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What is the base cancer rate for an arbitrary carcinogen?

What is the base cancer rate for an arbitrary carcinogen?



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Are all carcinogens equally potent? Is the relationship between dose and probability of cancer roughly equal, or are there some carcinogens that provoke cancer significantly more than their cousins?


To answer this question in its entirety we have to split it into two questions:

What are the underlying mechanisms of carcinogenity?

One of the main mechanism behind carcinogenity is the mutagenity of the cancerogens, i.e. the ability to cause mutations, that are abberations of the cell DNA leading to uncontrolled proliferation. This classical paper investigates the relation between cancerogenity and mutagenity.

One should mention here that there are many types of mutations possible, mutations are not equally dangerous for cells and some mutations can be successfully repaired using the intact strain.

Therefore the following parameters of the source substances need to be measured to estimate the cancerogenity:

  1. Substance concentrations or absolute amounts (both being indirect measures of their chemical activities, the lower concentration is needed for causing cancer the higher is the chemical activity and vise versa).
  2. Substance radioactivity (for the mutagenesis due to radiation).

How can we measure the carcinogenity of different substances?

The most general approach here is to introduce certain amount of cancerogen into the animal body or to the cultured cell and to see the effect. The effect is calculated as the percentage of cells that undergo the transformation from normal into cancer cells. Two metrics are available here:

DT = Tumorigenic Dose (the amount of substance causing certain percentage of cancer in treated animals, all treated animals are taken for 100%)
CT = Tumorigenic Concentration (same, but adjusted for concentration and used in cell cultures).

(They are written CT and DT because in science people tend to used Latin abbreviations where the adjective actually follows the noune).

The common metrics are DT5/CT5 (5% cells/animals get cancer) and DT50/CT50 (50% of the animals). Those are similar to other common metrics, the most common is LC50/LD50 -- lethal dose for 50% of the animals/cells.


Unfortunately I couldn't not find any pre-compiled list with most known cancerogens and their TD/TC values. These seem to be interesting primarily for scientists. But going back to your question: you are absolutely right: some cancerogens are much more potent in causing cancer than the others!


Significant cancer rates in California sea lions has major human health implications

IMAGE: The Marine Mammal Center's Chief Pathologist Dr. Padráig Duignan (right) and Pathology Fellow Dr. Maggie Martinez (left) make initial surgical cuts during a necropsy, or animal autopsy, on a diseased. view more

Credit: Bill Hunnewell © The Marine Mammal Center

Scientists at The Marine Mammal Center - the world's largest marine mammal hospital - have found that viral-caused cancer in adult California sea lions is significantly increased by their exposure to toxins in the environment. The study is the result of over 20 years of research and examination of nearly 400 California sea lion patients by The Marine Mammal Center.

The Marine Mammal Center has been on the forefront of researching and understanding cancer in California sea lions and its connection to both ocean and human health. Since the cancer in sea lions was first discovered in 1979, between 18-23 percent of adult sea lions admitted to the Center's hospital have died of the fatal disease - the highest prevalence for a single type of cancer in any mammal, including humans.

The study, which was published in Frontiers in Marine Science, a peer-reviewed research journal, concluded that efforts to prevent ecosystem contamination with pollutants must improve in order to prevent virally caused cancer development in both wildlife and humans.

"This paper's conclusions mark a significant milestone in piecing together the complicated puzzle of cancer development in California sea lions," said Dr. Pádraig Duignan, Chief Pathologist at The Marine Mammal Center and co-author of the study. "The decades of research looking into this deadly disease clearly shows the ocean environment we all share is in trouble and that we need to find solutions to protect our collective health."

The findings also show that California sea lions have among the highest levels of certain persistent organic pollutants in the blubber of any marine mammals - a disturbing report that is cause for concern for scientists across the globe.

"Even though some of the pollutants we're finding in the blubber have been out of use for years, these cancer-causing elements remain in the environment for a very long time and wreak havoc on opportunistic coastal feeders like sea lions," said Dr. Duignan. "It concerns me knowing that we consume very similar seafood as these cancer victims and that the ocean is raising a loud and clear alarm in the sick bodies of a sentinel species. We need to continue this critical research and collaborate with the human cancer doctors to find patterns to help discover the link between sea lions and ourselves."

Previously, researchers at The Marine Mammal Center determined that these sea lions are infected with a herpesvirus similar to one that causes Kaposi's sarcoma (a viral cancer) in humans. In this newly released study, scientists used complex statistical analysis and modeling to investigate the relative roles of the various factors in the development of fatal metastatic cancer. The results showed that the damage of the DNA in sea lions occurs due to a number of factors, including: * the interaction of many environmental factors, including chemical contaminants and pollutants and * infections by tumor-promoting viruses like Otarine herpesvirus-1.

Additionally, their findings found that the animals' own genetic predisposition was not a significant factor to developing the cancer.

"While there is more to be learned about the complex factors that play into the development of this disease, what we learn from these animals contributes to research that underpins the threat to human health from pollutants in the ocean," said Dr. Frances M. D. Gulland, the lead author of the study who worked at The Marine Mammal Center for 25 years.

The Marine Mammal Center is a leading contributor to the global body of research and knowledge about marine mammal medicine and ocean health. The Center generates research findings and scientific outputs at volumes comparable to top academic institutions and prides itself on gathering and providing open research data that is free to access, reuse, repurpose and redistribute.

In 2010, the Center brought together an array of international researchers to form the Sea Lion Cancer Consortium to further investigate this disease, multiple of whom helped co-author the paper. The research work was funded by the Geoffrey Hughes Fellowship, the National Institutes of Health and National Science Foundation joint program for the Ecology of Infectious Disease, the National Marine Fisheries Service Marine Mammal Health and Stranding Program, and the Natural Environment Research Council.

ABOUT THE MARINE MAMMAL CENTER: Headquartered on the site of a former Cold War missile base, The Marine Mammal Center is a global leader in marine mammal health, science and conservation, and is the largest marine mammal hospital in the world. The Center's teaching hospital and training programs operate globally, with its headquarters in the Golden Gate National Recreation Area, part of the National Park Service. Expert teams from the Center travel around the world to work with emerging first responders and has itself rescued more than 24,000 marine mammals from 600 miles of its authorized rescue area of California coastline and the Big Island of Hawai'i. The Center's mission is to advance global ocean conservation through marine mammal rescue and rehabilitation, scientific research, and education.

