Publication – Form FDA 483 – Time to Demystify the Myths and Misunderstandings


Target Health is very pleased to announce that a paper entitled “Form FDA 483 – Time to Demystify the Myths and Misunderstandings,“ authored by Glen Park, Michael Hamrell and Jules Mitchel, has been published by The Society for Clinical Research Sites in their journal InSite. A pdf. copy of the paper can also be found on the Target Health website.


The following is an excerpt from the paper and for sure says it all.“


Nobody wants to receive Form FDA 483 after an FDA inspection of a clinical site, drug/device company, manufacturing plant or other entities subject to regulatory inspections. Nevertheless, while inspection findings are inevitable, they are not intended to be “the end of the world.“  This paper will focus on the impact of Form FDA 483 activities associated with clinical investigators.


Check out this scenario!  After a new drug application (NDA) is submitted for a novel drug product, a U.S. Food and Drug Administration (FDA) inspector arrives at the door of a clinical research site.  As panic sets in, the contract research organization (CRO) and pharmaceutical company sponsoring the study are immediately notified.  Everyone, including the principal investigator, chant the following poem in the office cafeteria:


When FDA issues a 483

The hammer comes down, that’s the end of me.

We’re out of business, I lose my job

Get me outta this mess, I pray to God


FDA Limerick by Jules T. Mitchel and Joyce Hays


View From the 24th Floor



Sunset from the 24th Floor at Target Health ©Target Health Inc.


ON TARGET is the newsletter of Target Health Inc., a NYC-based, full-service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.


For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.


Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor


Test Your Knowledge of Bacteria


Archaea, a primitive life form, were first found in extreme environments, with no oxygen, such as volcanic hot springs. The source of this bacteria is Grand Prismatic Spring of Yellowstone National Park.


Bacteria were among the first life forms to appear on Earth, and are present in all habitats on the planet. The nature of the original predecessor involved in the origin of life is subject to considerable speculation. It has been suggested that the original cell might have used RNA as its genetic material, since investigations have shown that RNA molecules can have numerous catalytic functions. Organisms must evolve or adapt to changing environments, and it is clear that mutations, which are changes in the sequence of nucleotides in an organism’s DNA, occur constantly in all organisms. You can find microbes everywhere and they are extremely adaptable to conditions, and survive wherever they are.


Most bacteria have not been characterized, and only about half of the phyla of bacteria have species that can be grown in the laboratory. The study of bacteria is known as 1) ___, a branch of microbiology. There are approximately ten times as many bacterial cells in the human flora as there are human cells in the body, with the largest number of the human flora being in the 2) ___ flora, and a large number on the skin. The vast majority of the bacteria in the body are rendered harmless by the protective effects of the immune system, and some are beneficial. However, several species of bacteria are pathogenic and cause infectious diseases, including cholera, syphilis, anthrax, leprosy, and bubonic plague. The most common fatal bacterial diseases are respiratory infections, with 3) ___ alone killing about 2 million people a year. In developed countries, antibiotics are used to treat bacterial infections and are also used in farming, making antibiotic resistance a growing problem.


Once regarded as plants constituting the class Schizomycetes, bacteria are now classified as prokaryotes. Unlike cells of animals and other eukaryotes, bacterial cells do not contain a nucleus and rarely harbor membrane-bound organelles. The ancestors of modern bacteria were unicellular microorganisms that were the first forms of life to appear on Earth, about 4 billion years ago, before there was 4) ___. For about 3 billion years, all organisms were microscopic, and bacteria and archaea were the dominant forms of life.


Complex morphological changes are sometimes possible. For example, when starved of amino acids, Myxobacteria detect surrounding cells in a process known as quorum sensing, migrate toward each other, and aggregate to form fruiting bodies up to 500 micrometres long and containing approximately 100,000 bacterial cells. In these fruiting bodies, the bacteria perform separate tasks; this type of cooperation is a simple type of multicellular organization. For example, about one in 10 cells migrate to the top of these fruiting bodies and differentiate into a specialized dormant state called myxospores, which are more resistant to drying and other adverse environmental conditions than are ordinary cells.


