Sunday, September 21, 2014

Lymphadenopathy: a misnomer

Medical nomenclature contains numerous examples of outdated, but widely used terminology.

The term "lymphadenopathy", meaning lymph node disease, is a case in point. In former times, lymph nodes (as they are known now) were known as lymph glands. It was believed that the lymph fluid circulating in the lymph vessels, was produced by the lymph nodes. Organs that produce chemicals that are circulated to other tissues are referred to as glands (e.g., endocrine glands, exocrine glands). Hence the term "lymph gland". A disease of the lymph gland was termed "lymphadenopathy" from lymph + adenos (Greek for gland) + pathei (Greek for disease).
Derivation of lymph fluid.
Source: National Cancer Institute, public domain

The term for a neoplasm of a lymph node was "lymphadenoma"

The term for inflammation of a lymph node was "lymphadenitis"

Nearly everything about lymph node pathology was saddled to the ill-conceived notion that a lymph node is a type of gland.

We now know that lymph is not produced by the glandular activity of lymph nodes. Lymph is interstitial fluid (i.e., fluid between tissue cells) that is absorbed into lymph vessels. Lymph fluid is somewhat milky because it contains white cells, sloughed from lymph nodes, but the fluid comes from tissue interstitium and its composition is akin to blood plasma.

Modern pathologists have dropped the "adeno" in "lymphadenoma" and replaced it with the less confusing term, "lymphoma".

Regrettably, the terms "lymphadenopathy" and "lymphadenitis" persist into modern usage.

- Jules J. Berman, Ph.D., M.D. tags: lymph node, lymphoid, lymphedema, lymphatics, lymphatic vessels, common disease, orphan disease, orphan drugs, rare disease, subsets of disease, disease genetics, logophile, medical terminology, medical nomenclature, medical dictionary

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.

Wednesday, September 17, 2014

Patient identifiers

I have posted an article on patient identifiers. Here is a short excerpt from the article:

Imagine this scenario. You show up for treatment in the hospital where you were born, and in which you have been seen for various ailments over the past three decades. One of the following events transpires:

1. The hospital has a medical record of someone with your name, but it's not you. After much effort, they find another medical record with your name. Once again, it's the wrong person. After much time and effort, you are told that the hospital has no record for you.

2. The hospital has your medical record. After a few minutes with your doctor, it becomes obvious to both of you that the record is missing a great deal of information, relating to tests and procedures done recently and in the distant past. Nobody can find these missing records. You ask your doctor whether your records may have been inserted into the electronic chart of another patient or of multiple patients. The doctor does not answer your question.

3. The hospital has your medical record, but after a few moments, it becomes obvious that the record includes a variety of tests done on patients other than yourself. Some of the other patients have your name. Others have a different name. Nobody seems to understand how these records got into your chart.

4. You are informed that the hospital has changed its hospital information system, and your old electronic records are no longer available. You are asked to answer a long list of questions concerning your medical history. Your answers will be added to your new medical chart. You can't answer any of the questions with much certainty.

5. You are told that your electronic record was transferred to the hospital information system of a large multi-hospital system. This occurred as a consequence of a complex acquisition and merger. The hospital in which you are seeking care has not yet been deployed within the information structure of the multi-hospital system and has no access to your record. You are assured that the record has not been lost and will be accessible within the decade.

6. You arrive at your hospital to find that it has been demolished and replaced by a shopping center. Your electronic records are gone forever.


These are the kinds of problems that arise when hospitals lack a proper patient identifier system (a common shortcoming). The purpose of the article is to list the features of a patient identifier system, emphasizing the essential role of identifiers in healthcare services and biomedical research.

The full-length article is available at:

http://www.julesberman.info/book/id_deid.htm

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. tags: common disease, orphan disease, orphan drugs, rare disease, subsets of disease, disease genetics, identifiers, identification, ehr, emr, electronic health records, electronic medical record, health informatics, HITECH, medical informatics, pathology informatics

Three neglected principles of Big Data: identifiers, immutability, and introspection

My book, Principles of Big Data: Preparing, Sharing, and Analyzing Complex Information was published last year by Morgan Kaufmann.



There are three crucial topics related to data preparation that are omitted from virtually every other Big Data book: identifiers, immutability, and introspection.

A thoughtful identifier system ensures that all of the data related to a particular data object will be attached to the correct object, through its identifier, and to no other object. It seems simple, and it is, but many Big Data resources assign identifiers promiscuously, with the end result that information related to a unique object is scattered throughout the resource, attached to other objects, and cannot be sensibly retrieved when needed. The concept of object identification is of such overriding importance that a Big Data resource can be usefully envisioned as a collection of unique identifiers to which complex data is attached. Data identifiers are discussed in Chapter 2.

Immutability is the principle that data collected in a Big Data resource is permanent, and can never be modified. At first thought, it would seem that immutability is a ridiculous and impossible constraint. In the real world, mistakes are made, information changes, and the methods for describing information changes. This is all true, but the astute Big Data manager knows how to accrue information into data objects without changing the pre-existing data. Methods for achieving this seemingly impossible trick is described in detail in Chapter 6.