For more information, please visit MarineMammalCenter.org.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.


Enzyme Found to Be Key in Determining Response to Carcinogen

N-nitrosodimethylamine (NDMA) is a chemical found in both industrial and natural processes and is classified as a probable carcinogen. In recent years, the FDA has had to recall many drugs such as Zantac and drugs used to treat diabetes due to traces of NDMA being found. The carcinogen can cause DNA damage that can lead to cancer.

MIT researchers report they have discovered in a mouse model that the enzyme, AAG, can help determine whether NDMA exposure will lead to damage and cancer. The researchers observed that too little activity of AAG leads to much higher cancer rates, while too much activity can produce tissue damage, especially in the liver. Measuring levels of AAG can aid doctors in predicting how people might respond to NDMA exposure.

“NDMA is a DNA-methylating agent that has been discovered to contaminate water, food, and drugs. The alkyladenine DNA glycosylase (AAG) removes methylated bases to initiate the base excision repair (BER) pathway. To understand how gene-environment interactions impact disease susceptibility, we study Aag-knockout (Aag−/−) and Aag-overexpressing mice that harbor increased levels of either replication-blocking lesions (3-methyladenine [3MeA]) or strand breaks (BER intermediates), respectively. Remarkably, the disease outcome switches from cancer to lethality simply by changing AAG levels.”

This chemical causes specific types of DNA damage, one of which is a lesion of adenine. These lesions are repaired by AAG, enabling DNA polymerases to replace them with new ones. If AAG activity is very high and the polymerases cannot keep up with the repair, then the DNA may end up with too many unrepaired strand breaks, which can be fatal to the cell. But if AAG activity is too low, damaged adenines persist and can be read incorrectly by the polymerase, causing the wrong base to be paired with it.

The MIT researchers studied mice with high levels of AAG and mice with AAG knocked out. After exposure to NDMA, the mice with no AAG had many more mutations and higher rates of cancer in the liver, where NDMA has its greatest effect. Mice with high levels of AAG had fewer mutations and lower cancer rates. However, those mice had significant tissue damage and cell death in the liver.

Mice with normal amounts of AAG showed some mutations after NDMA exposure, but were much better protected against cancer and liver damage.

“Nature did a really good job establishing the optimal levels of AAG, at least for our animal model,” Engelward said. “What is striking is that the levels of one gene out of 23,000 dictates disease outcome, yielding opposite effects depending on low or high expression.”

People experience different ranges of AAG levels. Studies have found that some people can have up to 20 times more AAG activity than others. This suggests that people may respond very differently to damage caused by NDMA, Kay pointed out.

The researchers look forward to studying the effects of chronic, low-level exposure to NDMA in mice, to help them better understand how it can affect humans. “That’s one of the top priorities for us, to figure out what happens in a real-world, everyday exposure,” added Kay.

“…the results of this study provide a basis for advancements in predicting outcomes of exposure to DNA-alkylating agents that promise to help in both treating and preventing cancer,” concluded the researchers.


Tobacco smoke carcinogens and cancer

The potential role of tobacco smoke carcinogens in smoking-associated cancers can be evaluated by various means, but it is important to consider levels of the compounds in cigarette smoke and their ability to induce tumors in laboratory animals. In the following, we discuss these factors with respect to cancers of the lung, oral cavity, esophagus, pancreas, and bladder.

Established pulmonary carcinogens in cigarette smoke include PAH, aza-arenes, tobacco-specific nitrosamines, e.g. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 1,3-butadiene, ethyl carbamate, ethylene oxide, nickel, chromium, cadmium, polonium-210, arsenic, and hydrazine. These compounds convincingly induce lung tumors in at least one animal species and have been positively identified in cigarette smoke.

Among the PAH, benzo[a]pyrene (BaP) is the most extensively studied compound (Phillips, 1983 Besarati Nia et al., 2002a) and its ability to induce lung tumors upon local administration or inhalation has been convincingly established (Hecht, 1999 International Agency for Research on Cancer, 1983). Lung tumors were not observed when BaP was administered in the diet to B6C3F1 mice (Culp et al., 1998). In studies of lung tumor induction by implantation in rats, BaP is more carcinogenic than the benzofluoranthenes or indeno[1,2,3-cd]pyrene (Deutsch-Wenzel et al., 1983). Extensive analytical data convincingly demonstrate the presence of BaP in cigarette smoke. Its sales-weighted concentration in current ‘full-flavored’ cigarettes is about 9 ng per cigarette (Chepiga et al., 2000). The abundant literature on BaP tends to diminish attention to other PAH such as dibenz[a,h]anthracene, 5-methylchrysene, and dibenzo[a,i]pyrene which are substantially stronger lung tumorigens than BaP in mice or hamsters, but occur in lower concentrations in cigarette smoke than does BaP (Nesnow et al., 1995 Sellakumar and Shubik, 1974).

Among the N-nitrosamines, N-nitrosodiethylamine is an effective pulmonary carcinogen in the hamster, but not the rat (Reznik-Shuller, 1983 International Agency for Research on Cancer, 1978). Its levels in cigarette smoke (up to 3 ng/cigarette) are low compared to those of other carcinogens. The tobacco-specific N-nitrosamine NNK is a potent lung carcinogen in rodents (Hecht, 1998). Its activity is particularly impressive in rats, where total doses as low as 6 mg/kg, administered by s.c. injection, or 35 mg/kg administered in the drinking water, produced significant incidences of lung tumors. Even lower doses induced lung tumors when considered in dose-response trend analyses (Hecht, 1998). It is the only compound in cigarette smoke known to induce lung tumors systemically in all three commonly used rodent models. NNK has a remarkable affinity for the lung, causing mainly adenoma and adenocarcinoma, independently of the route of administration (Hecht, 1998). NNK is the most abundant systemic lung carcinogen in cigarette smoke. Multiple international studies definitively document the presence of NNK in cigarette smoke its sales-weighted concentration in current ‘full-flavored cigarettes’ is 131 ng/cigarette (Chepiga et al., 2000 Spiegelhalder and Bartsch, 1996 Hecht and Hoffmann, 1988).

