Backdrop: (1/19/16) -- As background, Michael called me on December 19th and asked if I could write another article about Provectus for insertion again into MicroCap Review, this time the Winter/Spring 2016 edition. He offered no explicit or implicit compensation to me at the time (nor since) for the proposed work. I agreed to write a draft article, turning it over to him in on the 28th, after which I assumed his Stock News Now/MicroCap Review and/or PLR staff might edit the material or shorten the article prior to printing in or submission to the magazine, respectively.
My draft article, reproduced in its entirely below, appears to have mostly formed the article Reproducibility, the Hallmark of Western Science that appeared on pages 91-94 of the Winter/Spring 2016 edition of MicroCap Review, a magazine published by SNN (although I believe SNN shortened my original article). The last sentence of the magazine articles notes the disclosure: "The company [Provectus] paid consideration to SSN or its affiliates for this article." I believe the consideration was payment to place the articles in the magazine editions. I neither sought nor received compensation (or its implicit or explicit promise) from Provectus, PLR or SNN/its affiliates for my writing.]
Reproducibility, the Hallmark of Western Science
When Provectus Biopharmaceuticals Chairman, CEO and co-founder Dr. Craig Dees, PhD talks about his company’s investigational cancer drug PV-10 (made from century’s old Rose Bengal), he points to a history of reproducible therapeutic features, and reproduced preclinical and clinical results by multiple clinicians and researchers in multiple cancer indications. Craig refers to reproducibility as the hallmark of Western science. If a scientist cannot repeat an experiment’s outcome, and if another scientist cannot replicate that result, the veracity of the original work and claims made from it may be questionable.
Wikipedia’s reproducibility entry provides historical background:
The first to stress the importance of reproducibility in science was the Irish chemist Robert Boyle, in England in the 17th century. Boyle's air pump was designed to generate and study vacuum, which at the time was a very controversial concept. Indeed, distinguished philosophers such as René Descartes and Thomas Hobbes denied the very possibility of vacuum existence. Historians of science Steven Shapin and Simon Schaffer, in their 1985 book Leviathan and the Air-Pump, describe the debate between Boyle and Hobbes, ostensibly over the nature of vacuum, as fundamentally an argument about how useful knowledge should be gained. Boyle, a pioneer of the experimental method, maintained that the foundations of knowledge should be constituted by experimentally produced facts, which can be made believable to a scientific community by their reproducibility. By repeating the same experiment over and over again, Boyle argued, the certainty of fact will emerge.In drug research and development there has been longtime and widespread lack of reproducibility. A 2011 Wall Street Journal article highlighted this:
This is one of medicine's dirty secrets: Most results, including those that appear in top-flight peer-reviewed journals, can't be reproduced. [1]A 2012 Reuters story [2] expanded on the two studies mentioned in the Journal article:
During a decade as head of global cancer research at Amgen, C. Glenn Begley identified 53 "landmark" publications – papers in top journals, from reputable labs – for his team to reproduce. Begley sought to double-check the findings before trying to build on them for drug development. Result: 47 of the 53 could not be replicated” [3]…Scientists at Bayer did not have much more success. In a 2011 paper titled, "Believe it or not," they analyzed in-house projects that built on "exciting published data" from basic science studies. "Often, key data could not be reproduced," wrote Khusru Asadullah, vice president and head of target discovery at Bayer HealthCare in Berlin, and colleagues. Of 47 cancer projects at Bayer during 2011, less than one-quarter could reproduce previously reported findings, despite the efforts of three or four scientists working full time for up to a year. Bayer dropped the projects. [4]Some in the pharmaceutical industry may not care about irreproducible work. Drs. Arturo Casadevall, MD, PhD and Ferric Fang, MD observed in their 2010 paper:
There may be no more important issue for authors and reviewers than the question of reproducibility, a bedrock principle in the conduct and validation of experimental science…Given the requirement for reproducibility in experimental science, we face two apparent contradictions. First, published science is expected to be reproducible, yet most scientists are not interested in replicating published experiments or reading about them…This leads to a second paradox that published science is assumed to be reproducible, yet only rarely is the reproducibility of such work tested or known. In fact, the emphasis on reproducing experimental results becomes important only when work becomes controversial or called into doubt…The assumption that science must be reproducible is implicit yet seldom tested, and in many systems the true reproducibility of experimental data is unknown or has not been rigorously investigated in a systematic fashion. Hence, the solidity of this bedrock assumption of experimental science lies largely in the realm of belief and trust in the integrity of the authors. [5]In Rose Bengal, PV-10’s active pharmaceutical ingredient [6], Provectus’ co-founders discovered a small molecule lying around in plain sight of Big Pharma for more than 130 years – from Rose Bengal’s creation by Gnehm in the 1880s [7], to American doctor G.D. Delprat’s anecodatal patient-reported outcomes in the 1920s [8], to Japanese researchers Ito et al.’s preclinical observations of dose-dependent increases in survival in the 1980s [9], to the co-founders’ formal discovery of Rose Bengal’s tumor inhibiting properties in the 1990s [10].