Introspection is a term borrowed from object oriented programming, not often found in the Big Data literature. It refers to the ability of data objects to describe themselves when interrogated. With introspection, users of a Big Data resource can quickly determine the content of data objects and the hierarchical organization of data objects within the Big Data resource. Introspection allows users to see the types of data relationships that can be analyzed within the resource and clarifies how disparate resources can interact with one another. Introspection will be described in detail in Chapter 4.

I urge you to read more about my book. Google books has prepared a generous preview of the book contents. 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: big data, metadata, data preparation, data analytics, data repurposing, datamining, data mining

Wednesday, September 10, 2014

Pitfalls in Medical Terminology

Back in 2008, I posted a list of medical terms that are easily confused, such as ileum (part of small intestine), and ilium (a pelvic bone). Medical transcriptionists and healthcare workers who input chart data (i.e., just about everybody), should be aware of medical term-pairs that have nearly the same orthography, are often pronounced identically, and have completely different meanings. These words are not picked up by spell checkers (because they are not misspelled). You can avoid such errors if you know what to look for.

Since 2008, there have been many updates to the list:

acinic, actinic
acinus, a sinus
anisakiasis, anisokaryosis
aptotic, apoptotic
arboreal, aboriginal
arteritis, arthritis
auxilliary, axillary
bilingual, by lingual
brachial, brachium, branchial
callous, callus
causality, casualty
chlorpropamide, chlorpromazine
cingula, singular
chondroid, chordoid
chondroma, chordoma
chorionic, chronic
coitus, colitis
colic, colonic
colitis, coitus
costal, coastal
cryptogam, cryptogram
cygnet, signet
decease, disease
deceased, desist
dioecious, deciduous
diploic, diploid
disc, disk
disease, decease
diseased, deceased
disk, disc
dyskaryosis, dyskeratosis
dysphasia, dysphagia
ectatic, ecstatic
endochondral, enchondral (these are synonyms)
epistasis, epistaxis, epitaxis (the latter being a misspelling of the former)
exxon, exon
facial, fascial
facies, faeces
fetal, fatal
firearm, forearm
foreword, forward
hallux, helicis
helicis, hallux
herpetic, herpangina
hydatid, hydatidiform
ileitis, iliitis
ileum, ilium
intubation, incubation
isotope, isotrope
isotrope, isotope
kerasin, keratin
kerasin, kerosene
keratinic, keratotic
keratinic, actinic
keratinocytic, keratinolytic
keratosis, ketosis
lipoma, lymphoma
lumbar, lumber
malleolus, malleus
metachronous, metacrinus
milia, milium
mitotic, meiotic
mitosis, meiosis
miotic, mitotic
miotic, meiotic
myiasis, meiosis
metacrinus, metachronous
monogenic, monogenetic, and Monogenetic (related to flatworms of class Monogenea)
myosis, meiosis
mucous, mucus
myelofibrosis, myofibrosis
myofibroma, myelofibroma
neuroplastic, neoplastic
nucleus, nucleolus
oncocyte, onychocyte
oncology, ontology
ontogeny, ontology
organic, organoid
paleodontology, paleontology
palette, palate
palatal, palatial
palpation, palpitation
palpitation, palpation
parasite, pericyte
parental, parenteral
pathogen, parthenogen
pathogenesis, parthenogenesis
pathogenic, pathogenetic (these two are synonyms)
penal, penile, pineal, panel
penicillamine, penicillin
perineal, peroneal
pleiotropic, pleiotypic
plural, pleural
porphyria, porphyruria
proptosis, ptosis
prostrate, prostate
protuberant, protruberant (the second term is simply a common misspelling)
quinine, quinidine
rachischisis, rachitis
rachischitic, rachitic
radial, radical
relics, relicts
reticle, reticule
rett, ret
rosacea, rosea
semantic, somatic
silicon, silicone
singleton, singultus
sinusitis, synositis
somatic, semantic
sonography, stenography
takoma, trachoma
taenia, tinea
thecoma, thekeoma
torsion, distortion
trichina, trichura
trichina, trachoma
trachoma, trachea
trichinosis, trichuriasis
trichinosis, trichosis
trochlear, tracheal
troglobite, troglodyte, trilobite
tunicate, tourniquet
urethral, ureteral
vagitis, vaginitis

If you know the meaning of half of the terms in this list, you have a good grasp of medical terminology; but please don't settle for half measures. Physicians, nurses, chart reviewers, and medical transcriptionists should be aware of the correct meaning of each alternate word in these listed pairs.

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. tags: common disease, orphan disease, orphan drugs, rare disease, medical terminology, medical errors, malaprop, malapropism, definition, confusing terms, confused medical terms, medical definitions, medical transcription, nomenclature, terminology, transcription errors, transcription mistakes, EMR, EHR, electronic medical record, electronic chart, electronic health record, avoidable errors, avoidable mistakes

Friday, July 18, 2014

Rare Diseases Hiding Among Common Diseases

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.