Lung is one of the multiple sites of tumorigenesis by 1,3-butadiene in mice, but is not a target in the rat (International Agency for Research on Cancer, 1992). B6C3F1 mice develop lung tumors at exposure concentrations that are three orders of magnitude lower than those that cause cancer in Sprague-Dawley rats. These interspecies differences are likely due to differences in metabolism of 1,3-butadiene. Mice convert a higher portion of the parent compound to highly carcinogenic 1,2,3,4-diepoxybutane, while the detoxification pathway via conjugation with glutathione is more prominent in rats (Thornton-Manning et al., 1995). Ethyl carbamate is a well-established pulmonary carcinogen in mice but not in other species (International Agency for Research on Cancer, 1974a). Ethylene oxide induces pulmonary tumors in mice, but not in rats (International Agency for Research on Cancer, 1986a). Nickel, chromium, cadmium, and arsenic are all present in tobacco and a percentage of each is transferred to mainstream smoke (Hoffmann et al., 2001). Levels of polonium-210 in tobacco smoke are insufficient to have a significant impact on lung cancer initiation in smokers (Harley et al., 1980). Hydrazine is an effective lung carcinogen in mice and has been detected in cigarette smoke (International Agency for Research on Cancer, 1973). Formaldehyde and acetaldehyde induce nasal tumors in rats when administered by inhalation (International Agency for Research on Cancer, 1982, 1985, 1999 Swenberg et al., 1980). Although they are not lung carcinogens, their concentrations in cigarette smoke are so high that they may nevertheless play a significant role. There is approximately 100 000 times more acetaldehyde in a cigarette than BaP (Chepiga et al., 2000).

Collectively, the available data indicate that PAH and NNK are important lung carcinogens in cigarette smoke most likely to be involved in lung cancer initiation in smokers. Their potent carcinogenic activities compensate for their relatively low concentrations in tobacco smoke. Other carcinogens mentioned here, as well as tumor promoters and co-carcinogens, may also play a role as causes of lung cancer in smokers.

The potent PAH carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) is routinely used for induction of oral tumors in the hamster (Solt et al., 1987). However, DMBA is not present in cigarette smoke. Other PAH have been less frequently tested in this model. A mixture of NNK and NNN induced oral tumors in rats treated repetitively by oral swabbing (Hecht et al., 1986). The rat oral cavity is one target of benzene carcinogenecity (National Toxicology Program 1986). The risk for oral cancer is markedly enhanced by alcohol consumption in smokers, perhaps due in part to enhancement of carcinogen metabolic activation by ethanol (Melikian et al., 1990 Mccoy and Wynder, 1979).

Numerous N-nitrosamines are potent esophageal carcinogens in rats (Preussmann and Stewart, 1984). Among these, N′-nitrosonornicotine (NNN) is by far the most prevalent in cigarette smoke. N-nitrosodiethylamine and N-nitrosopiperidine are two other smoke constituents that could be involved in esophageal tumor induction in smokers. BaP induces some esophageal tumors when administered to mice in the diet (Culp et al., 1998). The risk for esophageal cancer in humans is also enhanced by alcohol consumption (Mccoy and Wynder, 1979).

NNK and its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are the only known pancreatic carcinogens in cigarette smoke (Rivenson et al., 1988). Low doses of these nitrosamines induce pancreatic tumors in rats, in addition to lung tumors (Hecht, 1998). Pancreatic tumors are also observed in the offspring of pregnant rats treated with NNK, and this effect is markedly enhanced by ethanol (Schüller et al., 1993).

4-Aminobiphenyl and 2-naphthylamine are known human bladder carcinogens (International Agency for Research on Cancer, 1972, 1974b). Both are present in cigarette smoke. Hemoglobin adducts of 4-aminobiphenyl and other aromatic amines are associated with bladder cancer induction in smokers (Castelao et al., 2001). The evidence is strong that aromatic amines play a significant role as causes of bladder cancer in smokers (Vineis et al., 2001).

Cigarette smoke contains free radicals and induces oxidative damage (Arora et al., 2001 Pryor, 1997). The gas phase of freshly generated cigarette smoke has large amounts of nitric oxide and other unstable oxidants (Hecht, 1999). The particulate phase is postulated to contain long-lived radicals that may undergo quinone-hydroquinone redox cycling (Pryor, 1997). The presence of such free radicals and oxidants can lead to oxidative DNA damage. However, the role of oxidative damage in cancer induced by cigarette smoke is unclear.


Mutations arising from misincorporation by DNA polymerases

Mutations can also result from nucleotide misincorporation by DNA polymerases in copying non-damaged DNA templates during DNA replication or even during DNA repair synthesis. Studies on the fidelity of DNA synthesis indicate that purified DNA polymerases incorporate non-complementary nucleotides at rates much greater than one would predict based on the rare spontaneous mutations in human cells. The error rates of purified mammalian DNA polymerases in vitro thus far documented ( 13) vary from one in 5000 for DNA polymerase β, the enzyme responsible for the synthesis of short segments of DNA during repair synthesis, to one in 10 000 000 for DNA polymerases δ and ε, enzymes involved in DNA replication ( 14, 15). The latter polymerases contain a 3′→5′ exonucleolytic activity that excises non-complementary nucleotides immediately after misincorporation by the polymerase. The frequencies of misincorporation by any DNA polymerase can vary as much as 100-fold as a result of the nucleotide sequence in DNA ( 16). DNA polymerases pause at sites that have the potential to form secondary structures and these pause sites have been shown to be loci for enhanced misincorporation ( 17). Blocks to accuracy could be minimized by replication proteins that function in concert with DNA polymerase in DNA replication and/or DNA repair. In addition, misincorporated nucleotides are excised by the mismatch repair system ( 18) and this system may interact with a variety of adducted nucleotides in DNA ( 19). Thus, there are multiple systems with overlapping specificities for the repair of DNA.

There is increasing evidence for the interchangeability of DNA polymerases ( 20) and thus mutation rates might be altered by varying the relative expression of different DNA polymerases ( 21) as well as by mutations that render these enzymes error-prone ( 22). The increase in DNA polymerase β in certain tumors suggests the possibility that polymerase β could substitute for a more accurate DNA polymerase, resulting in increased mutagenesis ( 23). In Escherichia coli, DNA damage results in the induction of an error-prone response referred to as the SOS pathway ( 24). It has long been suspected that this pathway facilitates the bypass of blocking lesions during DNA replication through induction of proteins that render the normal DNA polymerases error-prone. Recently, one of the proteins involved in the SOS response, UmuD'2C, has been identified as an error-prone DNA polymerase that was designated as Pol V ( 25, 26). Moreover, a similar error-prone DNA polymerase has been identified in yeast ( 27) and found to be mutated in Xeroderma pigmentosum variant cells (XP-V) ( 28, 29). Conceivably, error-prone DNA polymerases are elevated in certain cancers and contribute to the accumulation of DNA mutations in these tumors.