Explaining how PV-10 worked was a secondary consideration for Craig who fervently believed Provectus had a ready-made drug product from the outset that worked very well. His fact-based belief, however, belied the arduous, not so straightforward, lengthy and opaque FDA drug approval process all drug companies must traverse, irrespective of Craig’s further belief that approval did not require explanation of mechanism. More daunting was the reality of attempting to bring to market the chemical-oriented cancer therapy of this forgotten compound that had not only an unappreciated treatment delivery route (intratumoral or intralesional), but also two unrecognized mechanisms of action (one local and one systemic).
Craig and his fellow Provectus co-founders, President Dr. Timothy Scott, PhD and CTO Dr. Eric Wachter, PhD, were outsiders to the pharmaceutical industry at the outset of this journey. Hailing from Tennessee’s Oak Ridge National Laboratory, a U.S. Department of Energy multi-program science and technology facility with a rich history of discovery and innovation, they had been technology inventors and R&D 100 Award winners [11]. But if, as Casadevall and Fang wrote, the value of science is inextricably linked to the integrity of the scientists and researchers experimenting on it, and if reproducibility, according to the Journal, Reuters and others [12], is a fundamental challenge for the pharmaceutical industry, how could Provectus’ outsiders convince the FDA, the medical community, Big Pharma, healthcare-focused Wall Street, biotechnology investors, and the media of the veracity of their claims about PV-10 and its potential groundbreaking therapeutic benefits for treating solid tumor cancer?
One way was to generate more data that further argued for PV-10’s clinical value proposition. Another was to conclusively demonstrate the reproducibility of Rose Bengal therapeutic benefit.
Provectus presented preliminary full study data of its Phase 2 trial of PV-10 in patients with advanced melanoma at the Melanoma 2010 Congress.[13] Final data were presented at the European Society for Medical Oncology 2012 Congress.[14] A 2015 peer-reviewed article about the data was published in the Annals of Surgical Oncology:
For target lesions, the best overall response rate was 51%, and the complete response rate was 26%. Median time to response was 1.9 months, and median duration of response was 4.0 months, with 8% of patients having no evidence of disease after 52 weeks. Response was dependent on untreated disease burden, with complete response achieved in 50% of patients receiving PV-10 to all of their disease. Response of target lesions correlated with bystander lesion regression and the occurrence of locoregional blistering. Adverse events were predominantly mild to moderate and locoregional to the treatment site, with no treatment-associated grade 4 or 5 adverse events. [15]Eric, who has led all aspects of Provectus’ clinical development program, met with the FDA in 2010 for the first of three end-of-Phase 2 meetings related to the company’s melanoma work (the others were held in 2011). He was told a consensus Phase 3 trial randomized against a control was necessary. [16] Eric continued to collaborate with the FDA on PV-10’s initial pathway to approval, ultimately reaching a 2013 agreement with the Agency on the indication of locally advanced cutaneous melanoma (Stage III disease). [17] Despite denying Provectus’ request in 2014 for breakthrough therapy designation for this indication [18], the FDA subsequently allowed the company’s pivotal Phase 3 trial that began treating patients in 2015. [19] The hypothesis of this trial is that the spread of melanoma from Stage III to Stage IV may be forestalled or prevented if all disease is treated with PV-10.
