Thursday, March 30, 2023

In ancient times, ignorance about the workings of nature and the universe resulted in almost all people having a belief in one or another deity as the primary causal agent in nature. This situation persisted until the dawn of the scientific age during the Renaissance, when scientific discovery began to introduce scientific explanations for many phenomena in nature. The result was a gradual diminution in spiritual beliefs that has continued to our day.

For me, the beauty and elegance of scientific verities provide a strengthening of religious belief, not a decrease. Newton’s laws of motion, Maxwell’s equations for electromagnetism, statistical thermodynamics, the order of the periodic table all speak to a higher being in a more profound way than prior ignorance did. But it is in medicine and physiology that this special natural order really comes to bear—was Vesalius religiously uplifted as he performed autopsies? I don’t know, but I found gross anatomy a spiritual experience as one tried to appreciate the structure and interplay of body parts.

But what has struck me as most exquisite and elegant is the way in which the human body has created defense mechanisms within itself. And most significantly, it has attempted to prioritize certain crucial areas of the body for special defenses. Truly awesome! Throughout the body, there is a free flow of nutrients, oxygen and fluids across capillary membranes into various tissues. These capillary membranes are also permeable to the passage of waste products, carbon dioxide and fluids coming back the other way for transport to the liver and kidneys for excretion.

But nature has created special sanctuaries in the body to protect special sites. Thus, there exists the blood-testis barrier. This is an actual physical barrier between the capillaries in the testis and the seminiferous tubules, where the germ cells are replicating and developing. This barrier prevents the passage of harmful chemicals, bacteria/viruses and toxins into the area where the germ cells are and highlights the idea that the body recognizes the vital importance of preserving the integrity of sperm and the germ line from generation to generation.

I have found a few papers about a blood-follicle barrier as well in the ovary to protect the germ cells in women, but this seems to be much less studied and much less developed than in the testis. Why it is physiologically less robust I do not know.

A similar sanctuary exists for the brain, which is protected by the blood-brain barrier. The blood-brain barrier is a semi-permeable layer of capillary cells that presents a barrier to certain substances crossing into the brain. It allows the passage of selected nutrients and macromolecules, but is highly selective in what is permitted to cross into the extracellular fluid that surrounds the brain. It does not permit the passage of pathogenic bacteria/viruses or of toxic chemicals or poisons.

The problem for our purposes is that the BBB perceives drugs/medications as chemicals/toxins, and therefore bars their passage into the brain. Therefore, systemic chemotherapy administered to a patient for a malignancy may be effective in the rest of the body, but does not necessarily penetrate into the brain. If somehow a clone of tumor cells has managed to metastasize to the brain, those cells will be protected from even effective chemotherapeutic agents and thus have the opportunity to proliferate in relative freedom.

While under certain circumstances a brain metastasis or primary brain tumor may disrupt the BBB and permit the entry of chemotherapy drugs, more commonly the barrier persists and complicates the treatment of tumors. Some drugs do indeed cross. An early chemotherapy drug for brain tumors was BCNU (Carmustine), a type of alkylating agent that crosses the BBB. It is still used but is not highly efficacious. More recently, newer drugs have proven capable of crossing the BBB and are significantly more efficacious, such as Temodar (temozolomide) and Avastin (bevacizumab).

Another approach has been to circumvent the blood as a means of drug distribution and to instead directly instill the drugs into the brain. One method was to develop biodegradable wafers out of plastics that were then infused with chemotherapeutic drugs, such as BCNU, and then implant these wafers directly into the brain or tumor space, usually at the time the brain tumor is being resected. The drug is slowly released from the wafer over several weeks. Another methodology is the Ommaya reservoir—this is the placement of a subcutaneous port on top of the head with a catheter inserted through the skull into the tumor or into the ventricles between the two sides of the brain. The chemotherapy drugs are injected into the reservoir and then pushed through the cavity directly into the brain or tumor. A variation on this is intrathecal chemotherapy in which a lumbar puncture is done—a needle is inserted into the fluid around the spinal cord—and chemotherapy is administered into that space. It can then circulate upward into the cerebrospinal fluid surrounding the brain. This is used for the treatment of lymphomas, leukemias and carcinomatous meningitis.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.

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