Many important biochemical reactions, such as energy generation, use concentration gradients across membranes. The general lack of internal membranes in bacteria means reactions such as electron transport occur across the cell 5) ___ between the cytoplasm and the periplasmic space. Some bacteria produce intracellular nutrient storage granules for later use, such as glycogen, polyphosphate, sulfur or polyhydroxyalkanoates. Certain bacterial species, such as the photosynthetic Cyanobacteria, produce internal gas vesicles, which they use to regulate their buoyancy – allowing them to move up or down into water layers with different light intensities and nutrient levels.




Structure and contents of a typical Gram positive bacterial cell


There are broadly speaking two different types of cell wall in bacteria, a thick one in the Gram-positives and a thinner one in the Gram-6) ___. The names originate from the reaction of cells to the Gram stain, a test long-employed for the classification of bacterial species.




Flagellum of Gram-negative Bacteria. The base drives the rotation of the hook and filament


The mechanisms inherent in bacteria are profound because they predict DNA evolutionary pathways of what is yet to come, first with more complex cells, which become more highly organized and ultimately more differentiated. One of the great mysteries of life was the beginning of bacterial organelle formation of the flagellum.


Although this short (bacteria) quiz can’t even begin to cover enough, we would be remiss to exclude a mention of the elegant flagellum of bacteria. Though no known multicellular organism is able to spin part of its body freely relative to another part of its 7) ___, there are two known examples of rotating molecular structures used by living cells. ATP synthase is an enzyme used in the process of energy storage and transfer, notably in photosynthesis and oxidative phosphorylation. It bears some similarity to the flagellar motors discussed below. The evolution of ATP synthase is thought to be an example of modular evolution, in which two subunits with their own functions have become associated and gained a new functionality. The only known example of a biological “wheel“ – a system capable of providing continuous propulsive torque about a fixed body – is the flagellum, a propeller-like tail used by single-celled prokaryotes for 8) ___. The bacterial flagellum is the best known example. About half of all known bacteria have at least one flagellum, indicating that rotation may in fact be the most common form of locomotion in living systems. At the base of the bacterial flagellum, where it enters the cell membrane, a motor protein acts as a rotary engine. The engine is powered by proton motive force, i.e., by the flow of protons (hydrogen ions) across the bacterial cell membrane due to a concentration gradient set up by the cell’s metabolism. (In species of the genus Vibrio, there are two kinds of flagella, lateral and polar, and some are driven by a sodium ion pump rather than a proton pump.) 9) ___ are quite efficient, allowing bacteria to move at speeds up to 60 cell lengths per second. The rotary motor at the base of the flagellum is similar in structure to that of ATP synthase. Spirillum bacteria have helically shaped bodies with flagella at either end, and spin about the central axis of their helical body as they move through the water.


Archaea, a group of prokaryotes distinct from bacteria, also feature flagella driven by rotary motor proteins, though they are structurally and evolutionarily distinct from bacterial flagella. Whereas bacterial flagella evolved from the bacterial Type III secretion system, archaeal flagella appear to have evolved from Type IV pili. The processes of evolution, as they are presently understood, can help explain why wheeled locomotion has not evolved in multicellular organisms; simply put, a complex structure or system will not evolve if its incomplete form provides no benefit to an organism. According to the modern evolutionary synthesis, adaptations are produced incrementally through natural selection, so major genetic changes will usually spread within populations only if they do not decrease the fitness of individuals. Although neutral changes that provide no benefit can spread through genetic drift, and detrimental changes can spread under some circumstances, large changes that require multiple steps will occur only if the intermediate stages increase fitness. The flagellum of bacteria, is the only known example of a freely rotating propulsive system in biology. In the 10) ___ of flagella, individual components were recruited from other structures, where they performed tasks unrelated to propulsion. The basal body that is now the rotary motor might have evolved from a structure used by the bacterium to inject toxins into other cells. This recruitment of previously evolved structures to serve new functions is called exaptation.


Bacteria, the first forms of life, are truly amazing and deserve our serious respect.