Provectus presented preliminary initial study data of the company’s Phase 1 trial of PV-10 in patients with hepatocellular carcinoma and cancer metastatic to the liver at the 2015 European Society for Medical Oncology World Congress on Gastrointestinal Cancer [20]:
For the current study two cohorts of patients, one with non-resectable HCC (n=6 patients overall, 7 tumors injected) and the second with other forms of cancer metastatic to the liver (n=7, 3 colorectal tumors, 2 non-small cell lung, 2 melanoma and 1 ovarian) underwent a single percutaneous injection of PV-10 guided by CT to one target lesion in the liver at least 1 cm in diameter…For the first analysis of five patients (six tumors) who had longer-term assessment, two patients showed no evidence of disease at more than 40 months follow-up according to RECIST and EASL criteria… Furthermore, at up to 54 months follow-up 10 out of the initial 13 patients were alive, with one death due to cardiac comorbidity, one to serious adverse events and one to HCC progression. [21]Returning to melanoma, in 2015 Provectus began a Phase 1b trial combining PV-10 and Merck & Co.’s approved immune checkpoint inhibitor Keytruda (pembrolizumab) in patients with advanced melanoma (Stage IV disease). The approach of this combination study, where not all tumor burden is accessible to PV-10 injection, would be for the latter to enhance the systemic immune response generated by the former. PV-10 elicits a functional anti-tumor T cell response in patients, while Keytruda increases the anti-tumor function of their T cells.
Starting in 2010 Eric also commenced a parallel effort to elucidate PV-10’s dual mechanisms of action. His goals were to fully validate the so-called bystander effect, whereby non-injected, distant tumors shrank or were completely destroyed as a result of injecting tumors elsewhere, and to assess immune markers in patients’ peripheral blood and tumor tissue. [22]
During an ASCO 2010 investor presentation, Eric presented about the bystander effect, which is a tumor-specific response brought on by PV-10 treatment:
Response in untreated proximal and visceral lesions consistent with immunologic process. PV-10 chemoablation yields immediate reduction in tumor burden. Ablation appears to recruit immune cells to exposed tumor antigens. [23]He sought to have a translational cancer research organization undertake arm’s length reproduction of Craig’s original murine model work, and what was being clinically observed in human trials, to independently establish PV-10’s bona fides. This work commenced in 2011 when Provectus agreed to have Tampa, Florida’s H. Lee Moffitt Cancer Center & Research Institute carry out this necessary initial research (after also considering MD Anderson Cancer Center in Houston, Texas). In 2014 Eric added the University of Illinois at Chicago to his list of stringers.
In the early-2000s, Craig Tim and Eric, while at Photogen (the precursor company to Provectus) and when they believed Rose Bengal required photoactivation to elicit its therapeutic benefit, published that the physical chemistry of the small molecule generated both local and systemic responses in multiple cancer indications [24] [25] [26]. A short time thereafter Provectus’ co-founders had their Eureka moment upon realizing Rose Bengal did not require light activation.
PV-10’s truly multi-faceted clinical value proposition comprises safety and sparing of tissue; local and systemic effectiveness, the investigational drug’s two-prong approach to fighting cancer; multi-cancer indication viability; synergy in combination with other cancer therapies; supportiveness of patient compliance; ease of use, re-use, shipment, storage and handling; and globally affordability. The key aspect of this proposition is the drug compound’s local effect of tumor ablation upon injection (the first of its dual mechanisms of action) that produces the systemic effect of a tumor-specific immune response and eventually anti-tumor immunity (the second mechanism).