The aforementioned results lead one to conclude that mutation rates in cells are maintained at a homeostatic equilibrium in which the extensive DNA damage is counterbalanced by multiple mechanisms for DNA repair (Figure 1 ). In normal cells, only infrequently do lesions in DNA escape the screen provided for by DNA repair and direct misincorporation at the time of DNA synthesis. In eukaryotic cells there is the emerging concept of checkpoints in which cells sterilize the DNA immediately prior to the onset of DNA replication ( 30). Mutations in G1/S checkpoint genes allow DNA replication in the presence of unrepaired lesions ( 31) and result in enhanced mutagenesis.


Ironically, given the brickbats that flew when the “bad luck” study was published in January, that paper’s authors don’t really disagree.

“We definitely didn’t say that two-thirds of cancers are due to intrinsic factors,” said statistician Christian Tomasetti of Johns Hopkins University, a coauthor of that controversial study. “It’s very clear that environmental factors affect cancer incidence.”

The earlier study, by Tomasetti and eminent cancer biologist Dr. Bert Vogelstein of Hopkins, was, on its surface, fairly simple. It examined whether there is a relationship between how often certain cells divide in different kinds of human tissue and the lifetime chance that cancer will develop in that tissue.

They found a relationship, and a strong one. The more often a tissue’s cells divide, the more likely that tissue is to develop cancer. Brain cells rarely divide, for instance, and brain cancers are rare colorectal cells divide like crazy and colorectal cancer is common. There are important exceptions, though. Lung and prostate cells rarely divide, but those organs account for a large fraction of cancers cells of the small intestine divide all the time, but cancer there is rare. Still, the general relationship made biological sense: when cells divide they duplicate their DNA duplicating DNA can introduce mistakes DNA mistakes can cause cancer.


Different Mutants Vary in Their Oncogenicity

p53 mutations in the core domain are classified into two types. Mutations such as those at the mutational hotspots 248R and 273R occur in the DNA contact areas on either the L3 loop or the nearby loop-sheet-helix motif of p53 (70) and are termed class I mutations. However, other mutations, like those at 175R, occur in areas important for the conformational stability of p53 protein, such as the L2 loop in the zinc region, and lead to conformational changes that expose the mutant-specific epitope of the PAb240 antibody and result in the loss the wild-type-specific epitope detected by PAb1620 (25 , 70 , 71) . These are termed class II mutations. This categorization, although useful, may be oversimplifying the situation, because the contact mutants may also evince some local conformational changes (72) and may vary in their degree of folding (see Table 1 ⇓ ). The conformational mutations were shown to be more oncogenic than the DNA binding mutations in several systems. The conformational mutants 175(R to H) and 249(R to S) resulted in immortalization of mammary epithelial cells, whereas the DNA contact mutants 248(R to W) and 273(R to H) did not (21) . The conformational mutants 175(R to H) and 179(H to Y) had a marked protective effect against etoposide-induced apoptosis, whereas contact mutants 248(R to W) and 273(R to H) had a much milder effect (41) . The same study showed, however, that there was no difference between 175(R to H) and 273(R to H) in the protective effect of these mutants against cisplatin-induced apoptosis. Conformational mutants 175(R to H), 245(G to D), 143(V to A), and 281(D to G) disrupted the spindle checkpoint and resulted in polyploidy in Colcemid-treated Li-Fraumeni fibroblasts, whereas the contact mutant 248(R to W) did not (73) . The contact mutant 273(R to H) has shown additional evidence of wild-type p53 function. When tumor-derived cell lines with missense p53 mutations were examined for wild-type p53 transcriptional activity, lines with the 273(R to H) mutant possessed it, whereas lines with mutants 156(R to P), 175(R to H), 248(R to W), 248(R to Q), and 280(R to K) did not (74) .

Success in the restoration of the wild-type p53 phenotype to cells with p53 mutants may also follow the general pattern outlined above if physiological criteria such as apoptosis, tumor regression, and inhibition of colony formation and proliferation are used. By these criteria, successful restoration to wild-type p53 function of mutants was shown thus far for mutations 273(R to H Refs. 10 , 75 , 76 ), 273(R to C Ref. 76 ), 280(R to K Ref. 10 ), 241(S to F Ref. 9 ), 248(R to Q Ref. 75 , , 76 ), and 249(R to S, Ref. 9 ). All of these mutations except the last are contact mutations, and the 249(R to S) has been shown to cause only local structural changes and has a degree of folding similar to p53 proteins mutated at 248R (Table 1) ⇓ .

What emerges from this analysis is the view that there is a spectrum of p53 oncogenic mutations, where at one end there are mutants that are weaker in their mutant p53 function and more amendable to restoration of wild-type p53 function. At the very edge of this end is inactive (cryptic) p53, which is not a mutant but nevertheless demands activation in the form of modifications to the negative regulatory COOH-terminal domain to exhibit the tumor suppressor response (77, 78, 79, 80, 81, 82, 83, 84, 85) . According to this view, what lies at the other end of the spectrum is a set of missense core domain mutations that cause widespread changes in the p53 protein (Table 1 ⇓ , Fig. 1 ⇓ ). The resulting mutants are stable and would be refractory to attempts to restore them to wild-type p53 function. The conformationally unstable mutants such as the temperature sensitive 143(V to A), which has a mutant conformation at 38°C and a wild-type conformation at 32°C, are expected to be somewhere in between. An illustration is the difference between the murine temperature sensitive 135(A to V) and the stable murine 132(C to F). The former exhibits pronounced gain of function at 38°C (40) , 3 but this is completely lost upon modification of the extreme COOH-terminus, important for mutant p53 stability (see below) by alternative splicing 3 . The 132(C to F) mutant also exhibits pronounced gain of function, but it is not lost with alternative splicing of the COOH-terminus (86) .

