Hyperbaric Oxygen Therapy in Cancer Research

All right, well this is psychobaric boxing therapy and the treatment of cancer. Some of these slides now you may have seen many times. I want to start by saying that this is a topic that a lot of us are not familiar with. and we have had very little interface with it as hyperbaric physicians, but if you just do a simple little PubMed search on hyperbaric oxygen and cancer... when you reverse it and feed it direction of cancer and hyperbaric oxygen and a thousand articles that come up and of course some of them are just oxygen and cancer but there's still quite a bit that's been written about this surprisingly and it goes back to 1950 so I'm obviously not going to review a thousand articles what I want to focus on are some principles that would give us a framework to how to look at this and see where it might go So I'm going to review pepper bed oxygen therapy and its characterization as a genomic drug again. You know back at school when you start out you're just overwhelmed with so much information. I mean daily lecture after lecture after lecture on material you've never seen before. Everybody gets overwhelmed and the main thought is will I ever be able to master and hit this. And along coming to the fourth year she was and the doctors who have been in their careers for a while. Just relax. It's repetition. You're going to see it a million times. And you do, and thankfully that's the way we learn things. So I'm going to repeat this about genomic drug. Review cancer biology and its genomic foundation. Got something going here. Review the animal and human data. And then soon we'll come to some fundamental conclusions about hyperbaric oxygen. treatment of cancer. So once again, what is hyperbaric oxygen? And although I've mentioned it's a drug, it's a drug in principle, but it's really like no other drug. It has both metabolic capabilities, but now we've got this whole world of effects on the genome. So it's really a drug that we have no equivalent for. And we can get into all the metaphysical, even theological reasons for that. It's purity, it's substance of life etc but it's an amazing substance and of course as I've tried to recharacterize this we have a treatment for wounds you've seen all of this again I'm just going to go through that and of course this kind of sums it up our 8101 known genes that are oxygen sensitive either for up regulation or down regulation and and tie this inadvertently to Dr. Moussier's lecture, what was this done on? Human microvascular endothelial cells. Now, if we go back and look at the talk or the information that's been presented on brain injury, as it turns out, there are a couple types of blood flow interruptions. There is global ischemia where you completely deprive the... the brain of blood flow and of course in the extremity or any other organ system, same thing and there are partial and or focal deprivations of blood flow. As it turns out some of the most noted physiologists have made a very strong argument that the difference between the two is whether or not you activate the microcirculation so if we end up with an endothelial activation... end up with a different type of injury. And in fact, that is probably the type that in a chronic sense is more susceptible to hypodermic oxygen. Okay, so once again, a drug for disease processes, not diseases, and primary activity at the DNA and chromosomal level. All right, let's start with a simple, seemingly simple thing, what is cancer? These are a couple definitions. The term used for diseases in which abnormal cells divide without control and are able to invade other tissues. And there's a little variation on it. Uncontrolled growth and the ability to migrate from the original site and spread to distant sites. So uncontrolled growth and invasion and migration. Well, here's a summary statement by Burt. The revolution in cancer research can be summed up in a single sentence. Cancer is in essence a genetic disease. Once again, hyperbaric oxygen is a genetic treatment. And what he says is that the alteration... And three types of genes. This was responsible for tumor genesis. Oncogenes, tumor suppressor genes, and stability genes. But maybe not so quick. The abnormal gene function states in cancer are driven, it turns out, by both genetic abnormalities through mutations in genetic instability and epigenetic alterations involving the epigenetic machinery. A lot of people have heard of epigenetics. I started using this when I first came to New Orleans. Everybody hears the adjective, New Orleans is a different place. Boy, is it different. Well, we have a lot of things down there that are very different. And the only way I've been able to explain it is that it is epigenetic. It is so embedded in the culture and now the genome that it is an irreversible part of the local culture. And I'm going to show you something here that's very interesting. Epigenetics refers to the establishment of, that word is key, heritable changes in gene expression without alterations in the primary DNA sequences. In other words, it's not in the DNA, it's on the DNA. And if we look at our DNA in chromosomes, we have a double helix. As it turns out... It's more than that. We have a double helix and the chromosomes are coiled. So it's like a very tight coil. And in the center of this is a core of a variety of proteins. Histones are one of them. And coming off of these histones are tails that you see here. And so if we look at our DNA and how it's coiled and wrapped with the histones in the center of it and their tails coming off as it turns out. De-escalation and methylation reactions occur which change these histones and a whole bunch of intermediaries involved. And what ends up happening is it begins gene transcription and now we run the gene. And so as it turns out, these changes that can occur are heritable. Now you remember the Lamarckian hypothesis of genetics and heritability. Use and disuse, if I pump my arm up and use weights and have a very big muscle and bicep, it was thought that you could transmit that to your progeny. And of course it was completely debunked. But in fact, when you think about it, if prior to reproduction you had induced changes that somehow involved or affect those gene expression, then in fact... are heritable, which explains more than just the simple DNA transmission to our oxygen. So, we can now look at examples of epigenetics in cancer. And look when this was published. What, seven days ago? This just goes online. Symptoms of depression are linked to shorter survival time. Depression is associated with abnormal stress hormone regulation, increased cortisol levels, and inflammatory gene expression. Well, everybody knows attitude and expectations and putting up the fight is very important to cancer as it is any disease. And now we're finding that this affects gene expression, inflammatory genes. Well, remember the 8,101 genes we turn on when we have a breath? What are the genes that are turned on the immunosuppressive genes? In other words, the anti-inflammatory genes. And which ones are suppressed? The pro-inflammatory genes. So in fact, we've got evidence that we are affecting the genome likely in an epigenetic way here. Well, now let's talk about the major risk factors. Let's look at all of these. Tobacco, alcohol, diet, sexual, reproductive behavior, infectious agents, family history, occupation, environment, pollution. What are many of these things? Injury and inflammation, and what are they affecting? We know they aren't going to necessarily change the genes, but maybe they're affecting this epigenetic apparatus. Turns out, these effects are exerted on both the genes and the epigenetic environment to cause We're called premalignant lesions, and these can be ischemic lesions, hypoxic, toxic, whatever. And they are then advanced to malignancy by local hypoxia, so it's felt that the initial insults may have a hypoxic, ischemic, and or toxic effect on genes and epigenes, in other words, desuppressing genes. affecting gene expression, and one was two-way, and then advanced to malignancy by more hypoxia. And this is key because that's something that we can deal with. Well, as it turns out, Otto Warburg, and this is his article in the 50s, but it started in the 30s, and I believe, who else sent me this article? But our human hyperbaric library, Dr. Philip James, Warburg postulated that the In fact, cancer began, or is, an irreversible injury to the mitochondrial respiration, precipitated by a shift to glycolysis in the presence or absence of oxygen, called the glycolytic shift, which caused a de-differentiation to cancer. So his hypothesis was cancer starts with a change in metabolism first. Well, people have disagreed with that. But if we just go and refresh ourselves about glycolysis without putting all the enzymes in, We burn protein, carbohydrate, and lipids, and come down to glucose, pyruvate, and if you're a yeast, you can ferment it to alcohol. Or, if we're aerobically metabolizing, we get citric acid cycle and turn out 38 ATP here, or we turn out 2 ATP by anaerobic