Here is an excerpt from Chapter 12:
It is easy to find cases wherein a rare disease accounts for a somewhat uncommon clinical presentation of a common disease.
12.1.2 Rule—Uncommon presentations of common diseases are sometimes rare diseases, camouflaged by a common clinical phenotype.
Brief Rationale—Common diseases tend to occur with a characteristic clinical phenotype and a characteristic history (e.g., risk factors, underlying causes). Deviations from the normal phenotype and history are occasionally significant.
Rare diseases may produce a disease that approximates the common disease; the differences being subtle findings revealed to the most astute observers. Here is some pithy wisdom that senior physicians love to impart to junior colleagues: “When you see hoof prints, look for horses, not zebras.” The message warns young doctors that most clinical findings can be accounted for by common diseases. Nonetheless, physicians must understand that zebras, unlike unicorns and griffins, actually exist. Occasionally, a rare disease will present with the clinical phenotype of a common disease.

For example, mutations of the JAK2 gene are involved in several myeloproliferative conditions, including myelofibrosis, polycythemia vera (see Glossary item, Polycythemia), and at least one form of hereditary thrombocythemia (i.e., increased blood platelets) [9–11]. Surprisingly, somatic blood cells with JAK2 mutations are found in 10% of apparently healthy individuals [12]. The high incidence of JAK2 mutations in the general population, and the known propensity for JAK2 mutations to cause thrombocythemia and thrombosis, should alert physicians to the possibility that some cases of idiopathic thrombosis may be caused by a platelet disorder caused by undiagnosed JAK2 mutation of blood cells. As it happens, it has been shown that a JAK2 mutation can be found in 41% of patients who present with idiopathic chronic portal, splenic and mesenteric venous thrombosis [13]. Such thrombotic events are uncommon in otherwise healthy patients. The search for a zebra, in this case a cryptic myeloproliferative disorder caused by a JAK2 mutation, pays off (see Glossary item, Myeloproliferative disorder).

Zebras can hide among the horses. Consider lung cancer, the number one cause of cancer deaths in the U.S. When lung cancer occurs in a young person, you might wonder if this is a rare disease cloaked as a common disease. Midline carcinoma of children and young adults is an extremely rare type of lung cancer. It is characterized by a NUT gene mutation, not typically found in commonly occurring lung cancers of adults [14]. Hence, midline carcinoma of children and young adults is an example of a rare disease hidden in a common disease. Secretory carcinoma, formerly known as juvenile breast cancer, is a rare form of breast cancer. It has a less aggressive clinical course than commonly occurring breast cancer, and occurs at a younger median age (i.e., about 25 years) than the median age of occurrence of common breast cancer (i.e., 61 years). In 2002, it was discovered that the expression of the ETV6-NTRK3 gene fusion is a primary event in the carcinogenesis of secretory breast carcinoma [15]. Once again, an uncommon presentation of a common tumor was found to hide a rare disease with its own characteristic genetic mutation.

Myelodysplastic syndrome, formerly known as preleukemia, is a rare blood disorder occurring almost exclusively in older individuals. The specific gene causing myelodysplastic syndrome is unknown, but recurrent cytogenetic alterations have been found in bone marrow cells, particularly losses of the long arm of chromosome 5 (i.e., 5q-) and of chromosome 7 (i.e., monosomy 7). Myelodysplastic syndrome occurs in very young children, with extreme rarity. Virtually all such childhood cases involve monosomy 7. An inherited predisposition to lose one copy of chromosome 7 in somatic cells has been reported in kindreds whose children have a high likelihood of developing myelodysplastic syndrome, or of acute leukemia. Hence, it seems that a somatic chromosomal abnormality associated with a rare disease occurring in adults is also associated with an even more rare childhood form of the disease. The childhood disease may occur when an inherited mutation predisposes children to the equivalent somatic chromosomal abnormality observed in the adult form of the disease [16,17].

As a final example, there are two recognized types of acute myelogenous leukemia (AML): AML following myelodysplasia, a preleukemia, and de novo AML, which develops in the absence of an observed preleukemic condition [18]. De novo AML can occur in children or in adults. The de novo AML cases in children have a different set of cytogenetic markers than those observed in adult de novo AML [19].

I urge you to read more about my 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: common disease, orphan disease, orphan drugs, rare disease, subsets of disease, disease genetics, genetics of complex disease, genetics of common diseases, cryptic disease

Thursday, July 17, 2014

Pareto's Principle and Long-Tailed Distribution Curves

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.



The book has an extensive glossary, that explains the meaning and relevance of medical terms appearing throughout the chapters. The glossary can be read as a stand-along document. Here is an example of one term, "Pareto's Principle", excerpted from the glossary.
Pareto’s principle - Also known as the 80/20 rule, Pareto’s principle holds that a small number of items account for the vast majority of observations. For example, a small number of rich people account for the majority of wealth. Just two countries, India plus China, account for 37% of the world population. Within most countries, a small number of provinces or geographic areas contain the majority of the population of a country (e.g., east and west coastlines of the U.S.). A small number of books, compared with the total number of published books, account for the majority of book sales.

Likewise, a small number of diseases account for the bulk of human morbidity and mortality. For example, two common types of cancer, basal cell carcinoma of skin and squamous cell carcinoma of skin, account for about 1 million new cases of cancer each year in the U.S. This is approximately the sum total for all other types of cancer combined. We see a similar phenomenon when we count causes of death. About 2.6 million people die each year in the U.S. [98]. The top two causes of death account for 1,171,652 deaths (596,339 deaths from heart disease and 575,313 deaths from cancer [99]), or about 45% of all U.S. deaths. All of the remaining deaths are accounted for by more than 7000 conditions.

