Precision Medicine and Public Health (from Precision Medicine and the Reinvention of Human Disease)

Excerpted from Precision Medicine and the Reinvention of Human Disease

Despite having the most advanced healthcare technology on the planet, life expectancy in the United States is not particularly high. Citizens from most of the European countries and the highly industrialized Asian countries enjoy longer life expectancies than the United States. According to the World Health Organization, the United States ranks 31st among nations, trailing behind Greece, Chile, and Costa Rica, and barely edging out Cuba [42]. Similar rankings are reported by the US Central Intelligence Agency [43]. These findings lead us to infer that access to advanced technologies, such as those offered by Precision Medicine, will not extend lifespan significantly.

Every healthcare professional knows that most of the deaths occurring in this country can be attributed to personal lifestyle choices: smoking, drinking, drug abuse, and over-eating. Lifestyle diseases account for the majority of deaths in the United States and in otherwestern countries, these being:heartdisease,diabetes, obesity, andcancer.Population-basedtrials that seek to improve theways inwhichindividuals live, by introducing adaily exercise routine, healthydiet, and cigarette abstinence, have yielded huge benefits, in terms of extending average lifespans [44]. At the front end of the human life cycle, it has been demonstrated that infant mortalities can be markedly reduced with simple measures, focusing on improved maternal education [45]. It has been credibly argued that cleanwater, clean air, clean housing, clean food, and clean living yieldgreater societal benefits than clean operating rooms [46,47]. If this be the case, should we be investing heavily in Precision Medicine, when simple, low-tech public health measures are likely to provide a greater return on investment, in terms of overallmorbidity andmortality? In a certain sense, public health is the opposite of personalized medicine. Whereas personalized medicine involves finding the best possible treatment for individuals, based on their uniqueness, public health involves finding ways of treating whole populations based on their collective sameness. Let’s not dwell on these somewhat contrived philosophic points. Precision Medicine, as viewed in this book, is a new way of understanding human diseases. As such, Precision Medicine provides opportunities to advance both personalized medicine and public health.

Precision Medicine tells us that we should think of diseases as developmental process, with each step in the process representing an opportunity for intervention. Perhaps the most important function of Precision Medicine will be to give society the opportunity to institute public health measures aimed at blocking the pathogenesis of human diseases. Here are just a few examples:

– Population screening for early stages of common diseases.

The successful reduction in deaths from cervical cancer demonstrates the effectiveness of screening for early stages of disease. Cervical cancer is a type of squamous cell carcinoma that develops at the junction between the ectocervix (the squamous lined epithelium) and the endocervix (the glandular lined epithelium) in the os of the uterine cervix of women. Before the introduction of cervical precancer treatment, cervical carcinoma was one of the leading causes of cancer deaths in women worldwide. Today, in many countries that have not deployed precancer treatment, cervical cancer remains the leading cause of cancer deaths in women [48– 50]. In the United States, a 70% drop in cervical cancer deaths followed the adoption of routine Papsmear screening[51–53].Noeffort aimedat treatinginvasive cancers has providedanequivalent reduction in the number of cancer deaths. [Glossary Age-adjusted incidence, Pap smear] Today, we know that cervical carcinogenesis begins with a localized infection by one of several strains of human papillomavirus, transmitted during sexual intercourse by an infected male partner. In the late 1940s (and really up until the early 1980s), the viral etiology of cervical cancer was unknown. We did know that squamous cells sampled from the uterine os had highly characteristic morphologic appearances that preceded the development of invasive cancer. Thanks largely to the persistence of Dr. Papanicolaou and his coworkers, a standard screening test, known as the Pap smear, was developed to detect cervical precancers. If precancerous changes were found in a smear, a gynecologist could remove a superficial portion of the affected epithelium, and this would, in the vast majority of cases, stop the cancer from ever developing.

Morphologic and epidemiologic observations on Pap smears provided clues that eventually led to the identification of several strains of human papillomavirus as the major causes of cervical cancer. Today, a vaccine protective against carcinogenic strains of human papilloma virus is available [54].

As discussed in Precision Medicine and the Reinvention of Human Disease, Section 7.5, “What Is Precision Diagnosis?” new biomarkers are being developed for the early stages of disease, often preceding the development of any clinical symptoms. In general, diseases are easiest to treat in early stages, before they have had the chance to do any harm to organs. For example, precancers can often be effectively treated by excision, or, in some cases, by withdrawal of the agents that would otherwise lead to the progression of the precancer to the cancerous stage (e.g., cessation of hormonal replacement therapy to block breast cancer, cessation of smoking to block lung cancer, treatment of Helicobacter pylori infection to block MALToma).

We can hope that in the future advances in the field of Precision Medicine will identify the intermediate stages of development for common diseases. With this information, public health measures aimed at detecting and blocking diseases, in an early stage of development, will be deployed.

– The aggressive prevention and treatment for the most common patterns of diseases that lead to death

As discussed in Precision Medicine and the Reinvention of Human Disease, Section 2.3, “Cause of Death,” a well-composed death certificate contains a thoughtful sequence of medical conditions that develop over time, and that ultimately lead to the death of the patient. This data, if properly recorded and aggregated into a mortality database, should provide the most frequently occurring chains of events that account for human deaths. A public health effort aimed at breaking the early steps of these processes has the potential of extending the life expectancy of the population.

