately powered along with evaluating the potential doses and range (note Tables 3 and 4 above).

The objectives of the study were met and the range of potential doses was determined. However, the level of higher than expected, positive results was realized. In such a study, the results were far better than anticipated. For full results, please refer to the UPenn Study attached.

There are additional studies being conducted, now, both here and in China.

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