Sets of data that follow Pareto’s principle are often said to follow a Zipf distribution, or a power law distribution. These types of distributions are not tractable by standard statistical descriptors because they do not produce a symmetric bell-shaped curve. Simple measurements such as average and standard deviation have virtually no practical meaning when applied to Zipf distributions. Furthermore, the Gaussian distribution does not apply, and none of the statistical inferences built upon an assumption of a Gaussian distribution will hold on data sets that observe Pareto’s principle.

I urge you to read more about my 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: 80/20 rule, common disease, data analysis, glossary, orphan disease, orphan drugs, rare disease, statistics

Tuesday, July 15, 2014

Relationship between Hamartoma and Cancer

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.



The book has an extensive glossary, that explains the meaning and relevance of medical terms appearing throughout the chapters. The glossary can be read as a stand-along document. Here is an example of one term, "hamartoma", excerpted from the glossary.
Hamartoma - Hamartomas are benign tumors that occupy a peculiar zone lying between neoplasia (i.e., a clonal expansion of an abnormal cell) and hyperplasia (i.e., the localized overgrowth of a tissue). Some hamartomas are composed of tissues derived from several embryonic lineages (e.g., ectodermal tissues mixed with mesenchymal tissue). This is almost never the case in cancers, which are clonally derived neoplasms wherein every cell is derived from a single embryonic lineage. Tuberous sclerosis is an inherited hamartoma syndrome. The pathognomonic lesion in tuberous sclerosis is the brain tuber, from which the syndrome takes its name. Tubers of the brain consist of localized but poorly demarcated malformations of neuronal and glial cells. Like other hamartoma syndromes, the germline mutation in tuberous sclerosis produces benign hamartomas as well as carcinomas, indicating that hamartomas and cancers are biologically related. Hamartomas and cancers associated with tuberous sclerosis include cortical tubers of brain, retinal astrocytoma, cardiac rhabdomyoma, lymphangiomyomatosis (very rarely), facial angiofibroma, white ash leaf-shaped macules, subcutaneous nodules, cafe-au-lait spots, subungual fibromata, myocardial rhabdomyoma, multiple bilateral renal angiomyolipoma, ependymoma, renal carcinoma, subependymal giant cell astrocytoma [62].

Another genetic condition associated with hamartomas is Cowden syndrome, also known as multiple hamartoma syndrome. Cowden syndrome is associated with a loss of function mutation in PTEN, a tumor suppressor gene. Features that may be encountered are macrocephaly, intestinal hamartomatous polyps, benign hamartomatous skin tumors (multiple trichilemmomas, papillomatous papules, and acral keratoses), dysplastic gangliocytoma of the cerebellum, and a predisposition to cancers of the breast, thyroid and endometrium.

I urge you to read more about my 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, orphan disease, orphan drugs, types of cancer, cancer types, tumor types, tumor biology, rare cancers, common cancers, hyperplasia, tissue overgrowth, disease genes, genetic disease, carcinogenesis, glossary

Aneuploidy and Carcinogenesis

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.



The book has an extensive glossary, that explains the meaning and relevance of medical terms appearing throughout the chapters. The glossary can be read as a stand-along document. Here is an example of one term, "aneuploidy", excerpted from the glossary.
Aneuploidy - The presence of an abnormal number of chromosomes (for the species) in a cell. Most cancers contain aneuploid cells; an observation that holds true for virtually every poorly differentiated cancer. Aneuploidy is seen less often in benign tumors and well-differentiated tumors. Aneuploidy is also found in epithelial precancers and other growing lesions that can sometimes regress spontaneously (e.g., keratoacanthoma). These observations have prompted speculation that chromosomal instability and the acquisition of aneuploidy is an underlying cause of the cancer phenotype (i.e., tumor growth, invasion into surrounding tissues, and metastases).

Such causal associations invite skepticism, particularly in the realm of cancer biology, as virtually every cellular process and constituent of cancer cells has been shown to deviate from the norm. Nonetheless, there is good reason to suspect that aneuploidy is at least a factor in tumor development, as mutations that cause aneuploidy are associated with a heightened risk of cancer (e.g., Brca1 gene mutations [13] and mutations of mitotic checkpoint genes [14]). Cancer researchers have warned that aneuploidy, by itself, may not cause cancer [15]. Aneuploidy may need to be accompanied by other factors associated with genetic instability, such as the accumulation of DNA damage, specific cancer-causing mutations, epigenomic and cytogenetic abnormalities, and reduced cell death [15].

As usual, a rare disease helps to clarify the role of aneuploidy in carcinogenesis. Mosaic variegated aneuploidy syndrome-1 (MVA1) is caused by a homozygous or compound heterozygous mutation in the BUB1B gene, which encodes a key protein in the mitotic spindle check point. This disease is characterized by widespread aneuploidy in more than 25% of the cells of the body, and a heightened risk of developing childhood cancers (e.g., rhabdomyosarcoma, Wilms tumor, and leukemia). Because the underlying cause of mosaic variegated aneuploidy syndrome-1 is a gene that produces aneuploidy, and because such aneuploidy is an early event (i.e., congenital) that precedes the development of cancer and that is found in the developed cancer cells, then it is reasonable to infer that aneuploidy is closely associated with events that lead to cancer. See Mutator phenotype, Carcinogenesis, Cytogenetics, and Karyotype.