– Aggressive screening for carriers of infectious diseases

As discussed in Section 6.2, “Our Genome Is a Book Titled ‘The History of Human Infections,’” organisms that were formerly thought to be purely pathogenic are now known to frequently live quietly within infected humans, without causing symptoms of disease, and this would include the organisms that cause Chagas disease, leishmaniases, toxoplasmosis, tuberculosis, viruses such as Herpes viruses and hepatitis viruses B and C, and bacterial organisms, some of which circulate in the blood without causing disease under normal circumstances.

Sensitive diagnostic techniques, including genome sequencing of DNA in blood, may provide us with the opportunity to perform population screening for organisms that are opportunistic pathogens, or that produce long-term damage to carriers, or that are transmissible from carriers.

– Finding targets for vaccines that confer effectiveness against more than one target organism.

Thanks in no small part to Precision Medicine, we are learning that organisms play a role in many diseases that were once thought to have no infectious component. In particular, it is now widely accepted that infections contribute to at least one-fifth of all cancers occurring in humans. Examples of cancer causing organisms are:

– Epstein-Barr virus (B-cell lymphomas, Burkitt lymphoma, 
nasopharyngeal cancer, Hodgkin disease and T-cell lymphomas)
– Hepatitis B virus (hepatocellular carcinoma)
– Human papillomavirus types 5, 8, 14, 17, 20, 
and 47 (skin cancer)
– Human papillomavirus types 16, 18, 31, 33, 35, 39, 
45, 52, 56, 58 (cervical cancer, anogenital cancer)
– Human papillomavirus types 6 and 11 (verrucous 
carcinoma)
– Human papillomavirus types 16, 18, 33, 57, 73 
(cancers of oral cavity, tongue, larynx, nasal cavity, 
and esophagus)
– Merkel cell polyomavirus (MCPyV) (Merkel cell carcinoma)
– HTLV-1 (adult T-cell leukemia)
– Human herpesvirus 8 (Kaposi sarcoma)
– Hepatitis C virus—hepatocellular carcinoma 
and low-grade lymphomas
– JC, BK, and SV40-like polyoma viruses (tumors 
of brain and pancreatic islet tumors, and mesotheliomas)
– Human endogenous retrovirus HERV-K 
(seminomas and germ cell tumors)
– Schistosomiasis and squamous cell carcinoma of 
bladder
– Opisthorchis viverrini and Clinorchis sinensis, 
flatworms (flukes), found in Southeast Asia, 
(cholangiocarcinoma)
– Helicobacter pylori and gastric MALToma 
(Mucosa-Associated Lympoid tissue
lymphoma) [55]

Carcinogenic viruses profoundly influence the number of cancer deaths, worldwide. These include hepatitis B virus (associated with an increased incidence of hepatocellular carcinoma) and human papillomavirus (which causes cervical cancer). Liver cancer is the third leading cause of cancer deaths worldwide, accounting for 611,000 deaths in 2000 [50]. It is easy to understand that the importance of vaccine development for infections that contribute to chronic diseases and cancers cannot be overstated. As we learn more about the biological steps involved in the infection process, hope looms that vaccines and preventive drugs will be developed that target different types of organisms, based on shared properties of infection, invasion, immunologic resistance, persistence, or phylogeny, as discussed in Precision Medicine and the Reinvention of Human Disease, Section 4.4, “Pathway-Directed Treatments for Convergent Diseases,” [56–60].

- Jules Berman

key words: public health, prevention, precision medicine, cancer, cancer vaccines, jules j berman, Ph.D., M.D.

Progress against cancer? Let's think about it.

It is difficult to pick up a newspaper these days without reading an article proclaiming progress in the field of cancer research. Here is an example, taken from an article posted on the MedicineNet site (1). The lead-off text is: "Statistics (released in 1997) show that cancer patients are living longer and even "beating" the disease. Information released at an AMA sponsored conference for science writers, showed that the death rate from the dreaded disease has decreased by three percent in the last few years. In the 1940s only one patient in four survived on the average. By the 1960s, that figure was up to one in three, and now has reached 50% survival."

Optimism is not confined to the lay press. In 2003, then NCI Director Andrew von Eschenbach, announced that the NCI intended to "eliminate death and suffering" from cancer by 2015 (2), (3). Update: it's 2016 and still no cancer cure.

Bullish assessments for progress against cancer are a bit misleading. There is ample historical data showing that the death rate from cancer has been rising throughout the twentieth century, and that the burden of new cancer cases will rise throughout the first half of the twenty-first century (4). If you confine your attention to the advanced common cancers (the cancers that cause the greatest number of deaths in humans), we find that the same common cancers that were responsible for the greatest numbers of deaths in 1950 are the same cancers killing us today, and at about the same rates (5), (6). Furthermore, the age-adjusted cancer death rate, the only valid measurement of progress against cancer, is about the same today as it was in 1950 (7). According the the U.S. National Center for Health Statistics, the age-adjusted cancer death rate in 1950 was 194 deaths per 100,000 population (8). In 2004, the death rate was the same, 194 per 100,000 population (8). Hardly an occasion for celebration.

In 1971, President Richard M. Nixon signed the National Cancer Act into law, marking the year that the United States launched its War on Cancer. For the next two decades, the U. S. cancer death rate rose steadily. Then in 1991, the U. S. cancer death rate began to decline, incrementally. It is tempting to conclude that 1991 marked the beginning of victory in our war against cancer, and that the steady, incremental declines in U. S. cancer death rates will continue in future decades, until cancer is fully eradicated. The decline in the cancer rate since 1991 is counter-balanced by the rise in the rate of cancer deaths between 1975 and 1991. What accounts for the rise in cancer deaths after 1975 and the restoration of the 1975 rates following 1991? There's no mystery here. The rise was due to smoking; the fall was due to smoking cessation (4). The post-1991 drop in the U.S. cancer death rate has only served to bring us full circle to our 1950 cancer death rate.