The spectrum of p53 mutations. Examples of mutation archetypes are placed according to their structural changes relative to activated p53 and their stability. More extensive and stable mutants are more refractory to reactivation and possess increased oncogenic gain of function. The contact mutant 273(R to H) has the least structural changes among the mutants shown and is the most amendable to reactivation. The mutant 143(V to A), similar to the murine 135(A to V), has more extensive structural changes, but it is conformationally unstable and hence more sensitive to modifications that will interfere with its mutant conformation. The stable conformational mutant 175(R to H), similar to the murine 132(C to F), is expected to be most refractory to reactivation. Cryptic (inactive) p53 is also included, as the p53 species demanding the mildest structural changes, in the form of physiological posttranslational modifications upon cellular stress, to assume its activated form. Wild-type p53 (wtp53).

Molecular epidemiological data shows that mutations at R175, R248, R249, R273, R282, and G245 are the most common missense mutations of p53 (87) . The most common is R273, although it seems to be selected against in leukemia (88) . This may indicate that it was selected for on the basis of its oncogenic potency or even perhaps that mutants that are too oncogenic are detrimental to the survival of the cancer in the long term. However, other processes, such as the mode of action of the mutagenizing agent, may determine which mutants are formed (5 , 89) . An interesting example is aflatoxin B1, associated in vitro with G:C to A:T mutation in the third base of codon 249 (42) .


Is Cancer a Fungus? A New Theory

This video and chapter offers crucial information about the relationships between cancer and infectious threats that every cancer patient and their family must be aware of. The truth that we must stare down is that cancer and infections cannot be separated from each other.

Cancer—always believed to be caused by genetic cell mutations—can in reality be caused by infections from viruses, bacteria, and fungi. &ldquoI believe that, conservatively, 15 to 20% of all cancer is caused by infections however, the number could be larger—maybe double,&rdquo said Dr. Andrew Dannenberg, director of the Cancer Center at New York-Presbyterian Hospital/Weill Cornell Medical Center. Dr. Dannenberg made the remarks in a speech in December 2007 at the annual international conference of the American Association for Cancer Research.

Whether caused by infections or not, once cancerous conditions are well underway the weakening of the immune system and the battle that ensues between the good guys and the bad is cheered on by hordes of infectious agents that increase in density, power and form as a patient&rsquos cancers get worse.

Cancer also involves inflammation, acid pH, low oxygen conditions accompanied by low CO2 levels, lower core body temperatures as well as nutritional deficiencies and high levels of tissue and cellular toxicity with heavy metals, chemicals and radiological exposure.

When the body&rsquos (immune system) weakens we get sick from one of a host of viruses, bacteria and fungi that already live within us but are dormant. Change pH, oxygen, cell voltage and hydration levels and these pathogens are ready to jump all over our blood streams and tissues.

Cancer cells love the conditions that healthy cells abhor. Same goes for all infectious agents. It is impossible to be dying of cancer and not be dying of infections and nutritional deficiencies at the same time!

Given enough time, cancer will develop whenever there is a proliferation of damaged cells. When cells are damaged, when their cell wall permeability changes, when toxins and free radicals build up, when the mitochondria lose functionality in terms of energy ATP production, when pH shifts strongly to the acidic, and when essential nutrients are absent, cells eventually, or sometimes quickly, decline into a cancerous condition.
We can see that when a person has cancer they are literally rotting inside and dying from the loss of function, gathering infectious forces, and losing strength from malnutrition as the cancer cells eat us out of house and home.

Science Daily reports, &ldquoWith infectious diseases, it is often not the pathogen itself, but rather an excessive inflammatory immune response (sepsis) that contributes to the patient&rsquos death, for instance as a result of organ damage. On intensive care units, sepsis is the second-most common cause of death worldwide. In patients with a severely compromised immune system specially, life-threatening candida fungal infections represent a high risk of sepsis.&rdquo


Credit: Image courtesy of Medical University of Vienna

&ldquoThe working group led by Karl Kuchler in the Christian Doppler Laboratory for Infection Biology (Max. F. Perutz Laboratories at the Vienna Biocenter Campus) has now deciphered the molecular causes of life-threatening inflammatory reactions that are triggered by fungal infections: two highly aggressive types of phagocytes in the immune system (neutrophils and inflammatory monocytes), which however also have a high potential for collateral destruction, mediate the inflammatory reaction during an infection with candida. Certain interferons, the messenger substances used by the immune system, which are excreted during fungal infections, stimulate the influx of immune cell types to infected organs and lead to sepsis.&rdquo

&ldquoWe have been able to demonstrate for the first time that the targeted blockade of this immune response with inflammation-inhibiting drugs can significantly reduce candida sepsis and therefore mortality,&rdquo says Karl Kuchler, who used an anti-inflammatory substance in the study.[1]

Science Daily said, &ldquoInfectious diseases are the world&rsquos number-one cause of death, with pathogenic fungi being responsible for extremely dangerous infections. Worldwide, more than €6 billion are spent each year on anti-fungal medications, and the total costs of the medical treatment of infectious diseases caused by pathogenic fungi are estimated in the order of hundreds of billions of Euros.&rdquo

Cancer cells and pre-cancerous cells are so common that nearly everyone by middle age or old age is riddled with them, said Dr. Thea Tlsty, a professor of pathology at the University of California, San Francisco. That was discovered in autopsy studies of people who died of other causes, with no idea that they had cancer cells or precancerous cells. They did not have large tumors or symptoms of cancer. &ldquoThe really interesting question,&rdquo Dr. Tlsty said, &ldquois not so much why do we get cancer as why don&rsquot we get cancer?&rdquo

The earlier a cell is in its path toward an aggressive cancer, researchers say, the more likely it is to reverse course and go back to being healthy again. So, for example, cells that are early precursors of cervical cancer are likely to revert. One study found that 60% of precancerous cervical cells, found with Pap tests, revert to normal within a year 90% revert within three years.

There are certain physical properties of cells that change that make us call them cancerous. Tumor cells display a characteristic set of features that distinguish them from normal cells. All cancer cells acquire the ability to grow and divide in the absence of appropriate signals and/or in the presence of inhibitory signals.

The spread or metastases of cancer is inversely proportional to the amount of oxygen and the acidity around the cancer cells. The more oxygen, the slower the cancer spreads. The less oxygen and the higher the acidity the faster the cancer spreads. If cancer cells get enough oxygen, they will die (cancer cells are anaerobic). If you deprive a group of cells of vital oxygen (their primary source of energy), some will die, but others will manage to alter their genetic software program and mutate and be able to live without oxygen.

