Merck Serono Has Named Dr. John Orloff as Head of Global Clinical Development
Our friend and colleague Dr. John Orloff has joined Merck Serono as Head of Global Clinical Development. We wish him success in his new position.
At Merck Serono, Dr. Orloff will lead the design and execution of global clinical development programs and projects, driving quality execution of the projects after proof-of-concept (POC). John will also oversee pipeline management and development, working collaboratively with the research teams, commercial partners and Medical Affairs to drive the efficient development of Merck’s portfolio.
Dr. Orloff comes from Novartis Pharma AG, where he was Senior Vice President and Chief Medical Officer, responsible for leading all processes within Global Development as well as ensuring quality control and regulatory compliance, and driving innovative solutions to support business needs. Previous to that position at Novartis, Dr. Orloff was Senior Vice President and Head, US Medical & Regulatory Affairs, serving on the executive leadership front across Clinical Development, Medical Affairs, and Evidence-based Medicine (Health Economics and Outcomes Research) for the US organization, as well as Regulatory Affairs for North America. Prior to Novartis, Dr. Orloff was Senior Director of the Bone Group, Endocrinology & Metabolism at Merck Research Labs, supporting clinical development of products for bone related disorders including osteoporosis and arthritis.
Dr. Orloff received his undergraduate degree from Dartmouth College, and his MD from the University Of Vermont College Of Medicine. He completed his residency at the University of Pittsburgh, and started his career in academic medicine at Yale University as a Fellow in Endocrinology & Metabolism.
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Deep Sequencing of Breast Cancer Tumors Predict Outcomes After Single Dose of Therapy
High-tech glasses developed at the School of Medicine help breast surgeon Julie Margenthaler, MD, visualize cancer cells in a patient. Inset: Still image from a video of the lymph node removal, as seen by Margenthaler as she wore the eyewear. A florescent marker injected into the patient and special lighting made cancer cells glow blue when viewed with the technology. The lighter the shade of blue, the more concentrated the cancer cells are. Credit: Photo by Robert Boston / Image courtesy of Washington University School of Medicine
New research from University Hospitals (UH) Case Medical Center Seidman Cancer Center and Case Comprehensive Cancer Center at Case Western Reserve University examined how changes in the genetic composition of breast cancer 1) ___ after brief exposure to either biologic therapy or chemotherapy can predict future clinical outcomes in patients. Results showed that through deep genome sequencing, a reduction in the most commonly mutated genes in breast cancer could be observed after just one dose of preoperative therapy. Deep sequencing is a process that involves sequencing the same region multiple times to identify mutations within tumors that have an importance in 2) ___ evolution. These new findings were presented during the December 2013 San Antonio Breast Cancer Symposium.
Genomics is the new frontier of cancer research, and this study shows that we may be able to accurately determine what treatment methods will and will not be effective for individual patients after just one dose of3) ___, said Lyndsay Harris, MD, study investigator and Director, Breast Cancer Program, UH Seidman Cancer Center and Professor of Medicine at Case Western Reserve University School of Medicine. The ability to understand potential clinical outcomes for patients earlier in the treatment process would provide physicians with better opportunity to personalize patients’ medicines according to their own tumor responses.
More than 209,000 patients in the U.S. are diagnosed with breast cancer each year. The anticipated outcome of studying the genetic makeup of breast cancer patients is to determine who will benefit most from certain drug therapies and to use that information to create a personalized treatment plan for each 4) ___ involved. Dr. Harris and team are currently integrating whole genome profiles with deep sequencing data as they spearhead a new study at UH Seidman Cancer Center to validate these initial findings presented in San Antonio.
By studying the genetic makeup of breast cancer patients, doctors are taking the next steps forward in delivering more personalized care to patients. Whole genome sequencing from cancers is not a new concept, but recently researchers have delved more deeply into the evolution of breast cancers identifying that it comes in four distinct types. Breaking down how the 5) ___ of each sub-type of the disease function is allowing for doctors to customize treatments for improved outcomes. Even more promising, clinical research trials at a few select institutions around the country, including Cleveland’s University Hospitals Case Medical Center Seidman Cancer Center, are part of a development in a rising trend toward targeted treatments as a result of 6) ___ profiling of tumors.
The knowledge of the molecular underpinnings of a particular kind of breast cancer can improve the cure rates and even in the advanced disease setting improve quality of life and length of life, says Lyndsay Harris, MD. The cure of the disease is really our goal, and we are moving quickly toward a time when we can expect to cure the vast majority of 7) ___ who are diagnosed with breast cancer at the earliest stages. Source: University Hospitals Case Medical Center, Cleveland, OH and San Antonio, TX; ScienceDaily.com
ANSWERS: 1) tumors; 2) cancer; 3) medicine; 4) patient; 5) cells; 6) genomic; 7) women
King Richard III (1452-1485) Sequencing His Genome in 2014
Now is the winter of our discontent
Made glorious summer by this sun of York;
And all the clouds that lour’d upon our house
In the deep bosom of the ocean buried
—–William Shakespeare, written around 1592
The earliest surviving portrait of Richard III (c. 1520, after a lost original), formerly belonging to the Paston family. Society of Antiquaries, London)
Richard III was King of England for two years, from 1483 until his death in 1485 in the Battle of Bosworth Field. He was the last king of the House of York and the last of the Plantagenet dynasty. His defeat at Bosworth Field, the last decisive battle of the Wars of the Roses, symbolizes the end of the Middle Ages in England. He is the subject of the play Richard III by William Shakespeare. At the time of the death of his father and older brother, at the Battle of Wakefield in 1460, Richard, who was eight years old, was sent by his mother, the Duchess of York, to the Low Countries, accompanied by his elder brother George. At this time Richard was named Duke of Gloucester as well as being made a Knight of the Garter and a Knight of the Bath. Richard was then sent to Warwick’s estate at Middleham for his knightly training. Richard stayed at Middleham until early 1465, when he was twelve. During his adolescence, he developed idiopathic scoliosis.
Richard became involved in the rough politics of the Wars of the Roses at an early age. His brother, Edward appointed him the sole Commissioner of Array for the Western Counties in 1464, when he was 11. By the age of 17, he had an independent command. At 18 years, Richard played crucial roles in battles that resulted in Edward’s restoration to the throne in spring 1471.