You may be thinking that cancer is a difficult problem, but at least the U.S. is working on the leading edge of cancer care. If cancer is a problem for us, it must be must worse for all the underdeveloped countries in the world. Nope. The U.S. has a high cancer death rate when compared to other countries (9). Kuwait, Panama, Ecuador, Mexico and Thailand have a much lower cancer death rate than the United States. American citizens intent on lowering their cancer death rate would be better off immigrating across the border, to Mexico, than waiting for the U.S. win its war against cancer.

Despite the many billions of dollars spent on research and treatment for cancer, we have made negligible progress toward reducing the number of people who die each year from cancer. The reason that cancer organizations can announce major gains against cancer and can promise to eliminate cancer deaths by 2015 is due entirely to the magic of data misinterpretation!

To see how the deception works in the cancer field, you need to start with the definition of "survival." To a layperson, the term "survival" indicates avoidance of death. For example, the survivors of a plane crash are the people who did not die in the crash. To an oncologist, survival is the time interval between diagnosis and death. Suppose that oncologists announce that a new treatment of pancreatic cancer produces a 1% increase in survival. Layman will interpret this to mean that a person with pancreatic cancer will have a 1 in 100 chance of being cured of his cancer above and beyond his chances for cure with the older treatment. To most people with cancer, that 1 in 100 improvement, though small, is worth any price. Unfortunately, this is not the case at all. To the oncologists who made the announcement, a 1% increase in survival indicates that if the life expectancy following diagnosis of pancreatic cancer is 100 days, then the life expectancy following diagnosis with the new treatment is 101 days. In either case, most patients with advanced pancreatic cancer will die. The patients receiving the new treatment may reasonably expect to survive a bit longer (in this hypothetical case, an average of one day longer).

You may be asking yourself about the validity of claims that we can now cure many childhood cancers that could not be cured in prior generations. Thankfully, these claims are true and accurate. Many children with cancer can now be cured. However, the overall incidence of childhood cancers has risen 36% since 1976 (10). This rise in childhood cancer incidence has erased about half of the overall benefits from the rising cure rates.

Real progress has been made towards curing rare cancers, such as gastrointestinal stromal tumors (GISTs), chronic myelocytic leukemia, and Hodgkin Disease. There is a biological reason why the rare cancers are easier to cure than the common cancers, and this fascinating topic is discussed in detail in my book, Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases. In a nutshell, research into the genetics of tumors has shown us that some cancers are characterized by simple genetic errors. It turns out that the tumors with simple genetic errors coincide with the rare tumors of childhood and certain rare tumors of adults. The small number of gene alterations in these rare tumors permits us to effectively target chemotherapeutic agents against a single vulnerable metabolic pathway. Complex common cancers may share key metabolic pathways with simple rare cancers, but it will take a while before we can effectively use this knowledge to develop effective treatments for the common cancers.

Cancer projections provided by the NCI's SEER program (the National Cancer Institute's Surveillance, Epidemiology, and End Results), indicate that between the years 2000 and 2050, the number of new cancer cases per year will more than double, from 1.3 million new cases in 2000 to 2.8 million new cases in 2050 (11). The projected yearly increase in cancer cases, if unchecked, will put additional strain on the wobbly American healthcare system.

After hundreds of billions of dollars were spent on cancer research and cancer treatment, with little to show for the effort, why did any of us believe that the dying would end by 2015? Humans live in hope; we would rather believe a hopeful lie than a hopeless truth.

- Jules Berman (copyrighted material)

key words: cancer, rare diseases, orphan diseases, cancer cure, cancer treatments, progress in cancer research, cancer statistics, jules j berman

References:

[1] MedicineNet. Better and Longer Survival for Cancer Patients. Available from: http://www.medicinenet.com/script/main/art.asp?articlekey=157

[2] Kaiser J. NCI Goal Aims for Cancer Victory by 2015. Science 299:1297-1298, 2003.

[3] Eschenbach AC. NCI sets goal of eliminating suffering and death due to cancer by 2015. Journal of the National Medical Association 95:637-639, 2003.

[4] Berman JJ. Precancer: The Beginning and the End of Cancer. Jones and Bartlett, Sudbury, 2010.

[5] Bailar JC, Gornik HL. Cancer undefeated. N Engl J Med 336:1569-1574, 1997.

[6] Leaf C. Why We're Losing The War On Cancer: And How To Win It. Fortune Magazine, March 22, 2004.

[7] Hoyert DL, Heron MP, Murphy SL, Kung H-C. Final Data for 2003. National Vital Statistics Report. 54:(13), April 19, 2006.

[8] Health, United States, 2004. National Center for Health Statistics, Hyattsville, Maryland, 2004.

[9] Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer, 2013.

[10] Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, et al. Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995, National Cancer Institute, SEER Program. NIH Pub. No. 99-4649. Bethesda, MD, 1999.

[11] Hayat MJ, Howlader N, Reichman ME, Edwards BK. Cancer Statistics, Trends, and Multiple Primary Cancer Analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. The Oncologist 12:20-37, 2007.

