Today, Erivedge (vismodegib) was approved by the U.S. Food and Drug Administration to treat adult patients with basal cell carcinoma, the most common type of skin cancer. The drug is intended for use in patients with locally advanced basal cell cancer who are not candidates for surgery or radiation and for patients whose cancer has spread to other parts of the body (metastatic).

Erivedge, reviewed under the agency’s priority review program, is the first FDA-approved drug for metastatic basal cell carcinoma. Erivedge was reviewed under the FDA’s priority review program that provides for an expedited six-month review of drugs that may offer major advances in treatment. The drug is being approved ahead of the March 8, 2012 prescription user fee goal date.

Basal cell carcinoma is generally a slow growing and painless form of skin cancer that starts in the top layer of the skin (epidermis). The cancer develops on areas of skin that are regularly exposed to sunlight or other ultraviolet radiation.

Erivedge is a pill taken once a day and works by inhibiting the Hedgehog pathway, a pathway that is active in most basal cell cancers and only a few normal tissues, such as hair follicles.

“Our understanding of molecular pathways involved in cancer, such as the Hedgehog pathway, has enabled the development of targeted drugs for specific diseases,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approach is becoming more common and will potentially allow cancer drugs to be developed more quickly. This is important for patients who will have access to more effective therapies with potentially fewer side effects.”

The safety and effectiveness of Erivedge was evaluated in a single, multi-center clinical study in 96 patients with locally advanced or metastatic basal cell carcinoma. The clinical study’s primary endpoint was objective response rate (ORR) or the percentage of patients who experienced complete and partial shrinkage or disappearance of the cancerous lesions after treatment. Of the patients with metastatic disease receiving Erivedge, 30 percent experienced a partial response and 43 percent of patients with locally advanced disease experienced a complete or partial response.

The most common side effects observed in patients treated with Erivedge were muscle spasms, hair loss, weight loss, nausea, diarrhea, fatigue, distorted sense of taste, decreased appetite, constipation, vomiting, and loss of taste function in the tongue.

Erivedge is being approved with a BOXED WARNING alerting patients and health care professionals of the potential risk of death or severe birth effects to a fetus (unborn baby). Pregnancy status must be verified prior to the start of Erivedge treatment. Male and female patients should be warned about these risks and the need for birth control.

Erivedge is marketed by South San Francisco based-Genentech, a member of the Roche Group.

As many as 91 per cent of the patients with mild memory impairment who had these risk markers went on to develop Alzheimer’s within a ten-year period. In contrast, those who had memory impairment but normal values for the markers did not run a higher risk of getting Alzheimer’s than healthy individuals.

Oskar Hansson previously carried out a study showing that pathological changes can be seen in the brain of an Alzheimer’s patient five years before the diagnosis. The new study has thus doubled this time span to ten years.

“This is a very important finding with regard to the development of new therapies against the disease. All prospective therapies have so far shown to be ineffective in stopping the disease, and many people are concerned that the pharmaceutical companies will give up their efforts in this field. But these failures may depend on the fact that the new therapies were initiated too late. When a patient receives a diagnosis today, the damage has already gone too far,” says Oskar Hansson.

With the help of the biomarkers studied by the group, pharmaceutical companies will now be able to identify the people with mild symptoms who run the highest risk of developing Alzheimer’s within a ten-year period. These individuals can then be offered the opportunity of taking part in trials for new medicines, while those who run a low risk of developing the disease do not need to be involved. A new trial of this kind is already underway, on the basis of the earlier study by the Hansson group.

The 90 per cent accuracy of the risk markers means that they are not sufficient as the only method for early diagnosis of Alzheimer’s. But if they can be combined with a clinical assessment and, for example, imaging of the blood flow in the brain, it should be possible to increase the level of accuracy, according to Oskar Hansson. However, this will only be relevant once drugs that are effective in slowing down the disease have been developed. Only then will it really be meaningful to identify patients earlier than is currently possible.

By observing how the levels of the biomarkers develop over the ten years before the patient’s diagnosis, the research group has also been able to map the progression of the disease in the brain. The results indicate that it starts with a modified turnover of beta-amyloid. Only later is this followed by changes in the tau protein and damage to nerve cells. This can be important information for those developing new therapies for Alzheimer’s.

Today’s ubiquitous MP3 players permit users to listen to crystal-clear tunes at high volume for hours on end — a marked improvement on the days of the Walkman. But according to Tel Aviv University research, these advances have also turned personal listening devices into a serious health hazard, with teenagers as the most at-risk group.

One in four teens is in danger of early hearing loss as a direct result of these listening habits, says Prof. Chava Muchnik of TAU’s Department of Communication Disorders in the Stanley Steyer School of Health Professions at the Sackler Faculty of Medicine and the Sheba Medical Center. With her colleagues Dr. Ricky Kaplan-Neeman, Dr. Noam Amir, and Ester Shabtai, Prof. Muchnik studied teens’ music listening habits and took acoustic measurements of preferred listening levels.