Polydore Vergil and Thomas More write about King Richard, emphasizing Richard’s outward physical deformities as a sign of his inwardly twisted mind. More describes him as little of stature, ill-featured of limbs, crook-backed and hard-favored of visage. Vergil also says he was deformed of body with one shoulder higher than the right. Both emphasize that Richard was devious and flattering, while planning the downfall of both his enemies and supposed friends. Richard’s good qualities were his cleverness and bravery. All these characteristics are repeated by Shakespeare, who portrays him as having a hunch, a limp and a withered arm.
During Richard’s reign, the historian John Rous praised him as a good lord who punished oppressors of the commons, adding that he had a great heart. After his death, Richard’s image was tarnished by propaganda fostered by his Tudor successors (who sought to legitimize their claim to the throne). Richard’s reputation as a promoter of legal fairness persisted, however. William Camden in his Remains Concerning Britain (1605) states that Richard, albeit he lived wickedly, made good laws. Francis Bacon also states that he was a good lawmaker for the ease and solace of the common people. Despite this, the image of Richard as a ruthless power-grabber remained dominant in the 18th and 19th centuries.
Richard’s Council of the North, greatly improved conditions for Northern England, as commoners of that region were formerly without any substantial economic activity independent of London. Its descendant position was Secretary of State for the Northern Department. In December 1483, Richard instituted what later became known as the Court of Requests, a court to which poor people who could not afford legal representation could apply for their grievances to be heard. He also introduced bail in January 1484, to protect suspected felons from imprisonment before trial and to protect their property from seizure during that time. He founded the College of Arms in 1484, he banned restrictions on the printing and sale of books, and he ordered the translation of the written Laws and Statutes from the traditional French into English.
Richard III’s remains received burial without pomp, but the original tomb is believed to have been destroyed during the Reformation, and the remains were lost for more than five centuries. In 2012, an archaeological excavation was conducted on a city council car park using ground-penetrating radar on the site once occupied by Greyfriars, Leicester. The University of Leicester confirmed on 4 February 2013 that a skeleton found in the excavation was, beyond reasonable doubt, that of Richard III. This conclusion was based on a combination of evidence from radiocarbon dating, comparison with contemporary reports of his appearance, and a comparison of his mitochondrial DNA with that of two matrilineal descendants of Richard III’s eldest sister, Anne of York. The genomes of King Richard III and one of his family’s direct living descendants are to be sequenced in a project funded by the Wellcome Trust, the Leverhulme Trust and Professor Sir Alec Jeffreys. The project will be led by Dr Turi King of the Department of Genetics at the University of Leicester. The aim is to shed new light on the ancestry and health of the last king of England to die in battle, and provide a complete archive of information that historians, scientists and the public will be able to access and use. His remains and any samples taken from them are scheduled to be reinterred and for this reason, Dr Turi King and colleagues plan to sequence his genome and make it freely accessible as a resource to researchers wishing to analyze and interrogate its genetic information.
Richard III will be one of only a small number of ancient individuals to have had their genomes sequenced. Others include Otzi the Iceman, Neanderthal specimens, a Denisovan and a Greenlandic Inuit and a hunter gatherer from Spain. Richard III will be the first ancient individual of known identity to have his genome sequenced. This will be carried out in collaboration with Professor Michael Hofreiter at the University of Potsdam.
Analysis of Richard III’s genome will allow insight into his genetic make-up, including susceptibility to certain diseases, hair and eye color, and as the genetic basis of other diseases becomes known, these too can be examined for. It is also expected to shed light on his genetic ancestry and relationship to modern human populations. In addition, next generation sequencing technologies will allow the researchers to detect DNA from other organisms such as pathogens. Whole genome sequencing from Otzi the Iceman found the first known human infection with Lyme disease, for example.
Dr King says: It is an extremely rare occurrence that archaeologists are involved in the excavation of a known individual, let alone a king of England. At the same time we are in the midst of a new age of genetic research, with the ability to sequence entire genomes from ancient individuals and with them, those of pathogens that may have caused infectious disease. Sequencing the genome of Richard III is a hugely important project that will help to teach us not only about him, but foment discussion about how our DNA informs our sense of identity, our past and our future. In addition to sequencing the remains of Richard III, Dr King and colleagues will also sequence one of his living relatives, Michael Ibsen. An initial analysis of the DNA of his mitochondria — the batteries that power the cells in our bodies — which is passed down the maternal line, confirmed the genealogical evidence that Ibsen and Richard III shared the same lineage. A more detailed analysis is due to be published shortly. This new project will allow researchers to look for any other segments of DNA that these distant relatives share.
Researchers based at the University of Cambridge and the University of Leicester have also uncovered evidence that Richard III suffered from a roundworm (Ascaris lumbricoides) infection, according to a Clinical Picture published in The Lancet. A team of researchers led by Dr Piers Mitchell, of the Department of Archaeology and Anthropology at the University of Cambridge, UK, used a powerful microscope to examine soil samples taken from the skeleton’s pelvis and skull, as well as from the soil surrounding the grave. The microscope revealed multiple roundworm eggs in the soil sample taken from the pelvis, where the intestines would have been situated in life. However, there was no sign of eggs in soil from the skull, and very few eggs in the soil that surrounded the grave, suggesting that the eggs found in the pelvis area resulted from a genuine roundworm infection during his life, rather than from external contamination by the later dumping of human waste in the area.
Roundworms are parasitic nematodes, which infect humans when people ingest their eggs via contaminated food, water, or soil. Once eaten, the eggs hatch into larvae, which migrate through the tissues of the body to the lungs where they mature. They then crawl up the airways to the throat to be swallowed back into the intestines, where they can grow into adults around a foot long. Roundworm infection is thought to be one of the commonest health conditions in the world, affecting up to a quarter of all people globally, although it is rare in the UK today.
