Innovation at Target Health – Target Document, THE eTMF Solution

 

While Target Document can be used by any industry to manage documents, it is ideal to manage an electronic Trial Master File (eTMF).

 

Target Document® is a secure, USER FRIENDLY, 21 CFR Part 11 compliant, web-based document distribution and management system which enables users, depending on their roles and responsibilities to post, share, electronically sign, and archive any electronic document, all within a web browser and without installing any software. Access to documents can also be timed to be viewed and/or expired, and there is a communication tool which allows for discussions about specific documents. Target Document reduces the need to distribute documents via email and is ideal for companies wanting their own system to communicate with customers, vendors, employees, etc. It is also ideal for managing due diligence.

 

Advantages

 

1.    Friendly user interface without any clutter or useless features

2.    Completely web-based, no need to install any software by the end-user

3.    Eliminates the need to send expensive document packages

4.    Speeds up document distribution and signoff

 

Target Document Feature List

 

1.    21 CFR Part 11 Compliant

2.    Web-based solution

3.    Login ID/password security (also used for sign-offs)

4.    User self-registration with department administrator approval

5.    Separate administration module

6.    Role-based access

7.    Templates for Trial Master File

8.    Create Template Folders

9.    Document routing for electronic signoff

10.  Document routing maps to routing multiple documents to same people

11.  User management

12.  Organized by project, client

13.  Secure folder and/or document access

14.  Upload and download any document type deliverable across the web

15.  Document check-in/check-out

16.  Document discussion forums

17.  Document scheduling with optional expiration date

18.  Notifications for document subscribers

19.  Locking/unlocking of folders and documents

20.  Document history includes all versions of uploaded documents

21.  Activity/change history (audit trail) for folders and documents

 

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

Human Microbiome

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Depiction of the human body and bacteria that predominate

 

The human microbiome (or human microbiota) is the aggregate of microorganisms, a microbiome that reside on the surface and in deep layers of skin, in the saliva and oral mucosa, in the conjunctiva, and in the gastrointestinal tracts. They include bacteria, 1) ___, and archaea. Some of these organisms perform tasks that are useful for the human host. However, the majority have been too poorly researched to understand the role they play. Those that are expected to be present, and that under normal circumstances do not cause disease, but instead participate in maintaining health, are deemed members of the normal flora. Though widely known as “microflora“, this is, in technical terms, a misnomer, since the word root “flora“ pertains to plants, and biota refers to the total collection of organisms in a particular ecosystem. Recently, the more appropriate term “microbiota“ is applied, though its use has not eclipsed the entrenched use and recognition of “flora“ with regard to bacteria and other microorganisms. Both terms are being used in different literature.

 

Studies in 2009 questioned whether the decline in biota (including microfauna) as a result of human intervention might impede human health. Most of the microbes associated with humans appear to be not harmful at all, but rather assist in maintaining processes necessary for a healthy body. A surprising finding was that at specific sites on the 2) ___, a different set of microbes may perform the same function for different people. For example, on the tongues of two people two entirely different sets of organisms will break down sugars in the same way. This suggests that medical science may be forced to abandon the one-microbe model of disease, and rather pay attention to the function of a group of microbes that has somehow gone awry.

 

Populations of microbes (such as bacteria and yeasts) inhabit the skin and mucosa. Their role forms part of normal, healthy human physiology, however if microbe numbers grow beyond their typical ranges (often due to a compromised immune system) or if microbes populate atypical areas of the body (such as through poor hygiene or injury), 3) ___ can result. In 2012 some 200 researchers from some 80 research institutions comprising the Human Microbiome Project (HMP) Consortium have used advanced DNA-sequencing to identify and catalogue the thousands of microorganisms co-existing with humans. This study examined, amongst other things, the carbohydrate active enzymes from microbial populations from twelve sites on and in the human body, and concluded that microbes colonize each site to utilize the available 4) ___. Considerable variation was found in the enzymes for carbohydrate metabolism from site to site, and the researchers suggested that the composition of local carbohydrate metabolites may be the most important factor shaping the composition of microbial sub-communities of the human microbiome.