When the oxygen level drops below 60%, the respiration process of making energy changes into fermentation in a cancer cell. Normal cells turn cancerous. Normal body cells need oxygen and are aerobic whereas cancer cells do not need oxygen and are anaerobic. Healthy cells metabolize, burn oxygen and glucose to produce ATP.

Dr. Ma Lan and Dr. Joel Wallach point out that one type of white blood cell kills cancer cells by injecting them with oxygen, creating hydrogen peroxide in the cells.

Dr. Luke Curtis is reporting on research that deals with 27 lung &ldquocancer&rdquo patients who were later diagnosed with lung &ldquofungus&rdquo instead of lung cancer. &ldquoFungal infection can present with clinical and radiological features that are indistinguishable from thoracic malignancy, such as lung nodules or masses.&rdquo Doctors who diagnose lung cancer are unaware of the fact that cancer mimics fungal infections.[2]

Over one million people worldwide are misdiagnosed with tuberculosis when in reality they have an incurable disease with a similar outlook to many cancers, says a recent report published in 2011 in the Bulletin of the WHO.[3] The disease called &ldquochronic pulmonary aspergillosis&rdquo (CPA) is a fungal infection not a bacterial infection. Is this incurable, totally drug-resistant TB infection fungal or bacterial? It looks very much like, or is identical to, TB when doctors look at it on a chest X-ray and it has very similar symptoms initially. Doctors mistake it for TB and prescribe antibiotics as standard practice.

Because the X-ray features and symptoms are so similar to bacterial tuberculosis, doctors fail to recognize it, resulting in many unnecessary fatalities. – World Health Organization

50% of all patients who develop pulmonary aspergillosis are unlikely to survive for more than five years, a similar outlook to many cancers. Deaths from fungal infections are a little like death from vaccines, invisible and off the radar from most of the medical establishment. Yet as high as 40% of cancers are provoked by infections, and even though in most late-stage cancers, the infection is fungal the medical profession considers it heresy to say cancer and fungus in the same breath.

According to Dr. Milton White, cancer is &ldquoneither the result of a virus nor the consequence of an inherited gene defect. Cancer is a hybrid. It is due to a plant bacterium (conidia) derived from an Ascomycete strain of fungus…&rdquo

We Better Get the Story Right with Cancer

In Nature we read, &ldquoAlthough viruses and bacteria grab more attention, fungi are the planet&rsquos biggest killers. Of all the pathogens being tracked, fungi have caused more than 70% of the recorded global and regional extinctions, and now threaten amphibians, bats and bees. The Irish potato famine in the 1840s showed just how devastating such pathogens can be. Phytophthora infestans (an organism similar to and often grouped with fungi) wiped out as much as three-quarters of the potato crop in Ireland and led to the death of one million people.&rdquo

Researchers estimate that there are 1.5-5 million species of fungi in the world, but only 100,000 have been identified. Reports of new types of fungal infection in plants and animals have risen nearly tenfold since 1995.

Fungi are dreadful enemies. During their life cycle fungi depend on other living beings, which must be exploited to different degrees for their feeding. Fungi can develop from the hyphae, the more or less beak-shaped specialized structures that allow the penetration of the host. The shape of a fungus is never defined it is imposed by the environment in which the fungus develops. Fungi are capable of implementing an infinite number of modifications to their own metabolism in order to overcome the defense mechanism of the host. These modifications are implemented through plasmatic and biochemical actions as well as by a volumetric increase (hypertrophy) and numerical hyperplasia[4] of the cells that have been attacked.

In 1999, Meinolf Karthaus, MD watched three different children with leukemia suddenly go into remission upon receiving a triple antifungal drug cocktail for their &ldquosecondary&rdquo fungal infections.[5]

Doctors and Dentists at Fault

Dr. Elmer Cranton, says that, &ldquoYeast overgrowth is partly iatrogenic (caused by the medical profession) and can be caused by antibiotics.&rdquo

Fungi (e.g.Aspergillus fumigatus) are not affected by antibiotics and neither are viruses. If not given correct treatment (antifungal medication) the prognosis is that 50% of those infected will die inside five years. In fact the overuse of antibiotics leads to fungal infections. Allopathic doctors practicing pharmaceutical medicine are a lost cause now that the world of pathogens is rebelling against what they have been doing with antibiotics these past decades.

When fungi become systemic from gut inflammation and the overuse of antibiotics, you can see how the whole body—again, the eyes, liver, gallbladder, muscles and joints, kidneys, and skin—becomes involved in inflammatory bowel disease. – Dr. Dave Holland

Heavy metals create contaminated environments both inside and outside the cells. These environments attract all kinds of pathogens—viruses, bacteria and fungi. Many cancers are caused by infections, which are themselves caused by heavy metal contamination. According to the observations made by the internationally recognized medical researcher, Dr. Yoshiaki Omura, all cancer cells have mercury in them. The single greatest source of mercury contamination is mercury containing dental amalgum and doctors around the world still inject children with mercury containing vaccines.

Each year in the U.S. an estimated 40 tons of mercury are used to prepare mercury-amalgam dental restorations. Scientific studies have concluded that the amalgam is the source for more than two thirds of the mercury in our human population. On a daily basis each amalgam releases on the order of 10 micrograms of mercury into the body. This mercury either accumulates in the body or is excreted via urine and feces into our wastewater systems.

Extremely Dangerous

&ldquoFungal infections cannot only be extremely contagious, but they also go hand in hand with leukemia—every oncologist knows this. And these infections are devastating: once a child who has become a bone marrow transplant recipient gets a &ldquosecondary&rdquo fungal infection, his chances of living, despite all the anti-fungals in the world, are only 20%, at best,&rdquo writes Dr. David Holland.

The day I wrote this, a young lady phoned into my syndicated radio talk show. Her three-year-old daughter was diagnosed last year with leukemia. She believes antifungal drugs and natural immune system therapy has been responsible for saving her daughter&rsquos life. She is now telling others with cancer about her daughter&rsquos case. After hearing her story, a friend of hers with bone cancer asked her doctor for a prescriptive antifungal drug. To her delight, this medication, meant to eradicate fungus, was also eradicating her cancer. She dared not share this with her physician, telling him only that the antifungal medication was for a &ldquoyeast&rdquo infection. When she could no longer get the antifungal medication, the cancer immediately grew back. Her physician contended that a few antifungal pills surely should have cured her yeast infection. It is my contention, however, that the reason this medication worked was because she did have a yeast infection not a vaginal infection for which this medication was prescribed a fungal infection of the bone that may have been mimicking bone cancer.