According to Dr Mitchell, Our results show that Richard was infected with roundworms in his intestines, although no other species of intestinal parasite were present in the samples we studied. We would expect nobles of this period to have eaten meats such as beef, pork and fish regularly, but there was no evidence for the eggs of the beef, pork or fish tapeworm. This may suggest that his food was cooked thoroughly, which would have prevented the transmission of these parasites. Dr Jo Appleby, Lecturer in Human Bioarchaeology at the University of Leicester, UK, said: Despite Richard’s noble background, it appears that his lifestyle did not completely protect him from intestinal parasite infection, which would have been very common at the time.
In addition to abdominal infection, Richard III may have undergone painful medical treatments for his spinal curvature, according to research from a University of Leicester researcher. The remains of Richard III discovered by University of Leicester archaeologists revealed that the King suffered from severe scoliosis, which he probably developed in early adolescence. Scoliosis — a lateral or side-to-side curvature of the spine — can be a very painful condition to live with. Dr Mary Ann Lund, of the University’s School of English, has carried out research into the kinds of scoliosis treatments available at the time Richard III was alive. But some of the treatments practiced in the late medieval period would have themselves caused sufferers a lot of anguish. Among the cures practiced was traction — the same principle on which the Rack worked as an instrument of torture. The patient would be tied under the armpits and round the legs. The ropes were then pulled at either end, often on a wooden roller, to stretch the patient’s spine. This treatment would probably have only been available to those who could afford it. Richard III would certainly have been able to afford the highest levels of medical care available — and his physicians would have been well aware of the standard traction methods for treating the condition.
Dr Lund charted the influence of Greek philosopher Hippocrates — who developed early prototype methods of dealing with spinal disorders — to the 11th century Persian polymath Avicenna, who utilized handed down treatments from the Greeks. These treatises on medicine and philosophy were well regarded in Medieval Europe. Avicenna’s documents on using traction in scoliosis treatment would have been widely read and practiced by doctors in Richard III’s lifetime. Avicenna also advocated the massage techniques practiced in Turkish baths, and herbal applications, as treatments for back disorders. In the longer term, patients might wear a long piece of wood or metal in an attempt to straighten their back. Dr Lund said: Scoliosis is a painful illness, and Richard would have been in quite a lot of pain on a daily basis. These methods could also have been very painful — but people would have expected treatments to be unpleasant. Medical practices could exacerbate conditions rather than improving them. These treatments would have only been open to people in the upper echelons. Richard would have probably received these treatments because he was a member of the nobility.
Later methods of treatment for scoliosis included the orthosis, which was developed by French physician Ambroise Pare in the late 16th century. This was a tightly fitting metal corset for treating scoliosis made by an armourer, which would have been worn by patients to brace the skeleton in an attempt to correct the curvature of the spine. Source: The University of Leicester; ScienceDaily.com
Journal Reference: Piers D Mitchell, Hui-Yuan Yeh, Jo Appleby, Richard Buckley. The intestinal parasites of King Richard III. The Lancet, 2013; DOI: 10.1016/S0140-6736(13)
English actor David Garrick as Richard III just before the battle of Bosworth Field. His sleep having been haunted by the ghosts of those he has murdered, he wakes to the realization that he is alone in the world and death is imminent. The painting, David Garrick as Richard III (1745), is by William Hogarth. Richard III is a historical play by William Shakespeare, believed to have been written in approximately 1592. It depicts the Machiavellian rise to power and subsequent short reign of Richard III of England.
At the battle of Bosworth Field, Lord Stanley (who is also Richmond’s stepfather) and his followers desert Richard’s side, whereupon Richard calls for the execution of George Stanley, Lord Stanley’s son. This does not happen, as the battle is in full swing, and Richard is left at a disadvantage. Richard is soon unhorsed on the field at the climax of the battle, and cries out, A horse, a horse, my kingdom for a horse! Richmond kills Richard in the final duel. Subsequently, Richmond succeeds to the throne as Henry VII, and marries Princess Elizabeth from the House of York.
Regular Aspirin Use May Reduce Ovarian Cancer Risk
It is estimated that over 20,000 women in the US will be diagnosed with ovarian cancer in 2014, and more than 14,000 will die from the disease. Early stage ovarian cancer may be successfully treated. However, symptoms associated with this disease can mimic more common conditions, such as digestive and bladder disorders, so for this reason and others, it is often not diagnosed until it has reached advanced stages. Late stage ovarian cancer leaves women with limited treatment options and poor prognoses, making preventive strategies potentially important for controlling this disease.
According to an article published online (6 February 2014) in the Journal of the National Cancer Institute, women who take aspirin daily may reduce their risk of ovarian cancer by 20%. However, according to the authors, further research is needed before clinical recommendations can be made.
It has been reported that chronic or persistent inflammation has been shown to increase the risk of cancer and other diseases. Previous studies have suggested that the anti-inflammatory properties of aspirin and non-aspirin NSAIDs (non-steroidal anti-inflammatory drugs), may reduce cancer risk overall. However, studies examining whether use of these agents may influence ovarian cancer risk have been largely inconclusive. This is the largest study to date to assess the relationship between these drugs and ovarian cancer risk.
For the study, the authors analyzed data pooled from 12 large epidemiological studies to investigate whether women who used aspirin, non-aspirin NSAIDs, or acetaminophen have a lower risk of ovarian cancer. These 12 studies (9 from the US) were part of the Ovarian Cancer Association Consortium. The scientists evaluated the benefit of these drugs in nearly 8,000 women with ovarian cancer and close to 12,000 women who did not have the disease.
Results showed that among study participants who reported whether or not they used aspirin regularly: 18% used aspirin, 24% used non-aspirin NSAIDs, and 16% used acetaminophen. Results of the analysis showed that participants who reported daily aspirin use had a 20% lower risk of ovarian cancer than those who used aspirin less than once per week. For non-aspirin NSAIDs, which include a wide variety of drugs, the picture was less clear: a 10% lower ovarian cancer risk among women who used NSAIDs at least once per week was observed compared with those who used NSAIDs less frequently. However, this finding did not fall in a range that was significant statistically. In contrast to the findings for aspirin and NSAIDs, use of acetaminophen, which is not an anti-inflammatory agent, was not associated with reduced ovarian cancer risk.