 

Microbial colonization in the human body begins shortly after birth, and average adults possess 10 times more microbial cells than human 5) ___. The skin acts as a barrier to deter the invasion of pathogenic bacteria. The human skin contains microbes that reside either in or on the skin and can be residential or transient. Resident microorganism types vary in relation to skin type on the human body. A majority of bacteria reside on superficial cells on the skin or prefer to associate with glands. These glands such as oil or sweat glands provide the bacteria with water, amino acids, and fatty acids that provide nutrients for the microbes. In addition, resident bacteria can be pathogenic and are characteristically gram positive bacteria. Certain gram positive bacteria can be associated with oil glands that play a role in acne and skin disease. Moreover, human 6) ___ is by nature odorless, but bacteria associated with the skin play a role in producing body odor. Researchers at Wageningen University in Netherlands discovered that humans with a large number of bacteria that possess a low level of diversity are more attractive to a particular species of mosquito. The experiments were conducted with Anopheles gambiae sensu stricto mosquito, which are associated with malaria.

 

Bacteria make up most of the flora in the colon and 60% of the dry mass of feces. This fact makes feces an ideal source to test for gut flora for any tests and experiments by extracting the nucleic acid from fecal specimens, and bacterial 16S rRNA gene sequences are generated with bacterial primers. This form of testing is also often preferable to more invasive techniques, such as biopsies. Somewhere between 300 and 1000 different species live in the 7) ___, with most estimates at about 500. However, it is probable that 99% of the bacteria come from about 30 or 40 species. Fungi and protozoa also make up a part of the gut flora, but little is known about their activities.

Research suggests that the relationship between gut flora and humans is not merely commensal (a non-harmful coexistence), but rather is a mutualistic, symbiotic relationship. Though people can survive with no gut 8) ___, the microorganisms perform a host of useful functions, such as fermenting unused energy substrates, training the immune system, preventing growth of harmful species, regulating the development of the gut, producing vitamins for the host (such as biotinand vitamin K), and producing hormones to direct the host to store fats. Extensive modification and imbalances of the gut microbiota and its microbiome or gene collection are associated with obesity. However, in certain conditions, some species are thought to be capable of causing disease by causing infection or increasing cancer risk for the host.

 

On 13 June 2012, a major milestone of the Human Microbiome Project (HMP) was announced by the NIH director Francis Collins. The announcement was accompanied with a series of coordinated articles published in Nature and several journals in the Public Library of Science (PLoS) on the same day. By mapping the normal microbial make-up of healthy humans using genome sequencing techniques, the researchers of the HMP have created a reference database and the boundaries of normal microbial variation in 9) ___.

 

From 242 healthy U.S. volunteers, more than 5,000 samples were collected from tissues from body sites such as mouth, nose, skin, lower intestine (stool) and vagina. All the DNA, human and microbial, were analyzed with DNA sequencing machines. The microbial genome data were extracted by identifying the bacterial specific ribosomal RNA,16S rRNA. The researchers calculated that more than 10,000 microbial species occupy the human ecosystem and they have identified 81 – 99% of the genera. In addition to establishing the human 10) ___ reference database, the HMP project also discovered several “surprises“, which include:

 

1.    Microbes contribute more genes responsible for human survival than humans’ own genes. It is estimated that bacterial protein-coding genes are 360 times more abundant than human genes.

2.    Microbial metabolic activities; for example, digestion of fats; are not always provided by the same bacterial species. The presence of the activities seems to matter more.

3.    Components of the human microbiome change over time, affected by a patient disease state and 11) ___. However, the microbiome eventually returns to a state of equilibrium, even when the composition of bacterial types has changed.

 

Clinical Application

 

Among the first clinical applications utilizing the HMP data, as reported in several PLoS papers, the researchers found a shift to less species diversity in vaginal microbiome of pregnant women in preparation for birth, and high viral DNA load in the nasal microbiome of children with unexplained fevers. Other studies using the HMP data and techniques include role of microbiome in various diseases in the digestive tract, skin, reproductive organs and childhood disorders.