I urge you to read more about my 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, orphan disease, orphan drugs, types of cancer, cancer types, tumor types, tumor biology, rare cancers, common cancers, aneuploidy, cytogenetics, euploidy, carcinogenesis, glossary

Monday, July 14, 2014

Most Types of Cancer are Rare Cancers

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.



Here is an excerpt from Chapter 8:
There are about 6000 types of cancer that have been assigned names by pathologists [4–6]. About a dozen of these cancers are common diseases. The remaining cancers (i.e., about 6000 entities) comfortably qualify as “rare” under U.S. Public Law 107-280, the Rare Diseases Act of 2002 [7]. Consequently, healthcare workers must somehow come to grips with 6000 types of rare cancers.

Moreover, the variety of rare cancers is increasing rapidly. As we learn more and more about the genetics of cancers, we find that the common cancers can be subtyped into genetically distinct groups. Furthermore, we are finding an increasing number of alternate alleles and heterogeneous genes that account for rare diseases.

Hence, the trend is leading us to divide the common cancers into genetically distinct subtypes that qualify as rare cancers, and to divide the known rare cancers into ultra-rare subtypes.

I urge you to read more about my 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, orphan disease, orphan drugs, types of cancer, cancer types, tumor types, tumor biology, rare cancers, common cancers

Sunday, July 13, 2014

Clinical trial failures: help from the Rare Diseases

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.



For a variety of reasons, clinical trials for rare diseases tend to have much greater likelihood of success than clinical trials on common diseases. Moreover, treatments developed for the rare diseases will almost always find some value in the treatment of one or more common diseases [a major theme discussed developed in the book]. Here is a short excerpt from Chapter 14.
It can be difficult or impossible to enroll all the patients required for a clinical trial. In an analysis of 500 planned cancer trials, 40% of trials failed to accrue the minimum necessary number of patients. Of cancer trials that have passed through preclinical, phase I clinical, and phase II clinical trials, three out of five failed to achieve the necessary patient enrollment to move into the final phase III clinical trial [12]. Most clinical trials for cardiovascular disease, diabetes, or depression are designed to be even larger than cancer trials [12].

Overall, about 95% of drugs that move through the clinical trial gauntlet will fail [13]. Of the 5% of drugs that pass, their value may be minimal. To pass a clinical trial, a drug must have proven efficacy. It need not be curative; only effective. Of the drugs that pass clinical trials, some will have negligible or incremental benefits. After a drug has reached market, its value to the general population might be less than anyone had anticipated. Clinical trials, like any human endeavor, are subject to error [14–16]. Like any human endeavor, clinical trials need to be validated in clinical practice [10]. It may take years or decades to determine whether a treatment that demonstrated a small but statistically significant effect in a clinical trial will have equivalent value in everyday practice.

Funders of medical research are slowly learning that there simply is not enough money or time to conduct all of the clinical trials that are needed to advance medical science at a pace that is remotely comparable to the pace of medical progress in the first half of the twentieth century.
14.2.2 Rule—Clinical trials for common diseases have limited value if the test population is heterogeneous; as is often the case.
Brief Rationale—Abundant evidence suggests that most common diseases are heterogeneous, composed of genotypically and phenotypically distinct disease populations, with each population responding differently with the clinical trial.

The population affected by a common disease often consists of many distinct genetic and phenotypic subtypes of the disease; essentially many different diseases. A successful clinical trial for a common disease would require a drug that is effective against different diseases that happen to have a somewhat similar phenotype. One-size-fits-all therapies seldom work as well as anticipated, and more than 95% of the clinical trials for common diseases fail [13].
14.2.3 Rule—Clinical trials for the rare diseases are less expensive, can be performed with less money, and provide more definitive results than clinical trials on common diseases. Brief Rationale—Common diseases are heterogeneous and produce a mixed set of results on subpopulations. This in turn dilutes the effect of a treatment and enlarges the required number of trial participants. Rare diseases are homogeneous, thus producing a uniform effect in the trial population, and thus lowering the number of trial participants required to produce a statistically convincing result.

Rare diseases often have a single genetic aberration, driving a single metabolic pathway that results in the expression of a rather uniform clinical phenotype. This means that a drug that succeeds in one patient will likely succeed in every patient who has the same disease. Likewise, a drug that fails in one patient will fail in all the other patients. This phenomenon has enormous consequences for the design of clinical trials. When the effects of drugs are consistent, the number of patients enrolled in clinical trials can be reduced, compared with the size of clinical trials wherein the effects of drugs are highly variable among the treated population. In general, clinical trials targeted on rare diseases or on genotypically distinct subsets of common diseases require fewer enrolled participants than trials conducted on heterogeneous populations that have a common disease [13].