fermentation, which is the glycolytic pathway. And what's the cause of this glycolytic shift? It turns out that Borg-Rigthard was initially seen in Hypoxia. And he cites a later article after he had made this observation where Dr. Goldblatt took rat-mine cardiofibroblasts. And this is a very interesting type of apparatus. The picture in the article looked like a Gatling gun with all these chambers. And what they did was they subjected the fibroblasts to repeated short exposures of nitrogen. Short of 15 minutes. Over the course of two and a half years, what happened? The cells became malignant. So from repeated hypoxic exposures, they were able to change the metabolism of the cells to a glycolytic pathway, and with that, it became malignant. So the damage to respiration in cancer cells, he found was irreversible and never returned to normal and was terrible. So this was a permanent change in the genome or the epigenome that was causing this and the progression to cancer. And then he cited a bunch of examples of this where chronic irritation of skin resulting in cancerous lesions or mucosa or plugging of expiratory ducts in our body, bile ducts, scarring, chronic inflammation, cirrhosis of tissues. Respiratory poisons arsenic, in other words, another way of poisoning the aerobic metabolism of the cell, forcing it to a glycolytic pathway. Hydrogen sulfide derivatives, urethane, etc. And he had quite a few examples of this. Well, what he also said was that any respiratory injury from live energy must be cumulative, and such that frequent small doses of these poisons We're more dangerous than a single large dose. We think about a single large dose, what often happens is we kill the organism. Well, this actually goes to what causes apoptosis and necrosis. The figures are that between a 25% and 75% reduction in oxygen will send the cell into programmed cell death. But you have to hit about 85% hypoxia to get to full-blown necrosis. So what do we think here? Chronic chemical exposure in our society. or chronic insults, lifestyle things that have a little effect every day. Look at smoking. How long does it take to cause cancer with smoking? How many cigarettes a day? It doesn't happen immediately, which is part of why it's so difficult to stop. People can't see the damage over time. As opposed to crack, which will take you straight down the hill faster than anything. Maybe not necessarily producing cancer. So, if we could sum up... carcinogenesis by Gatton his first step appears to be an alteration in restriction on growth and that's arguable but it's very close the second step is closely tied to that is some alteration in metabolism to adapt to the hypoxic conditions of pre-malignant cells so if we Change the restrictions on growth so the cells grow very shortly, you can outstrip your blood supply. So at the same time, you have to be developing a metabolic adaptation that allows you to now exist in a hypoxic environment. And that's anaerobic glycolysis shifts through genetic and epigenetic mechanisms. It turns out increased glucose uptake coincides with this transition from pre-malignant to invasive cancer. And then the third step is an adaptation to the low pH lactic acid environment caused by glycolysis. You've heard people talk about acid environments and trying to alkalinate yourself for treatment of cancer. And this is the root of that. There's really kind of a fourth step in here. you've got to be able to turn on the vasculature to make new blood vessels so that you can supply some oxygen to the rapidly dividing cells. Well, as it turns out, increased glucose uptake, in other words, the glycolytic shift and aerobic metabolism, consistently correlates with poor prognosis and tumor aggressiveness and greater invasiveness and metastatic disease. And this, as you will see, is affected by hyperbaric oxygen. So increased glycolysis, derivatively hypoxia, is a component of and drives tumor aggressiveness. And this is just a little schematic. It's hard to find something on the Internet that shows actually cancer activation genes, but I thought it was pretty. So, back up, I'm sorry. And I'm going to remind everybody of the slide I put up the other day. At least with some of what we are doing, we are affecting gene activation at various levels. How this interacts with cancer genes, it's not really known. Are we affecting things here or are we affecting something downstream? Nobody really knows. Well, as it turns out, tumor hypoxia is not only caused, but it is an effect in cancer. So we have hypoxia as a very dominant theme in cancer. And it's very common in human tumors. If we look at solid tumors, 4 to 10 millimeter sized tumors have large reasons of hypoxia, less than 20 millimeters. Think of your transcutaneous oxygen measurements in extremity peripheral vascular disease. This is pretty severe hypoxia. And despite the tumor vascularity, we all know about this, tumors are extremely vascular. How do you image it? Perfusion imaging. If you're a contrast agent, look at the blood vessels, the blush. Surprisingly, the lower vascularity is hypoxic. And if we look at the tumor periphery, in normal tissue or out to normal tissue, the values are what you expected, 30 to 60 millimeters. What's this resemble? Our MARCS radiation model and our model of microvascular wounding in the brain. I love it. What did Dr. Mozegheni talk about? Microvascular wounding in the white man. Does this ring a bell? How many of the hyperbaric response of CNS diseases are white matter diseases? Brain decompression illness? What's the pathology on diverse studies out of England? Where's the pathology? It's in the small blood vessels primarily that supply the white matter. Carbon monoxide poisoning, lipid peroxidation, white matter disease. Traumatic brain injury, white matter disease. Microvascular stroke. white man disease. So since parts of the tumor are hypoxic and ischemic, or ischemic and hypoxic, as it turns out, they're going to be resistant to vascular delivery of chemotherapy, and it turns out they are also less susceptible to radiation. And in addition, and this is key, or one of them, hypoxic tumor cells undergo arrest that they enter a non-proliferative phase of the mitotic cycle. Well, what does chemo radiation do? We target rapidly proliferating cells with the production of reactive oxygen species, which we're going to talk about in a minute. Turns out, those surviving cells are the reason the cancer is back. And essentially, it's the resistant cancer. Cancer is a very smart disease. And it's what we don't kill initially that is the big problem. These hypoxic cells, well, it turns out cancer has maintained their hypoxia and keep the process going by three different mechanisms. Angiogenic switch, a deregulation of apoptosis, and a glycolytic shift. In the angiogenic switch, hypoxia activates a proliferation of pro-angiogenic growth factors that stimulate the growth of the... blood vessels. Turns out the new vasculature is highly disorganized and causes the hypoxia at the center of these tumors. And what you get is stagnated blood flow, hypoxia, and more hypoxia, driving more angiogenesis. And here's just a little schematic of normal blood flow in artery down to the capillary bed, becomes deoxygenated red blood to the bluer blood, and in an organized fashion, exits at the vein. If you look at a cancer cell, it's a highly disorganized growth of blood vessels, and it's relatively hypoxic throughout the tumor, or at least towards the center of it. And it's not drained by lymphatics as normal circulatory tissue is. How about deregulation of apoptosis? It turns out in response to hypoxia, tumors increase their metabolic rate, result in DNA damage, activation of the apoptotic cascade, and they develop cellular mechanisms then to avoid misapoptosis. Well, one of these is upregulation of telomerase. Telomerase normally adds segments to the telomeres, resulting in uncontrolled replication of cells. Telomeres are the tail ends of the chromosomes and then the focal point for replication. Every time a cell is devised, it starts here, replicates the DNA, and then you lose a little chunk of the telomere at the end here. Well, eventually you get to a critical point where the telomere is no longer long enough to replicate, the cell becomes senescent and dies. So where is aging? In fact, it's right there. It's in all our cells. In 2004, I was invited to the American Academy of Anti-Aging Medicine to give a talk on hyperbaric oxygen effects on aging. Well, we've been treating dementia patients for years and extending their lifespan, their cognition, quality of life, etc. at the end of life. Well, what we know about hyperbarics is it's a genome-made treatment. Aging is a genomic phenomenon. My argument was, you put the two together, we have to be doing something with the DNA. Last year, the Japanese published a study in rats, and they looked at telomere length with hyperbaric oxygen. What they found was hyperbaric oxygen maintained telomere length as the cells divide. So what do we have? Basic science evidence for rhythm found on youth. They can't talk about it too