History of Bacteria Videos


Brief History of Bacteria – Part 1


Brief History of Bacteria – Part 2


Brief History of Bacteria – Part 3


Brief History of Bacteria – Part 4


ANSWERS: 1) bacteriology; 2) gut; 3) tuberculosis; 4) oxygen; 5) membrane; 6) negatives;7) body; 8)propulsion; 9) Flagella; 10) evolution


Roger Stanier (1916-1982) Erudite Microbiologist


Roger Stanier (1916-1982) was an erudite researcher and life-long scholar whose studies spanned many years and concerned the basic tenets of evolution and adaptation. This distinguished Canadian-born (Victoria,British Columbia) scientist first embarked on the study of microorganisms many decades ago and spent his working life as a microbiologist in the United States and later in France. Early on, he spent a period of research on bacterial metabolism and physiology with modern pioneer microbiologist Marjorie Stephenson through a Guggenheim fellowship at Cambridge University (UK). Beginning in 1947, he devoted 24 years to the University of California at Berkeley where he attained the position of professor and chairman. During his years at Berkeley, Stanier made many fundamental contributions to our understanding of the microbial world. In 1957, with outstanding collaborators, he produced what was to become the leading textbook on microbiology during his time, entitled The Microbial World. This text was subsequently published in five editions over 30 years.


Roger Yate Stanier was born to British immigrant parents on 22 October 1916 in Victoria, Canada. His father studied medicine at the University of Toronto and later established a private practice in diagnostic radiology. His mother, a teacher, studied English literature at the University of Cambridge. At the age of 15, Stanier enrolled at the local junior college, Victoria College, where he studied biology, literature, and history. He subsequently transferred to the University of British Columbia (UBC) with the intention to study literature and history. His parents demurred, however, so he settled on bacteriology in order to placate his physician father, ultimately graduating with first-class Honors in bacteriology in 1936. Because he felt he had had insufficient exposure to the physical sciences at UBC, Stanier sought chemistry training at the University of Munich in 1936. As the rise of Nazism poisoned the environment at the university, he cut short his studies there and decided to attend graduate school in the United States. Because of the presence of his friend, Mike Lerner, Stanier chose to enroll in the Department of Bacteriology at the University of California, Berkeley, but found himself disinterested in the phage research done under A.P. Krueger. He subsequently accepted a teaching assistantship at UCLA for the 1938-1939 term. During his time at UCLA, he attended the famous summer course taught by C. B. van Niel at the Hopkins Marine Station in Pacific Grove, California. His experience there drove his decision to pursue general microbiology. After receiving his M.A. from UCLA in 1939 he returned to Pacific Grove as van Niel’s student. After graduation, he worked with Marjory Stephenson at the University of Cambridge as a Guggenheim fellow beginning in 1945.


Upon his return to the United States he served a short appointment at the University of Indiana before accepting an invitation to join the Department of Bacteriology at the University of California, Berkeley, where he remained for most of his career. In 1971 he left Berkeley and moved to Paris, where he worked at the Institut Pasteur for the last decade of his life. He described the reasons for his departure as both academic and political: 1) academic disruptions amid the campus turmoil associated with the Free Speech Movement; 2) then Governor Ronald Reagan’s ouster of University of California president Clark Kerr; 3) and the election of President Richard Nixon. Along with his wife Germaine, he accepted the invitation of Elie Wollman to take over the former lab space of Francois Jacob and Jacques Monod, with the stipulation that he be allowed to work on cyanobacteria exclusively. He was elected a Fellow of the Royal Society in 1978.


Stanier’s research career included a diverse variety of research problems bound by a desire to synthesize the general and specific patterns observed in bacteria into a more unified understanding of biology as a whole. Together with C. B. van Niel, Stanier was described by Carl Woese as one of the “only consistently insightful and articulate reporters of the early search for a microbial phylogeny“. Stanier participated in Bergey’s Manual Trust during its conception. He invented the technique of simultaneous adaption for the analysis of metabolic pathways.


