Complete response of a recurrent, multicentric malignant glioma in a patient treated with phenylbutyrate

Complete response of a recurrent, multicentric malignant glioma in a patient treated with phenylbutyrate
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http://www.ncbi.nlm.nih.gov/pubmed/12241121/
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J Neurooncol. 2002 Sep;59(3):239-42
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http://www.ncbi.nlm.nih.gov/m/pubmed/12241121/
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Journal of Neuro-Oncology
Volume 59, Issue 3 , pp 239-242
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http://link.springer.com/article/10.1023%2FA%3A1019905127442
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DOI
10.1023/A:1019905127442
Journal of Neuro-Oncology 59: 239–242, 2002
2002 Kluwer Academic Publishers. Printed in the Netherlands
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http://ketonutrition.net/wp-content/uploads/2013/01/Baker_Complete_response_of_GBM_with_Phenylbutyrate_2002.pdf
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Neuro-Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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REFERENCES:
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6. Gore SD, SAMID D, Weng LJ: Impact of the putative differentiating agents sodium phenylbutyrate and sodium phenylacetate on proliferation, differentiation, and apoptosis of primary neoplastic myeloid cells. Clin Cancer Res 3(10): 1755–1762, 1997
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7. Ram Z, SAMID D, Walbridge S, Oshiro EM, Viola JJ, Tao-Cheng JH, Shack S, Thibault A, Myers CE, Oldfield EH: Growth inhibition, tumor maturation, and extended survival in experimental brain tumors in rats treated with phenylacetate. Cancer Res 54: 2923–2927, 1994
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8. Thibault A, SAMID D, Cooper MR, Figg WD, Tompkins AC, Patronas N, Headlee DJ, Kohler DR, Venzon DJ, Myers CE: Phase I study of phenylacetate administration twice daily to patients with cancer. Cancer 75: 2932–2938, 1995
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9. SAMID D, Hudgins WR, Shack S, Liu L, Prasanna P, Myers CE: Phenylacetate and phenylbutyrate as novel, non-toxic differentiation inducers. Adv Exp Med Biol 400A: 501–505, 1997
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10. Chang SM, Kuhn JG, Robins HI, Schold SC, Spence AM, Berger MS, Mehta MP, Bozik ME, Pollack I, Schiff D, Gilbert M, Rankin C, Prados MD: Phase II study of phenylacetate in patients with recurrent malignant glioma: a North American Brain Tumor Consortium report. J Clin Oncol 17(3): 984–990, 1999
http://m.jco.ascopubs.org/content/17/3/984.full.pdf
SAMID D References
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11. Buckner JC, Malkin MG, Reed E, Cascino TL, Reid JM, Ames MM, Tong WP, Lim S, Figg WD: Phase II study of antineoplastons A10 (NSC 648539) and AS2-1 (NSC 620261) in patients with recurrent glioma. Mayo Clin Proc 74(6): 641–642, 1999
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12. SAMID D, Ram Z, Hudgins WR, Shack S, Liu L, Walbridge S, Oldfield EH, Myers CE: Selective activity of phenylacetate against malignant gliomas: resemblance to fetal brain damage in phenylketonuria. Cancer Res 54: 891–895, 1994
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Antineoplastons: Phenylacetylglutaminate (PG or PAG), Phenylacetate (PN), and Phenylbutyrate (PB):
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https://stanislawrajmundburzynski.wordpress.com/2013/06/17/phenylacetylglutaminate-pg-or-pag-phenylacetate-pn-and-phenylbutyrate-pb/
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Phenylbutyrate (PB):
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https://stanislawrajmundburzynski.wordpress.com/2013/06/18/phenylbutyrate-pb/
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Phenylacetate (PN):
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https://stanislawrajmundburzynski.wordpress.com/2013/06/18/phenylacetate-pn/
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Phenylacetylglutamine (PG or PAG):
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https://stanislawrajmundburzynski.wordpress.com/2013/06/18/phenylacetylglutamine-pg-or-pag/
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Burzynski, China, and Dvorit D. Samid:
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https://stanislawrajmundburzynski.wordpress.com/2013/02/21/burzynski-china-dvorit-d-samid/
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Critiquing: Dr. David H. “Orac” Gorski and The Skeptics™ http://www.scienceblogs.com/Insolence
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https://stanislawrajmundburzynski.wordpress.com/2013/08/08/critiquing-dr-david-h-orac-gorski-and-the-skeptics/
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Critiquing: Wikipedia – Burzynski Clinic

[1] – Wikipedia, claims:
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“There is a scientific consensus that antineoplaston therapy is unproven and of little promise in treating cancer””
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“… a Mayo Clinic study found no benefit from antineoplaston treatment.[1]””
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“The Memorial Sloan-Kettering Cancer Center has stated: “Bottom Line: There is no clear evidence to support the anticancer effects of antineoplastons in humans.”[1]””
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Interestingly, the above 1st claim by “Wikipedia” does NOT provide any specific citation(s), reference(s), or link(s) to support this claim
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[2] – 2/1999 – What “Wikipedia” does NOT advise the reader about the 2nd and 3rd claims, is that the conclusion of the study was:

“Although we could not confirm any tumor regression in patients in this study, the small sample size precludes definitive conclusions about treatment efficacy
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[3] – 6/1999 – Wikipedia also does NOT point out that Burzynski replied to the 2/1999 publication, that:

[A] – Study tested dosing regimen known to be ineffective

[B] – Dosages of A10 and AS2–1 used in study were meant for treatment of single small lesion (<5 cm)

5 of the 6 evaluable patients had either multiple nodules or tumors larger than 5 cm

[C] – As the provider of A10 and AS2–1, I strongly suggested to the National Cancer Institute (NCI) that these patients receive a much higher dose, consistent with greater tumor load

[D] – Study was closed when I insisted the NCI either increase the dosage or inform the patients that the drug manufacturer believed that the treatment was unlikely to be effective at the dosages being used
(letter to Dr M. Sznol, NCI, on 4/20/1995)

[E] – Review of clinical data in the article by Buckner et al proves validity of my position

[F] – Study patients had extremely low plasma antineoplaston levels

My phase 2 study dosage regimen produced plasma phenylacetylglutamine (PG) levels 35 times greater, phenylacetylisoglutamine (isoPG) levels 53 times greater, and phenylacetate (PN) levels 2 times greater than those reported by Buckner et a1 [1]

[G] – Clinical outcomes reported by Buckner et al, based on inadequate dosage schedule, differ dramatically from my phase 2 studies in which higher dosage regimen was used

[H] – They reported no tumor regression

In contrast, in 1 of my ongoing studies on protocol BT-9, 4 of 8 evaluable patients with astrocytoma had objective responses [2]

[I] – Difference in outcomes primarily due to difference in dosage schedules

[J] – Another factor that may have caused a lack of response in the study by Buckner et al is duration of treatment was too brief

Almost all patients in their study received treatment for less than 30 days

1 patient received only 9 days of treatment

Current studies indicate objective tumor responses usually observed after 3 months of therapy

Additional 8 months of treatment usually needed to obtain maximal therapeutic effect

[K] – Ambiguities in response evaluation and analysis in article by Buckner et al

In.2 patients, tumor necrosis attributed to “radio-necrosis”

Interpretation’s clouded by fact antineoplaston-induced necrosis can be indistinguishable from radionecrosis

[L] – Analysis by Buckner et al could’ve highlighted 2 patients with recurrent glioblastoma who survived for more than 1 year

This is of interest because patients typically have life expectancy of 3 to 6 months

[M] – At time of the study by Buckner et al, the sponsor, NCI, decided against higher dosing regimen I proposed and closed the study

Study used dosing regimen known to be ineffective
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[4] – 10/4/1991 – Five doctors (3 from the Cancer Therapy Evaluation Branch (CTEP); including the Head of the Quality Assurance and Compliance Section, Regulatory Affairs Branch, Cancer Therapy Evaluation Program, Department of Health &Human Services, Public Health Service, National Institutes of Health, National Cancer Institute, and 2 invited consultants; including one from the National Institutes of Health (NIH) Clinical Center) visited the offices of Dr. Stanislaw R. Burzynski
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[5] – 10/31/1991 – Michael A. Friedman, M.D. Associate Director, Cancer Therapy Evaluation Program (CTEP), Department of Health &Human Services, National Institutes of Health, National Cancer Institute, sent a one page Memorandum to Bruce A. Chabner, M.D., Director, Division of Cancer Treatment, which stated, in part:

“I thought you would be interested in this for several reasons:”

“3. Antineoplastons deserve a closer look”

“It turns out that the agents are well defined, pure chemical entities
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“The human brain tumor responses are real”

20130911-102213.jpg
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[6] – 11/15/1991 – Michael J. Hawkins, M.D., Chief, Investigational Drug Branch, Department of Health &Human Services, Public Health Service, National Institutes of Health, National Cancer Institute, sent a 7 page letter to Decision Network, which stated, in part, on page one:
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“It was the opinion of the site visit team that antitumor activity was documented in this best case series … “

20130911-122216.jpg
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[7] – 12/2/91 – NCI (National Cancer Institute), Decision Network Report on Antineoplastons, states in part, on page 11:
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“The site visit team determined that antitumor activity was documented in this best case series … “

20130911-134634.jpg
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[8] – CANCER FACTS
National Cancer Institute • National Institutes of Health Department of Health and Human Services, Antineoplastons, pg. 1

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“The reviewers of this series found evidence of antitumor activity … “

20130911-094155.jpg
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[9] – Page 1 of 6, BlueCross BlueShield of Alabama, Antineoplaston Cancer Therapy, Policy #: 280, Category: Medicine, states, in part, on page 2 of 6:

Key Points:
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“The reviewers of this series found evidence of antitumor activity … “
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[10] – ANTINEOPLASTON THERAPY, HS-183, pg. 2
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“After the reviewers found some evidence of antitumor activity … “
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These facts indicate to me that Wikipedia’s claim about “antineoplastons”, is “debatable”