loudly, but in fact... we have the evidence now for what we're doing clinically. So here we are in cancer. How do cancer cells avoid apoptosis? They upregulate telomerase, lengthen the telomere segments so the cells can just keep dividing. And then, of course, the glycolytic shift, increased energy demands, hypoxic environments. You've got a switch to anaerobic metabolism. It occurs under the influence of, we've seen this, HIF-1-alpha. And other cell signaling mechanisms that are driven by hypoxia. Turns out this increased glycolysis is the basis for what? All the PET scan tumors. Increased glycolytic rate, fluorine, deoxyglucose, taken up by the cancer cells, and indigenergy. Well, what's the problem? In many types of cancers, it turns out there are multiple genetic and epigenetic alterations. The cancer itself is very heterogeneous, which is part of the reason why it's so tough to kill. You've got the alterations in genes and epigenes in different ways in multiple different parts of the cancer, and you've got this heterogeneous population of cells, which over time alter and change as you treat it. So the cancer is smart, and you've got to be adept and agile. Rather than try to target a single gene or a few genes, since so many are involved and there's so many potential targets, alternate strategies take advantage of the fundamental difference between cancer cells and normal cells. It's their biological metabolism and glycolysis. Why don't we target the glycolytic pathway and maybe preferentially kill cancer cells? So I'll go back to this again. And what happened in 2007? 3-BP came up, 3-bromopyruthate. Which it turns out is an alkylating agent that alkylates purine bases, which is part of the early chemotherapy agents, and actually you can muster it for one, and influences this whole anaerobic pathway preferentially. It turns out there are a number of doctors now using this directly injecting cancers, and it's having a dramatic effect on the problem if you have to have a large amount of tumor to directly inject. systemic effect as it's been here. Well, another method would be the Pasteur effect, inhibition of oxygen and carbohydrate fermentation of living cells. And it turns out more aggressive cancers have higher glucose consumption in the presence of oxygen, again the glycolytic Warburg effect, as consistent with our PET studies, and that correlates with these more aggressive cancers. But it turns out you can still inhibit this by oxygen. And this is from a study in breast and... Cancer and there are two cancers here, a less aggressive one and a much more aggressive one. And what it shows is that under conditions of hypoxia, they have significant glucose consumption and anaerobic metabolism. But when you expose them to just normoxia, you inhibit their metabolic glucose effect. Now that's not a huge one, but it still has some effect on the cancer cells. Well, how... Are reactive oxygen species involved? Because this is much the base of treatment of cancer, and it's what we're going to deal with with hyperbaric oxygen. Turns out, reactive oxygen species have been implicated in both the initiation and the progression of tumors, and these reactive oxygen species are induced by both hypoxia and reperfusion, which is inflammatory reaction, and hyperoxia, which is where we may have a role. Turns out, reactive oxygen species induce DNA strand breaks, causes mutations, and prolonged exposure to chemotherapeutic agents also leads to excessive reactive oxygen species and apoptosis. Well, it turns out there's a threshold effect. So once you reach a certain level of reactive oxygen species, that's where you get toxicity to the cells, and it amounts to exceeding the antioxidant capabilities. Dr. Rubison does this, and you've seen these words, I share these names as potential contraindications to hyperbaric oxygen. In fact, when combined in the right way, it has a synergistic effect, but also radiation and photodynamic therapy. All of these induce reactive oxygen species, and that's how we're going to take advantage of the hyperbaric oxygen. Well, osteodeficient tumors. It turns out it's a problem, should be a problem. Attendance to stevia limits chemotherapy with drug delivery. Radiotherapy is dependent on the oxygen level to induce the reactive oxygen species. Hypoxia induces cell cycle arrest, which leads to our resistant cells. And hypoxia drives the angiogenesis and the testes. Well, hypoxia is in all of this. So if we can do something about hypoxia, maybe we can do something about the cancer. And it turns out hypoxia resulting in reactive oxygen species that produce mutations in cancers. Some of these, it turns out, are favorable adaptations for the cancer. Hypoxia favors deregulation of apoptosis. We talked about the telomerase of regulation, production of genomic instability, resulting in highly aggressive tumors. And as it turns out, there are a bunch of interventions to overcome this hypoxia. Hyperbaric oxygen. We can try to radio-sensitize hypoxic cells with different mechanisms. We can modulate oxygen unloading capacity of hemoglobin to increase the oxygen at the tumor level. Blood flow modifier is nicotinamide and carbogen, which is 5% CO2. What does CO2 do? Massive dilator of blood vessels increase blood flow, deliver oxygen. Oxygen-carrying releasing substances have been tried. Perfluoro carbons are one of those that have been tried years ago. It just hasn't been completely developed and applied correctly. Destruction of hypoxic cells by hypothermia and bioreactive drugs. But as it turns out, only HBOT has been shown as a beneficial adjunct in radiotherapy, particularly. And what's the evidence for this? If we look in vitro, just a simple return to normoxia of mammalian cells, you turn off HIF1-alpha. In animal studies, we can genetically delete HIF1-alpha, decrease the vascular endothelial growth factor, which keeps the cycle going with angiogenesis. And this was done in mouse endothelial cells. In humans, hyperbaric oxygen promotes increased reactive oxidative species during hyperbaric oxygen and shortly thereafter. We know that increased reactive oxygen species are toxic to cancer cells in vitro. It's been shown in colon and liver, leukemic and ovarian, and in mice, in fibroblastic cancers, and S1A and sarcoma cells. So if we look at a review, Darwala in 2006, 24 animal studies, 91 and a half... 8.5% demonstrated a tumor inhibitory or neutral effect of hyperbaric oxygen in cancer. 8.5% demonstrated a tumor stimulatory effect. Turns out, stimulatory studies were in two mouse... models. So, not necessarily applicable to humans. Of 21 clinical studies, however, 81% showed cancer inhibitory or neutral effect. 19% showed stimulatory effect. However, of the stimulatory studies, two case reports, totally four cases, in bladder, urethral, and head and neck cancer. The other two were radiotherapy in lung, bladder, and advanced cervical cancer. Well, when this was all critically reviewed, it turns out hyperbaric oxygen was concluded to have no stimulatory effect on cancer. And that's pretty consistent, I think, with what we've seen. If you think of hyperbaric medicine, the majority of the clinical cases in the United States are now for osteoradioma process. And primarily for head and neck radiation necrosis. Well, what is the pattern in natural history of head and neck radiation necrosis? It's a primary tumor, surgery plus radiation, and then a secondary primary. A new one forms years later. And then a tertiary primary. And of course, it's all those genetic cigarette insults and epigenetic ones which are accumulating slowly over time and now developing separate cancer genes. Well, as it turns out, it only makes sense that some of these patients we are treating in ORN and focal active protocol for dental extractions have to have residual cancer and or new primaries. And yet we're not seeing stimulation of cancers. In fact, Marx, when he collected a large series of his patients over the years, he showed that in fact those who were treated with hyperbaric oxygen had a decreased incidence of new. primary secondary tertiary clients so in summary in general and animals and humans basically has no effect when delivered alone turns out the greatest benefit is in combination with chemo radiation of photodynamic therapy and why because we're generating reactive oxygen species In the inhibitory studies, it turns out HVLT generally caused overall tumor reduction with a decrease in occurrence and distribution of metastasis. Remember, hypoxia is one of the main drivers of metastasis. And of course, we have hyperoxygenating patients. Unfortunately, we can't keep them hyperoxygenated all day long with the greatest effect we can give. It turns out that the biggest effect was in head and neck cancer patients plus radiotherapy. Increase in survival. of about 40% of cases, and that's the review of the literature. And it turns out it's dependent on multiple factors. Tumor tightening stage, timing of intervention, dose of hyperbaric oxygen. And as a result, the studies are heterogeneous, and they're not necessarily generalizable, so