It is wrong to assume that because rare diseases affect fewer individuals than do the common diseases, it would be difficult to recruit a sufficient number of patients into an orphan drug trial. Due to the energetic and successful activities of rare disease organizations, registries of patients have been collected for hundreds of different conditions. For the most part, patients with rare diseases are eager to enroll in clinical trials. The rare disease registries, made available to clinical trialists, eliminate the hit-or-miss accrual activities that characterize clinical trials for common diseases.

I urge you to read more about my 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, orphan disease, orphan drugs, clinical trials, complex disease, ancillary studies, trial design, statistical significance, reproducibility,

Treating precancers reduces breast cancer deaths

Breast cancer deaths rose through the '70s and '80s, but declined in the '90s. For nearly the past 20 years, American women have had about a 2% annual drop in the breast cancer death rate.

Here is the mortality graph provided by the National Cancer Institutes SEER (Surveillance, Epidemiology and End Results) program.



Though nobody wants to take the blame for the rise in breast cancer deaths in the '70s and '80s, lots of people want credit for the fall of breast cancer deaths that began in the '90s. Was it due to a reduction to the exposure of carcinogens, or to better treatment, or to earlier diagnosis?

The fall in breast cancer deaths does not seem to be due to cancer prevention. While the deaths from breast cancer were falling, there was an apparent rise in the incidence of breast cancer cases. Here is the SEER graph for the incidence in breast cancer in the U.S.



Since the breast cancer incidence rose while the deaths from breast cancer dropped, it seemed as though the benefit must have come from better treatment or earlier detection.

A major study, attempting to resolve this issue, was published in the New England Journal of Medicine, in 2005:

Effect of screening and adjuvant therapy on mortality from breast cancer.
Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, Mandelblatt JS, Yakovlev AY, Habbema JD, Feuer EJ; Cancer Intervention and Surveillance Modeling Network (CISNET) Collaborators. N Engl J Med 353:1784-1792, 2005.


They concluded that that 28 to 65 percent of the sharp decrease in breast cancer
deaths from 1990 to 2000 was due to mammograms. The remainder of the improvement was was attributed improved breast cancer treatment.

The study did not take into account the great contribution of precancer treatment to the reduction of breast cancer deaths.

Let's review this SEER data, this time taking into account the diagnosis of DCIS (ductal carcinoma in situ) a precancer that precedes the development of invasive breast cancer. Here is the SEER data for the incidence of all breast cancer and of DCIS (the precancer for breast cancer).



In the past few decades, there has been a huge rise in the number of diagnosed cases of breast precancers. This is due largely to the use of mammography, which can detect lesions that cannot be found by palpation. When a precancer is detected and removed, the patient does not develop invasive cancer.

The total number of breast cancer cases includes cases of DCIS. If we subtract the number of breast precancer cases (DCIS) from the total number of breast cancer cases, we get the incidence of invasive breast cancer cases. Here is the SEER data.



The middle bars in the graph represent the incidence of invasive breast cancers. The graph shows that incidence of invasive breast cancers has actually dropped since the early '90s, as the diagnosis and treatment of DCIS has risen.

Much of the decrease in breast cancer mortality can be accounted for by the diagnosis and treatment of breast precancers. In fact the drop in breast cancer deaths follows the same slope, and has about the same magnitude, as the drop in invasive breast cancers that follows the increase in breast precancer treatments.

- © 2010 Jules Berman


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.


Friday, July 11, 2014

Causality: Single Gene Disorders Can be Biologically Complex

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.



One of the points discussed in the book is disease causation, and how we often fool ourselves into thinking that we understand how a disease develops, simply because we can name the gene or agent that precipitates the disease.

A gene may code for a single protein, but complex genetic and epigenetic conditions will effect the individual's response to a specific gene defect. Hence, different individuals, each with their own unique genome and epigenome, will respond differently to the same genetic aberration. Here is an excerpt from Chapter 9:
If a disease were truly caused by an aberration of a single gene, then all of the consequences of the genetic aberration would be identical in every person with the gene. In fact, some monogenic diseases have remarkably uniform clinical phenotypes in affected populations (e.g., sickle cell disease). What would happen if the same genetic aberration were recapitulated in a mouse? If the mouse homologue served the same purpose as the human gene, and if the gene were the sole cause of the disease, then you might expect the disease to be the same in man and mouse.

Lesch–Nyhan disease is a rare syndrome caused by a deficiency of HGPRT (hypoxanthine-guanine phosphoribosyl transferase), an enzyme involved in purine metabolism. In humans, HGPRT deficiency results in high levels of uric acid, with resultant renal disease and gout. A vast array of neurologic and psychologic signs accompanies the syndrome, including self-mutilation. Neurologic features tend to increase as the affected child ages. The same HGPRT deficiency of humans can be produced in mice. Mice with HGPRT deficiency do not have disease. As far as anyone can tell, mice with HGPRT deficiency are totally normal [18]. How can this be?

A single gene cannot cause a disease all by itself. Every monogenic disease is expressed in a complex system wherein the defective gene is a participant in various pathways that eventually lead to a disease. The mouse, evidently, has a set of pathways that compensates for the deficiency in HGPRT.