Maybe they should have learned how to use the Freedom of Information Act (FOIA)
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REFERENCES:
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[1]
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http://en.wikipedia.org/wiki/Burzynski_Clinic
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http://en.m.wikipedia.org/wiki/Burzynski_Clinic
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Antineoplastons, Memorial Sloan-Kettering Cancer Center
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[2] – 2/1999 – A10 and AS2-1 – Phase II
Mayo Clinic Proceedings
http://www.ncbi.nlm.nih.gov/m/pubmed/10069350
Phase II Study of Antineoplastons A10 (NSC 648539) and AS2-1 (NSC 620261) in Patients With Recurrent Glioma

Material & Methods:

Patients received escalating doses of A10 and AS2-1 by multiple intermittent intravenous injections with use of portable programmable pump to the target daily dose of 1.0 g/kg for A10 and of 0.4 g/kg for AS2-1

Mean steady-state plasma concentrations of phenylacetate & phenylacetylglutamine after escalation to the target doses of A10 and AS2-1 were 177 +/-101 ug/mL & 302 +/- 102 ug/mL, respectively

Results:

9 patients were treated, in 6 of whom treatment response was assessable in accordance with protocol stipulations
http://linkinghub.elsevier.com/retrieve/pii/S0025-6196(11)63835-4
Comment in Jun; 74 (6): 641-2
http://www.sciencedirect.com/science/article/pii/S0025619611638354
Mayo Clin Proc 74(2):9 (1999), PMID .10069350
http://www.mayoclinicproceedings.org/article/S0025-6196(11)63835-4/fulltext
DOI: 10.4065/74.2.137
http://download.journals.elsevierhealth.com/pdfs/journals/0025-6196/PIIS0025619611638354.pdf
Mayo Clin Proc 1999; 74: 137–145
http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2796.2003.01098.x/full
Mayo Clin Proc 1999; 74: 137–45
http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2796.2003.01098.x/references
J C Buckner, M G Malkin, E Reed, T L Cascino, J M Reid, M M Ames, W P Tong, S Lim, W D Figg
http://onlinelibrary.wiley.com/store/10.1046/j.1365-2796.2003.01098.x/asset/j.1365-2796.2003.01098.x.pdf?v=1&t=hbs6xce2&s=3423e3cd1955667e8e8cdf33323faf0bd85b6a29
Department of Oncology, Mayo Clinic Rochester, Minnesota USA
http://onlinelibrary.wiley.com/store/10.1046/j.1365-2796.2003.01098.x/asset/j.1365-2796.2003.01098.x.pdf?v=1&t=hbrndkdf&s=e0af2d3bfb13841852d92a839d3a4932a5f4bb48
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[3] – 6/1999 – A10 and AS2-1
http://www.ncbi.nlm.nih.gov/pubmed/10377942
Efficacy of antineoplastons A10 and AS2-1
http://www.ncbi.nlm.nih.gov/m/pubmed/10377942
S R Burzynski
Mayo Clin Proc 74 (6): 641-2 (1999),
Mayo Clin Proc. 1999 Jun; 74 (6): 641-2
http://linkinghub.elsevier.com/retrieve/pii/S0025-6196(11)64143-8
Comment on
Mayo Clin Proc. 1999 Feb; 74 (2): 137-45 PMID .10377942
http://www.mayoclinicproceedings.org/article/S0025-6196(11)64143-8/fulltext
Mayo Clin Proc. 1999
http://download.journals.elsevierhealth.com/pdfs/journals/0025-6196/PIIS0025619611641438.pdf
Comment on
Mayo Clinic Proc. 1999; 74: 641–642 (letter)
http://linkinghub.elsevier.com/retrieve/pii/S0025-6196(11)64143-8
Mayo Clin Proc
74 (6): 641-2
http://download.journals.elsevierhealth.com/pdfs/journals/0025-6196/PIIS0025619611641438.pdf
Mayo Clin Proc 74 (6): 1 (1999),
Elsevier Ltd.
DOI: 10.4065/74.6.641
1999 – A10 and AS2-1 – Mayo
Buckner, Reid, & Malkin
Mayo Clin Proc 74 (6): 2 (1999),
Elsevier Ltd.
DOI: 10.4065/74.6.641-a
http://www.mayoclinicproceedings.org/article/S0025-6196(11)64144-X/fulltext
Mayo Clinic Proceedings
74(6):2 1999 Elsevier Ltd.
http://download.journals.elsevierhealth.com/pdfs/journals/0025-6196/PIIS002561961164144X.pdf
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[8]
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http://www.emory.edu/KomenEd/PDF/Treatment/Antineoplastons.pdf
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[9]
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https://www.bcbsal.org/providers/policies/final/280.pdf
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[10]
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https://www.wellcare.com/WCAssets/corporate/assets/HS183_Antineoplaston_Therapy.pdf
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