you can't take this general conclusion and apply it to all cancers. Well, you know, does this sound familiar? And what are we talking about here? Well, I'm going to be redundant again, but we're talking about dosing of hyperbaric oxygen. And these were the parameters I put up yesterday, but in fact, maybe we also have to consider tissue type and diagnosis. What is the pathological target of treatment? Like Dr. Mosigini is pointing out, and begs the question, are we treating active barbinella? Or are we treating the microvascular scheming damage to neural tissue? And you may have to pick between those when you adjust your dose. Well, how about radiotherapy? What's the effect? What we know is radiation induces DNA damage to production of reactive oxygen species, which is directly dependent on PO2. And when cells are deprived of oxygen, their radio sensitivity decreases by a factor of three. In other words, it takes three times as much radiation to try to kill hypoxic tumor cells. So the best way to treat a cancer is to elevate that PO2 and irradiate them. And you can see, where does this go back to? 1953, with Gray, summarized by Churchill Davidson when he started first using microbaric oxygen with cancer, turns out the effectiveness is severely compromised also by lower hemoglobin and anemia. Why? Because you're carrying less oxygen. So we have less reactive oxygen species. So we want someone who has a good hematocrit. Well, it turns out Churchill Davidson was the first one in 1954 to apply radiotherapy to microgravity oxygen. What they did was... They had the patients in the chamber at 3 ATA and they were directly irradiated through a porthole. Well, guess what? This was in New Orleans in the early 70s, and they didn't realize that radiation porthole, the acrylic, has radiation fatigue. And they ended up with a blowout with the chamber under pressure. Fortunately, nobody was severely injured, but I don't know what kind of set the doctor back who was doing it. I can't remember his name. It started with an S. And it turns out he unfortunately died a couple years later of other causes. And so this didn't really gain much traction until finally the late 90s when the Japanese started. using it in the most aggressive form of cancer, one of them, which is brain cancer, gluoblastoma. And what they found was they were able to take the average life expectancy of their patients from 13 months to 22 months, so doubling. And what they did was hyperoxygenate them in the chamber, take them out, and within 10 to 15 minutes have them in a radiation therapy machine and directly irradiate the brain. And what happened? The kill fraction goes up. So it turns out you can deliver the hyperbaric either simultaneously, which is probably best, or very shortly after removal, or even prior to the radiation, to increase the tumor kill. And it's beneficial, it's been shown mostly in head and neck swim cell cancer, breast, bowel, and uterus. Results for bladder have been very negative in cervical, and in general they achieve local regional control, better local regional control. and once again, reduction of metastatic spread. And here are the references for this. In fact, all the references on these slides, if you pull them up, there are two of them, by Elwalili and by Daruwala in 2005 and 2006, respectively. And there have been many more studies since then. Well, it turns out, and we all know this, microcarboxy has vanished in post-radiation therapy damage. And you can start that as soon as you start seeing the damage to the tissue. It's an inflammatory reaction, primarily vasculitis, and we know that hyperbaric oxygen is both immunosuppressive and is beneficial to vascular injury. Well, how about chemotherapy? This is a little different. What's the rationale? Resistance to chemo is common in hypoxic tumors, partly because they're ischemic and you can't reach them with blood flow delivery. Turns out, HVLT may increase perfusion, may increase cellular uptake of the chemo agents. and the susceptibility of the cells to it with some type of synergistic action. And the rationale was alkylating agents, nitrogen mustard was one of the original ones, it turns out has effect on tumors akin to what is produced by ionizing radiation. And the akin means it's in fact due to production of reactive oxygen species. So the effect of these drugs, we thought, might be enhanced by hyperoxygenating the tumor. Turns out... tumor-silo-affected nitrogen mustard was potentiated by increased oxygenation in animal models of these tumors. This was shown back in the 60s. It turns out in both animals, HVLT increases susceptibility of the malignant tumor cells to destruction with Taxol, doxorubicin, and 5-FU. And there are probably more agents out there as well. And in one clinical team trial with misonidin, myosol. had a 15% increase in local tumor control in one year. Now that's not a huge effect, but it was done in a randomized control study, in advanced head and exclimus carcinoma, so it's a good study. Well, the other thing that chemotherapy and hyperglycogen may be having an effect, a combination, is in the reduction and prevention of chemo side effects. And this is the case of Ken Locklear, who of course freely allowed us to Describe this case and as you know he died a year ago. Well Ken at 38 was diagnosed with stage 4 metastatic colon cancer. Liver and adrenal at least. And he went to the literature and started looking at hypergryph oxygen effects. As everybody probably might remember he started as an 80 diver, had an air embolism, hypergryph oxygen saved his life. And that's how he ended up in hypergryph oxygen and hypergryph medicine field. So what he did, he started using brachybaric oxygen and I believe 2.8 ATA in combination with his chemotherapy. Well normally the full FOX regimen for colon cancer is usually stopped out less than the full course by the reaction, I should say the severe side effects of cisplatin, or oxaloplatin, excuse me, of the platin family. And what it does is usually cause An extreme peripheral neuropathy, numb hands and feet, people have trouble walking, they can't function. And of course, you know, it was a human. There are people who lose their hair, get anemia, and intrapenia, susceptibility to infections, lose weight. It's a wasting process. As you poison a tumor, you poison yourself. Ken, as it turns out, had not the full eight courses. They gave him 13 full courses of Folfox. He never had any intrapenia, never had anemia, didn't lose his hair, kept his weight and his appetite, and was able to beat the cancer back to... undetected cancer. And he went and applied for a patent for the use of this in the chemotherapy computer, not talking about it as an anti-cancer treatment, but a treatment to minimize side effects of chemotherapy. Well, turns out, chemo side effects are also potentially treated. Bill Maxfield was the first one to do this with chemotherapeutic brain effects. We've now had a number of cases as well. I've had a number of cases of peripheral neuropathy. One, methotrexate-induced peripheral neuropathy. So there are all sorts of possibilities here suggested by these few cases. Well, lastly, how about photodynamic therapies? It turns out, what is photodynamic therapy? Specific wavelengths of light that activate IV pre-administered photosensitizing agents. And here's the problem, though. You have to be able to access the tumor to get direct application of the light. And when you do, you generate singlet oxygen, reactive species, and of course, tumor kill. It turns out it's dependent on adequate tumor oxygenation and getting the photosensitizing agent there. So if you have an ischemic tumor, and of course you have apoptosia, there's going to be a problem. How do you rectify that? Use hyperparameter oxygen simultaneously. It turns out in humans, the benefit's been shown in inoperable soft and field cancers. and steni in the bronchial cancers. So if you get to it with an endoscope, inject a photodynamic agent while you're under hyperbaric oxygen, immediately after removal, kill rate goes up, and they've had success with this. And you can read about it in the Elvall-Ealy article. So, conclusions. Hypoxia is common in cancers. We know how to deal with hypoxia. Hypoxic cancer cells are resistant to radiation and chemotherapy. The effectiveness of radiation and chemotherapy are dependent on oxygen levels and reactive oxygen species and of all the methods looking at trying to increase delivery of oxygen to hypoxic tumors, hyperbaric oxygen is the only one that reliably does that. And of course it does that by dissolving oxygen in plasma. So in altered endo-asthemic circulation, you're going to increase your plasmanic flow. Turns out hyperbaric oxygen in general has a neutral effect on cancer. So done in the absence of chemo, radiation, or photodynamic therapy, it's really not going to have much effect at all. And hyperbaric can be adjunctively combined with these. Its effectiveness is dependent on dose, time of intervention, type of cancer, and stage. And really, we are still in the infancy of this despite 50 years. Thanks.