At the 2012 annual meeting of the Society for Immunotherapy of Cancer, Craig, Tim, Eric and others presented:
PV-10 (10% Rose Bengal in 0.9% saline) has been used to chemoablate a wide variety of tumors in human clinical trials and in animal patients when delivered by intralesional (IL) injection…Tumor models examined include: hepatocellular carcinoma (HCC), melanoma, pancreatic and colon adenocarcinomas. PV-10 was found to chemoablate all tumors tested with no apparent side effects…Untreated tumors in the opposite flank of mice completely regressed or were reduced in size in immunocompetent mice (i.e., 8/8 untreated HCC tumors)... [27]At the 2013 annual meeting of the American Association for Cancer Research, Moffitt Cancer Center presented:
PV-10 is a 10% solution of Rose Bengal that is currently being examined as a novel cancer therapeutic. In melanoma patients, intralesional injection (IL) of PV-10 has led to regression of injected lesions as well as distant metastases… In BALB/c mice bearing MT-901 breast cancer, injection of PV-10 led to regression of injected and untreated contralateral subcutaneous lesions (p<0.05 compared to IL-PBS-treated mice)…MT901-bearing mice treated with IL-PV-10 demonstrated enhanced IFN-gamma production (992 ± 453 pg/ml) compared to splenocytes from PBS-treated mice (174 ± 105, p<0.05)…Treatment of the subcutaneous lesion with a single injection of IL-PV-10 led to regression of the injected lesion as well as distant B16 melanoma lung metastases. In B16-bearing mice, treatment with IL-PV-10 led to the induction of T cells that produced IFN-gamma in response to B16 tumors but not irrelevant tumor (p<0.05) and demonstrated specific lysis of B16 (p<0.01 compared to T cells isolated from PBS-treated mice). [28]A member of the Moffitt PV-10 study team called iFN-gamma/γ the “quintessential antitumor cytokine”. [29] Cytokines are the messengers of the immune system; in cancer therapy cytokines are used to enhance immunity. [30]
At the 2015 annual meeting of the Society of Surgical Oncology, the University of Illinois at Chicago presented:
Early phase studies using intratumoral injection of PV-10 (10% Rose Bengal) have shown regression of in-transit melanoma deposits and non-treated bystander lesions. The effects of PV-10 on colorectal cancer (CRC) cells and established tumors is unknown…To determine an underlying immune mechanism, a murine CT26 syngeneic CRC model was utilized…Treatment of subcutaneous tumors with a single injection of intralesional PV-10 led to near complete responses in all animals within days of exposure and significant regression of the injected lesions compared to controls (n=6 per group, p=0.027). PV-10 treatment was associated with occasional bystander responses in contralateral untreated tumors and trended towards a decreased rate of growth in these lesions. Splenocytes isolated from tumor bearing mice treated with PV-10 displayed enhanced tumor-specific IFN-γ production compared to splenocytes from PBS-treated mice (p = 0.025). [31]Moffitt Cancer Center and the University of Illinois independently, and independently from each other, reproduced Craig’s original work, which first demonstrated PV-10’s two-prong approach to successfully fighting cancer in multiple indications: Tumor ablation, the local effect of destroying injected tumors; a tumor-specific immune response, the systemic effect of destroying non-injected tumors; tumor-specific IFN-gamma/γ production; and multi-indication viability in at least melanoma, breast cancer and colorectal cancer.
Other affiliated and independent researchers around the world have noted the cancer-fighting benefits of Rose Bengal. Their observations and conclusions have been consistent with those of Craig (US), Moffitt Cancer Center (US) and the University of Illinois (US) as well as Delprat (US) and Ito (Japan): Koevary (2012, ovarian cancer cells, US) [32], Nascimento et al. (2013, melanoma cells, Australia) [33], Tan et al. (2013, clinical refractory scalp sarcoma, Australia) [34], Zamani et al. (2014, gastric cancer cells, Iran) [35], and Panzarini et al. (2014, cervical cancer cells, Italy) [36].
Consider Wikipedia’s reproducibility entry’s opening:
Reproducibility is the ability of an entire experiment or study to be duplicated, either by the same researcher or by someone else working independently. Reproducing an experiment is called replicating it. Reproducibility is one of the main principles of the scientific method.Provectus management has some way to go in their stewardship of the company to converge its market capitalization with its intrinsic value. There should be no disagreement, however, about the veracity of their claims about Rose Bengal/PV-10 and its therapeutic benefits for the treatment of solid tumor cancer. After all, Craig, Tim and Eric’s original work achieved [global] reproducibility, the hallmark of Western science.
