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gdpawel · 05-11-2013, 10:30 PM

Larry M. Weisenthal, M.D., PhD.

I have read with interest the recent tributes to Emil “Tom” Frei III, MD, who passed away in April. I was backstage at the ASCO meetings in 1981, when Dr. Frei was giving his Karnofsky acceptance address. I had a slide presentation at the combined ASCO/AACR session which followed immediately thereafter. Back then, the ASCO and AACR meetings were held during the same week, at the same venue. The ASCO meeting was held on the first 3 days, with the AACR meeting following.

On the afternoon of the final day of the ASCO meeting and on the first day of the AACR meeting, there was a combined ASCO/AACR session, which consisted of about 10 papers felt to be of interest to both ASCO and AACR membership (papers that today would be broadly considered “translational research”). This session followed immediately after the Karnofsky address. I recall the venue as having an actual stage, with a curtained-off waiting area, from where I watched the speech.

Two Types of Researchers

I was thrilled in particular by a portion of Dr. Frei's address, wherein he described two types of clinical cancer researchers, namely "investigators" versus "discoverers." The investigators proceed in a very orderly fashion, are esteemed by their peers, typically succeed (at least in answering the often rather ordinary question being addressed by their work), but produce, at most, single step advances and don't create new paradigms.

Discoverers, on the other hand, follow a path of inquiry which often seems disordered, tend not to be esteemed by their peers, often fail, but, on occasions where they do succeed, produce multi-step advances and create new paradigms. Dr. Frei's point was that the clinical oncology research establishment would be well advised to be more supportive of the work of discoverers.

Since that 1981 speech, the best example of discovery-oriented clinical research since that 1981 speech of which I am aware comes from gastroenterology -- the central role of bacterial infection (helicobactor pylori) in peptic ulcer disease. We've had some breakthroughs of lesser magnitude in oncology: anti-Her2 treatment of breast cancer, anti-CD20 in lymphatic neoplasms, tyrosine kinase inhibitors, etc. When his Karnofsky address was subsequently published in the journal Cancer, there was only passing mention of what had been a major point in the address itself, and this point didn't even appear in the abstract:

http://www.ncbi.nlm.nih.gov/pubmed/7127245

Encouraging Would-be Discoverers

If anyone ever wished to honor Dr. Frei with some type of ASCO award to be presented in his name, it might be, for example, an award for the most creative discovery oriented research presented at the previous year's ASCO meeting. This might focus more attention on the need for more out of the box thinking, in a world where investigators control the peer review pipeline, investigators beget more investigators, and there are decreasing opportunities for would-be discoverers.

Note that the "Emil Frei Award" (1) would be different from the usual awards, which require confirmation through years of follow up work. As Dr. Frei pointed out that discovers often fail, what is honored is a potentially breakthrough idea, supported by credible pilot data.

One important purpose of the award is to focus attention on the new idea, so that it will receive scrutiny and early confirmation or refutation. The fact that the work would attract such scrutiny should serve to discourage fraud and encourage the would be discover to have reasonable certainty that he/she is on a sound path.

1. Frei E 3rd: Clinical cancer research: An embattled species. Cancer 50:1979-1992, 1982.

Every year, at the International Angiogenesis meeting in LaJolla, they have a whole session devoted to predictive biomarkers. Every year, they conclude that nothing really works.

This brings me back to angiogenesis predictions and the annual LaJolla meetings. For three years in a row, I've presented posters, which show an entirely new way of approaching the problem. I know that it works. It's a breakthrough discovery. But the INVESTIGATORS have no interest whatsoever. The only people who ever came by to look at my posters were fellows in training and the odd weirdo from Southeast Asia or whatever. No one is even curious enough to spend 5 minutes looking at something which is brand new, partly because it's brand new and partly because they don't believe anything which doesn't emanate from the Hallowed Halls of St. Ivory Tower.

I've got two of the posters plus some other stuff posted on the Nature Precedings website. Nature used to do this as a service to people who made discoveries and wanted to just put it up without formal peer review. But they quit doing this a year ago. However, they are maintaining the site. This is brand new, ground breaking stuff. It's real. It's really important. But no one cares, because cancer research has been entirely taken over by INVESTIGATORS who can't see past the end of their nose.

Weisenthal, L., H. Liu, Rueff-Weisenthal, C. (2010). "Death of human tumor endothelial cells in vitro through a probable calcium-associated mechanism induced by bevacizumab and detected via a novel method." Nature Precedings 28 May 2010. http://precedings.nature.com/documents/4499/version/1.

Weisenthal, Larry . Endothelial Massive Calcium Accumulation Death (MCAD): Mechanism, Target, and Predictive Biomarker for Anti-Angiogenic Therapy. 13th international symposium on anti-angiogenic therapy: recent advances and future directions in basic and clinical cancer research. LaJolla, CA. February 2011 Available from Nature Precedings http://dx.doi.org/10.1038/npre.2011.6647.1

Bevacizumab-induced tumor calciﬁcations can be elicited in glioblastoma microspheroid culture and represent massive calcium uptake death (MCAD) of tumor endothelial cells. Larry Weisenthal, Summer Williamson, Cindy Brunschwiler, and Constance Rueff-Weisenthal, 14th International Anti-Angiogenesis Symposium, LaJolla CA, Feb 2012. Available from Nature Precedings http://dx.doi.org/10.1038/npre.2012.7069.1 (2012)