and we have had very little interface with it as hyperbaric physicians, but if you just do a simple little PubMed search on hyperbaric oxygen and cancer... when you reverse it and feed it direction of cancer and hyperbaric oxygen and a thousand articles that come up and of course some of them are just oxygen and cancer but there's still quite a bit that's been written about this surprisingly and it goes back to 1950 so I'm obviously not going to review a thousand articles what I want to focus on are some principles that would give us a framework to how to look at this and see where it might go So I'm going to review pepper bed oxygen therapy and its characterization as a genomic drug again. You know back at school when you start out you're just overwhelmed with so much information. I mean daily lecture after lecture after lecture on material you've never seen before. Everybody gets overwhelmed and the main thought is will I ever be able to master and hit this.

And along coming to the fourth year she was and the doctors who have been in their careers for a while. Just relax. It's repetition. You're going to see it a million times. And you do, and thankfully that's the way we learn things.

So I'm going to repeat this about genomic drug. Review cancer biology and its genomic foundation. Got something going here.

Review the animal and human data. And then soon we'll come to some fundamental conclusions about hyperbaric oxygen. treatment of cancer. So once again, what is hyperbaric oxygen? And although I've mentioned it's a drug, it's a drug in principle, but it's really like no other drug.

It has both metabolic capabilities, but now we've got this whole world of effects on the genome. So it's really a drug that we have no equivalent for. And we can get into all the metaphysical, even theological reasons for that.

It's purity, it's substance of life etc but it's an amazing substance and of course as I've tried to recharacterize this we have a treatment for wounds you've seen all of this again I'm just going to go through that and of course this kind of sums it up our 8101 known genes that are oxygen sensitive either for up regulation or down regulation and and tie this inadvertently to Dr. Moussier's lecture, what was this done on? Human microvascular endothelial cells. Now, if we go back and look at the talk or the information that's been presented on brain injury, as it turns out, there are a couple types of blood flow interruptions.

There is global ischemia where you completely deprive the... the brain of blood flow and of course in the extremity or any other organ system, same thing and there are partial and or focal deprivations of blood flow. As it turns out some of the most noted physiologists have made a very strong argument that the difference between the two is whether or not you activate the microcirculation so if we end up with an endothelial activation... end up with a different type of injury. And in fact, that is probably the type that in a chronic sense is more susceptible to hypodermic oxygen.

Okay, so once again, a drug for disease processes, not diseases, and primary activity at the DNA and chromosomal level. All right, let's start with a simple, seemingly simple thing, what is cancer? These are a couple definitions.

The term used for diseases in which abnormal cells divide without control and are able to invade other tissues. And there's a little variation on it. Uncontrolled growth and the ability to migrate from the original site and spread to distant sites.

So uncontrolled growth and invasion and migration. Well, here's a summary statement by Burt. The revolution in cancer research can be summed up in a single sentence.

Cancer is in essence a genetic disease. Once again, hyperbaric oxygen is a genetic treatment. And what he says is that the alteration... And three types of genes. This was responsible for tumor genesis.

Oncogenes, tumor suppressor genes, and stability genes. But maybe not so quick. The abnormal gene function states in cancer are driven, it turns out, by both genetic abnormalities through mutations in genetic instability and epigenetic alterations involving the epigenetic machinery.

A lot of people have heard of epigenetics. I started using this when I first came to New Orleans. Everybody hears the adjective, New Orleans is a different place. Boy, is it different.

Well, we have a lot of things down there that are very different. And the only way I've been able to explain it is that it is epigenetic. It is so embedded in the culture and now the genome that it is an irreversible part of the local culture. And I'm going to show you something here that's very interesting. Epigenetics refers to the establishment of, that word is key, heritable changes in gene expression without alterations in the primary DNA sequences.

In other words, it's not in the DNA, it's on the DNA. And if we look at our DNA in chromosomes, we have a double helix. As it turns out... It's more than that. We have a double helix and the chromosomes are coiled.

So it's like a very tight coil. And in the center of this is a core of a variety of proteins. Histones are one of them.

And coming off of these histones are tails that you see here. And so if we look at our DNA and how it's coiled and wrapped with the histones in the center of it and their tails coming off as it turns out. De-escalation and methylation reactions occur which change these histones and a whole bunch of intermediaries involved.

And what ends up happening is it begins gene transcription and now we run the gene. And so as it turns out, these changes that can occur are heritable. Now you remember the Lamarckian hypothesis of genetics and heritability.

Use and disuse, if I pump my arm up and use weights and have a very big muscle and bicep, it was thought that you could transmit that to your progeny. And of course it was completely debunked. But in fact, when you think about it, if prior to reproduction you had induced changes that somehow involved or affect those gene expression, then in fact...

are heritable, which explains more than just the simple DNA transmission to our oxygen. So, we can now look at examples of epigenetics in cancer. And look when this was published.

What, seven days ago? This just goes online. Symptoms of depression are linked to shorter survival time. Depression is associated with abnormal stress hormone regulation, increased cortisol levels, and inflammatory gene expression. Well, everybody knows attitude and expectations and putting up the fight is very important to cancer as it is any disease.

And now we're finding that this affects gene expression, inflammatory genes. Well, remember the 8,101 genes we turn on when we have a breath? What are the genes that are turned on the immunosuppressive genes? In other words, the anti-inflammatory genes.

And which ones are suppressed? The pro-inflammatory genes. So in fact, we've got evidence that we are affecting the genome likely in an epigenetic way here. Well, now let's talk about the major risk factors.

Let's look at all of these. Tobacco, alcohol, diet, sexual, reproductive behavior, infectious agents, family history, occupation, environment, pollution. What are many of these things?

Injury and inflammation, and what are they affecting? We know they aren't going to necessarily change the genes, but maybe they're affecting this epigenetic apparatus. Turns out, these effects are exerted on both the genes and the epigenetic environment to cause We're called premalignant lesions, and these can be ischemic lesions, hypoxic, toxic, whatever. And they are then advanced to malignancy by local hypoxia, so it's felt that the initial insults may have a hypoxic, ischemic, and or toxic effect on genes and epigenes, in other words, desuppressing genes.

affecting gene expression, and one was two-way, and then advanced to malignancy by more hypoxia. And this is key because that's something that we can deal with. Well, as it turns out, Otto Warburg, and this is his article in the 50s, but it started in the 30s, and I believe, who else sent me this article?

But our human hyperbaric library, Dr. Philip James, Warburg postulated that the In fact, cancer began, or is, an irreversible injury to the mitochondrial respiration, precipitated by a shift to glycolysis in the presence or absence of oxygen, called the glycolytic shift, which caused a de-differentiation to cancer. So his hypothesis was cancer starts with a change in metabolism first. Well, people have disagreed with that. But if we just go and refresh ourselves about glycolysis without putting all the enzymes in, We burn protein, carbohydrate, and lipids, and come down to glucose, pyruvate, and if you're a yeast, you can ferment it to alcohol. Or, if we're aerobically metabolizing, we get citric acid cycle and turn out 38 ATP here, or we turn out 2 ATP by anaerobic fermentation, which is the glycolytic pathway.

And what's the cause of this glycolytic shift? It turns out that Borg-Rigthard was initially seen in Hypoxia. And he cites a later article after he had made this observation where Dr. Goldblatt took rat-mine cardiofibroblasts.

And this is a very interesting type of apparatus. The picture in the article looked like a Gatling gun with all these chambers. And what they did was they subjected the fibroblasts to repeated short exposures of nitrogen. Short of 15 minutes.

Over the course of two and a half years, what happened? The cells became malignant. So from repeated hypoxic exposures, they were able to change the metabolism of the cells to a glycolytic pathway, and with that, it became malignant.

