Richard G. Petty, MD

Judah Folkman R.I.P.

I just heard that Judah Folkman just passed away at the age of 74. That is a name that is not widely known outside the scientific world, although a couple of years ago an excellent book –Dr. Folkman’s War – was written about him and his work.

His major work and his enduring legacy was in the field of angiogenesis: the production of new blood vessels. In the 1960s he came up with the idea that a way to kill tumors was to starve them of the blood supply that they need to survive. He was initially ridiculed, but history is now proving him correct. I got to know him twenty years ago after publishing a paper in which I described the discovery of a growth factor that is involved in the production of new blood vessels at the back of the eye in people with diabetes. Judah was very supportive and we had many good discussions about the potential role of angiogenesis not only in tumors and diabetic retinopathy, but also in diseases like rheumatoid arthritis and psoriasis.

Last November, at the 12th Annual Society for Neuro-Oncology Meeting in Dallas, researchers from the University of Virginia and several other leading brain tumor centers in the United States presented data on the successful use of an inhibitor of angiogenesis in the treatment of glioblastoma multiforme (GBM), the most common form of primary brain cancer. It is hard to treat, and if it recurred after surgery, radiation and/or chemotherapy there was often not much to be done.

Building on Judah’s work, they wanted to see if they could inhibit vascular endothelial growth factor (VEGF) that has an important role in the disease. VEGF fosters the growth of a tumor by
stimulating the growth of new blood vessels to feed it. According to earlier studies, bevacizumab (BV) (Avastatin), a humanized monoclonal antibody that specifically targets VEGF, in combination with irinotecan (also called CPT-11) could have a role in recurrent glioblastoma multiforme. The researcher was an attempt to establish the clinical benefit of BV, both alone and in combination with CPT-11, in a multicenter, randomized phase II trial.

The results were very promising, substantially exceeded the pre-specified thresholds set for this work.

They looked at 6-month progression-free survival (PFS) defined as no clinical or MRI tumor growth and the objective response rate (ORR), which measures tumor shrinkage. Secondary endpoints included safety and survival. Response assessments were conducted by an independent radiographic facility that did not know which patients had been treated. All patients were followed for 24 weeks to determine efficacy and safety.

When taking BV, 35.6 percent of patients on average had a 6-month survival with no progression of their cancer, and an objective response rate of 21.2 percent on average.

The combination of BV and CPT was even more effective, with results of 51 percent and 34.1 percent, respectively.

The investigator group found similar results when they evaluated the patients. Those results showed that 44.7 percent of patients on average had a 6-month survival with no progression of their cancer, and an objective response rate of 38.8 percent on average. The combination therapy yielded results of 60.9 percent and 46.3 percent, respectively.

The surviving patients have remained in the study and are still being treated and followed, so we shall be seeing some longer-term results in the future.

In the United States bevacizumab has already been approved for the treatment of metastatic colon cancer and most forms of metastatic non-small cell lung cancer.

This is very encouraging research and a fitting tribute to a genuine medical pioneer.

Glaucoma and Alzheimer’s Disease

There is a fascinating study by colleagues from University College London (UCL) that has just been published in the Proceedings of the National Academy of Sciences that has found a “clear link between what causes Alzheimer’s and one of the basic mechanisms behind glaucoma.”

The research could speed up the development of new treatments for Alzheimer’s and revolutionize the treatment of glaucoma, the most common cause of blindness in the Western world.

If glaucoma is indeed confirmed as a marker or risk factor for Alzheimer’s then the early warning signs it gives could help ensure that patients have more opportunities to delay the onset of dementia.

The researchers discovered that the same “plaque” proteins are a key process in the development of both diseases. Clumps – or plaques – of beta-amyloid proteins that kill brain cells in Alzheimer’s patients, also kill optic nerve cells in the eyes of glaucoma sufferers. A link has bee suspected for some time: around 1.8-2.0% of the population will develop glaucoma, the figures in Alzheimer’s is as high as 25%.

Dr Francesca Cordeiro, who led the team at UCL’s Institute of Ophthalmology, said:

“We’ve seen for the first time that there is a clear link between what causes Alzheimer’s and one of the basic mechanisms behind glaucoma.”

Glaucoma is a group of diseases of the optic nerve involving loss of retinal ganglion cells in a characteristic pattern of optic neuropathy. People with glaucoma gradually lose their wider field of vision. Many do not realize it until they barge into things.

The textbooks will tell you that glaucoma is caused by increased pressure in the eye, known as intraocular pressure. Standard treatments attempt to lower this pressure, but with only limited success. People with normal pressure can also suffer from glaucoma, suggesting it is not the only cause.

The researchers have shown that drugs that prevent the build-up of “plaque” proteins in the brains of people with Alzheimer’s disease were successful in treating glaucoma in rats. One such drug, bapineuzumab, is already being used to treat Alzheimer’s patients in clinical trials in Britain and the United States.

The UCL researchers showed that the effects on glaucoma were even stronger when combined with two other novel Alzheimer’s treatments – “Congo Red” and a drug called a beta-secretase inhibitor.

This is very exciting work and we should know fairly soon whether these new approaches to treatment will help both glaucoma and Alzheimer’s disease.

Clearly this does not mean that everyone with Alzheimer’s will develop glaucoma or vice versa. Both problems have multiple causes and can follow quite different trajectories. But links like these are the stuff of medical progress.