What Rare Diseases Teach Us About the Cellular Basis of Aging

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

Chapter 4 explains that much what we think we know about the aging process comes from studying rare diseases of premature aging, such as Hutchinson–Gilford progeria syndrome, Bloom syndrome, Werner syndrome, Cockayne syndrome, dyskeratosis congenita, Fanconi anemia, Wolfram syndrome, and xeroderma pigmentosum. Lessons learned from these rare diseases are summarized in Chapter 4.

From Chapter 4:

4.4.3 Rule—On a cellular basis, aging is a process confined to non-renewable cell populations. Brief Rationale—Long-lived cells that cannot replace themselves, such as fully differentiated neurons, muscle cells, and cartilage cells, have no biological destiny other than degeneration and death.

As non-dividing cells undergo wear and tear, or suffer damage that cannot be repaired, they will die. The tissues in which these damaged cells reside will function with diminished capacity. For example, osteoarthritis is a chronic disease that occurs from repeated episodes of bone crunching on its cartilage cushion within joints. Osteoarthritis occurs primarily in weight-bearing joints, such as knees and hips. Over a lifetime, the cartilage is frayed and eroded. Injured chondrocytes do not divide, or they divide with insufficient zest to restore a normal cartilaginous cushion. As erosion of the cartilaginous lining continues, an inflammatory reaction develops in the joint. The inflammatory reaction produces pain, swelling, and associated clinical symptoms.

Consider oocytes. All of the oocytes that a woman will produce are present in utero, reaching a peak of about 7 million cells at 5 months’ gestation. After the peak is reached, about 3 months before birth, the oocytes begin to die; they are not replaced. The number of live oocytes declines until the number falls below a threshold of 1000, triggering menopause [28]. In this instance, as in every other example of human tissues undergoing aging, the process involves cells that cannot regenerate.

Frailty is a universal feature of old age. After the age of about 50, muscle mass gradually declines. The frailty associated with extreme aging is due, in part, to progressive sarcopenia. Muscle cells atrophy (i.e., reduce their size), die, and are not renewed. Frailty occurs because muscle cells were not designed to renew themselves continuously and indefinitely.

It was once thought that the brain cells you were born with are the same cells that you will die with; that brain cells do not divide. It is now known that regeneration (i.e., the growth of new neurons) occurs throughout life. This may be so, but new growth comes from reserve cells, not from fully differentiated neurons. Cell division cannot occur in a cell that becomes very large, like a neuron, and has appendages (i.e., an axon and dendrites) extending to and from other cells, sometimes over great distances (up to several feet in the case of motor neurons innervating foot muscles). Axons are ensheathed by a dependent network of periaxonal cells (i.e., oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system). Neurons are transfixed anatomically, and cannot round up to divide. Hence, the fully mature neuron has little or no regenerative opportunity. Consequently, many of the cellular changes that we associate with aging take place in neurons. The dementia that accompanies aging is due to the inability of injured neurons to repair or replace

The tauopathies are disorders wherein tau protein accumulates within neurons. Tau proteins are involved in the stabilization of microtubules in every cell throughout the body, but they accumulate to the greatest extent in the neurons of the central nervous system. If a fully differentiated neuron cannot clear its tau proteins, it will suffer progressive damage, leading to cell death. Though tau proteins are ubiquitous, the tauopathies always develop as neurodegenerative disorders. Examples of diseases in which tau proteins are found include: Alzheimer’s disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, dementia pugilistica, a form of Parkinsonism known as Lytico–Bodig disease or as Parkinson–dementia complex of Guam, a form of Parkinsonism linked to chromosome 17, frontotemporal dementia, frontotemporal lobar degeneration, Hallervorden–Spatz disease, lipofuscinosis, meningioangiomatosis, Pick’s disease, a rare tumor of neurons known as ganglioglioma [29], subacute sclerosing panencephalitis, lead encephalopathy, tangle-predominant dementia, and tuberous sclerosis.

Agin The prion diseases are another example of disorders that target non-dividing neurons. The term prion was introduced in 1982 by Stanley Prusiner [30]. Prions are the only infectious agent that contains neither DNA nor RNA. A prion is a misfolded protein that can serve as a template for proteins of the same type to misfold, producing globs of non-functioning protein, causing cells to degenerate. The site of greatest accumulation of prion protein is in brain cells. Though few scientists would consider prions to be organisms, living or otherwise, they are undoubtedly transmissible infectious agents. The most common mode of transmission of prion disease is through the consumption of brains of infected animals.

The cells of the body that are most vulnerable to prion disease are the neurons of the brain. The reason for the particular sensitivity of neurons to prion disease relates to the limited ability of neurons to replicate (i.e., to replace damaged neurons with new neurons), reconnect (to replace damaged connections between a neuron and other cells), and to remove degenerated cells and debris. There are five known prion diseases of humans, and all of them produce encephalopathies characterized by decreasing cognitive ability and impaired motor coordination. They are: Kuru, Creutzfeldt–Jakob disease, bovine spongiform encephalopathy (known in humans as new variant Creutzfeldt–Jakob disease), Gerstmann–Straussler–Scheinker syndrome, and fatal familial insomnia. At present, all of the prion diseases are progressive and fatal. Prions have been observed in fungi, where their accumulation does not seem to produce any deleterious effect, and may even be advantageous to the organism [31].