Stanier’s work on Cyanobacteria focused on obligate autotrophy, fatty acid composition, structure of phycobiliproteins and phycobilisomes, chromatic adaptation, nitrogen fixation, and their nutrition and taxonomy. Stanier also authored an influential textbook, The Microbial World. The Microbial World played an important role in the promulgation of the concepts of “prokaryote“ and “eukaryote“ as negative definitions of Bacteria and Archea. From his early days, taxonomy was a constant challenge to Stanier and his interest in the subject drew him into the Bergey’s Manual Trust (USA) during the years of its gestation. The Bergey’s Manual Trust developed into the scholarly authority for species recognition. Roger Stanier did much for its character and content, which gave him a wide view of microbiology and his interest evolved on a broad scale. His brilliant effort to bridge the gaps in our knowledge of complex evolutionary development helped characterize the microbial world.




As with any prokaryotic organism, cyanobacteria do not have nuclei or an internal membrane system. However, many species of cyanobacteria have folds on their external membranes that function in photosynthesis. Cyanobacteria are arguably the most successful group of microorganisms on earth. They are the most genetically diverse; they occupy a broad range of habitats across all latitudes, widespread in freshwater, marine and terrestrial ecosystems, and they are found in the most extreme niches such as hot springs, salt works, and hypersaline bays. Photoautotrophic, oxygen-producing cyanobacteria created the conditions in the planet’s early atmosphere that directed the evolution of aerobic metabolism and eukarotic photosynthesis. Cyanobacteria fulfill vital ecological functions in the world’s oceans, being important contributors to global carbon and nitrogen budgets. By producing oxygen as a gas, as a by-product of photosynthesis, cyanobacteria are thought to have converted the early reducing atmosphere into an oxidizing one, which dramatically changed the composition of life forms on Earth by stimulating biodiversity and leading to the near-extinction of oxygen-intolerant organisms. According to endosymbiotic theory, the chloroplasts found in plants and eukaryotic algae evolved from cyanobacterial ancestors via endosymbiosis.


By depicting the course of evolution in terms of efficient endocytosis, Stanier directed attention to organellar structures and their eventual symbiotic relationships. He explained that the variety of cytoplasmic structures bearing color pigments actually reflected ancient evolutionary diversity. Photo pigment synthesis of free-living forms would have been preserved in the photosynthetic organelles. In time, nuclear organization prevented the evolutionary paths of cosymbionts from freely going their own way. His exceptional insight led him to appreciate the evolutionary significance of bacterial photosynthesis; it was the basis by which he traced the adaptation of organisms from anoxygenic (anaerobic) to oxygenic (aerobic) lifeforms. This produced a turning point in evolution when he realized that pigments in microorganisms played the important role of trapping energy from light. Selection in the emerging eukaryotic cell would have centered on improved efficacy of predation. He then fathomed that special relationships of microbial groups with unique physiological properties tend to occur to establish a shared opportunity for their survival.


When Stanier turned his attention to the habitat of microorganisms to explain the selective pressures in a natural environment, he was able to foresee the connection between symbiotic relationships and microbial ecology. He was concerned that real changes would not be recognizable except under authentic environmental conditions that ensured the significant connections in the microenvironment. Stanier understood that the key to change was the availability of energy and diversity of mechanisms for its generation. Roger Stanier’s intense interest in adaptation concerned multiple simultaneous adaptation in enzyme formation conceived as a systematic format at a basic biochemical level. The presence of a control mechanism was considered a stable character, which eventually showed that pathways could be regulated and that the control would in turn be conserved for this purpose in a particular biological group. He not only systematically clarified pathway metabolism, he also provided the basis on which the linkage to other biochemical pathways could be envisioned. It illustrated alternative pathways and detailed proof of microbial behavior in a particular biochemical niche.


In emphasizing evolution and adaptation, Stanier described the organic environment as consisting of both systematic and fluctuating occurrences, thus enabling organisms to move toward successive adaptation. He defined systematic variations as those that involved gradual unidirectional and fluctuating variations as short-term changes. Systematic events dealt with molding of the genotype, allowing for an organism to be selected to fit conditions of its environment in a geological time slot. Fluctuating events dealt with the change during a period of observation that was just sufficient to assess and pinpoint any pattern in those events that permitted possible selection of different genotypes. However, even with successive adaptation in nature, he recognized that any mutation could result in a disaster if it interfered with the competitive edge of an organism. Hence, an organism must retain that certain array of genes that gives it maximum fitness to ensure its environmental survival.