 

The Human Microbiome Project (HMP) is a United States National Institutes of Health initiative with the goal of identifying and characterizing the microorganisms which are found in association with both healthy and diseased humans (the Human microbiome). Launched in 2008, it is a five-year project, best characterized as a feasibility study, and has a total budget of $115 million. The ultimate goal of this and similar NIH-sponsored microbiome projects is to test how changes in the human microbiome are associated with human health or disease. This topic is currently not well understood.

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Total microbial cells found in association with humans may exceed the total number of cells making up the human body by a factor of ten-to-one. The total number of genes associated with the human microbiome could exceed the total number of human genes by a factor of 100-to-one. Many of these organisms have not been successfully cultured, identified, or otherwise characterized. Organisms expected to be found in the human microbiome, however, may generally be categorized as 12) ___ (the majority), members of domain Archaea, yeasts, and single-celled eukaryotes as well as various helminthparasites and viruses, the latter including viruses that infect the cellular microbiome organisms (e.g., bacteriophages, the viruses of bacteria).

 

The HMP will address some of the most inspiring, vexing and fundamental scientific questions today. Importantly, it also has the potential to break down the artificial barriers between medical microbiology and environmental microbiology. It is hoped that the HMP will not only identify new ways to determine health and predisposition to diseases but also define the parameters needed to design, implement and monitor strategies for intentionally manipulating the human microbiota, to optimize its performance in the context of an individual’s physiology.

 

The HMP includes the following goals:

1.    To develop a reference set of microbial genome sequences and to perform preliminary characterization of the human microbiome

2.    To explore the relationship between disease and changes in the human microbiome

3.    To develop new technologies and tools for computational analysis

4.    To establish a resource repository

5.    To study the ethical, legal, and social implications of human microbiome research

 

ANSWERS: 1) fungi; 2) body; 3) disease; 4) sugars; 5) cells; 6) sweat; 7) gut; 8) flora; 9) humans; 10) microbiome; 11) medication; 12) bacteria

Helicobacter pylori

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A team of researchers from Boston University, Harvard Medical School and Massachusetts Institute of Technology have shown that the bacterium that causes human stomach ulcers uses a clever biochemical strategy to alter the physical properties of its environment, allowing it to move and survive and further colonize its host. Contact with stomach acid keeps the mucin lining the epithelial cell layer in a spongy gel-like state. This consistency is impermeable to the bacterium Heliobacter pylori. However, the bacterium releases urease which neutralizes the stomach acid. This causes the mucin to liquefy, and the bacterium can swim right through it.

 

 

Helicobacter pylori may be the most successful pathogen in human history. While not as deadly as the bacteria that cause tuberculosis, cholera, and the plague, it infects more people than all the others combined.  This bacterium occupies half the stomachs on earth.

 

Helicobacter pylori migrated out of Africa along with its human host circa 60,000 years ago; however, it coexisted for hundreds of millions of years from the earlier evolution of Australopithecus to the present. Its subsequent evolution created seven prototypes from Europe, the Middle East, , NE Africa, Africa (2), Asia (2). The precursors of these prototypes have been named ancestral Europe1, ancestral Europe2, ancestral East Asia, ancestral Africa1, ancestral Africa2 and ancestral Sahul. These ancestral prototypes appear to have originated in Africa, Central and East Asia. European and African strains were introduced into the Americas along with its colonization – both thousands of years ago and more recently – the slave trade.

 

Recent research states that genetic diversity in H. pylori increases with geographic distance from East Africa, the birthplace of modern humans. Using the genetic diversity data, the researchers have created simulations that indicate the bacteria seem to have spread from East Africa around 58,000 years ago. Their results indicate modern humans were already infected by H. pylori before their migrations out of Africa, and it has remained associated with human hosts since that time.