Diabetes is usually a common polygenic disease. There are rare subtypes of type 2 diabetes that have a monogenic origin. As you would expect, these rare subtypes arise in children, and have a Mendelian pattern of inheritance. One such monogenic form of diabetes is MODY-8 (maturity-onset diabetes of the young), caused by a mutation in the carboxyl-ester lipase gene. This same mutation was delivered to a transgenic mouse, intended as an animal model for MODY (see Glossary item, Transgenic). Mice carrying the same altered gene as the human failed to develop any signs of diabetes, or pancreatic damage, or any dysfunction caused by the mutated gene [19].

I urge you to read more about my 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, orphan disease, orphan drugs, monogenic disease, complex disease, causality, disease causation, cause of disease, pathogenesis

Thursday, July 10, 2014

Causality versus Pathogenesis

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.



One of the points discussed in the book is disease causation, and how we often fool ourselves into thinking that we understand how a disease develops, simply because we can name the gene or agent that precipitates the disease.

Here is an excerpt from Chapter 8 [Note: Pathogenesis is the sequence of cellular events that eventually leads to the clinical expression of a disease]:
In the field of medicine, we often cannot assign a specific cause to a particular disease without seriously misleading ourselves. For example, what is the cause of rheumatic fever? Rheumatic fever is an autoimmune process that targets the heart. Rheumatic fever occurs in people who have been infected with a Group A strain of Streptococcus pyogenes. The infection, which usually presents as a pharyngitis, elicits an immune response against a bacterial antigen. The antibody species that target the bacterial antigen happen to cross-react with proteins in normal heart and vessels. These cross-reacting antibodies damage the heart and vessels to produce rheumatic fever.

Rheumatic fever is one of the most thoroughly studied and best understood diseases known to man. Knowing all that we know about the pathogenesis, pathology, and clinical features of rheumatic fever, it should be easy to specify the cause of the disease. Alas, this is not the case. For example, we cannot assert that rheumatic fever is caused by Streptococcus pyogenes because not all cases of infection lead to rheumatic fever, and because the clinical features of the disease are not actually caused by the infection. Likewise, we cannot assert that rheumatic fever is an autoimmune disease because it does not result from a defect in the autoimmune response. Basically, rheumatic fever involves a normal immune response to a foreign antigen (i.e., a protein of Streptococcus pyogenes bacteria) that happens to cross-react with the heart proteins. Furthermore, we cannot claim that rheumatic fever is caused by a heart defect; the heart is an innocent bystander in a process that evolved over time in tissues other than the heart (i.e., the pharynx and other tissues in which immunocytes reside). The more we know about the pathogenesis of rheumatic fever, the more difficult it becomes to specify its cause.

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, orphan disease, orphan drugs, rheumatic fever, rheumatic heart disease, heart disease, immune disease, strep infection, causality, disease causation, cause of disease, pathogenesis

Wednesday, July 9, 2014

Rare Cancer are Subsets of Common Cancers

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.



One of the key ideas developed in the book is that each common diseases is actually an aggregate of cellular processes that are present, individually, in rare diseases. In the case of the common cancers, we can find specific rare diseases that are subsets of the common diseases.

Here is an excerpt from Chapter 8:

8.3.3 Inherited syndromes that cause rare cancers are often associated with increased risk for developing common cancers; hence, the causes of rare cancers are related to the causes of common cancers. Many of the greatest advances in our understanding of common cancers have come through the study of rare familial cancer syndromes in which common types of cancer occur. Here are a few common cancers and the familial syndromes that account for a small percentage of cases.

Colon tumors (benign and malignant)
- Colorectal cancer hereditary non-polyposis
- Polyposis syndrome, mixed hereditary
- Turcot syndrome (central nervous system cancer and familial polyposis of the colon)
- Mismatch repair gene pmsl1 colorectal cancer hereditary, non-polyposis type 3 included
- Checkpoint kinase 2 S. pombe homologue of breast and colorectal cancer susceptibility
- Colorectal adenomatous polyposis autosomal recessive
- Oligodontia–colorectal cancer syndrome
- Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
- Adenomatous polyposis of the colon (APC)
- Peutz–Jeghers syndrome
- Colorectal cancer hereditary non-polyposis type 2
- Colorectal cancer susceptibility on chromosome 9
Lung cancer
- Lung cancer 1
- Lung cancer, alveolar cell carcinoma included
Breast cancer
- Brca1 breast cancer type 1
- Breast cancer 11–22 translocation associated
- Brca2 breast cancer type 2
- Brca3 breast cancer type 3
Basal cell carcinoma of skin (see Glossary item, Basal cell carcinoma)
- Basal cell carcinomas with milia and coarse sparse hair
- Basal cell nevus syndrome
- Basal cell carcinoma, multiple
- Basaloid follicular hamartoma syndrome (see Glossary item, Hamartoma)
- Basal cell carcinoma with follicular differentiation
- Xeroderma pigmentosum complementation group b
- Xeroderma pigmentosum 1
Renal cell carcinoma
- Renal carcinoma, familial associated 1 included
- Renal cell carcinoma, papillary
- Non-papillary renal carcinoma 1
- Renal cell carcinoma, papillary 3
- Leiomyomatosis and renal cell cancer hereditary
Thyroid cancer
- Thyroid carcinoma, familial medullary
- Familial non-medullary thyroid cancer
- Papillary thyroid microcarcinoma
- Thyroid carcinoma, papillary with papillary renal neoplasia
- Thyroid carcinoma, non-medullary 1
- Thyroid carcinoma, Hürthle cell
- Thyroid carcinoma, follicular
Ovarian cancer
- Epithelial ovarian cancer
- Ovarian cancer, epithelial, susceptibility to
Melanoma
- Melanoma, cutaneous malignant 4
- Melanoma, cutaneous malignant 3
- Familial atypical multiple mole melanoma-pancreatic carcinoma syndrome
- Dysplastic nevus syndrome, hereditary b-k mole syndrome
Prostate cancer
- Prostate cancer, hereditary x-linked
- Prostate cancer, hereditary 1
- Prostate cancer, hereditary 20
- Prostate cancer, hereditary 7
- Prostate cancer, hereditary 3
- Prostate cancer/brain cancer, susceptibility
When we look at individual inherited cancer syndromes, we see that both rare and common cancers may result. Here is the list of different types of cancer associated with the Li–Fraumeni syndrome [15]. The syndrome-associated cancers are divided into common and rare cancers.