05-11-2013, 10:30 PM	#2
gdpawel Senior Member Join Date: Aug 2006 Location: Pennsylvania Posts: 1,080	Emil Frei just died this week Larry M. Weisenthal, M.D., PhD. I have read with interest the recent tributes to Emil “Tom” Frei III, MD, who passed away in April. I was backstage at the ASCO meetings in 1981, when Dr. Frei was giving his Karnofsky acceptance address. I had a slide presentation at the combined ASCO/AACR session which followed immediately thereafter. Back then, the ASCO and AACR meetings were held during the same week, at the same venue. The ASCO meeting was held on the first 3 days, with the AACR meeting following. On the afternoon of the final day of the ASCO meeting and on the first day of the AACR meeting, there was a combined ASCO/AACR session, which consisted of about 10 papers felt to be of interest to both ASCO and AACR membership (papers that today would be broadly considered “translational research”). This session followed immediately after the Karnofsky address. I recall the venue as having an actual stage, with a curtained-off waiting area, from where I watched the speech. Two Types of Researchers I was thrilled in particular by a portion of Dr. Frei's address, wherein he described two types of clinical cancer researchers, namely "investigators" versus "discoverers." The investigators proceed in a very orderly fashion, are esteemed by their peers, typically succeed (at least in answering the often rather ordinary question being addressed by their work), but produce, at most, single step advances and don't create new paradigms. Discoverers, on the other hand, follow a path of inquiry which often seems disordered, tend not to be esteemed by their peers, often fail, but, on occasions where they do succeed, produce multi-step advances and create new paradigms. Dr. Frei's point was that the clinical oncology research establishment would be well advised to be more supportive of the work of discoverers. Since that 1981 speech, the best example of discovery-oriented clinical research since that 1981 speech of which I am aware comes from gastroenterology -- the central role of bacterial infection (helicobactor pylori) in peptic ulcer disease. We've had some breakthroughs of lesser magnitude in oncology: anti-Her2 treatment of breast cancer, anti-CD20 in lymphatic neoplasms, tyrosine kinase inhibitors, etc. When his Karnofsky address was subsequently published in the journal Cancer, there was only passing mention of what had been a major point in the address itself, and this point didn't even appear in the abstract: http://www.ncbi.nlm.nih.gov/pubmed/7127245 Encouraging Would-be Discoverers If anyone ever wished to honor Dr. Frei with some type of ASCO award to be presented in his name, it might be, for example, an award for the most creative discovery oriented research presented at the previous year's ASCO meeting. This might focus more attention on the need for more out of the box thinking, in a world where investigators control the peer review pipeline, investigators beget more investigators, and there are decreasing opportunities for would-be discoverers. Note that the "Emil Frei Award" (1) would be different from the usual awards, which require confirmation through years of follow up work. As Dr. Frei pointed out that discovers often fail, what is honored is a potentially breakthrough idea, supported by credible pilot data. One important purpose of the award is to focus attention on the new idea, so that it will receive scrutiny and early confirmation or refutation. The fact that the work would attract such scrutiny should serve to discourage fraud and encourage the would be discover to have reasonable certainty that he/she is on a sound path. 1. Frei E 3rd: Clinical cancer research: An embattled species. Cancer 50:1979-1992, 1982. Every year, at the International Angiogenesis meeting in LaJolla, they have a whole session devoted to predictive biomarkers. Every year, they conclude that nothing really works. This brings me back to angiogenesis predictions and the annual LaJolla meetings. For three years in a row, I've presented posters, which show an entirely new way of approaching the problem. I know that it works. It's a breakthrough discovery. But the INVESTIGATORS have no interest whatsoever. The only people who ever came by to look at my posters were fellows in training and the odd weirdo from Southeast Asia or whatever. No one is even curious enough to spend 5 minutes looking at something which is brand new, partly because it's brand new and partly because they don't believe anything which doesn't emanate from the Hallowed Halls of St. Ivory Tower. I've got two of the posters plus some other stuff posted on the Nature Precedings website. Nature used to do this as a service to people who made discoveries and wanted to just put it up without formal peer review. But they quit doing this a year ago. However, they are maintaining the site. This is brand new, ground breaking stuff. It's real. It's really important. But no one cares, because cancer research has been entirely taken over by INVESTIGATORS who can't see past the end of their nose. Weisenthal, L., H. Liu, Rueff-Weisenthal, C. (2010). "Death of human tumor endothelial cells in vitro through a probable calcium-associated mechanism induced by bevacizumab and detected via a novel method." Nature Precedings 28 May 2010. http://precedings.nature.com/documents/4499/version/1. Weisenthal, Larry . Endothelial Massive Calcium Accumulation Death (MCAD): Mechanism, Target, and Predictive Biomarker for Anti-Angiogenic Therapy. 13th international symposium on anti-angiogenic therapy: recent advances and future directions in basic and clinical cancer research. LaJolla, CA. February 2011 Available from Nature Precedings http://dx.doi.org/10.1038/npre.2011.6647.1 Bevacizumab-induced tumor calciﬁcations can be elicited in glioblastoma microspheroid culture and represent massive calcium uptake death (MCAD) of tumor endothelial cells. Larry Weisenthal, Summer Williamson, Cindy Brunschwiler, and Constance Rueff-Weisenthal, 14th International Anti-Angiogenesis Symposium, LaJolla CA, Feb 2012. Available from Nature Precedings http://dx.doi.org/10.1038/npre.2012.7069.1 (2012)