Photo-pigments are of great biological significance, their importance being to permit the coexistence of different kinds of photosynthetic organisms in one habitat. Their ability to absorb light from certain regions of the solar spectrum benefited the coexisting symbionts. Thus, Stanier formulated the ingredients for analyzing symbiosis according to the degree of intimacy, the balance of advantage and the extent of dependence of each symbiont. The concurrent development in genetic structure led to a more consistent gene makeup.


Roger Stanier’s approach was highly influential because he thought that the difficult questions facing biology should also include microorganisms. Stanier brought microbiology into the mainstream of the biological sciences. He became renowned for his enormous studies on the fundamentals of microbiology and related biochemistry. His pioneering research concerned enzyme adaptation, the role of pigments, the assimilation of components with regard to chlorophyll, the oxidative processes of aromatic compounds, the comparative biochemistry and evolution of microorganisms and the establishment of blue-green algae as cyanobacteria. This interest in blue-green algae stemmed from his earlier passion for taxonomy and photosynthesis, and the need to determine the distinction between prokaryotes and higher microbial eukaryotes. In the novel investigation of the blue-green algae, Stanier and his wife, Germaine, stressed structure and function relationships, receiving overwhelming substantiation from increasing microscopy studies.


Over his lifetime, Stanier received many awards and much international recognition including the Chevalier de la L?gion d’Honneur (1977), Fellow of the Royal Society-London (1978) and also Foreign Associate of the National Academy of Sciences (1979). The year 2014 marks 98 years since Roger Stanier’s birth and 2014 notes 25 years since his passing and 57 years since the appearance of his influential text, The Microbial World, published in 1957, which resulted in five editions. Stanier was a pioneer with a life filled with a compelling constellation of events, leaving a profound legacy! Sources: Roger Stanier: Diversity as the key to a new era for biology. Perspect Biol Med 1993;37:48-54′; Josephine Accaputo-Gendron, Morris Goldner; Johns Hopkins University Press;; Wikipedia


Schizophrenia – Suspected Common Genetic Variants Soar From 30 to 108


According to an article published online in the journal Nature (21 July 2014), the largest genomic dragnet of any psychiatric disorder to date has unmasked 108 chromosomal sites harboring inherited variations in the genetic code linked to schizophrenia, 83 of which had not been previously reported. By contrast, the “skyline“ of such suspect variants associated with the disorder contained only 5 significant peaks in 2011. The newfound genomic signals are not simply random sites of variation, but converge around pathways underlying the workings of processes involved in the disorder, such as communication between brain cells, learning and memory, cellular ion channels, immune function and a key medication target.  The publication comes out of The Schizophrenia Working Group of the Psychiatric Genomic Consortium (PGC) report on its genome-wide analysis of nearly 37,000 cases and more than 113,000 controls. The NIMH-supported PGC represents more than 500 investigators at more than 80 research institutions in 25 countries.


According to the NIH, while the suspect variation identified so far only explains about 3.5% of the risk for schizophrenia, these results warrant exploring whether using such data to calculate an individual’s risk for developing the disorder might someday be useful in screening for preventive interventions. The NIH added that even based on these early predictors, people who score in the top 10% of risk may be up to 20-fold more prone to developing schizophrenia.


Prior to the new study, schizophrenia genome-wide studies had identified only about 30 common gene variants associated with the disorder. Sample sizes in these studies were individually too small to detect many of the subtle effects on risk exerted by such widely shared versions of genes. The PGC investigators sought to maximize statistical power by re-analyzing not just published results, but all available raw data, published and unpublished. Their findings of 108 illness-associated genomic locations were winnowed from an initial pool of about 9.5 million variants.


A comparison of the combined study data with findings in an independent sample of cases and controls suggest that considerably more such associations of this type are likely to be uncovered with larger sample sizes. There was an association confirmed with variation in the gene that codes for a receptor for the brain chemical messenger dopamine, which is known to be the target for antipsychotic medications used to treat schizophrenia. Yet evidence from the study supports the view that most variants associated with schizophrenia appear to exert their effects via the turning on and off of genes rather than through coding for proteins. The study also found a notable overlap between protein-related functions of some linked common variants and rare variants associated with schizophrenia in other studies. These included genes involved in communication between neurons via the chemical messenger glutamate, learning and memory, and the machinery controlling the influx of calcium into cells.