In Section 4.3, we listed the many causative mechanisms underlying the rare diseases of premature aging. Without exception, every disease of premature aging creates a defect in the normal process of cellular renewal. If we understood how to control and maintain stem cell renewal, a feat that nematodes seem to have mastered, then we might understand how to defeat the aging process. In Chapter 7, we will be discussing cancer, another disorder of cell renewal. Whereas aging is a disease of cells that cannot divide, cancer is a disease of cells that cannot stop dividing.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, aging, ageing, cell renewal, cancer, cause of aging, biology of aging, orphan disease, orphan drugs

Updated and new files on neoplasm occurrences, by age

Happy New Year!

I've just uploaded a new version of my previously published file on the age distribution of occurrences for 626 different types of cancers.

http://www.julesberman.info/seerdist.pdf

This file is intended to be a resource for pathologists, epidemiologists and cancer researchers.

I've also uploaded a new file on cancers with multimodal age distributions (i.e., more than one peak in the age distribution for the neoplasm).

http://www.julesberman.info/bimode.pdf

I'll be discussing this file in the next several blog posts.

-© 2009 Jules Berman

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Science is not a collection of facts. Science is what facts teach us; what we can learn about our universe, and ourselves, by deductive thinking. From observations of the night sky, made without the aid of telescopes, we can deduce that the universe is expanding, that the universe is not infinitely old, and why black holes exist. Without resorting to experimentation or mathematical analysis, we can deduce that gravity is a curvature in space-time, that the particles that compose light have no mass, that there is a theoretical limit to the number of different elements in the universe, and that the earth is billions of years old. Likewise, simple observations on animals tell us much about the migration of continents, the evolutionary relationships among classes of animals, why the nuclei of cells contain our genetic material, why certain animals are long-lived, why the gestation period of humans is 9 months, and why some diseases are rare and other diseases are common. In “Armchair Science”, the reader is confronted with 129 scientific mysteries, in cosmology, particle physics, chemistry, biology, and medicine. Beginning with simple observations, step-by-step analyses guide the reader toward solutions that are sometimes startling, and always entertaining. “Armchair Science” is written for general readers who are curious about science, and who want to sharpen their deductive skills.

National Cancer Institute Thesaurus

The National Cancer Institute (NCI) Thesaurus is a free medical vocabulary available in OWL format from:

ftp://ftp1.nci.nih.gov/pub/cacore/EVS/NCI_Thesaurus/

It's really quite an impressive document, and there are very few standardized vocabularies that have been prepared as formal ontologies. The creators wisely used the semantics of OWL (Web Ontology Language), a dialect of RDF.

The NCI thesaurus contains terms related to the interests of the NCI and contains the names of many neoplasms.

This vocabulary has been curated for over a decade by in-house ontologists (NCI employees), contractors, and through the use of domain consultants (including some pathologists). It is updated monthly. A lot of money has gone into the development of the NCI Thesaurus, and it is one of the most worked-on vocabularies in the medical field.

The NCI Thesaurus has been reviewed by Barry Smith and colleagues, who found it somewhat lacking.

http://ontology.buffalo.edu/medo/NCIT.pdf

"RESULTS: We found many mistakes and inconsistencies 
with respect to the term-formation principles used, 
the underlying knowledge representation system,
and missing or inappropriately assigned verbal and 
formal definitions.."
Ceusters W, Smith B, Goldberg L.
A terminological and ontological analysis of the 
NCI Thesaurus. Methods Inf Med. 2005;44(4):498-507.

My question is, "If the Thesaurus contains many different knowledge domains (medications, general diseases, neoplasms, etc.) how can it adequately cover all of its constituent domains?" In the neoplasm domain, it is missing many thousands of names of neoplasms. The terminology may be sufficient for its intended purpose (meeting the needs of the NCI community), but because the terminology is not comprehensive, the NCI Thesaurus will not necessarily serve those who want a thesaurus that comes close to including the names of ALL neoplasms.

Also, there doesn't seem to be any single organizing principle for the neoplasm domain. Some neoplasms are subclassed by their anatomic site (e.g. urinary tract neoplasm). Others are subclassed by their tissue type (e.g. soft tissue neoplasm). And so on. This is allowable under an ontology, so long as the ontology maintains consistency and competence (ability to answer questions about the members of classes). But I wonder if this is the best way of organizing tumors. Of course, I'm deeply biased. The Developmental Lineage Classification and Taxonomy of Neoplasms has a single organizing principle.

The NCI Thesaurus is an impressive piece of work and definitely worth looking over.

tags: biomedical informatics, cancer, classification, nomenclature, thesaurus, vocabulary, ontology, rare diseases, orphan drugs, genetics of disease, pathology, common diseases, complex diseases

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In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

I urge you to read more about my book. There's a generous preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D.

List of inherited syndromes associated with neoplasms

I've been trying to assemble a list of inherited conditions that carry an heightened risk of developing one or more neoplasms. The following are syndromes collected from OMIM (Online Mendelian Inheritance in Man) and each item is preceded by the OMIM identifier number. If anyone thinks that any of these items should be omitted or knows of additional items that should be added, please post them as a comment to this blog.

Familial syndromes associated with neoplastic development.