[1] Scientists' Elusive Goal: Reproducing Study Results, Gautam Naik, The Wall Street Journal, December 2, 2011
[2] In cancer science, many "discoveries" don't hold up, Sharon Begley, Reuters, March 28, 2012
[3] Drug development: Raise standards for preclinical cancer research, Begley et al., Nature 483, 531–533 (29 March 2012)
[4] Believe it or not: how much can we rely on published data on potential drug targets? Prinz et al., Nature Reviews Drug Discovery 10, 712 (September 2011)
[5] Reproducible Science, Casadevall et al., Infect Immun. 2010 Dec; 78(12): 4972–4975
[6] PV-10 is the drug product. Rose Bengal is the drug substance.
[7] Gnehm R.Ueber Tetrachlorphtalsäure. Justus Liebigs Annalen der Chemie, 1887; 238: 318-338
[8] The Rose Bengal test for liver function, Delprat, G.D. et al., The Journal of Laboratory and Clinical Medicine, Volume 16, Issue 9, 923-925
[9] Induction of thyroid tumors in (C57BL/6N x C3H/N) F1 mice by oral administration of 9-3',4',5',6'-tetrachloro-o-carboxy phenyl-6-hydroxy-2,4,5,7-tetraiodo-3-isoxanthone sodium (Food Red 105, rose bengal B), Ito et al., J Natl Cancer Inst. 1986 Jul;77(1):277-81
[10] American Society of Clinical Oncology, 2010 Annual Meeting and Rose Bengal: From a Wool Dye to a Cancer Therapy, Alexander, W., Pharmacy & Therapeutics. 2010 Aug; 35(8): 469-474, 478
[11] Oak Ridge National Laboratory Awards and Appointments for 1996, see http://web.ornl.gov/info/ornlreview/rev30-12/text/awards.htm
[12] E.g., Should we believe published scientific research? Luke Timmerman and Meg Tirrell, Stat and Signal Podcast, December 3, 2015
[13] Provectus Reports Full Phase 2 Study Data on PV-10 for Metastatic Melanoma, November 5, 2010
[14] Immuno-chemoablation of metastatic melanoma with intralesional rose bengal, European Society for Medical Oncology 2012 Congress, October 2012
[15] Phase 2 Study of Intralesional PV-10 in Refractory Metastatic Melanoma, Thompson et al., Annals of Surgical Oncology, July 2015, Volume 22, Issue 7, pp 2135-2142
[16] Provectus Reports on Successful End-of-Phase 2 Meeting with U.S. FDA and Gains Clarity for Licensure of PV-10 for Metastatic Melanoma, April 29, 2010
[17] Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes, January 24, 2014
[18] Provectus Biopharmaceuticals Inc. Reaffirms Its Commitment to Bringing PV-10 to Market Notwithstanding FDA Decision on Breakthrough Therapy Designation, May 23, 2014
[19] Provectus Biopharmaceuticals Opens Patient Enrollment; Begins Phase 3 International FDA Comparative Clinical Trial of PV-10 for Melanoma, April 15, 2015
[20] Provectus Biopharmaceuticals' Data on PV-10 for Chemoablation of Liver Cancers Presented at ESMO 17th World Congress on Gastrointestinal Cancer, July 2, 2015
[21] ESMO GI: PV-10 shows potential in hepatocellular carcinoma and metastatic liver disease, Janet Fricker, ecancernews, July 7, 2015
[22] ASCO 2010 Investor Briefing Presentation, Clinical Program Overview, Provectus, Dr. Eric Wachter, PhD, slide 39 of 55
[23] Ibid, slide 42 of 55
[24] Immune-mediated regression of tumors and production of anti-tumor immunity induced by chemoablative or photodynamic therapy, Dees et al., Counsel of Research Workers in Animal Disease, Chicago, Illinois, 2001: abstract.