Among the strongest associations detected, as in in previous genome-wide genetic studies, was for variation in tissues involved in immune system function. Although the significance of this connection for the illness process remains a mystery, epidemiologic evidence has long hinted at possible immune system involvement in schizophrenia. Findings confirm that it’s possible to develop risk profile scores based on schizophrenia-associated variants that may be useful in research — but for now aren’t ready to be used clinically as a predictive test. The authors noted that the associated variations detected in the study may not themselves be the source of risk for schizophrenia, rather, they may be signals indicating the presence of disease-causing variation nearby in a chromosomal region.


Follow-up studies are being designed to pinpoint the specific sequences and genes that confer risk. The PGC is also typing genes in hundreds of thousands of people worldwide to enlarge the sample size, in hopes of detecting more genetic variation associated with mental disorders. Successful integration of data from several GWAS studies suggests that this approach would likely be transferrable to similar studies of other disorders, say the researchers.


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Four Subtypes of Stomach Cancer Identified


Stomach cancers are a leading cause of cancer-related mortality worldwide, resulting in an estimated 723,000 deaths annually.


According to a study published online in Nature (23 July 2014), and performed by The Cancer Genome Atlas (TCGA) Network, it was observed that stomach cancers fall into four distinct molecular subtypes. According to the authors, this discovery could change how researchers think about developing treatments for stomach cancer, also called gastric cancers or gastric adenocarcinomas, and instead of considering gastric cancer as a single disease, as has been done in the past, researchers will now be able to explore therapies in defined sets of patients whose tumors have specific genomic abnormalities. Previous attempts to examine the clinical characteristics of gastric cancer were hindered by how differently cancer cells can look under a microscope, even when from the same tumor. It is hoped that the new classification system will serve as a valuable adjunct to the current pathology classification system, which has two categories: diffuse and intestinal.


The study used six molecular analysis platforms including DNA sequencing, RNA sequencing, and protein arrays to identify the new subgroups through complex statistical analyses of molecular data from 295 tumors. Tumors in the first group, which represented 9% of the tumors, were positive for Epstein-Barr virus (EBV) and had several other molecular commonalities. Tumors in a second subgroup (22% of the tumors) had high microsatellite instability (MSI), which is the tendency for mutations to accumulate in repeated sequences of DNA. The remaining subgroups differed in the level of somatic copy number alterations (SCNAs), which can result from duplication or deletion of sections of the genome. The tumors in the third subgroup, which comprised 20% of the tumors, were considered to have a low level of SCNAs and were called genomically stable. The remaining 50% of tumors were classified as chromosomally unstable, with a high level of SCNAs.


The EBV-positive subgroup of tumors was of particular interest. EBV is best known in the United States as the cause of infectious mononucleosis, which is characterized by fever, sore throat, and swollen lymph glands, especially in the neck. EBV is also suspected of causing certain cancers, including nasopharyngeal carcinoma and some types of lymphoma. Previous research had shown that EBV can be detected in a minority of gastric adenocarcinomas and that EBV genes are expressed in those tumors. However, this study found that the presence of EBV in gastric tumors is associated with a number of other molecular characteristics.


In the study, the authors observed that EBV-positive tumors displayed a high frequency of mutations in the PIK3CA gene, which codes for a component of a protein, PI3-kinase, which is essential for cell growth and division and many other cellular activities that are important in cancer. Although 80% of EBV-positive tumors harbored a protein-changing alteration in PIK3CA, PIK3CA mutations were found in 3% to 42% of tumors of the other gastric cancer subtypes. The authors suggested that EBV-positive tumors might respond to PI3-kinase inhibitors, some of which are in the early stages of testing in clinical trials but are not yet approved by the US FDA for general use.


Some tumors in the EBV-positive subgroup also showed more gene copies being produced in a chromosomal region that contains the JAK2 gene. The JAK2 protein facilitates cell growth and division, and the increased expression of JAK2 may inappropriately activate cell growth. The amplified region also contains the genes for two proteins, PD-L1 and PD-L2, which suppress immune responses; their increased expression may help tumors escape destruction by the immune system. The authors suggested that these findings support the evaluation of JAK2 inhibitors and PD-L1/2 antagonists for the treatment of EBV-positive gastric cancers.