Acupuncture and Anxiety During Medical Procedures

Over the years I have become impressed with the increasing research on something close to my own heart: how to use the best of scientific medicine in conjunction with less orthodox approaches. And, for that matter, when each is best left on its own.

I have mentioned that a few years ago I had to have surgery for a potentially serious problem. The surgeon – widely regarded as one of the best in this neck of the woods – was stunned by the speed of my recovery.

“I have seen it with my own eyes, “ He said, “But how did you do it?”

“Well,” I said, “You are an excellent surgeon. But I also some outside help: acupressure, homeopathic remedies, qigong and three prayer groups. We call it Integrated Medicine. You may think that it’s odd, but that’s what I did.”

“Oh no,” he said, “I have been in practice for over 35 years: I trust my senses far more than I trust some graph with p values on it!”

Although anxiety has never been one of my problems, I was pleased to see two new publications on the use of acupuncture to reduce anxiety during medical procedures.

A randomized controlled study was carried out to determine whether a combination of auricular and body acupuncture is effective as an adjunctive treatment for pre-procedural anxiety and pain, in 56 patients undergoing lithotripsy (ultrasonic destruction of kidney stones). In the acupuncture group, pre-procedural auricular acupuncture was combined with intra-procedural electro-acupuncture stimulation, while in the control group both treatments were sham. Patients in the acupuncture group were less anxious pre-procedure than those in the sham group and they also used a significantly smaller amount of analgesic during the procedure than those in the sham control group. Patients in the acupuncture group also reported significantly lower pain scores on admission to the recovery room.

Meanwhile an Italian study has found that patients undergoing cataract removal are less anxious after receiving acupuncture. People underwent phacoemulsification, in which the cloudy eye lens is emulsified with an ultrasound probe, before being aspirated and replaced by an artificial lens. The procedure is carried out under topical anesthesia while the patient is awake and can therefore provoke significant anxiety. In this prospective randomized double-blind controlled trial, anxiety levels were assessed before and after surgery in three groups (no acupuncture, true acupuncture and sham acupuncture) of 25 patients. Preoperative anxiety levels were significantly lower only in the true acupuncture group. The difference in postoperative anxiety levels between the real acupuncture and no acupuncture groups was also significant.

These studies are particularly interesting in the light of a recent analysis of the published research on acupuncture and anxiety, that did not include these studies. There is not much research out there, but what we have suggests that it may perhaps help with generalized anxiety disorder. The best evidence is indeed in using it to allay anxiety before, during or after surgery, though we still need a lot more research to be sure.

I have heard people say that using acupuncture like this somehow belittles it: that an ancient and self-contained system should not become the handmaiden of Western medicine.

That is only half true. First, traditional Chinese medicine was developed at a time and placed very different from today. Human beings have changed radically in the intervening centuries. That is why acupuncturists in modern China are discovering and developing new way to treat people that do not always conform to the precepts laid down hundreds of years ago.

Second, many of us have failed to recognize the treasures in our midst. Acupuncture and acupressure are two of them. If using them together with conventional medicine is the best way for people to come to know of them, that is all to the good.

There are several other similar studies that will be coming out in the next few months, and I shall keep you informed.

A Breakthrough in the Pharmacological Treatment of Diabetic Retinopathy

One of the most distressing complication of diabetes is damage to the retina of the eyes. It is more likely to occur in people with poor metabolic control, but no diabetes sufferers seem to be totally immune from it. But there is no question, that in contrast to some diabetic complications, the level of blood glucose is closely related to the risk of getting retinopathy.In people of working age living in the Western world, diabetes is the number one cause of blindness, and blindness is twenty times more common in people with diabetes than in those without it.

It is such a major problem, that I had the privilege of spending several years working on the problem at the Royal Postgraduate Medical School in London, and diabetic retinopathy was a key part of my doctoral dissertation.

So if something new turns up, I always prick up my ears.

Well, we do seem to have something new. The trouble has been that there are complex mechanisms underlying the effects of diabetes on causing complications like retinopathy. At the American Diabetes Association’s 66th Annual Scientific Sessions in Washington, DC Eli Lilly announced on June 11th, that a study headed by Aaron Vinik of The Strelitz Diabetes Institute at the Eastern Virginia Medical School, in Norfolk, Virginia of a new medicine called ruboxistaurin, almost halved the rate of the development of diabetic retinopathy over a two year period. This is astonishing, though it is important to point out that the medicine did not abolish the problem, and it was funded by the manufacturer. The medicine works by a completely new mechanism. In people with diabetes, high levels of glucose are one of the triggers of a cascade of chemical reactions in the cells of the retina, that turn on a chemical messenger called protein kinase C-β.

Though this is only a first study, and the medicine does not help with diabetic neuropathy, this is a very promising finding. Not least because most of us have failed to achieve much benefit from unorthodox medicine. I have colleagues who tell me that they have helped people with retinopathy with homeopathy and different kinds of electrical stimulation, but I’m just not sure how good those other treatments are. My guess is that if they were really effective, that independent research foundations would be falling over themselves to do research on them. But I could be convinced otherwise!

Ruboxistaurin, added to psychological, social, subtle and spiritual approaches is already looking like a very promising option for preventing problems.

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