This study adds to a growing list of malignancies, such as colorectal and other cancers, that appear to be potentially preventable by aspirin usage.
Adverse side effects of daily aspirin use include upper gastrointestinal bleeding and hemorrhagic stroke. Therefore, a daily aspirin regimen should only be undertaken with a doctor’s approval, caution the scientists.
NCI Launches Trial to Assess the Utility of Genetic Sequencing to Improve Patient Outcomes
A pilot trial to assess whether assigning treatment based on specific gene mutations can provide benefit to patients with metastatic solid tumors has been launched by the National Cancer Institute (NCI). The Molecular Profiling based Assignment of Cancer Therapeutics, or M-PACT, trial is one of the first to use a randomized trial design to assess if assigning treatment based on genetic screening can improve the rate and duration of response in patients with advanced solid tumors. A trial in which patients are randomly assigned to various treatment options is the gold-standard method for determining which treatment option is best.
It is hoped that in addition to the knowledge gained from the trial about assigning therapy based on results of genetic sequencing of tumors, this trial could identify patient sub-groups that are likely to benefit from certain treatments and result in new treatments being developed quickly for some cancers. This could ultimately lead to smaller, more definitive clinical trials, which would be helpful to clinicians and patients in terms of cost and time.
Very few types of tumors have just one mutated gene that triggers cancer progression. Once a gene is mutated, it can lead to the activation of multiple pathways, resulting in disease progression and potentially requiring multiple interventions. Therefore, NCI’s M-PACT trial is designed to determine whether people with specific mutations that have been demonstrated in laboratory systems to affect drug effectiveness will benefit from a specifically chosen targeted intervention and if these interventions lead to better outcomes.
For NCI’s M-PACT study, after screening hundreds of people, 180 patients with advanced refractory solid tumors (those resistant to standard therapy) will be enrolled based on their genetic profile. During the screening process, samples of the tumors will be genetically sequenced to look for a total of 391 different mutations in 20 genes that are known to affect the utility of targeted therapies. If mutations of interest are detected, using a molecular sequencing protocol for tumor biopsy samples evaluated by the U.S. FDA, those patients will be enrolled in the trial and randomly assigned to one of two treatment arms to receive one of the four treatment regimens that are part of this study.
To ensure that patients receive the best treatment already known to provide benefit, patients with specific tumor types should have received certain therapies prior to being enrolled in NCI’s M-PACT. For instance:
1. Patients with melanoma whose tumors have mutations in the V600E region of the BRAF gene should have received and progressed on a specific BRAF inhibitor therapy to be eligible for NCI’s M-PACT trial.
2. Patients with lung cancer should have had their tumors tested for the presence of EGFR and ALK gene mutations, and, if mutations were detected, they should have received and progressed on therapies targeting EGFR or ALK, respectively.
Patients with all types of solid tumors will be considered for trial eligibility. For the randomization, patients will be assigned to Arm A (they will receive a treatment regimen prospectively identified to target their specific mutation or relevant pathway) or Arm B (they will receive a treatment regimen not prospectively identified to target their specific mutation or relevant pathway). Patients in Arm B will have the option to cross over to Arm A to receive therapy identified to target their specific mutation or relevant pathway if their disease progresses on their initial study treatment. As of January 2014, the study is open for patient accrual. The clinicians hope that they can rapidly enroll patients and report results of their findings by 2017.
TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.
Imbruvica Approved to Treat Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is a rare blood and bone marrow disease that usually gets worse slowly over time, causing a gradual increase in white blood cells called B lymphocytes, or B cells. The National Cancer Institute estimates that 15,680 Americans were diagnosed and 4,580 died from the disease in 2013.
The U.S. FDA has expanded the approved use of Imbruvica (ibrutinib) for CLL patients who have received at least one previous therapy. Imbruvica works by blocking the enzyme that allows cancer cells to grow and divide. In November 2013, the FDA granted Imbruvica accelerated approval to treat patients with mantle cell lymphoma, a rare and aggressive type of blood cancer, if those patients received at least one prior therapy.
The FDA completed its review of Imbruvica’s new indication under the agency’s accelerated approval process, which played a vital role in rapidly making this new therapy available to those who need it most. Under the agency’s accelerated approval process, the FDA may approve a drug based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. Drugs receiving accelerated approval are usually subject to an agreement to conduct confirmatory trials verifying and describing clinical benefit. Imbruvica for CLL also received priority review and orphan-product designation because the drug demonstrated the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition and is intended to treat a rare disease, respectively.
The FDA’s accelerated approval of Imbruvica for CLL is based on a clinical study of 48 previously treated participants. On average, participants were diagnosed with CLL 6.7 years prior to the study and had received four previous therapies. All study participants received a 420 milligram orally administered dose of Imbruvica until the treatment reached unacceptable toxicity or the disease progressed. Results showed nearly 58% of participants had their cancer shrink after treatment (overall response rate). At the time of the study, the duration of response ranged from 5.6 to 24.2 months. An improvement in survival or disease-related symptoms has not been established.
The most common side effects observed in the clinical study include low levels of platelets in the blood (thrombocytopenia), diarrhea, bruising, a decrease in infection-fighting white blood cells (neutropenia), low red blood cells (anemia), upper respiratory tract infection, fatigue, pain in the muscles and bones (musculoskeletal pain), rash, fever (pyrexia), constipation, swelling of tissues (peripheral edema), joint pain (arthralgia), nausea, mouth sores (stomatitis), sinus infection (sinusitis) and dizziness.
Imbruvica is manufactured by Pharmacyclics (Sunnyvale, CA.)