Finally, the EBV-positive subgroup showed a far higher prevalence of DNA hypermethylation than any other reported cancer subtype. Methylation is the process of adding methyl groups to DNA, which reduces gene expression. Hypermethylation occurs when this mechanism continues aberrantly, quieting genes that should be active. In the EBV-positive tumor subgroup, hypermethylation was most often observed in the promoter regions of genes, which would prevent the expression of the genes.


Important insights also came from analyses of the three other gastric cancer subgroups. For example, tumors of the genomically stable subtype contained frequent mutations in a gene called RHOA, whose product interacts with other cellular proteins to help cells change shape and migrate, which may be important in tumor growth. This finding suggests possible targets for treating tumors of this subtype. And tumors of the chromosomal unstable subtype contained frequent amplifications of genes that encode receptor proteins on the outside of the cell, leading to the promotion of aberrant cell growth. Drugs are already available to curb the activity of some of these proteins.


TCGA is jointly managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both parts of the National Institutes of Health (NIH), to comprehensively characterize the genomes of more than 30 types of cancer.

TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.


Zydelig (idelalisib) Approved to Treat 3 Types of Blood Cancers


FDA has approved Zydelig (idelalisib) to treat patients whose chronic lymphocytic leukemia (CLL) has returned (relapsed). Used in combination with Rituxan (rituximab), Zydelig is to be used in patients for whom Rituxan alone would be considered appropriate therapy due to other existing medical conditions (co-morbidities). Zydelig is the fifth new drug with breakthrough therapy designation to be approved by the FDA and the third drug with this designation approved to treat CLL.


The FDA is also granting Zydelig accelerated approval to treat patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL), another type of non-Hodgkin lymphoma. Zydelig is intended to be used in patients who have received at least two prior systemic therapies.


The FDA approved Gazyva (obinutuzumab) in November 2013, Imbruvica (ibrutinib) in February 2014 and a new use for Arzerra (ofatumumab) in April 2014 to treat CLL. Both Gazyva and Arzerra also received breakthrough therapy designation for this indication. Like the other two drugs, Zydelig was also granted orphan product designation because it is intended to treat a rare disease.


Zydelig’s safety and effectiveness to treat relapsed CLL were established in a clinical trial of 220 participants who were randomly assigned to receive Zydelig and Rituxan or placebo and Rituxan. The trial was stopped for efficacy following the first pre-specified interim analysis point, which showed participants treated with Zydelig and Rituxan had the possibility of living at least 10.7 months without their disease progressing (progression-free survival) compared to about 5.5 months for participants treated with placebo and Rituxan. Results from a second interim analysis continued to show a statistically significant improvement for Zydelig and Rituxan over placebo and Rituxan.


Zydelig’s safety and effectiveness to treat relapsed FL and relapsed SLL were established in a clinical trial with 123 participants with slow-growing (indolent) non-Hodgkin lymphomas. All participants were treated with Zydelig and were evaluated for complete or partial disappearance of their cancer after treatment (objective response rate, or ORR). Results showed 54% of participants with relapsed FL and 58% of participants with SLL experienced ORR.


The FDA approved Zydelig to treat FL and SLL under the agency’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials.


Zydelig carries a Boxed Warning alerting patients and health care professionals of fatal and serious toxicities including liver toxicity, diarrhea and colon inflammation (colitis), lung inflammation (pneumonitis) and intestinal perforation that can occur in Zydelig-treated patients. Zydelig is also being approved with a Risk Evaluation and Mitigation Strategy (REMS) comprised of a communication plan to ensure healthcare providers who are likely to prescribe Zydelig are fully informed about these risks.


Common side effects include diarrhea, fever (pyrexia), fatigue, nausea, cough, pneumonia, abdominal pain, chills and rash. Common laboratory abnormalities include decreased levels of white blood cells (neutropenia), high levels of triglycerides in the blood (hypertriglyceridemia), high blood sugar (hyperglycemia) and elevated levels of liver enzymes.