A medical textbook used to educate Johns Hopkins medical students in 1957, Clinical and Immunologic Aspects of Fungous Diseases, declared that many fungal conditions look exactly like cancer! – Doug A. Kaufmann
The Germ That Causes Cancer

Cancer is a biologically-induced
spore (fungus) transformation disease. – Dr. Milton W. White

&ldquoTumor-inducing cells have many of the properties of stem cells,&rdquo said Dr. Michael F. Clarke, a professor at the University of Michigan Cancer Center. &ldquoThey make copies of themselves—a process called self-renewal—and produce all the other kinds of cells in the original tumor.&rdquo[6]

According to the Mayo Clinic, cancer refers to any one of a large number of diseases characterized by the development of abnormal cells that divide uncontrollably and have the ability to infiltrate and destroy normal body tissue.

Our DNA is like a set of instructions for our cells, telling them how to grow and divide. Normal cells often develop mutations in their DNA, but they have the ability to repair most of these mutations. Or, if they can&rsquot make the repairs, the cells frequently die. However, certain mutations aren&rsquot repaired, causing the cells to grow and become cancerous…or so the story goes. Yeasts and fungi are, in human terms, abnormal cells that divide uncontrollably and have the ability to infiltrate and destroy normal body tissue. We know so little about these terrible invaders but oncologist&rsquos think they understand a lot about cancer even though they have not cured it.


The shape of the fungus is never defined it is imposed by the environment in which the fungus develops.

&ldquoIn some cases, the aggressive power of fungi is so great as to allow it, with only a cellular ring made up of three units, to tighten in its grip, capture and kill its prey in a short time notwithstanding the prey&rsquos desperate struggling. Fungus, which is the most powerful and the most organized micro-organism known, seems to be an extremely logical candidate as a cause of neoplastic proliferation, Dr.Tullio Simoncini says, &ldquoCandida albicans clearly emerges as the sole candidate for tumoral proliferation.&rdquo

Face the Fungi

Fungi&rsquos relationship to disease remains a difficult and controversial topic and is not really popular with doctors who hold tightly to their antibiotics and obsession with bacteria and viruses. Mainstream orthodox medicine misses the boat entirely on the treatment of fungi, yeast and molds with both the cancer and diabetes establishments &ldquostandards of care&rdquo lacking antifungal medications.

A new area of research being driven by Dundee life scientists is revealing remarkable abilities of fungi to interact with minerals and metals. Led by Professor Geoffrey Gadd in the College of Life Sciences, the research explores the unique taste that fungi seems to have for rock and heavy metal.[7] This environmental science has demonstrated the incredible power of fungi, to eat through concrete and to absorb heavy metals such as mercury and uranium in the environment.

What no one has thought of until now, is the possibility that fungi may have a stealth mode or several stealth modes with one of them being subversion through DNA convergence.

New Theory Unveiled

Cryptococcus neoformans is a fungus that &ldquoescapes phagocytosis because the spores are surrounded by a thick viscous capsule.&rdquo In the case of histoplasma capsulatum, which itself is a sac fungus, when confronted by the macrophages, they ingest the fungus, but instead of killing it and digesting it, something else can take place.

The white cells can end up protecting the fungus and its DNA as &ldquofriend&rdquo because it has been incorporated inside the macrophages effectively hiding the invader from our other immune defenses. Unfortunately for us fungal cells always become the dominant cells.

An entirely new way of looking at the relationship between cancer and fungus is seeing that cancer begins when the DNA from Fungus and the DNA from our white blood cells merge to form a new hybrid &ldquotumor, or sac.&rdquo This hybrid attains a life of it&rsquos own now, bypassing our immune defenses because it is 50% human, and therefore just enough to be recognized as &ldquoself.&rdquo

A large and significant number of independent cancer researchers, scientists, microbiologists and prominent medical practitioners over the past 100 years have found overwhelming evidence supporting this cancer-fungus link or link between cancer and microbes in general. Microbes have always been found to be present in cancer/tumor cells. There is nothing unusual or new about this but don&rsquot try to talk to your oncologist about any of this for I can assure you the odds are high that he or she will not want to know.

The Vitally Important p53 Gene

Along with phagocytosis, our p53 gene plays one of the most important roles in protecting us against cancer. It not only stops cancer invasion, but it also kills tumor cells, thereby preventing cancer from even starting. But in over 50% of all cancers, scientists have discovered that the patient&rsquos p53 gene was mutated and unable to stop cancer from initiating. According to the American Cancer Society, the p53 gene is the most studied of all genes because damage to this gene allows cells with damaged DNA, like cancer cells, to proliferate.

&ldquoAflatoxin genotoxicity is associated with a defective DNA damage response bypassing p53 activation.&rdquo This means that the mycotoxin, aflatoxin, found in our food supply, is capable of inactivating the p53 gene. The Proceedings of the National Academy of Science stated in 1993, that the mycotoxin, aflatoxin b1, made by Aspergillus fungus, is known to cause p53 mutations. Mycotoxins, made by fungi, are among the most carcinogenic substances known to science.

The Aspergillus mold toxin, aflatoxin B1, inhibits the breakdown of both glucose, or simple sugar, and glycogen.[8] Fungi and the mycotoxins they produce impacts our genetic code, causing alterations that are found in a majority of cancers, reports Doug Kaufman. &ldquoAltering a cell&rsquos DNA amounts to changing the environmental code of that cell. Once changed the cell may respond differently – or not at all to outside hormones and enzymes that normally stimulate it to perform necessary functions. As one example of genetic alteration, aflatoxin B1 causes a break in DNA that alters the p53 tumor expression gene. Changes in this particular gene allow the cell to proliferate out of control. So it&rsquos no accident that this same mycotoxin can also go on to cause liver cancer&rdquo

Fungi and their mycotoxins manipulate their hosts on the cellular level, and prevent us from defending ourselves by subverting the immune system[9].

Fungi are found in foods that we eat every day.[10] Our primary concern is the long-term effects of ingesting food contaminated with low levels of mycotoxins," and that carcinogenic toxins, such as aflatoxin, a by-product of the Aspergillus molds, is a "common contaminant of peanuts, soybeans, grains and cassava. It’s a "frequent contaminant of wheat and corn." Without a properly-functioning immune system, we’re at risk of succumbing to various infectious and chronic diseases. Fungi invade our grain food supply because grains-a source of carbohydrates-are their favorite food.