Moroccan Stew with Butternut Squash, Cauliflower, Lentils and Tomatoes
Veggie Stew with Moroccan Spices — ©Joyce Hays, Target Health Inc
1/2 cauliflower, roasted
2 Tablespoons olive oil
1 yellow onion, chopped
4 cloves garlic, minced
1/2-1 teaspoon ground cumin (to your taste)
1/2-1 teaspoon coriander (to your taste)
1 cup pistachio nuts, chopped
2/3 cup fresh cilantro, chopped
1 teaspoon sweet paprika
Pinch cayenne pepper (or to your taste)
1 teaspoon turmeric
1 (3-inch) cinnamon stick (use the stick and not powdered form)
Salt and freshly ground black pepper
1 pound butternut squash, large dice
1 large red potato, washed and diced with skin left on
2 cups low-sodium chicken stock or broth
1 cup cooked chickpeas, drained
1 cup golden raisins
1 cup cooked lentils
1 (14-ounce) can diced tomatoes, with juices
Pinch saffron threads
1/2 lemon, juiced, and zest of ? lemon
1 cup brined green olives (Italian Cerignola)
Jasmine rice, cooked
Garnish: toasted marcona almonds, chopped cilantro (or parsley), pomegranate arils
Optional on the table: Plain yogurt, or sour cream, mango chutney
Heat olive oil in a 3- to 4-quart heavy saucepan with a tight fitting lid over medium heat. When oil shimmers, add onion, garlic, cumin, and cinnamon, turmeric, coriander, cayenne, and season with salt and freshly ground black pepper. Cook, stirring occasionally, until spices are aromatic and onions are soft and translucent, about 5 minutes.
Add squash and potatoes, season with salt and freshly ground black pepper, stir to coat, and cook until just tender, about 3 minutes. Add broth, chickpeas, tomatoes and their juices, cilantro, raisins, pistachios, olives and saffron. Bring mixture to a boil then reduce heat to low. Cover and simmer until squash is fork tender, about 10 minutes.
Remove from heat and stir in lemon. Serve over couscous or jasmine rice, garnished with cilantro, nuts, arils and yogurt or sour cream.
Baked lamb patties — ©Joyce Hays, Target Health Inc.
We decided to stay home for dinner on Valentine’s Day and were we glad we did! This recipe turned out to be absolutely delicious. We’re not used to lots of spices, but I’m experimenting with them, anyway, so we’re having a real adventure trying them out. Jules suggested we start with some hummus and pita (one of our favorite things to eat), and opened a bottle of red velvet, a lovely Merlot. We find that a full-bodied red is the best accompaniment for spices.
I kept my fingers crossed and brought out the Moroccan dish with jasmine rice and all the garnishes. I also served lamb patties just in case the spicy veggies disappointed. But everything
was perfect! With gusto we devoured the Moroccan stew on jasmine rice, and came back for seconds.
The spices in this recipe were just the right amount and blend, for our palate. Important to get the green Italian cerignola olives, which have a unique taste and to use a fresh cinnamon stick which gives off just the right amount of light sweet flavor. Using cilantro rather than parsley, is the better choice. We found that adding a dollop of sour cream was a great addition, as well as lots of pomegranate arils. Usually the lamb patties are the star of a meal, but this time they took second place.
©Joyce Hays, Target Health Inc.
Hope Your Valentine’s Day Went Well!
What Makes Target Health Different From Other CROs?
TARGET HEALTH INC. is a New York City based full service eCRO with full-time staff dedicated to all aspects of Strategic Planning on How to Develop New Drugs and Devices, Regulatory Affairs, Clinical Research, Biostatistics, Data Management and Medical Writing. In addition, TARGET HEALTH has developed, and continues to develop, innovative web-based software tools that provide our clients with a significant productivity edge.
We get asked from time-to-time, What makes Target Health different from other CROs. We figured that we should share this with our more than 5,100 readers of ON TARGET.
1. In the area of regulatory affairs, we are agents for 35 companies at FDA. We are very strong in regulatory strategy and the companies we represent are from all over the world.
2. We run a paperless operation and have developed integrated software tools to allow for the paperless clinical trial with associated saving of about $10,000/site/year when doing clinical trial monitoring. Our suite includes:
a. Target e*CRF® (EDC Made Simple)
b. Target e*CTR™ (eClinical Trial Record, a patented eSource solution for clinical trials)
c. Target e*Monitoring Reports™
d. Target e*Pharmacovigilance™
e. Target Document®
f. Target Encoder®
g. Target e*CTMS™
h. Target Newsletter®
3. We are able to take a drug or device from the nonclinical toxicology stage to NDA/PMA submissions.
4. We have over 35 approvals including 25 that used our EDC system. Approved products have been licensed to major pharmaceutical companies.
ON TARGET is the newsletter of Target Health Inc., a NYC-based contract research organization (CRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services, including the paperless clinical trial, to the pharmaceutical and device industries.
Joyce Hays, Founder and Chief Editor of On Target
Jules Mitchel, Editor
Vanessa Hays, Editorial Contributor
Facial nerve: the facial nerve’s nuclei are in the brainstem. Orange: nerves coming from the left hemisphere of the brain. Yellow: nerves coming from the right hemisphere of the brain. Note that the forehead muscles receive innervation from both hemispheres of the brain (represented in yellow and orange).
Bell’s palsy is a form of facial paralysis resulting from a dysfunction of the cranial nerve VII (the facial nerve) causing an inability to control facial muscles on the affected side. Bell’s palsy is characterized by a one sided facial droop that comes on within 72 hours. Several conditions can cause facial paralysis, e.g., brain tumor, stroke, myasthenia gravis, and Lyme disease. However, if no specific cause can be identified, the condition is known as Bell’s palsy. Named after Scottish anatomist Charles Bell, who first described it, Bell’s palsy is the most common acute mononeuropathy(disease involving only one nerve) and is the most common cause of acute facial nerve 1) ___ (>80%).
Bell’s palsy is defined as an idiopathic unilateral facial nerve paralysis, usually self-limiting. The hallmark of this condition is a rapid onset of partial or complete paralysis that often occurs overnight. In rare cases (<1%), it can occur bilaterally resulting in total facial paralysis. It is thought that an inflammatory condition leads to swelling of the facial nerve. The nerve travels through the skull in a narrow bone canal beneath the ear. Nerve swelling and compression in the narrow bone canal are thought to lead to nerve inhibition, damage or death. Corticosteroids have been found to improve outcomes, when used early, while anti-viral drugs have not. Most people recover spontaneously and achieve near-normal to normal functions. Many show signs of improvement as early as 10 days after the onset, even without treatment. Often the eye in the affected side cannot be closed. The eye must be protected from drying up, or the cornea may be permanently damaged resulting in impaired 2) ___. In some cases denture wearers experience some discomfort.