Zydelig is marketed by Foster City, California-based Gilead Sciences. Rituxan and Gazyva are marketed by Genentech, a member of the Roche Group, based in South San Francisco, California. Imbruvica is co-marketed by Sunnyvale, California-based Pharmacyclics and Raritan, New Jersey-based Janssen Biotech, Inc. Arzerra is marketed by Research Triangle Park, North Carolina-based GlaxoSmithKline.


Insouciant Shrimp Summer Salad with Avocado




1 pound large or colossal size shrimp, shelled and deveined or pre-cooked

2 firm-ripe avocados, cut into small squares

2 cups chopped tomatoes, drained

1 white onion, very finely chopped, or 4 sliced shallots, very finely chopped

Pinch red pepper flakes

1 teaspoon turmeric

1 teaspoon cardamom

1 teaspoon cumin (optional)

Drizzle of olive oil

Juice of 2 limes, plus zest 1 lime, before juicing

Pinch Kosher Salt

2/3 cup fresh cilantro, chopped

2 garlic cloves, juiced

1/2 can black beans, rinsed and dried (you could cook your own, if you want to, I didn’t)

1/2 box frozen corn kernals (you could boil fresh corn and scrape the kernels off the cob, but I didn’t)

Tortilla chips, to serve (optional)


Cut off tails and cut (cooked) shrimp into half and put in salad bowl. Scoop avocados into bowl. Add the chopped tomatoes, white onion or shallots, and a drizzle of olive oil. Add the lime juice and zest, and all seasoning. Add salt to taste, then cilantro. Toss and serve with tortilla chips, Italian bread or hearty 7-grain bread or rolls.


Working 5 1/2 days a week, I took the easy way out with this recipe. But, it’s so good you’d think it took longer than it really did. I bought the shrimp from FreshDirect, precooked. Of all the stores, FreshDirect seems to have the most fresh fish and seafood. (Our local fish store, which I swore by, went out of business due to a rent increase.) I also opted to use black beans from the can and frozen corn kernels instead of husking and boiling ears of corn. Even using the one onion, instead of slicing 4 shallots, saved time. (however, I do love the slightly less bold but delicious favor of shallots). You could also do the following with shrimp, if you have the time (which I didn’t do).


Make shrimp stock: If you have more time, you can first make a shrimp stock with about 3 cups water, 1 cup beer or wine, the reserved shrimp shells, additional lime juice or the peels from the lime juice you’ll use in the salad and some peppercorns or red pepper flakes. Boil these together for 20 minutes, then strain the mixture. Cook the shrimp in this stock instead.


Cooking shrimp as usual: Or, to cook the shrimp the usual way: Bring salted water to a boil and turn off heat. Add shrimp, cover pot and let stand until firm and pink, about 5 to 7 minutes. Check shrimp at 3 minutes or 5 minutes to be sure they stay light and crunchy. If you leave them too long they will get rubbery, which ruins the whole experience of eating shrimp. Drain shrimp, pat dry with paper towel and either add to salad and serve right away or chill until you’re ready for them.


This is a delicious meal in itself providing good protein which is also very low in calories (each shrimp is about 7 calories each), black beans also have excellent protein. You have red (lycopene), green (magnesium and vitamin B) and yellow veggies (beta-carotine or provitamin A), plus healthy extra virgin olive oil and lime juice. The sweetness of red seedless grapes offsets some of the kick of the antioxidant spices, plus red grapes have anti-aging, resveratol.


We had this simple summer meal with chilled glasses of Pinot Grigio. For dessert we love fresh peaches topped with vanilla activia yogurt.


BTW, if you’re planning to be in Manhattan, and you like cutting edge modern dance, try to get tickets to see our favorite dance company, PILOBOLUS (headquartered in Connecticut). They are appearing now at the Joyce Theater, which is the main contemporary dance theater in New York. PILOBOLUS is an outstanding, highly creative group using metaphors from philosophy, science, religion, mathematics (computer science), literature, art, theater and music, of course. You may have a transcendental experience, as I did, or you may find your mind drifting toward answers to questions, lurking in your own unconscious depths.


No matter what you do this weekend, relax, stretch out and have a good one!




From Our Table to Yours!


Bon Appetit !