 

Helicobacter pylori was first discovered in the stomachs of patients with gastritis and stomach ulcers in 1982 by Dr. Barry Marshall and Dr. Robin Warren of Perth, Western Australia. At the time, the conventional thinking was that no bacterium can live in the human stomach, as the stomach produced extensive amounts of acid of a strength similar to the acid found in a car battery. Marshall and Warren rewrote the textbooks with reference to what causes gastritis and gastric ulcers. In recognition of their discovery, they were awarded the 2005 Nobel Prize in Physiology or Medicine.

 

Previous to the research of Marshall and Warren, German scientists found spiral-shaped bacteria in the lining of the human stomach in 1875, but they were unable to culture it, and the results were eventually forgotten. The Italian researcher Giulio Bizzozero described similarly shaped bacteria living in the acidic environment of the stomach of dogs in 1893. Professor Walery Jaworski of the Jagiellonian University in Krakow investigated sediments of gastric washings obtained from humans in 1899. Among some rod-like bacteria, he also found bacteria with a characteristic spiral shape, which he called Vibrio rugula. He was the first to suggest a possible role of this organism in the pathogenesis of gastric diseases. This work was included in the Handbook of Gastric Diseases, but it had little impact, as it was written in Polish. Several small studies conducted in the early 20th century demonstrated the presence of curved rods in the stomach of many patients with peptic ulcers and stomach cancer. Interest in the bacteria waned, however, when an American study published in 1954 failed to observe the bacteria in 1180 stomach biopsies.

 

Interest in understanding the role of bacteria in stomach diseases was rekindled in the 1970s, with the visualization of bacteria in the stomach of gastric ulcer patients. The bacterium had also been observed in 1979, by Australian pathologist Robin Warren, who did further research on it with Australian physician Barry Marshall beginning in 1981. After numerous unsuccessful attempts at culturing the bacteria from the stomach, they finally succeeded in visualizing colonies in 1982, when they unintentionally left their Petri dishes incubating for 5 days over the Easter weekend. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by infection by this bacterium and not by stress or spicy food, as had been assumed before.

 

Although there was some skepticism initially, within several years numerous research groups verified the association of H. pylori with gastritis and, to a lesser extent, ulcers. To demonstrate H. pylori caused gastritis and was not merely a bystander, Marshall drank a beaker of H. pylori culture. He became ill with nausea and vomiting several days later. An endoscopy ten days after inoculation revealed signs of gastritis and the presence of H. pylori. These results suggested H. pylori was the causative agent of gastritis. Marshall and Warren went on to demonstrate that antibiotics are effective in the treatment of many cases of gastritis. In 1987, the Sydney gastroenterologist Thomas Borody invented the first triple therapy for the treatment of duodenal ulcers. In 1994, the National Institutes of Health (USA) published an opinion stating most recurrent duodenal and gastric ulcers were caused by H. pylori, and recommended antibiotics be included in the treatment regimen.

 

Over human evolution, H. pylori has adapted to humans, colonizing children and persisting throughout life. Most strains possess factors that subtly modulate the host environment, increasing the risk of peptic ulceration, gastric adenocarcinoma, and possibly other diseases. H. pylori genes encoding these and other factors rapidly evolve through mutation and recombination, changing the bacteria-host interaction. Although immune and physiologic responses to H. pylori also contribute to pathogenesis, humans have evolved in concert with the bacterium, and its recent absence throughout the life of many individuals has led to new human physiological changes. These may have contributed to recent increases in esophageal adenocarcinoma and, more speculatively, other modern diseases.

 

At least half the world’s population are infected by the bacterium, making it the most widespread infection in the world. Actual infection rates vary from nation to nation; the developing world has much higher infection rates than the West (Western Europe, North America, Australasia), where rates are estimated to be around 25%. The age at which this bacterium is acquired seems to influence the possible pathologic outcome of the infection. People infected with it at an early age are likely to develop more intense inflammation that may be followed by atrophic gastritis with a higher subsequent risk of gastric ulcer, gastric cancer or both. Acquisition at an older age brings different gastric changes more likely to lead to duodenal ulcer. Infections are usually acquired in early childhood in all countries. However, the infection rate of children in developing nations is higher than in industrialized nations, probably due to poor sanitary conditions. In developed nations it is currently uncommon to find infected children, but the percentage of infected people increases with age, with about 50% infected for those over the age of 60 compared with around 10% between 18 and 30 years. The higher prevalence among the elderly reflects higher infection rates when they were children rather than infection at later ages. In the United States, prevalence appears to be higher in African-American and Hispanic populations, most likely due to socioeconomic factors. The lower rate of infection in the West is largely attributed to higher hygiene standards and widespread use of antibiotics. Despite high rates of infection in certain areas of the world, the overall frequency of H. pylori infection is declining. However, antibiotic resistance is appearing in H. pylori; there are already many metronidazole- and clarithromycin-resistant strains in most parts of the world.