The facial nerves control a number of functions, such as blinking and 3) ___ the eyes, smiling, frowning, lacrimation, salivation, flaring nostrils and raising eyebrows. They also innervate the stapedial (stapes) muscles of the middle ear and carry taste sensations from the anterior two-thirds of the tongue. Because both the nerve to the stapedius and the chorda tympani nerve (taste)are branches of the facial nerve, patients with Bell’s palsy may present with hyperacusis or loss of taste sensation in the anterior 2/3 of the tongue. The forehead 4) ___ are usually affected. Although defined as a mononeuritis (involving only one nerve), patients diagnosed with Bell’s palsy may have myriad neurological symptoms including facial tingling, moderate or severe headache/neck pain, memory problems, balance problems, ipsilateral limb paresthesias, ipsilateral limb weakness, and a sense of clumsiness that are unexplained by facial nerve dysfunction.
Some viruses are thought to establish a persistent (or latent) infection without symptoms, e.g., the varicella-zoster virus and Epstein-Barr viruses, both of the herpes family. Reactivation of an existing (dormant) viral infection has been suggested as a cause of acute Bell’s palsy. Studies suggest that this new activation could be preceded by trauma, environmental factors, and metabolic or emotional disorders, thus suggesting that a host of different conditions may trigger reactivation. Once the facial paralysis sets in, many people may mistake it as a symptom of a 5) ___. But there are a few subtle differences. A stroke will usually cause a few additional symptoms, such as numbness or weakness in the arms and legs. And unlike Bell’s palsy, a stroke will usually let patients control the upper part of their faces. A person with a stroke will usually have some wrinkling of their forehead.
One disease that may be difficult to exclude in the differential diagnosis is involvement of the facial nerve in infections with the herpes zoster virus. The major differences in this condition are the presence of small blisters, or vesicles, on the external ear and hearing disturbances, but these findings may occasionally be lacking (zoster sine herpete). Reactivation of existing herpes zoster infection leading to facial paralysis in a Bell’s palsy type pattern is known as Ramsay Hunt syndrome type 2. Lyme disease may produce the typical palsy, and may be easily diagnosed by looking for Lyme-specific antibodies in the 6) ___ or erythema migrans. In endemic areas Lyme disease may be the most common cause of facial palsy.
Babies can be born with facial palsy. In a few cases, bilateral facial palsy has been associated with acute HIV infection. In some research, the herpes simplex virus type 1 (HSV-1) has been identified in a majority of cases diagnosed as Bell’s palsy. This has given hope for anti-inflammatory and anti-viral drug therapy (prednisone and acyclovir). Other research, however, identifies HSV-1 in only 31 cases (18%), herpes zoster (zoster sine herpete) in 45 cases (26%) in a total of 176 cases clinically diagnosed as Bell’s Palsy. That infection with herpes simplex virus should play a major role in cases diagnosed as Bell’s palsy therefore remains a hypothesis that requires further research. In addition, the herpes simplex virus type 1 (HSV-1) infection is associated with demyelination of nerves. This 7) ___ damage mechanism is different from the above mentioned – that edema, swelling and compression of the nerve in the narrow bone canal is responsible for nerve damage. Demyelination may not even be directly caused by the virus, but by an unknown immune system response.
Bell’s palsy is a diagnosis of exclusion, meaning it is diagnosed by elimination of other reasonable possibilities. By definition, no specific cause can be determined. There are no routine lab or imaging tests required to make the diagnosis. The degree of nerve damage can be assessed using the House-Brackmann score. One study found that 45% of patients are not referred to a specialist, which suggests that Bell’s palsy is considered by physicians to be a straightforward diagnosis that is easy to manage. Other conditions that can cause similar symptoms include: herpes zoster, sarcoidosis, and brain tumors. Steroids have been shown to be effective at improving recovery in Bell’s palsy while antivirals have not. In those who are unable to close their eyes, eye protective measures are required. Corticosteroid such as 8) ___ significantly improves recovery at 6 months and are thus recommended. Early treatment (within 3 days after the onset) is necessary for benefit with a 14% greater probability of recovery. Antivirals (such as acyclovir) are ineffective in improving recovery from Bell’s palsy beyond steroids alone. They were however commonly prescribed due to a theoretical link between Bell’s palsy and the herpes simplex and varicella zoster virus. There is still the possibility that they might result in a benefit less than 7% as this has not been ruled out.
Physiotherapy can be beneficial to some individuals with Bell’s palsy as it helps to maintain muscle tone of the affected facial muscles and stimulate the facial nerve. It is important that muscle re-education exercises and soft tissue techniques be implemented prior to recovery in order to help prevent permanent contractures of the paralyzed facial muscles. To reduce 9) ___, heat can be applied to the affected side of the face. Surgery may be able to improve outcomes in facial nerve palsy that has not recovered. A number of different techniques exist. Smile surgery or smile reconstruction is a surgical procedure that may restore the smile for people with facial nerve paralysis. It is unknown if early surgery is beneficial or harmful. Adverse effects include hearing loss which occurs in 3-15% of people. As of 2007 the American Academy of Neurology did not recommend surgical decompression. The efficacy of acupuncture remains unknown because the available studies are of low quality (poor primary study design or inadequate reporting practices).
Most people with Bell’s palsy start to regain normal facial function within 3 weeks, even those who do not receive treatment. In a 1982 study, when no treatment was available, of 1,011 patients, 85% showed first signs of recovery within 3 weeks after onset. For the other 15%, recovery occurred 3-6 months later. After a follow-up of at least 1 year or until restoration, complete recovery had occurred in more than two-thirds (71%) of all patients. Recovery was judged moderate in 12% and poor in only 4% of patients. Another study found that incomplete palsies disappear entirely, nearly always in the course of one month. The patients who regain movement within the first two weeks nearly always remit entirely. When remission does not occur until the third week or later, a significantly greater part of the patients develop sequelae. A third study found a better prognosis for young patients, aged below 10 years old, while the patients over 61 years old presented a worse prognosis.