So the damage to respiration in cancer cells, he found was irreversible and never returned to normal and was terrible. So this was a permanent change in the genome or the epigenome that was causing this and the progression to cancer. And then he cited a bunch of examples of this where chronic irritation of skin resulting in cancerous lesions or mucosa or plugging of expiratory ducts in our body, bile ducts, scarring, chronic inflammation, cirrhosis of tissues.

Respiratory poisons arsenic, in other words, another way of poisoning the aerobic metabolism of the cell, forcing it to a glycolytic pathway. Hydrogen sulfide derivatives, urethane, etc. And he had quite a few examples of this.

Well, what he also said was that any respiratory injury from live energy must be cumulative, and such that frequent small doses of these poisons We're more dangerous than a single large dose. We think about a single large dose, what often happens is we kill the organism. Well, this actually goes to what causes apoptosis and necrosis. The figures are that between a 25% and 75% reduction in oxygen will send the cell into programmed cell death.

But you have to hit about 85% hypoxia to get to full-blown necrosis. So what do we think here? Chronic chemical exposure in our society.

or chronic insults, lifestyle things that have a little effect every day. Look at smoking. How long does it take to cause cancer with smoking? How many cigarettes a day? It doesn't happen immediately, which is part of why it's so difficult to stop.

People can't see the damage over time. As opposed to crack, which will take you straight down the hill faster than anything. Maybe not necessarily producing cancer. So, if we could sum up... carcinogenesis by Gatton his first step appears to be an alteration in restriction on growth and that's arguable but it's very close the second step is closely tied to that is some alteration in metabolism to adapt to the hypoxic conditions of pre-malignant cells so if we Change the restrictions on growth so the cells grow very shortly, you can outstrip your blood supply.

So at the same time, you have to be developing a metabolic adaptation that allows you to now exist in a hypoxic environment. And that's anaerobic glycolysis shifts through genetic and epigenetic mechanisms. It turns out increased glucose uptake coincides with this transition from pre-malignant to invasive cancer. And then the third step is an adaptation to the low pH lactic acid environment caused by glycolysis.

You've heard people talk about acid environments and trying to alkalinate yourself for treatment of cancer. And this is the root of that. There's really kind of a fourth step in here.

you've got to be able to turn on the vasculature to make new blood vessels so that you can supply some oxygen to the rapidly dividing cells. Well, as it turns out, increased glucose uptake, in other words, the glycolytic shift and aerobic metabolism, consistently correlates with poor prognosis and tumor aggressiveness and greater invasiveness and metastatic disease. And this, as you will see, is affected by hyperbaric oxygen. So increased glycolysis, derivatively hypoxia, is a component of and drives tumor aggressiveness.

And this is just a little schematic. It's hard to find something on the Internet that shows actually cancer activation genes, but I thought it was pretty. So, back up, I'm sorry. And I'm going to remind everybody of the slide I put up the other day. At least with some of what we are doing, we are affecting gene activation at various levels.

How this interacts with cancer genes, it's not really known. Are we affecting things here or are we affecting something downstream? Nobody really knows.

Well, as it turns out, tumor hypoxia is not only caused, but it is an effect in cancer. So we have hypoxia as a very dominant theme in cancer. And it's very common in human tumors. If we look at solid tumors, 4 to 10 millimeter sized tumors have large reasons of hypoxia, less than 20 millimeters. Think of your transcutaneous oxygen measurements in extremity peripheral vascular disease.

This is pretty severe hypoxia. And despite the tumor vascularity, we all know about this, tumors are extremely vascular. How do you image it? Perfusion imaging. If you're a contrast agent, look at the blood vessels, the blush.

Surprisingly, the lower vascularity is hypoxic. And if we look at the tumor periphery, in normal tissue or out to normal tissue, the values are what you expected, 30 to 60 millimeters. What's this resemble? Our MARCS radiation model and our model of microvascular wounding in the brain.

I love it. What did Dr. Mozegheni talk about? Microvascular wounding in the white man.

Does this ring a bell? How many of the hyperbaric response of CNS diseases are white matter diseases? Brain decompression illness?

What's the pathology on diverse studies out of England? Where's the pathology? It's in the small blood vessels primarily that supply the white matter. Carbon monoxide poisoning, lipid peroxidation, white matter disease.

Traumatic brain injury, white matter disease. Microvascular stroke. white man disease.

So since parts of the tumor are hypoxic and ischemic, or ischemic and hypoxic, as it turns out, they're going to be resistant to vascular delivery of chemotherapy, and it turns out they are also less susceptible to radiation. And in addition, and this is key, or one of them, hypoxic tumor cells undergo arrest that they enter a non-proliferative phase of the mitotic cycle. Well, what does chemo radiation do? We target rapidly proliferating cells with the production of reactive oxygen species, which we're going to talk about in a minute.

Turns out, those surviving cells are the reason the cancer is back. And essentially, it's the resistant cancer. Cancer is a very smart disease. And it's what we don't kill initially that is the big problem.

These hypoxic cells, well, it turns out cancer has maintained their hypoxia and keep the process going by three different mechanisms. Angiogenic switch, a deregulation of apoptosis, and a glycolytic shift. In the angiogenic switch, hypoxia activates a proliferation of pro-angiogenic growth factors that stimulate the growth of the...

blood vessels. Turns out the new vasculature is highly disorganized and causes the hypoxia at the center of these tumors. And what you get is stagnated blood flow, hypoxia, and more hypoxia, driving more angiogenesis.

And here's just a little schematic of normal blood flow in artery down to the capillary bed, becomes deoxygenated red blood to the bluer blood, and in an organized fashion, exits at the vein. If you look at a cancer cell, it's a highly disorganized growth of blood vessels, and it's relatively hypoxic throughout the tumor, or at least towards the center of it. And it's not drained by lymphatics as normal circulatory tissue is. How about deregulation of apoptosis? It turns out in response to hypoxia, tumors increase their metabolic rate, result in DNA damage, activation of the apoptotic cascade, and they develop cellular mechanisms then to avoid misapoptosis.

Well, one of these is upregulation of telomerase. Telomerase normally adds segments to the telomeres, resulting in uncontrolled replication of cells. Telomeres are the tail ends of the chromosomes and then the focal point for replication.

Every time a cell is devised, it starts here, replicates the DNA, and then you lose a little chunk of the telomere at the end here. Well, eventually you get to a critical point where the telomere is no longer long enough to replicate, the cell becomes senescent and dies. So where is aging? In fact, it's right there.

It's in all our cells. In 2004, I was invited to the American Academy of Anti-Aging Medicine to give a talk on hyperbaric oxygen effects on aging. Well, we've been treating dementia patients for years and extending their lifespan, their cognition, quality of life, etc. at the end of life. Well, what we know about hyperbarics is it's a genome-made treatment. Aging is a genomic phenomenon.

My argument was, you put the two together, we have to be doing something with the DNA. Last year, the Japanese published a study in rats, and they looked at telomere length with hyperbaric oxygen. What they found was hyperbaric oxygen maintained telomere length as the cells divide. So what do we have?

Basic science evidence for rhythm found on youth. They can't talk about it too loudly, but in fact... we have the evidence now for what we're doing clinically.

So here we are in cancer. How do cancer cells avoid apoptosis? They upregulate telomerase, lengthen the telomere segments so the cells can just keep dividing.

And then, of course, the glycolytic shift, increased energy demands, hypoxic environments. You've got a switch to anaerobic metabolism. It occurs under the influence of, we've seen this, HIF-1-alpha.