[25] Use of halogenated xanthenes to specifically target diseased tissue, Dees et al., 29th Annual Meeting of the American Society for Photobiology, Chicago, Illinois, 2001: abstract.
[26] Topical Rose Bengal: Pre-Clinical Evaluation of Pharmacokinetics and Safety, Wachter et al. Lasers in Surgery and Medicine. 32:101–110 (2003)
[27] Generation of an Antitumor Response and Immunity Using a Small Molecule Drug (PV-10), Dees et al., J Immunother. Volume 35, Number 9, November–December 2012
[28] Intralesional injection with PV-10 induces a systemic anti-tumor immune response in murine models of breast cancer and melanoma, Pilon-Thomas et al., Cancer Res. April 15, 2013 73; 1248.
[29] Intralesional therapy for metastatic melanoma, Cheryl Guttman Krader, DermatologyTimes, May 14, 2015
[30] See Cytokines and Cancer Therapy by Dr. Jeffrey Weber, MD, PhD
[31] Intralesional Injection of Rose Bengal Induces an Anti-tumor Immune Response and Potent Tumor Regressions in a Murine Model of Colon Cancer, 2015 Society of Surgical Oncology Annual Cancer Symposium, March 2015: abstract
[32] Selective toxicity of rose bengal to ovarian cancer cells in vitro. Koevary, Int J Physiol Pathophysiol Pharmacol. 2012;4:99–107
[33] Rose Bengal - Phototoxicity versus intrinsic cytotoxicity [abstract]. Nascimento et al. Journal der Deutschen Dermatologischen Gesellschaft. 2013;11
[34] Novel use of Rose Bengal (PV-10) in two cases of refractory scalp sarcoma. Tan et al., ANZ J Surg. 2013;83:93
[35] Rose Bengal suppresses gastric cancer cell proliferation via apoptosis and inhibits nitric oxide formation in macrophages. Zamani et al., J Immunotoxicol. 2014;11:367–375
[36] Rose Bengal Acetate PhotoDynamic Therapy (RBAc-PDT) Induces Exposure and Release of Damage-Associated Molecular Patterns (DAMPs) in Human HeLa Cells. Panzarini et al., (2014) PLoS ONE 9(8): e105778
[2] In cancer science, many "discoveries" don't hold up, Sharon Begley, Reuters, March 28, 2012
[3] Drug development: Raise standards for preclinical cancer research, Begley et al., Nature 483, 531–533 (29 March 2012)
[4] Believe it or not: how much can we rely on published data on potential drug targets? Prinz et al., Nature Reviews Drug Discovery 10, 712 (September 2011)
[5] Reproducible Science, Casadevall et al., Infect Immun. 2010 Dec; 78(12): 4972–4975
[6] PV-10 is the drug product. Rose Bengal is the drug substance.
[7] Gnehm R.Ueber Tetrachlorphtalsäure. Justus Liebigs Annalen der Chemie, 1887; 238: 318-338
[8] The Rose Bengal test for liver function, Delprat, G.D. et al., The Journal of Laboratory and Clinical Medicine, Volume 16, Issue 9, 923-925
[9] Induction of thyroid tumors in (C57BL/6N x C3H/N) F1 mice by oral administration of 9-3',4',5',6'-tetrachloro-o-carboxy phenyl-6-hydroxy-2,4,5,7-tetraiodo-3-isoxanthone sodium (Food Red 105, rose bengal B), Ito et al., J Natl Cancer Inst. 1986 Jul;77(1):277-81
[10] American Society of Clinical Oncology, 2010 Annual Meeting and Rose Bengal: From a Wool Dye to a Cancer Therapy, Alexander, W., Pharmacy & Therapeutics. 2010 Aug; 35(8): 469-474, 478
[11] Oak Ridge National Laboratory Awards and Appointments for 1996, see http://web.ornl.gov/info/ornlreview/rev30-12/text/awards.htm
[12] E.g., Should we believe published scientific research? Luke Timmerman and Meg Tirrell, Stat and Signal Podcast, December 3, 2015
[13] Provectus Reports Full Phase 2 Study Data on PV-10 for Metastatic Melanoma, November 5, 2010