-1010000 Acoustic schwannomas bilateral

-1026600 Adamantinoma of long bones

-1027000 Severe combined immunodeficiency due to ada deficiency

-1035800 Albright hereditary osteodystrophy

-1056000 Anemia with multinucleated erythroblasts erythroreticulosis hereditary benign included

-1060700 Angioma hereditary neurocutaneous spinal arterial venous malformations with cutaneous hemangiomas included

-1062000 Aniridia

-1064000 Ankylosing vertebral hyperostosis with tylosis diffuse idiopathic skeletal hyperostosis included

-1074000 Serpina1 alpha-1-antitrypsin deficiency autosomal recessive included

-1093500 Gastroesophageal reflux pediatric adenocarcinoma of esophagus included

-1093900 Basal cell carcinomas with milia and coarse sparse hair

-1094000 Basal cell nevus syndrome

-1122000 Blue rubber bleb nevus

-1122500 Diaphyseal medullary stenosis with malignant fibrous histiocytoma

-1137050 Brca1 breast cancer type 1 included

-1139700 Burkitt lymphoma

-1140300 Cafe-au-lait spots multiple

-1144000 Lynch cancer family syndrome ii

-1153100 Carotid body tumors and multiple extraadrenal pheochromocytomas

-1168600 Cerebral capillary malformations cerebral cavernous malformations 1 included

-1175500 Sotos syndrome

-1182000 Charcot-marie-tooth neuropathy type 1b

-1183500 Chemodectoma intraabdominal with cutaneous angiolipomas

-1184500 Alagille-watson syndrome

-1188650 Choroidal osteoma bilateral

-1204350 Colorectal cancer hereditary nonpolyposis type 1

-1240300 Debrisoquine 4-hydroxylase codeine ultrarapid metabolism of included

-1240800 Aldosterone deficiency due to deficiency of 18-hydroxysteroid dehydrogenase included

-1242000 Keratosis follicularis (darier disease)

-1263370 Dna damage-inducible transcript 3 (gadd153 myxoid liposarcoma and chop/fus fusion gene included)

-1306500 Wiedemann-beckwith syndrome

-1311000 Multiple endocrine neoplasia type i

-1314400 Myeloproliferative disorder chronic with eosinophilia

-1314450 Ependymoma familial

-1326000 Pilomatrixoma

-1327000 Cylindromatosis familial

-1328100 Diphenylhydantoin defect lymphoproliferative disorders susceptibility to included

-1331000 Polycythemia familial

-1331800 Erythroleukemia familial

-1334500 Ews gene neuroepithelioma peripheral included

-1335100 Xeroderma pigmentosum complementation group b

-1337000 Exostoses multiple type i

-1351500 Birt-hogg-dube syndrome fibrofolliculomas with trichodiscomas and acrochordons

-1353000 Fibromatosis gingival hereditary

-1373570 Genitourinary dysplasia component of wagr syndrome

-1373600 Genochondromatosis

-1375500 Giant pigmented hairy nevus

-1375750 Gigantiform cementoma familial

-1378000 Glioma of brain familial glioblastoma multiforme included

-1388000 Goiter nontoxic with intrathyroidal calcification

-1410000 Hemangioma-thrombocytopenia syndrome kasabach-merritt syndrome

-1429810 Homeobox d4 hoxd4 acute lymphoblastic susceptibility to included

-1447000 Renal carcinoma familial associated 1 included

-1465100 Pallister-hall syndrome hypothalamic hamartoblastoma hypopituitarism imperforate anus and postaxial polydactyly

-1480000 Kaposi sarcoma

-1485000 Tylosis with esophageal cancer

-1490000 Klippel-trenaunay-weber syndrome angioosteohypertrophy syndrome

-1506990 Leiomyoma uterine

-1508000 Leiomyoma hereditary multiple of skin

-1516230 Li-fraumeni syndrome 1

-1534800 Bannayan-zonana syndrome macrocephaly pseudopapilledema and multiple hemangiomata bannayan-riley-ruvalcaba syndrome included

-1535500 5q- syndrome macrocytic anemia refractory due to 5q deletion

-1552400 Thyroid carcinoma familial medullary

-1556000 Dysplastic nevus syndrome hereditary b-k mole syndrome

-1583200 Muir-torre syndrome cutaneous sebaceous neoplasms and keratoacanthomas multiple with gastrointestinal and other carcinomas

-1583500 Cowden syndrome multiple hamartoma syndrome lhermitte-duclos disease included

-1595500 Myelocerebellar disorder

-1595550 Myeloid/lymphoid or mixed lineage leukemia trithorax drosophila homolog of mll/fbp17 fusion gene included

-1609800 Carney myxoma-endocrine complex carney syndrome

-1615500 Nasopharyngeal carcinoma

-1620910 Neurilemmomatosis congenital cutaneous

-1622000 Neurofibromatosis type i

-1622200 Nf3b

-1622400 Neurofibromatosis-pheochromocytoma-duodenal carcinoid syndrome

-1623000 Neuromata mucosal with endocrine tumors

-1630000 Nevi flammei familial multiple

-1632000 Linear sebaceous nevus syndrome

-1643300 Odontoma-dysphagia syndrome

-1660000 Osteochondromatosis

-1669500 Ovarian teratoma

-1680000 Paragangliomas familial 1

-1695450 Pelvic lipomatosis with crossed renal ectopia

-1714000 Multiple endocrine neoplasia type ii pheochromocytoma and amyloid-producing medullary thyroid carcinoma

-1714200 Pheochromocytoma--islet cell tumor syndrome

-1748000 Albright syndrome polyostotic fibrous dysplasia

-1750500 Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

-1751000 Adenomatous polyposis of the colon apc

-1752000 Peutz-jeghers syndrome

-1764500 Sacral agenesis hereditary with presacral mass anterior meningocele and/or teratoma and anorectal malformation included