And other cell signaling mechanisms that are driven by hypoxia. Turns out this increased glycolysis is the basis for what? All the PET scan tumors. Increased glycolytic rate, fluorine, deoxyglucose, taken up by the cancer cells, and indigenergy. Well, what's the problem?

In many types of cancers, it turns out there are multiple genetic and epigenetic alterations. The cancer itself is very heterogeneous, which is part of the reason why it's so tough to kill. You've got the alterations in genes and epigenes in different ways in multiple different parts of the cancer, and you've got this heterogeneous population of cells, which over time alter and change as you treat it.

So the cancer is smart, and you've got to be adept and agile. Rather than try to target a single gene or a few genes, since so many are involved and there's so many potential targets, alternate strategies take advantage of the fundamental difference between cancer cells and normal cells. It's their biological metabolism and glycolysis.

Why don't we target the glycolytic pathway and maybe preferentially kill cancer cells? So I'll go back to this again. And what happened in 2007? 3-BP came up, 3-bromopyruthate.

Which it turns out is an alkylating agent that alkylates purine bases, which is part of the early chemotherapy agents, and actually you can muster it for one, and influences this whole anaerobic pathway preferentially. It turns out there are a number of doctors now using this directly injecting cancers, and it's having a dramatic effect on the problem if you have to have a large amount of tumor to directly inject. systemic effect as it's been here.

Well, another method would be the Pasteur effect, inhibition of oxygen and carbohydrate fermentation of living cells. And it turns out more aggressive cancers have higher glucose consumption in the presence of oxygen, again the glycolytic Warburg effect, as consistent with our PET studies, and that correlates with these more aggressive cancers. But it turns out you can still inhibit this by oxygen.

And this is from a study in breast and... Cancer and there are two cancers here, a less aggressive one and a much more aggressive one. And what it shows is that under conditions of hypoxia, they have significant glucose consumption and anaerobic metabolism. But when you expose them to just normoxia, you inhibit their metabolic glucose effect.

Now that's not a huge one, but it still has some effect on the cancer cells. Well, how... Are reactive oxygen species involved? Because this is much the base of treatment of cancer, and it's what we're going to deal with with hyperbaric oxygen. Turns out, reactive oxygen species have been implicated in both the initiation and the progression of tumors, and these reactive oxygen species are induced by both hypoxia and reperfusion, which is inflammatory reaction, and hyperoxia, which is where we may have a role.

Turns out, reactive oxygen species induce DNA strand breaks, causes mutations, and prolonged exposure to chemotherapeutic agents also leads to excessive reactive oxygen species and apoptosis. Well, it turns out there's a threshold effect. So once you reach a certain level of reactive oxygen species, that's where you get toxicity to the cells, and it amounts to exceeding the antioxidant capabilities.

Dr. Rubison does this, and you've seen these words, I share these names as potential contraindications to hyperbaric oxygen. In fact, when combined in the right way, it has a synergistic effect, but also radiation and photodynamic therapy. All of these induce reactive oxygen species, and that's how we're going to take advantage of the hyperbaric oxygen.

Well, osteodeficient tumors. It turns out it's a problem, should be a problem. Attendance to stevia limits chemotherapy with drug delivery.

Radiotherapy is dependent on the oxygen level to induce the reactive oxygen species. Hypoxia induces cell cycle arrest, which leads to our resistant cells. And hypoxia drives the angiogenesis and the testes. Well, hypoxia is in all of this.

So if we can do something about hypoxia, maybe we can do something about the cancer. And it turns out hypoxia resulting in reactive oxygen species that produce mutations in cancers. Some of these, it turns out, are favorable adaptations for the cancer. Hypoxia favors deregulation of apoptosis.

We talked about the telomerase of regulation, production of genomic instability, resulting in highly aggressive tumors. And as it turns out, there are a bunch of interventions to overcome this hypoxia. Hyperbaric oxygen. We can try to radio-sensitize hypoxic cells with different mechanisms.

We can modulate oxygen unloading capacity of hemoglobin to increase the oxygen at the tumor level. Blood flow modifier is nicotinamide and carbogen, which is 5% CO2. What does CO2 do? Massive dilator of blood vessels increase blood flow, deliver oxygen.

Oxygen-carrying releasing substances have been tried. Perfluoro carbons are one of those that have been tried years ago. It just hasn't been completely developed and applied correctly. Destruction of hypoxic cells by hypothermia and bioreactive drugs.

But as it turns out, only HBOT has been shown as a beneficial adjunct in radiotherapy, particularly. And what's the evidence for this? If we look in vitro, just a simple return to normoxia of mammalian cells, you turn off HIF1-alpha. In animal studies, we can genetically delete HIF1-alpha, decrease the vascular endothelial growth factor, which keeps the cycle going with angiogenesis.

And this was done in mouse endothelial cells. In humans, hyperbaric oxygen promotes increased reactive oxidative species during hyperbaric oxygen and shortly thereafter. We know that increased reactive oxygen species are toxic to cancer cells in vitro. It's been shown in colon and liver, leukemic and ovarian, and in mice, in fibroblastic cancers, and S1A and sarcoma cells. So if we look at a review, Darwala in 2006, 24 animal studies, 91 and a half...

8.5% demonstrated a tumor inhibitory or neutral effect of hyperbaric oxygen in cancer. 8.5% demonstrated a tumor stimulatory effect. Turns out, stimulatory studies were in two mouse... models. So, not necessarily applicable to humans.

Of 21 clinical studies, however, 81% showed cancer inhibitory or neutral effect. 19% showed stimulatory effect. However, of the stimulatory studies, two case reports, totally four cases, in bladder, urethral, and head and neck cancer. The other two were radiotherapy in lung, bladder, and advanced cervical cancer. Well, when this was all critically reviewed, it turns out hyperbaric oxygen was concluded to have no stimulatory effect on cancer.

And that's pretty consistent, I think, with what we've seen. If you think of hyperbaric medicine, the majority of the clinical cases in the United States are now for osteoradioma process. And primarily for head and neck radiation necrosis. Well, what is the pattern in natural history of head and neck radiation necrosis? It's a primary tumor, surgery plus radiation, and then a secondary primary.

A new one forms years later. And then a tertiary primary. And of course, it's all those genetic cigarette insults and epigenetic ones which are accumulating slowly over time and now developing separate cancer genes. Well, as it turns out, it only makes sense that some of these patients we are treating in ORN and focal active protocol for dental extractions have to have residual cancer and or new primaries.

And yet we're not seeing stimulation of cancers. In fact, Marx, when he collected a large series of his patients over the years, he showed that in fact those who were treated with hyperbaric oxygen had a decreased incidence of new. primary secondary tertiary clients so in summary in general and animals and humans basically has no effect when delivered alone turns out the greatest benefit is in combination with chemo radiation of photodynamic therapy and why because we're generating reactive oxygen species In the inhibitory studies, it turns out HVLT generally caused overall tumor reduction with a decrease in occurrence and distribution of metastasis. Remember, hypoxia is one of the main drivers of metastasis. And of course, we have hyperoxygenating patients.

Unfortunately, we can't keep them hyperoxygenated all day long with the greatest effect we can give. It turns out that the biggest effect was in head and neck cancer patients plus radiotherapy. Increase in survival.

of about 40% of cases, and that's the review of the literature. And it turns out it's dependent on multiple factors. Tumor tightening stage, timing of intervention, dose of hyperbaric oxygen.

And as a result, the studies are heterogeneous, and they're not necessarily generalizable, so you can't take this general conclusion and apply it to all cancers. Well, you know, does this sound familiar? And what are we talking about here?