 

The historical origins H. pylori dating back to the halcyon epoch of microbe hunting in the late 19th and early 20th centuries is summarized below.

 

1.    1875: bacteria were discovered in the floor and margins of gastric ulcers by Bottcher and Letulle. First hypothesis that bacteria caused ulcer disease.

2.    1889: “spiral“ bacterium were found in gastric aspirations by Jaworski.

3.    1893: spirochetes were noted by Bizzozero in the gastric mucosa (infiltrating gastric glands and found within the cytoplasm and vacuoles of parietal cells) of dogs. These organisms were named Helicobacter bizzozeronii in 1996.

4.    1896: Mice successfully infected with H. bizzozeronii by Salomon.

5.    1906: Krienitz noted spirochetes in the gastric aspiration of a stomach cancer patient.

6.    1921: Edkins (the discoverer of gastrin in 1905) investigated the physiology of Helicobacter felis in the cat.

7.    1938: the association between spirochetes and gastric inflammation was noted in the Macacus monkey and in man by Doenges.

8.    1940: Freedberg and Barron “confirmed“ that this organism had no etiologic role in gastric disease in man.

9.    1940: The hypothesis that an “acidophilic bacteria“ caused ulcer disease was first postulated by Gorham.

10.  1979: Campylobacter pylori was identified as a putative causative agent of human gastritis by Warren.

11.  1983: C. pylori was isolated and cultured by Marshall.

12.  1985-1987: Ingestion of C. pylori was demonstrated to cause gastritis in human volunteers.

13.  1994: NIH concludes that there is a strong association between H. pylori and ulcer disease.

14.  1994: The IARC, part of the WHO classifies H. pylori as a group I carcinogen.

15.  1997: Genome of H. pylori released by TIGR.

 

Mounting evidence suggests that H. pylori has an important role in protecting humans from some diseases. The incidence of acid reflux disease, Barrett’s esophagus, and esophageal cancer have been rising dramatically at the same time as H. pylori’s presence decreases. In 1996, Martin J. Blaser advanced the hypothesis that H. pylori has a beneficial effect: by regulating the acidity of the stomach contents. The hypothesis is not universally accepted as several randomized controlled trials failed to demonstrate worsening of acid reflux disease symptoms following eradication of H. pylori. Nevertheless, Blaser has refined his view to assert that H. pylori is a member of the normal flora of the stomach. He postulates that the changes in gastric physiology caused by the loss of H. pylori account for the recent increase in incidence of several diseases, including type 2 diabetes, obesity, and asthma. His group has recently shown that H. pylori colonization is associated with a lower incidence of childhood asthma.

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H. pylori colonized on the surface of regenerative epithelium (Warthin-Starry’s silver).

First Genomic Survey of Human Skin Fungal Diversity

 

Human skin surfaces are complex ecosystems for microorganisms, including fungi, bacteria and viruses, which are known collectively as the skin microbiome. Although fungal infections of the skin affect about 29 million people in the US, fungi can be slow and hard to grow in laboratories, complicating diagnosis and treatment of even the most common fungal skin conditions, such as toenail infections.

 

While humans have harnessed the power of yeast to ferment bread and beer, the function of yeast or other types of fungi that live in and on the human body is not well understood. In the first study of human fungal skin diversity, NIH researchers sequenced the DNA of fungi at skin sites of healthy adults to define the normal populations across the skin and to provide a framework for investigating fungal skin conditions.