The results, published in the International Journal of Audiology, demonstrate clearly that teens have harmful music-listening habits when it comes to iPods and other MP3 devices. “In 10 or 20 years it will be too late to realize that an entire generation of young people is suffering from hearing problems much earlier than expected from natural aging,” says Prof. Muchnik.

Hearing loss before middle age

Hearing loss caused by continuous exposure to loud noise is a slow and progressive process. People may not notice the harm they are causing until years of accumulated damage begin to take hold, warns Prof. Muchnik. Those who are misusing MP3 players today might find that their hearing begins to deteriorate as early as their 30′s and 40′s — much earlier than past generations.

The first stage of the study included 289 participants aged 13 to 17. They were asked to answer questions about their habits on personal listening devices (PLDs) — specifically, their preferred listening levels and the duration of their listening. In the second stage, measurements of these listening levels were performed on 74 teens in both quiet and noisy environments. The measured volume levels were used to calculate the potential risk to hearing according to damage risk criteria laid out by industrial health and safety regulations.

The study’s findings are worrisome, says Prof. Muchnik. Eighty percent of teens use their PLDs regularly, with 21 percent listening from one to four hours daily, and eight percent listening more than four hours consecutively. Taken together with the acoustic measurement results, the data indicate that a quarter of the participants are at severe risk for hearing loss.

Dangerous decibels

Currently, industry-related health and safety regulations are the only benchmark for measuring the harm caused by continuous exposure to high volume noise. But there is a real need for additional music risk criteria in order to prevent music-induced hearing loss, Prof. Muchnik says. In the meantime, she recommends that manufacturers adopt the European standards that limit the output of PLDs to 100 decibels. Currently, maximum decibel levels can differ from model to model, but some can go up to 129 decibels.

Steps can also be taken by schools and parents, she says. Some school boards are developing programs to increase awareness of hearing health, such as the “Dangerous Decibels” program in Oregon schools, which provides early education on the subject. Teens could also choose over-the-ear headphones instead of the ear buds that commonly come with an iPod.

In the near future, the researchers will focus on the music listening habits of younger children, including pre-teens, and the development of advanced technological solutions to enable the safe use of PLDs.

“On the basis of a simple neuroimaging study, we can now predict which patients with Parkinson’s disease will experience long-term cognitive decline or develop dementia in the future,” said the study’s lead author, Daniel Weintraub, MD, associate professor of Geriatric Psychiatry with Penn’s Perelman School of Medicine and the Philadelphia Veterans Affairs Medical Center. “Diagnostic tests like this can help us determine which patients would benefit from future clinical trials of medications aiming to stave off or prevent dementia progression in Parkinson’s disease.”

This research raises the possibility that both Alzheimer’s disease and Parkinson’s disease pathology contribute to cognitive decline in Parkinson’s disease. Researchers are still uncertain whether the neurodegeneration seen in these patients is caused by primary Parkinson’s disease pathology, Alzheimer’s pathology, a combination of the two, or is a form of compensation.

As biomarkers for Alzheimer’s and Parkinson’s disease continue to emerge, the researchers suggest at least an overlap in regions undergoing neurodegeneration with cognitive decline, and point to the Spatial Pattern of Abnormalities for Recognition of Alzheimer’s disease (SPARE-AD) classification system to detect brain atrophy in Parkinson’s disease, to detect patients at imminent risk of cognitive decline before clinically identifiable symptoms emerge.

Around 80 percent of Parkinson’s patients become demented over the course of the illness. Some patients experience cognitive impairment relatively soon after the disease strikes, while others won’t experience dementia until the very end of their disease. Duration and severity of the disease and advanced age are risk factors for dementia, while nearly 20 percent of patients never have dementia. Over half of Parkinson’s patients with dementia have significant signs of Alzheimer’s disease-related plaques and neurofribrillary tangles on autopsy, and similar brain regions, such as the hippocampus and medial temporal lobe, have been reported to be affected in both diseases.

The Penn research team applied a pattern classification individual-based score, the SPARE-AD score, to a cross-sectional cohort of 84 Parkinson’s patients including patients with dementia, mild cognitive impairment and no dementia. In the cross-sectional analyses, the SPARE-AD score correlated to cognitive impairment across all groups. From this group, 59 Parkinson’s patients without dementia were followed for an additional two years. Researchers determined that a higher baseline SPARE-AD score predicted worsening cognitive performance over time, even in those patients with normal cognition at baseline.

The process is reported in the Dec. 5 Early Edition of the journal Proceedings of the National Academy of Sciences (PNAS). The process, outlined in the paper, titled “Structure-based design of conformation- and sequence-specific antibodies against amyloid β,” could be used as a tool to understand complex disease pathology and develop new antibody-based drugs in the future.

Antibodies are large proteins produced by the immune system to combat infection and disease. They are comprised of a large Y-shaped protein topped with small peptide loops. These loops bind to harmful invaders in the body, such as a viruses or bacteria. Once an antibody is bound to its target, the immune system sends cells to destroy the invader. Finding the right antibody can determine the difference between death and recovery.