Major complications of the condition are chronic loss of taste (ageusia), chronic facial spasm, facial pain and corneal infections. To prevent the latter, the eyes may be protected by covers, or taped shut during sleep and for rest periods, and tear-like eye drops or eye ointments may be recommended, especially for cases with complete paralysis. Where the eye does not close completely, the blink reflex is also affected, and care must be taken to protect the eye from injury. Another complication can occur in case of incomplete or erroneous regeneration of the damaged facial nerve. The nerve can be thought of as a bundle of smaller individual nerve connections that branch out to their proper destinations. During regrowth, nerves are generally able to track the original path to the right destination – but some nerves may sidetrack leading to a condition known as synkinesis. For instance, regrowth of nerves controlling muscles attached to the eye may sidetrack and also regrow connections reaching the muscles of the mouth. In this way, movement of one also affects the other. For example, when the person closes the eye, the corner of the mouth lifts involuntarily.
Around 9% of patients have some sort of sequelae after Bell’s palsy, typically the synkinesis already discussed, or spasm, contracture, tinnitus and/or hearing loss during facial movement or crocodile tear syndrome. This is also called gustatolacrimal reflex or Bogorad’s Syndrome and involves the sufferer shedding 10) ___ while eating. This is thought to be due to faulty regeneration of the facial nerve, a branch of which controls the lacrimal and salivary glands. Gustatorial sweating can also occur.
The annual incidence of Bell’s palsy is about 20 per 100,000 population, and the incidence increases with age. Bell’s palsy affects about 40,000 people in the United States every year. It affects approximately 1 person in 65 during a lifetime. Familial inheritance has been found in 4-14% of cases. Bell’s palsy is three times more likely to strike 11) ___ women than non-pregnant women. It is also considered to be four times more likely to occur in diabetics than the general population.
A range of annual incidence rates have been reported in the literature: 15, 24, and 25-53 (all rates per 100,000 population per year). Bell’s palsy is not a reportable disease, and there are no established registries for patients with this diagnosis, which complicates precise estimation. Although it is named after Sir Charles 12) ___, the Scottish anatomist who provided the first anatomic basis for trigeminal neuralgia and facial palsy, other European physicians provided earlier clinical descriptions of peripheral cranial nerve 7 palsy. In a recent review article describing history of facial palsy by Greek, Roman, and Persian physicians. Cornelis Stalpart van der Wiel (1620-1702) in 1683 gave an account of Bell’s palsy and credited Avicenna (980-1037) for describing this condition before him. James Douglas (1675-1742) and Nicolaus Anton Friedreich (1761-1836) also described it. One well known television personality with Bell’s Palsy is lawyer, Greta Van Susteren.
ANSWERS: 1) paralysis; 2) vision; 3) closing; 4) muscles; 5) stroke; 6) blood; 7) nerve; 8) prednisone; 9) pain; 10) tears; 11) pregnant; 12) Bell
Sir Charles Bell MD (1774-1842)
Engraving by Charles Bell MD
Charles Bell was a Scottish anatomist and physician whose, New Idea of Anatomy of the Brain (1811) has been called the Magna Carta of neurology. Born at Edinburgh in November 1774, the youngest son of the Rev. William Bell, a clergyman of the Episcopal Church of Scotland; among his brothers were the anatomist, John Bell, and the jurist, G. J. Bell. After attending the high school and the University of Edinburgh, he embraced the profession of medicine, and devoted himself chiefly to the study of anatomy, under the direction of his brother John. His first work, entitled A System of Dissections, explaining the anatomy of the human body, the manner of displaying the parts, and their varieties in disease, was published in Edinburgh in 1798, while he was still a pupil, and for many years was considered to be a valuable guide to the student of practical anatomy.
In 1802 he published a series of engravings of original drawings, showing the anatomy of the brain and nervous system. These drawings, which are remarkable for artistic skill and finish, were taken from dissections made by Bell for the lectures or demonstrations he gave on the nervous system as part of the course of anatomical instruction of his brother. In 1804 he wrote the third volume, containing the anatomy of the nervous system and of the organs of special sense, of The Anatomy of the Human Body, by John and Charles Bell. In November of the same year he migrated to London, and from that date, for nearly forty years, he kept up a regular correspondence with his brother George, much of which was published in the Letters of Sir Charles Bell, etc., 1870. The earlier letters of this correspondence show how rapidly he rose to distinction in a field where success was difficult, as it was already occupied by such men as John Abernethy, Sir Astley Cooper and Henry Cline. Before leaving Edinburgh, he had written his work on the Anatomy of Expression, which was published in London soon after his arrival and at once attracted attention. His practical knowledge of anatomy and his skill as an artist qualified him in an exceptional manner for such a work. The object of this treatise was to describe the arrangements by which the influence of the mind is propagated to the muscular frame, and to give a rational explanation of the muscular movements which usually accompany the various emotions and passions. One special feature was the importance attributed to the respiratory arrangements as a source of expression, and it was shown how the physician and surgeon might derive information regarding the nature and extent of important diseases by observing the expression of bodily suffering. This work, apart from its value to artists and psychologists, is of interest historically, as there is no doubt the investigations of the author into the nervous supply of the muscles of expression induced him to prosecute inquiries which led to his great discoveries in the physiology of the nervous system.
In 1811 Bell published his New idea of the Anatomy of the Brain, in which he announced the discovery of the different functions of the nerves corresponding with their relations to different parts of the brain; his latest researches were described in The Nervous System of the Human Body (1830), a collection of papers read by him before the Royal Society. He discovered that in the nervous trunks there are special sensory filaments, the office of which is to transmit impressions from the periphery of the body to the sensorium, and special motor filaments which convey motor impressions from the brain or other nerve center to the muscles. He also showed that some nerves consist entirely of sensory filaments and are therefore sensory nerves, that others are composed of motor filaments and are therefore motor nerves, while a third variety contains both kinds of filaments and are therefore to he regarded as sensory-motor. Furthermore, he indicated that the brain and spinal cord may be divided into separate parts, each part having a special function — one part ministering to motion, the other to sensation, and that the origin of the nerves from one or other or both of those sources endows them with the peculiar property of the division, from which they spring. He also demonstrated that no motor nerve ever passes through a ganglion. Lastly, he showed, both from theoretical considerations and from the result of actual experiment on the living animal, that the anterior roots of the spinal nerves are motor, while the posterior are sensory. These discoveries as a whole must be regarded as the greatest in physiology since that of the circulation of the blood by William Harvey. They were not only a distinct and definite advance in scientific knowledge, but from them flowed many practical results of much importance in the diagnosis and treatment of disease. It is not surprising that Bell should have viewed his results with exultation. On the 26th of November 1807, he wrote to his brother George: I have done a more interesting nova anatomia cerebri humani than it is possible to conceive. I lectured it yesterday. I prosecuted it last night till one o’clock; and I am sure it will be well received. On the 31st of the same month he wrote: I really think this new anatomy of the brain will strike more than the discovery of the lymphatics being absorbents.