 

The research team from the National Human Genome Research Institute (NHGRI) and the National Cancer Institute (NCI), both parts of NIH, extended their recent genome sequencing study of skin bacteria, using DNA sequencing techniques optimized for identifying fungi. The study appears in the May 22, 2013 early online issue of Nature.

 

The study found that a single type of fungus, belonging to the genus Malassezia, is predominant on the head and trunk and hands, which harbor a great diversity of bacteria, are home for relatively few types of fungi. In contrast, feet, including toenails, heels and toe webs contain tremendous diversity.

 

“Applying DNA sequencing to a study of the skin’s fungi is the natural progression in understanding microbial life that co-exists on our bodies,“ said NHGRI Scientific Director Daniel Kastner, M.D., Ph.D. “Along with recent genome sequencing to define bacterial diversity, this analysis of fungal diversity provides a more complete human microbiome picture.“

 

The researchers collected samples at 14 body sites from 10 healthy adults. DNA sequencing of the fungi in the samples identified fragments of DNA, called phylogenetic markers, which can be counted and used to distinguish one type of fungus from another. The sequencing efforts generated more than 5 million markers, from the samples, representing more than 80 fungal types, or genera. In contrast, traditional culturing methods produced 130 colonies of fungi that represented only 18 fungal genera.

 

In 20% of the study participants, the study observed problems such as heel and toe web scaling or toenail changes consistent with possible fungal infections. From genome sequencing analysis, it was found that different individuals with heel site infections have common fungal communities at that site, while those with toenail infections display tremendously different fungal communities. Fungi from two phyla, Ascomycetes and Basidiomycetes, were identified as part of the normal fungal census at the 14 skin sites. The most common genus Malassezia was present in 11 of 14 sites sampled on the body. The study found Malassezia fungus on every skin surface of healthy volunteers, whether on the back of the head, behind the ears, in nostrils and on the heels. Heels were also home to many additional fungi, including the genera Aspergillus, Cryptococcus, Rhodotorula, and Epicoccum.

 

The most complex site, the heel, is home to about 80 genus-level types of fungi. The study found about 60 types in toenail swab samples and 40 types in samples from the webs of the toes. Sites with moderate fungal diversity are inside the bend of the arm, inside of the forearm and palm, with each location supporting 18 to 32 genera of fungi. Surprisingly, head and trunk body sites — including the back, back of the neck, inside the ears, behind the ears, and between the eyebrows — have far fewer fungi types, with just two to 10 genera each.

 

The research team compared fungal diversity data with the skin bacteria on the same healthy adults. They found that while arms have high measures of bacterial diversity, they have lower fungal diversity. They found the reverse to be true for sites on the feet. Core body sites had neither a high bacterial diversity nor a high fungal diversity. The researchers had previously shown that bacterial diversity can be predicted by whether skin is moist, dry or oily. Fungal diversity, instead, seems to depend upon where a particular skin site is on the body. In addition, it was observed that there is greater similarity in the fungal community structure on the left and right sides of the same person’s body compared to the same body parts on any two individuals. Fungal communities also appear to be quite stable over time, with little change when tested on two separate occasions, up to three months apart.

 

Click here for fluorescent microscope images of fungi on the skin.

Propionibacterium acnes Strain Populations in the Human Skin Microbiome Associated with Acne

 

The human skin microbiome has important roles in skin health and disease. However, bacterial population structure and diversity at the strain level is poorly understood. As a result, a study published online in the Journal of Investigative Dermatology (28 February 2013) compared the skin microbiome at the strain level and genome level of Propionibacterium acnes, a dominant skin commensal, between 49 acne patients and 52 healthy individuals by sampling the pilosebaceous units on their noses. Metagenomic analysis demonstrated that although the relative abundances of P. acnes were similar, the strain population structures were significantly different in the two cohorts. Certain strains were highly associated with acne, and other strains were enriched in healthy skin. By sequencing 66 previously unreported P. acnes strains and comparing 71 P. acnes genomes, the study identified potential genetic determinants of various P. acnes strains in association with acne or health. The analysis suggested that acquired DNA sequences and bacterial immune elements may have roles in determining virulence properties of P. acnes strains, and some could be future targets for therapeutic interventions. This study demonstrated a previously unreported paradigm of commensal strain populations that could explain the pathogenesis of human diseases and underscores the importance of strain-level analysis of the human microbiome to define the role of commensals in health and disease.