[14] Immuno-chemoablation of metastatic melanoma with intralesional rose bengal, European Society for Medical Oncology 2012 Congress, October 2012
[15] Phase 2 Study of Intralesional PV-10 in Refractory Metastatic Melanoma, Thompson et al., Annals of Surgical Oncology, July 2015, Volume 22, Issue 7, pp 2135-2142
[16] Provectus Reports on Successful End-of-Phase 2 Meeting with U.S. FDA and Gains Clarity for Licensure of PV-10 for Metastatic Melanoma, April 29, 2010
[17] Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes, January 24, 2014
[18] Provectus Biopharmaceuticals Inc. Reaffirms Its Commitment to Bringing PV-10 to Market Notwithstanding FDA Decision on Breakthrough Therapy Designation, May 23, 2014
[19] Provectus Biopharmaceuticals Opens Patient Enrollment; Begins Phase 3 International FDA Comparative Clinical Trial of PV-10 for Melanoma, April 15, 2015
[20] Provectus Biopharmaceuticals' Data on PV-10 for Chemoablation of Liver Cancers Presented at ESMO 17th World Congress on Gastrointestinal Cancer, July 2, 2015
[21] ESMO GI: PV-10 shows potential in hepatocellular carcinoma and metastatic liver disease, Janet Fricker, ecancernews, July 7, 2015
[22] ASCO 2010 Investor Briefing Presentation, Clinical Program Overview, Provectus, Dr. Eric Wachter, PhD, slide 39 of 55
[23] Ibid, slide 42 of 55
[24] Immune-mediated regression of tumors and production of anti-tumor immunity induced by chemoablative or photodynamic therapy, Dees et al., Counsel of Research Workers in Animal Disease, Chicago, Illinois, 2001: abstract.
[25] Use of halogenated xanthenes to specifically target diseased tissue, Dees et al., 29th Annual Meeting of the American Society for Photobiology, Chicago, Illinois, 2001: abstract.
[26] Topical Rose Bengal: Pre-Clinical Evaluation of Pharmacokinetics and Safety, Wachter et al. Lasers in Surgery and Medicine. 32:101–110 (2003)
[27] Generation of an Antitumor Response and Immunity Using a Small Molecule Drug (PV-10), Dees et al., J Immunother. Volume 35, Number 9, November–December 2012
[28] Intralesional injection with PV-10 induces a systemic anti-tumor immune response in murine models of breast cancer and melanoma, Pilon-Thomas et al., Cancer Res. April 15, 2013 73; 1248.
[29] Intralesional therapy for metastatic melanoma, Cheryl Guttman Krader, DermatologyTimes, May 14, 2015
[30] See Cytokines and Cancer Therapy by Dr. Jeffrey Weber, MD, PhD
[31] Intralesional Injection of Rose Bengal Induces an Anti-tumor Immune Response and Potent Tumor Regressions in a Murine Model of Colon Cancer, 2015 Society of Surgical Oncology Annual Cancer Symposium, March 2015: abstract
[32] Selective toxicity of rose bengal to ovarian cancer cells in vitro. Koevary, Int J Physiol Pathophysiol Pharmacol. 2012;4:99–107
[33] Rose Bengal - Phototoxicity versus intrinsic cytotoxicity [abstract]. Nascimento et al. Journal der Deutschen Dermatologischen Gesellschaft. 2013;11
[34] Novel use of Rose Bengal (PV-10) in two cases of refractory scalp sarcoma. Tan et al., ANZ J Surg. 2013;83:93
[35] Rose Bengal suppresses gastric cancer cell proliferation via apoptosis and inhibits nitric oxide formation in macrophages. Zamani et al., J Immunotoxicol. 2014;11:367–375
[36] Rose Bengal Acetate PhotoDynamic Therapy (RBAc-PDT) Induces Exposure and Release of Damage-Associated Molecular Patterns (DAMPs) in Human HeLa Cells. Panzarini et al., (2014) PLoS ONE 9(8): e105778
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