Fungi are parasites whose mission is to invade a larger host. Given a chance they will alter our body chemistries to suit their needs.

In their refutation of the theory of autoimmunity Kaufman and Holland[11] explain that in Type 1 diabetes it is entirely plausible that invading fungi have altered beta cells, remained undetected, yet set off the body&rsquos immune defense system, which is unable to destroy the offending fungi allowing them to continue to invade other beta cells and progressively lead to total destruction and a complete lack of insulin. The extremely manipulative ways that fungi work to ensure their own food supply is highly characteristic of their nature.

A recent Japanese study suggests that fungal mold toxins have the ability to signal the beta cells in the pancreas to shut them off by killing them.[12]

A.V. Constantini, MD, former head of the WHO Collaborating Center for Mycotoxins in Food has spent 20 years studying and collecting data on the role fungi and mycotoxins play in devastating diseases. In his research he found a number of fungi that demonstrate specific toxicity to the pancreas.


Candida A

When fungal colonization and mycotoxin contamination is maximal one finds cancer
growing and mestastizing at a maximal rate.

Beating Back Late Stage Infections (Cancer & Fungus) with Sodium Bicarbonate

Sodium bicarbonate acts as a powerful, natural and safe antifungal agent,[13] which when combined with iodine, would probably cover the entire spectrum of microbial organisms. The efficacy of sodium bicarbonate against certain bacteria and fungi[14] has been documented. Its role as a disinfectant against viruses, however, is not generally known. Sodium bicarbonate at concentrations of 5% and above was found to be effective with 99.99% reduction viral titers on food contact surfaces within a contact time of 1 min.[15]

It was not until oncologist Dr. Tullio Simoncini came along that the concept arose that cancer can be treated with sodium bicarbonate. My book Sodium Bicarbonate, Rich Man&rsquos Poor Man&rsquos Cancer Treatment continues to be the only medical bible on this subject.

Over 90, 000 people a year die from secondary infections in hospitals.

In my Natural Allopathic protocol we approach the problem of cancer and fungal infections from a number of different angles. When it comes to dealing with pathogenic microbes we want to take them head on. If we eliminate these microbes we lighten the load on the immune system so it can do its job of eliminating cancer.

Immune systems are normally, in late stage cancer patients, choking on these harmful microbes. When we rid patients of these microbes the immune system immediately begins to be supercharged. Many have experimented through past decades of passing small electric currents and high frequencies through people and have seen anti-pathogenic effects with viruses, bacteria and fungi.

What we are talking about here fits the military tactics that Natural Allopathic Medicine employs when facing off against cancer. A platoon of white cells are sent to rescue hostages (organs overrun by cancer), but en route get pinned down by heavy fire from ground forces (parasites, viruses, fungi and bacteria tying up the immune system). Then air support (magnesium, bioresonance treatments, iodine, CBD and sodium bicarbonate) come and obliterate the ground forces leaving the platoon (immune system agents) free to go and recover hostages (us). We also directly increase immune system strength using far infrared treatments that raise core body temperature.


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DISCUSSION

Radiosensitivity of the Histologic Groups

Hoppe et al. 15 and Mesic et al. 16 first reported that lymphoepitheliomas were more likely to be cured by ionizing radiation than similar-staged keratinizing squamous cell or undifferentiated carcinomas of the nasopharynx. Both groups of investigators noted a higher rate of locoregional failure for the keratinizing carcinoma than lymphoepitheliomas, which resulted in better survival for the lymphoepithelioma cases despite a higher rate of distant metastases. Reddy et al. 17 subsequently confirmed that WHO-2 nonkeratinizing and WHO-3 undifferentiated carcinomas of the nasopharynx more often were controlled by ionizing radiation than keratinizing histologies and that the observed 5-year survival rate was significantly greater for the WHO-2 and WHO-3 than the WHO-1 carcinomas of the nasopharynx (51% vs. 6%). These reports clearly demonstrated that WHO-2 nonkeratinizing and WHO-3 undifferentiated carcinomas of the nasopharynx are more responsive and more likely to be cured by ionizing radiation than WHO-1 keratinizing squamous cell carcinomas of the nasopharynx.

Genetics and Epstein-Barr Antigen Expression

Neel et al. 18 demonstrated that Epstein-Barr virus (EBV) antibody titers to early antigen and viral capsid antigen are elevated in patients with nonkeratinizing and undifferentiated carcinomas of the nasopharynx whereas these same antibody titers are no different than controls for patients with the keratinizing variety. Incorporation of the virus into the genome of nasopharyngeal epithelium undoubtedly affects phenotypic expression of antigens on the cell surface. The most definitive evidence that nasopharyngeal carcinoma is induced by a virus was the presence of EBV-encoded RNA in lymphoepitheliomas of the nasopharynx that was not present in lymphoepithelioma-like bladder carcinoma. 19

Patient Origin and Survival Outcome

This study showed that WHO-1 keratinizing squamous cell carcinomas were more common in non-Asians than Asians in the U.S. It also showed that the survival outcome in irradiated patients with nasopharyngeal carcinoma differed for individual origin groups according to the histologic composition of nasopharyngeal carcinoma for each group. Those origin groups with the highest proportion of radioresponsive nonkeratinizing and undifferentiated carcinomas had the best survival whereas those with the highest proportion of more poorly responsive keratinizing carcinomas had the lowest survival after radiation. In this study survival after treatment of nasopharyngeal carcinoma was highest among the Japanese and Chinese from Hong Kong, Taiwan, and Macao and lowest among Hispanics, all origins, and African-Americans.

Comparability of Results

Investigations of nasopharyngeal cancer or nasopharyngeal carcinoma have been characterized by inconsistent histologic classification schemes in their overall case inclusion, 20 their number and content of classification categories, 3 , 5 and their method of assignment of individual cases to the categories. 15-18 The multiple approaches have agreed broadly in their overall conclusions even if they differed in their numeric details. For this study, the histologic codes assigned by the participating hospitals were used to categorize the cases into WHO types 1-3, 10 , 11 and no independent pathologic review was performed. The percentage of cases that were classified as WHO-1 keratinizing squamous cell carcinoma (75%) was higher than that found by many other investigators. This may reflect the exclusion of carcinoma not otherwise specified (8010), a category that lacked the information necessary to determine whether the criteria for inclusion were met or to classify the cases.