-1802000 Retinoblastoma

-1802950 Rhabdomyosarcoma embryonal 2

-1845000 Steatocystoma multiplex

-1866000 Syringomas multiple

-1873000 Telangiectasia hereditary hemorrhagic of rendu osler and weber

-1884000 Digeorge syndrome

-1884700 Thyroid carcinoma follicular

-1885500 Familial nonmedullary thyroid cancer

-1903450 Trichoepitheliomas multiple desmoplastic

-1906850 Leukemia megakaryoblastic of down syndrome

-1911000 Tuberous sclerosis

-1933000 Von hippel-lindau syndrome
-1940700 Wilms tumor 1

-1940800 Denys-drash syndrome nephropathy wilms tumor and genital anomalies

-1944000 Xeroderma pigmentosum autosomal dominant mild

-2019100 Adrenal hyperplasia congenital due to 21-hydroxylase deficiency

-2065500 Angiolipomatosis familial

-2089000 Ataxia-telangiectasia

-2109000 Bloom syndrome

-2119800 Lung cancer alveolar cell carcinoma included

-2276500 Fanconi anemia

-2285500 Fibromatosis congenital generalized

-2311000 Hemochromatosis neonatal

-2352000 Hemochromatosis

-2464000 Histiocytosis x acute disseminated

-2464700 Leukemia acute myelocytic with polyposis coli and colon cancer

-2544500 Myelofibrosis familial

-2547000 Myeloproliferative disease autosomal recessive

-2567000 Neuroblastoma

-2595000 Osteogenic sarcoma

-2595500 Osteoid osteoma

-2605000 Choroid plexus papilloma

-2633000 Polycythemia vera

-2670000 Nephroblastomatosis fetal ascites macrosomia and wilms tumor

-2677000 Hemophagocytic reticulosis familial

-2699500 Sideroblastic anemia autosomal

-2731200 Teratoma pineal

-2733000 Testicular tumors teratoma testicular included

-2763000 Turcot syndrome malignant tumors of the central nervous system associated with familial polyposis of the colon

-2787000 Xeroderma pigmentosum i

-3001470 Prostate cancer hereditary x-linked

-3018450 Follicular atrophoderma and basal cell carcinomas

-3053500 Epidermodysplasia verruciformis x-linked

-3082400 Lymphoproliferative disease x-linked

-3083000 Incontinentia pigmenti familial male-lethal type

-3089400 Leiomyomatosis esophageal and vulval with nephropathy

-3128200 Sarcoma synovial x-chromosome-related 1

-3128700 Dysplasia gigantism syndrome x-linked

-6000480 Breast cancer 11-22 translocation associated

-6000800 Myelocytic leukemia-like syndrome familial chronic

-6001390 Subependymoma

-6001850 Brca2 breast cancer type 2 included

-6001950 Venous malformations multiple cutaneous and mucosal

-6002580 Mismatch repair gene pmsl1 colorectal cancer hereditary nonpolyposis type 3 included

-6003760 Osler-rendu-weber syndrome 2

-6005420 Chondrosarcoma myxoid extraskeletal fused to ews

-6006780 Gtbp colorectal cancer hereditary nonpolyposis type 5 included

-6012230 Nid2

-6012280 Polyposis syndrome mixed hereditary

-6013210 Noonan-neurofibromatosis syndrome

-6013470 Myelodysplasia immunodeficiency facial dysmorphism short stature and psychomotor delay

-6013590 Sebaceous nevus syndrome and hemimegalencephaly

-6013630 Familial wilms tumor 1

-6013990 Platelet disorder familial with associated myeloid malignancy

-6015180 Prostate cancer hereditary 1

-6015830 Wilms tumor 5

-6016060 Trichoepithelioma multiple familial

-6016500 Glomus tumors familial 2

-6018030 Pallister-killian syndrome

-6018590 Canale-smith syndrome autoimmune lymphoproliferative syndrome type i autosomal dominant autoimmune lymphoproliferative syndrome type ia included

-6020890 Hemangioma capillary infantile

-6024500 Severe combined immunodeficiency with sensitivity to ionizing radiation

-6025960 Pancreatic lymphoma familial

-6033720 Thyroid carcinoma with thyrotoxicosis included

-6034390 Expansile bone lesions

-6035540 Reticuloendotheliosis familial with eosinophilia

-6036410 Neuroendocrine carcinoma of salivary glands sensorineural hearing loss and enamel hypoplasia

-6036560 Exostosis dupuytren subungual

-6036690 Eccrine syringofibroadenomatosis with eyelid abnormalities

-6036700 Blue nevi familial multiple

-6036880 Prostate cancer/brain cancer susceptibility

-6037370 Ovarian germ cell cancer

-6037440 Papillary thyroid microcarcinoma

-6042870 Carney triad

-6042870 Gastric leiomyosarcoma pulmonary chondroma and extraadrenal paraganglioma

-6043700 Epithelial ovarian cancer

-6043730 Checkpoint kinase 2 s. pombe homolog of breast and colorectal cancer susceptibility to included