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

 

FDA Approves Two Drugs, Companion Diagnostic Test for Advanced Skin Cancer

 

Melanoma is the leading cause of death from skin disease. The National Cancer Institute estimates 76,690 Americans will be diagnosed with melanoma and 9,480 will die from the disease in 2013.

 

The FDA has approved two new drugs, Tafinlar (dabrafenib) and Mekinist (trametinib), for patients with advanced (metastatic) or unresectable (cannot be removed by surgery) melanoma, the most dangerous type of skin cancer.

 

Tafinlar, a BRAF inhibitor, is approved to treat patients with melanoma whose tumors express the BRAF V600E gene mutation. Mekinist, a MEK inhibitor, is approved to treat patients whose tumors express the BRAF V600E or V600K gene mutations. Approximately half of melanomas arising in the skin have a BRAF gene mutation. Tafinlar and Mekinist are being approved as single agents, not as a combination treatment. Zelboraf (vemurafenib) and Yervoy (ipilimumab) were approved in 2011 for the treatment of metastatic or unresectable melanoma.

 

The FDA approved Tafinlar and Mekinist with a genetic test called the THxID BRAF test, a companion diagnostic that will help determine if a patient’s melanoma cells have the V600E or V600K mutation in the BRAF gene.

 

The FDA’s approval of the THxID BRAF test is based on data from clinical studies that support the Tafinlar and Mekinist approvals. Samples of patients’ melanoma tissue were collected to test for the mutation.

 

Tafinlar was studied in 250 patients with BRAF V600E gene mutation-positive metastatic or unresectable melanoma. Patients were randomly assigned to receive Tafinlar or the chemotherapy drug dacarbazine. Patients who took Tafinlar had a delay in tumor growth that was 2.4 months later than those receiving dacarbazine.

 

The most serious side effects reported in patients receiving Tafinlar included an increased risk of skin cancer (cutaneous squamous cell carcinoma), fevers that may be complicated by hypotension (low blood pressure), severe rigors (shaking chills), dehydration, kidney failure and increased blood sugar levels requiring changes in diabetes medication or the need to start medicines to control diabetes.

 

The most common side effects reported in patients receiving Tafinlar included thickening of the skin (hyperkeratosis), headache, fever, joint pain, non-cancerous skin tumors, hair loss and hand-foot syndrome.

 

Mekinist was studied in 322 patients with metastatic or unresectable melanoma with the BRAF V600E or V600K gene mutation. Patients were randomly assigned to receive either Mekinist or chemotherapy. Patients receiving Mekinist had a delay in tumor growth that was 3.3 months later than those on chemotherapy. Patients who previously used Tafinlar or other inhibitors of BRAF did not appear to benefit from Mekinist.

 

The most serious side effects reported in patients receiving Mekinist included heart failure, lung inflammation, skin infections and loss of vision. Common side effects included rash, diarrhea, tissue swelling (peripheral edema) and skin breakouts that resemble acne.

 

Women of child bearing years should be advised that Tafinlar and Mekinist carry the potential to cause fetal harm. Men and women should also be advised that Tafinlar and Mekinist carry the potential to cause infertility.

 

Tafinlar and Mekinist are marketed by GlaxoSmithKline, based in Research Triangle Park, N.C. The THxID BRAF Kit is manufactured by bioMerieux of Grenoble, France. Yervoy is marketed by New York City-based Bristol-Myers Squibb, and Zelboraf is marketed by South San Francisco-based Genentech, a member of the Roche Group.