Common tumors associated with Li-Fraumeni syndrome
- Breast cancer
- Lung adenocarcinoma
- Colon cancer
- Pancreatic cancer
- Prostate cancer
Rare tumors associated with Li-Fraumeni syndrome
- Soft tissue sarcomas
- Osteosarcomas
- Brain tumors
- Acute leukemias
- Adrenocortical carcinomas
- Wilms tumor
- Phyllodes tumor of breast
It is worth noting that the common cancers associated with rare cancer syndromes have a similar morphologic appearance as their sporadic counterparts. This suggests that regardless of underlying genetic cause, the pathogenesis of each named common cancer tends to converge to its characteristic phenotype.

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, orphan disease, orphan drugs, carcinogenesis, common cancers, rare cancers, cancer syndromes, familial cancer syndromes

Tuesday, July 8, 2014

Direct Assault on Advanced Stage Common Cancers Has Not Yielded Cures

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.



Here is a short excerpt from Chapter 8:
Though there are thousands of types of human cancer, the bulk of cancer cases in humans are accounted for by just a few, under a dozen, types of cancer. The two most commonly occurring cancers of humans are basal cell carcinoma of skin and squamous cell carcinoma of skin. Together, these two tumors account for about 1.2 million new cancers each year in the U.S., nearly equal to the number of all the other types of cancers combined. These tumors are so common that, frequently, more than one basal cell carcinoma or squamous cell carcinoma will occur in the same individual. Fortunately for us, these two tumors seldom cause deaths; most cases are cured by simple excision. Cancer registries do not bother to collect records on these two cancers, and the published data on cancer incidence, compiled from registries and surveillance databases, typically ignores these two tumors. Nonetheless, we will see later in this chapter that basal cell carcinoma of skin and squamous cell carcinoma of skin tell us much about the biology of cancer in humans.

In Section 2.1, we discussed Pareto’s principle, wherein a few common items account for the majority of instances of any collection. Cancer obeys Pareto’s principle: a few cancers account for most cases of cancer occurring in humans. Collected U.S. data for the year 2008 indicate that, after excluding basal cell carcinomas and squamous cell carcinomas of skin, there were 1,437,180 new cancers. In the same year, there were 565,650 cancer deaths, of which 161,840 individuals died of lung cancer [1]. The percentage of U.S. cancer deaths from lung cancer was 28.6% (161,840/565,650). Also in 2008, there were 49,960 deaths from colorectal cancer, accounting for 8.8% of U.S. cancer deaths (49,960/565,650). Just two cancers (lung and colorectal) accounted for 37.4% of deaths from cancer in the U.S. When age-adjusted data are examined, the top five cancer killers (lung, colon, breast, pancreas, and prostate) account for 57% of all cancer deaths [1] (see Glossary item, Age-adjusted).

Observing that a few types of cancers account for the bulk of human cancer deaths, funding agencies have concentrated their efforts on finding cures for the most common cancers. Just seven types of common cancer, out of about 6000 known cancers, account for over 36% of cancer funding [2]. The justification for distributing cancer research funding toward research in the common cancers is simple. If cures can be found for the most common cancers, we could drastically reduce the number of cancer deaths in the U.S. and in the world. Curing a rare cancer that might affect a few hundred people worldwide would seem to be an ill-advised investment of our limited resources. Hence the rare cancers receive relatively little cancer funding compared with the common cancers.

The drawback to this straightforward approach is that it has failed. Despite decades of funding, we still do not know how to cure common cancers when they are diagnosed at an advanced disease stage. New discoveries in cancer genetics have highlighted the incredible complexity of the commonly occurring cancers. The complexity of the common cancers has been a seemingly insurmountable barrier blocking the development of simple and effective cures. Despite the long-term efforts of an army of cancer researchers, the age-adjusted death rate from cancers in the year 2000 was about the same as it was in 1975. A significant drop in the cancer death rate since the year 2000 is largely attributed to smoking cessation and other preventive measures; not due to effective new cures for the advanced stage common cancers[3].
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, orphan disease, orphan drugs, advanced stage cancer, cures for advanced stage cancers, cancer priorities, cancer funding, cancer research funding