Well, I'm going to be redundant again, but we're talking about dosing of hyperbaric oxygen. And these were the parameters I put up yesterday, but in fact, maybe we also have to consider tissue type and diagnosis. What is the pathological target of treatment? Like Dr. Mosigini is pointing out, and begs the question, are we treating active barbinella? Or are we treating the microvascular scheming damage to neural tissue?

And you may have to pick between those when you adjust your dose. Well, how about radiotherapy? What's the effect? What we know is radiation induces DNA damage to production of reactive oxygen species, which is directly dependent on PO2. And when cells are deprived of oxygen, their radio sensitivity decreases by a factor of three.

In other words, it takes three times as much radiation to try to kill hypoxic tumor cells. So the best way to treat a cancer is to elevate that PO2 and irradiate them. And you can see, where does this go back to?

1953, with Gray, summarized by Churchill Davidson when he started first using microbaric oxygen with cancer, turns out the effectiveness is severely compromised also by lower hemoglobin and anemia. Why? Because you're carrying less oxygen.

So we have less reactive oxygen species. So we want someone who has a good hematocrit. Well, it turns out Churchill Davidson was the first one in 1954 to apply radiotherapy to microgravity oxygen. What they did was... They had the patients in the chamber at 3 ATA and they were directly irradiated through a porthole.

Well, guess what? This was in New Orleans in the early 70s, and they didn't realize that radiation porthole, the acrylic, has radiation fatigue. And they ended up with a blowout with the chamber under pressure.

Fortunately, nobody was severely injured, but I don't know what kind of set the doctor back who was doing it. I can't remember his name. It started with an S. And it turns out he unfortunately died a couple years later of other causes.

And so this didn't really gain much traction until finally the late 90s when the Japanese started. using it in the most aggressive form of cancer, one of them, which is brain cancer, gluoblastoma. And what they found was they were able to take the average life expectancy of their patients from 13 months to 22 months, so doubling. And what they did was hyperoxygenate them in the chamber, take them out, and within 10 to 15 minutes have them in a radiation therapy machine and directly irradiate the brain. And what happened?

The kill fraction goes up. So it turns out you can deliver the hyperbaric either simultaneously, which is probably best, or very shortly after removal, or even prior to the radiation, to increase the tumor kill. And it's beneficial, it's been shown mostly in head and neck swim cell cancer, breast, bowel, and uterus.

Results for bladder have been very negative in cervical, and in general they achieve local regional control, better local regional control. and once again, reduction of metastatic spread. And here are the references for this.

In fact, all the references on these slides, if you pull them up, there are two of them, by Elwalili and by Daruwala in 2005 and 2006, respectively. And there have been many more studies since then. Well, it turns out, and we all know this, microcarboxy has vanished in post-radiation therapy damage.

And you can start that as soon as you start seeing the damage to the tissue. It's an inflammatory reaction, primarily vasculitis, and we know that hyperbaric oxygen is both immunosuppressive and is beneficial to vascular injury. Well, how about chemotherapy?

This is a little different. What's the rationale? Resistance to chemo is common in hypoxic tumors, partly because they're ischemic and you can't reach them with blood flow delivery.

Turns out, HVLT may increase perfusion, may increase cellular uptake of the chemo agents. and the susceptibility of the cells to it with some type of synergistic action. And the rationale was alkylating agents, nitrogen mustard was one of the original ones, it turns out has effect on tumors akin to what is produced by ionizing radiation.

And the akin means it's in fact due to production of reactive oxygen species. So the effect of these drugs, we thought, might be enhanced by hyperoxygenating the tumor. Turns out... tumor-silo-affected nitrogen mustard was potentiated by increased oxygenation in animal models of these tumors. This was shown back in the 60s.

It turns out in both animals, HVLT increases susceptibility of the malignant tumor cells to destruction with Taxol, doxorubicin, and 5-FU. And there are probably more agents out there as well. And in one clinical team trial with misonidin, myosol.

had a 15% increase in local tumor control in one year. Now that's not a huge effect, but it was done in a randomized control study, in advanced head and exclimus carcinoma, so it's a good study. Well, the other thing that chemotherapy and hyperglycogen may be having an effect, a combination, is in the reduction and prevention of chemo side effects. And this is the case of Ken Locklear, who of course freely allowed us to Describe this case and as you know he died a year ago. Well Ken at 38 was diagnosed with stage 4 metastatic colon cancer.

Liver and adrenal at least. And he went to the literature and started looking at hypergryph oxygen effects. As everybody probably might remember he started as an 80 diver, had an air embolism, hypergryph oxygen saved his life.

And that's how he ended up in hypergryph oxygen and hypergryph medicine field. So what he did, he started using brachybaric oxygen and I believe 2.8 ATA in combination with his chemotherapy. Well normally the full FOX regimen for colon cancer is usually stopped out less than the full course by the reaction, I should say the severe side effects of cisplatin, or oxaloplatin, excuse me, of the platin family.

And what it does is usually cause An extreme peripheral neuropathy, numb hands and feet, people have trouble walking, they can't function. And of course, you know, it was a human. There are people who lose their hair, get anemia, and intrapenia, susceptibility to infections, lose weight. It's a wasting process. As you poison a tumor, you poison yourself.

Ken, as it turns out, had not the full eight courses. They gave him 13 full courses of Folfox. He never had any intrapenia, never had anemia, didn't lose his hair, kept his weight and his appetite, and was able to beat the cancer back to...

undetected cancer. And he went and applied for a patent for the use of this in the chemotherapy computer, not talking about it as an anti-cancer treatment, but a treatment to minimize side effects of chemotherapy. Well, turns out, chemo side effects are also potentially treated. Bill Maxfield was the first one to do this with chemotherapeutic brain effects.

We've now had a number of cases as well. I've had a number of cases of peripheral neuropathy. One, methotrexate-induced peripheral neuropathy. So there are all sorts of possibilities here suggested by these few cases. Well, lastly, how about photodynamic therapies?

It turns out, what is photodynamic therapy? Specific wavelengths of light that activate IV pre-administered photosensitizing agents. And here's the problem, though.

You have to be able to access the tumor to get direct application of the light. And when you do, you generate singlet oxygen, reactive species, and of course, tumor kill. It turns out it's dependent on adequate tumor oxygenation and getting the photosensitizing agent there. So if you have an ischemic tumor, and of course you have apoptosia, there's going to be a problem.

How do you rectify that? Use hyperparameter oxygen simultaneously. It turns out in humans, the benefit's been shown in inoperable soft and field cancers. and steni in the bronchial cancers.

So if you get to it with an endoscope, inject a photodynamic agent while you're under hyperbaric oxygen, immediately after removal, kill rate goes up, and they've had success with this. And you can read about it in the Elvall-Ealy article. So, conclusions.

Hypoxia is common in cancers. We know how to deal with hypoxia. Hypoxic cancer cells are resistant to radiation and chemotherapy.

The effectiveness of radiation and chemotherapy are dependent on oxygen levels and reactive oxygen species and of all the methods looking at trying to increase delivery of oxygen to hypoxic tumors, hyperbaric oxygen is the only one that reliably does that. And of course it does that by dissolving oxygen in plasma. So in altered endo-asthemic circulation, you're going to increase your plasmanic flow. Turns out hyperbaric oxygen in general has a neutral effect on cancer. So done in the absence of chemo, radiation, or photodynamic therapy, it's really not going to have much effect at all.

And hyperbaric can be adjunctively combined with these. Its effectiveness is dependent on dose, time of intervention, type of cancer, and stage. And really, we are still in the infancy of this despite 50 years. Thanks.

Transcript for:Hyperbaric Oxygen Therapy in Cancer Research

Transcript for:
Hyperbaric Oxygen Therapy in Cancer Research