In 1807 he produced a System of Comparative Surgery, in which surgery is regarded almost wholly from an anatomical and operative point of view, and there is little or no mention of the use of medicinal substances. It placed him, however, in the highest rank of English writers on surgery. In 1809 he relinquished his professional work in London, and rendered meritorious services to the wounded from Coruna, who were brought to the Haslar hospital at Portsmouth. In 1810 he published a series of Letters concerning the Diseases of the Urethra, in which he treated a stricture from an anatomical and pathological point of view. In 1812 he was appointed surgeon to the Middlesex hospital, a post he retained for 24 years. He was also professor of anatomy, physiology and surgery to the College of Surgeons of London, and for many years teacher of anatomy in the school which used to exist in Great Windmill Street. In 1815 he went to Brussels to treat the wounded of the battle of Waterloo. In 1816, 1817 and 1818, he published a series of Quarterly Reports of Cases in Surgery; in 1821 a volume of colored plates with descriptive letterpress, entitled Illustrations of the great operations of Surgery, Trepan, Hernia, Amputalion and Lithotomy, and in 1824 Observations on Injuries of the Spine and of the Thigh Bone. On the formation of University College, Gower Street, he was for a short time head of the medical department. In 1832 he wrote a paper for the Royal Society of London on the Organs of the Human Voice, in which he gave many illustrations of the physiological action of these parts, and in 1833 a Bridgewater treatise, The Hand: its Mechanism and Vital Endowments as evincing Design. Along with Lord Brougham he annotated and illustrated an edition of Paley’s Natural Theology, published in 1836. The Royal Society of London awarded to him in 1829 the first annual medal of that year given by King George IV for discoveries in science; and when King William IV ascended the throne, Charles Bell received the honor of knighthood along with a few other men distinguished in science and literature.
In 1836 the chair of surgery in the University of Edinburgh was offered to him. He was then one of the foremost scientific men in London, and he had a large surgical practice. But his opinion was London is a place to live in, but not to die in; and he accepted the appointment. In Edinburgh he did not earn great local professional success; and, it must be confessed, he was not appreciated as he deserved. But honors came thick upon him. On the continent of Europe he was spoken of as greater than Harvey. It is narrated that one day P.J. Roux, a celebrated French physiologist, dismissed his class without a lecture, saying C’est assez, messieurs, vous avez vu Charles Bell. During his professorship he published the Institutes of Surgery, arranged in the order of the lectures delivered in the University of Edinburgh (1838); and in 1841 he wrote a volume of Practical Essays, two of which, On Squinting, and On the action of purgatives, are of great value. He died at Hallow Park near Worcester on the 28th of April 1842.
Bell served as a military surgeon, making elaborate recordings of neurological injuries at the Royal Hospital Haslar and famously documenting his experiences at Waterloo in 1815. Bell was also instrumental in the creation of the Middlesex Hospital Medical School, and became, in 1824, the first professor of Anatomy and Surgery of the College of Surgeons in London. In 1829, the Windmill Street School of Anatomy was incorporated into the new King’s College London. Bell was invited to be its first professor of physiology. Bell’s studies on emotional expression, flawed though they were, played a catalytic role in the development of Darwin’s considerations of the origins of human emotional life; and Darwin very much agreed with Bell’s emphasis on the expressive role of the muscles of respiration. Darwin detailed these opinions in his The Expression of the Emotions in Man and Animals (1872), written with the active collaboration of the psychiatrist James Crichton-Browne. Bell was one of the first physicians to combine the scientific study of neuroanatomy with clinical practice. In 1821, he described in the trajectory of the facial nerve and a disease, Bell’s Palsy which led to the unilateral paralysis of facial muscles, in one of the classics of neurology, a paper to the Royal Society entitled On the Nerves: Giving an Account of some Experiments on Their Structure an Functions, Which Lead to a New Arrangement of the System.
Bell also combined his many artistic, scientific, literary and teaching talents in a number of wax preparations and detailed anatomical and surgical illustrations, paintings and engravings in his several books on these subjects, such as in his book Illustrations of the Great Operations of Surgery: Trepan, Hernia, Amputation, Aneurism, and Lithotomy (1821). He wrote also the first treatise on notions of anatomy and physiology offacial expression for painters and illustrators, titled Essays on the Anatomy of Expression in Painting (1806). In 1833 he published the fourth Bridgewater Treatise, The Hand: Its Mechanism and Vital Endowments as Evincing Design.
A number of discoveries received his name:
1. Bell’s (external respiratory) nerve: The long thoracic nerve.
2. Bell’s palsy: a unilateral idiopathic paralysis of facial muscles due to a lesion of the facial nerve.
3. Bell’s phenomenon: A normal defense mechanism — upward and outward movement of the eye which occurs when an individual closes their eyes forcibly. It can be appreciated clinically in a patient with paralysis of the orbicularis oculi (e.g. Guillain-Barre or Bell’s palsy), as the eyelid remains elevated when the patient tries to close the eye.
4. Bell’s spasm: Involuntary twitching of the facial muscles.
5. Bell-Magendie law or Bell’s Law: States that the anterior branch of spinal nerve roots contain only motor fibers and the posterior roots contain only sensory fibers.
Wishing to return to Scotland, he accepted in 1836 the position of Professor of Surgery at the University of Edinburgh. Bell died in the Midlands, travelling back from Edinburgh to London, in 1842.