-6044420 Nonpapillary renal carcinoma 1

-6044510 Basal cell carcinoma with follicular differentiation

-6048560 Langerhans cell histiocytosis

-6049190 Becker nevus syndrome

-6050270 Lymphoma non-hodgkin familial

-6050410 Spiegler-brooke syndrome

-6050740 Renal cell carcinoma papillary

-6050750 Renal cell carcinoma papillary 3

-6052330 Autoimmune lymphoproliferative disease without fas mutations

-6052440 Carney myxoma-endocrine complex type ii

-6052880 Primordial germ cell tumor susceptibility locus 1

-6053650 Breast cancer 3 brca3

-6053730 Paragangliomas 3

-6053730 Glomus tumors familial 3

-6054620 Basal cell carcinoma multiple

-6056420 Thyroid carcinoma papillary with papillary renal neoplasia

-6058270 Basaloid follicular hamartoma syndrome generalized autosomal dominant

-6058390 Leiomyomatosis and renal cell cancer hereditary

-6059820 Familial wilms tumor 2

-6061790 Aneurysmal bone cysts

-6061900 Meningioma radiation-induced

-6062400 Thyroid carcinoma nonmedullary 1

-6062430 Alveolar soft-part sarcoma

-6064450 Persistent polyclonal b-cell lymphocytosis

-6065190 Phace association

-6066600 Melanoma uveal susceptibility to 1

-6066900 Lymphangioleiomyomatosis

-6066900 Lymphangiomyomatosis lymphangioleiomyomatosis somatic included

-6067190 Familial atypical multiple mole melanoma-pancreatic carcinoma syndrome

-6067640 Gastrointestinal stromal tumor gist

-6068640 Paraganglioma and gastric stromal sarcoma

-6068930 Hemangioma intraosseous

-6071740 Meningioma familial meningioma caused by somatic mutation included

-6072480 Glioma familial 1

-6072780 Osteofibrous dysplasia

-6074640 Thyroid carcinoma hurthle cell

-6076850 Hypereosinophilic syndrome idiopathic

-6077850 Juvenile myelomonocytic leukemia

-6078590 Tufted angioma

-6078930 Ovarian cancer epithelial susceptibility to

-6079070 Dermatofibrosarcoma protuberans

-6080350 Melanoma cutaneous malignant 4

-6082320 Leukemia chronic myeloid

-6082660 Parathyroid carcinoma

-6083540 Capillary malformation-arteriovenous malformation

-6084560 Colorectal adenomatous polyposis autosomal recessive

-6086150 Oligodontia-colorectal cancer syndrome

-6086230 Neuroectodermal tumors supratentorial primitive with cafe-au-lait spots

-6086560 Prostate cancer hereditary 20

-6086580 Prostate cancer hereditary 7

-6088120 Colorectal cancer susceptibility to on chromosome 9

-6088370 Carney complex variant

-6089350 Lung cancer 1

-6090480 Melanoma cutaneous malignant 3

-6092990 Prostate cancer hereditary 3

-6093100 Colorectal cancer hereditary nonpolyposis type 2

-6093220 Rhabdoid tumor

-6093630 Colloid cysts of third ventricle

-Jules J. Berman

---

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

I urge you to read more about my book. There's a generous preview of the book at the Google Books site.

- Jules J. Berman, Ph.D., M.D. tags: common disease, orphan disease, orphan drugs, genetics of disease, disease genetics, rules of disease biology, rare disease, pathology, cancer, genetics, neoplasia, neoplasms, tumor, tumour

Latest update of Neoplasm Classification available

The latest version of the Developmental Lineage Classification and Taxonomy of Neoplasms is now available as a gzipped file at:

http://www.julesberman.info/neoclxml.gz

This Neoplasm Classification has been described at:

http://www.biomedcentral.com/1471-2407/4/10

It contains 5,827 neoplasm classified concepts and 130,283 different terms (codes beginning with "C"). It is more than ten times larger than any other neoplasm classification.

In addition to specific neoplasm concepts, it also contains general neoplastic terms (coded as C0000000), inherited conditions associated with neoplasms (codes beginning with "S") and terms related to the stage or anatomic location of neoplasms (codes beginning with "ST").

---

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

I urge you to read more about my book. There's a generous preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D.

New version of neoplasm classification available

The latest version of the Developmental Lineage Classification and Taxonomy of Neoplasms is now available at:

NEOCLXML.GZ 716,963 bytes and
NEOSELF.GZ 1,086,677 bytes

Neoclxml.gz expands to over 10 Megabytes and is an XML file.
Neoself.gz expands to over 20 Megabytes and is a flat-file.

Each file contains over 145,000 neoplasm terms grouped in >6,000 concepts, and classified according to embryonic lineage. This is, by far, the most extensive nomenclature and classification of neoplasms in existence. It is copyrighted to Jules J. Berman and distributed under a GNU document license.

Detailed information on the classification is available in my article:
Tumor classification: molecular analysis meets Aristotle

tags: cancer, medical terminology, nomenclature, open access, open source

---

Science is not a collection of facts. Science is what facts teach us; what we can learn about our universe, and ourselves, by deductive thinking. From observations of the night sky, made without the aid of telescopes, we can deduce that the universe is expanding, that the universe is not infinitely old, and why black holes exist. Without resorting to experimentation or mathematical analysis, we can deduce that gravity is a curvature in space-time, that the particles that compose light have no mass, that there is a theoretical limit to the number of different elements in the universe, and that the earth is billions of years old. Likewise, simple observations on animals tell us much about the migration of continents, the evolutionary relationships among classes of animals, why the nuclei of cells contain our genetic material, why certain animals are long-lived, why the gestation period of humans is 9 months, and why some diseases are rare and other diseases are common. In “Armchair Science”, the reader is confronted with 129 scientific mysteries, in cosmology, particle physics, chemistry, biology, and medicine. Beginning with simple observations, step-by-step analyses guide the reader toward solutions that are sometimes startling, and always entertaining. “Armchair Science” is written for general readers who are curious about science, and who want to sharpen their deductive skills.