Salmon Patties with Tartar Sauce

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These salmon patties were such a success, my husband started eating the leftovers for breakfast! I’m making them again, this Monday, and will double the recipe, so he can eat them to his heart’s content. He works so hard and travels so much, my heart sings when something makes him happy. I guess you’d call this a “good marriage.” J

 

Ingredients

 

 

1 pound salmon fillet, cleaned, then steamed for 5 minutes or baked in preheated oven (350 degrees) for 8 minutes.

1/3 Cup almond flour

1/2 Cup wheat germ

2 eggs, beaten

Fresh dill, chopped (use to your taste)

1 onion, chopped

1 garlic clove, juice

1/2 teaspoon turmeric

1/2 red bell pepper, chopped (You can use green, yellow or orange if you prefer.)

Zest and juice from 1 large lemon (I used Meyer lemons)

Pinch sea salt

Pinch fresh ground pepper

Olive oil for cooking

 

Directions

 

1.    Make the tartar sauce first and let it sit in fridge for two hours. When tartar sauce is ready to take out, start making the salmon patties.

2.    Put the cooked salmon into a large bowl, using a fork to break apart. Not only are you breaking the fish up, but look for any bones and take them out.

3.    Add the almond flour, wheat germ, turmeric, salt, and pepper. Mix these dry ingredients, into the fish.

4.    In a separate, small bowl, lightly beat eggs.

5.    Into the salmon mixture, mix in the eggs, lemon zest and juice; stir well. Add the onions, garlic juice, fresh dill and peppers.

6.    In a large cast iron pan or your favorite heavy pan, heat oil until very hot, but not smoking. You only want about 1/4 inch of oil in the pan,

7.    Make patties in the palm of your hand, and using a pancake turner, very carefully place the patties in the hot oil. Cook for about 2-3 minutes on one side, then flip over (again, very carefully!) and cook the other side for 2-3 minutes more. Remove cooked patties from oil and place on paper towels to drain.

8.    Sprinkle some extra fresh dill on top of the patties and serve with the Tartar Sauce

 

Quick Tartar Sauce

 

1-1/2 Cup Kraft mayonnaise (my favorite store bought mayo)

1 large dill pickle, well chopped

1/2 sweet onion, chopped

1/2 teaspoon dry mustard

2 teaspoons fresh parsley, well chopped

1/8 teaspoon paprika

1/2-1 teaspoon fresh-squeezed lemon juice (to taste)

 

Directions

 

Mix all ingredients in a bowl. Cover and place in refrigerator for 2 hours. Serve with the Salmon Patties.

 

I actually made a special yogurt sauce for these salmon patties that didn’t turn out well at all, so I’m not sharing it. If I can put together a sauce that works, I will definitely post it. I did serve the patties with our favorite fragrant jasmine rice and a tossed salad, with tomatoes, avocados, endive, green olives, thin skin cucumbers (you can eat the delicate skin) and extra virgin olive oil with fresh lemon juice, dressing. We tried a new ros? wine from Provence (91 pts) that we loved, called Miraval. Life is good!

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Enjoy!

 

Dry rose is popular, particularly during the summer months. Its style, traditionally dry and light, appeals both to white and red wine drinkers seeking something cool and refreshing to help beat the heat. Winemakers produce ros? by preventing the red grapes from extended contact with the juice which gives red wines their robust flavor and tannic structure or as a result of the saignee process. The Mediterranean nations, most notably France, Italy and Spain, reign supreme in rose production, but an increasing number of American wineries have begun producing world-class rose wines.

Target Health (www.targethealth.com) a full service e*CRO, is committed to serve the pharmaceutical community through knowledge, experience, technology and connectivity. Target Health strives to optimize the life cycle of drugs, biologics and devices with expertise, leadership, innovation and teamwork. Target Health Inc. has fulltime staff dedicated to all aspects of Regulatory Affairs, Clinical Research, Biostatistics, Data Management, Strategic Planning and Drug and Device Development. Target Health is committed to the paperless clinical trial and has developed a full suite of eClinical Trial software including:

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7) Target Newsletter®

8) Target e*CTR™ (eSource, electronic medical record for clinical trials).

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