Scientists have long sought methods for designing antibodies to combat specific ailments. However, the incredible complexity of designing antibodies that only attached to a target molecule of interest has prevented scientists from realizing this ambitious goal.

When trying to design an antibody, the arrangement and sequence of the antibody loops is of utmost importance. Only a very specific combination of antibody loops will bind to and neutralize each target. And with billions of different possible loop arrangements and sequences, it is seemingly impossible to predict which antibody loops will bind to a specific target molecule.

The new antibody design process was used to create antibodies that target a devastating molecule in the body: the Alzheimer’s protein. The research, which was led by Assistant Professor of Chemical and Biological Engineering Peter Tessier, uses the same molecular interactions that cause the Alzheimer’s proteins to stick together and form the toxic particles that are a hallmark of the disease.

“We are actually exploiting the same protein interactions that cause the disease in the brain to mediate binding of antibodies to toxic Alzheimer’s protein particles,” Tessier said.

Alzheimer’s disease is due to a specific protein – the Alzheimer’s protein – sticking together to form protein particles. These particles then damage the normal, healthy functions of the brain. The formation of similar toxic protein particles is central to diseases such as Parkinson’s and mad cow disease.

Importantly, the new Alzheimer’s antibodies developed by Tessier and his colleagues only latched on to the harmful clumped proteins and not the harmless monomers or single peptides that are not associated with disease.

Tessier and his colleagues see the potential for their technique being used to target and better understand similar types of protein particles in disorders such as Parkinson’s disease.

“By binding to specific portions of the toxic protein, we could test hypotheses about how to prevent or reverse cellular toxicity linked to Alzheimer’s disease,” Tessier said.

In the long term, as scientists learn more about methods to deliver drugs into the extremely well-protected brain tissue, the new antibody research may also help to develop new drugs to combat disorders such as Alzheimer’s disease.

According to background information in the article, lentigo maligna (LM) is a common premalignant skin lesion typically seen in older populations with a history of chronic sun damage and it is commonly located in the head and neck region. The lesion may progress to LM melanoma (LMM), which has the same prognosis as other forms of melanoma.

Haemi Lee, M.D., and colleagues at the University of Western Ontario, London, Ontario, Canada, conducted a retrospective case series review of all patients with primary lentigo maligna diagnosed and treated in London, Ontario between July 2, 1991 and June 29, 2010. The researchers assessed outcomes in managing primary LM through surgical excision (removal), radiation therapy, and carbon dioxide laser ablation. The carbon dioxide laser exerts its effect on tissue by vaporization of water-containing cells.

Among 73 patients ages 39 to 93 years who chose treatment, 27 were treated with surgical excision, 31 were treated with radiation therapy, and 15 were treated with carbon dioxide laser ablation. The patients were followed an average of 16.6 months for surgical excision, 46.3 months for radiation therapy, and 77.8 months for carbon dioxide laser ablation.

“A trend toward lower recurrence rates with surgical excision and carbon dioxide laser ablation was identified, but the results were not statistically significant,” the authors report.

The recurrence rates were 4.2 percent for surgical excision, 29 percent for radiation therapy, and 6.7 percent for carbon dioxide laser ablation.

“Although surgical excision is established as the gold standard of LM and LMM treatment, complete excision is not always feasible in large lesions of the head and neck,” the authors write. “The decision to perform complete excision in the setting of LM, a non-invasive disease, must weigh the benefits of excision against the morbidity of the procedure.”

“Carbon dioxide laser ablation may be advantageous because it treats large lesions in cosmetically sensitive regions of the head and neck in a short period, with minimal morbidity,” they conclude.

“Many inconsistent concerns have been voiced about the safety of long-term use of antibiotics,” the authors write as background information in the study. “Because of the high prevalence of acne and the frequent use of antibiotics to control acne, individuals undergoing therapy to treat their acne are an ideal group in which to study the effects of long-term antibiotic use.”

David J. Margolis, M.D., Ph.D., and colleagues with the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, conducted two concurrent studies (a cross-sectional study and a longitudinal study) to examine the association between antibiotics used to treat acne and pharyngitis. The authors also examined the association between oral antibiotics and colonization rates of group A streptococcus (GAS; form bacteria responsible for most cases of streptococcal illness) as previous research has shown a link between oral antibiotics and higher rates of GAS. Participants in both studies included college students, who were asked to fill out a self-administered survey form, were swabbed for culture and had a visual examination for acne.

In the cross-sectional study, the authors found that 10 of 15 students receiving oral antibiotics for acne reported an episode of pharyngitis in the past 30 days, and 47 of 130 students not receiving oral antibiotics, but who had acne, reported an episode of pharyngitis in the previous month. Combining all 251 students not receiving oral antibiotics, 82 (32.7 percent) reported an episode of pharyngitis in the previous 30 days. Three of 145 students with acne (2.1 percent) were found to be colonized with GAS, however none of the three was receiving oral antibiotics.

The longitudinal study included 358 female and 218 male participants; 36 (6.2 percent) received oral antibiotics for acne during the study and 96 (16.6 percent) received topical antibiotics for acne. The authors found that the use of oral antibiotics was strongly associated with a health care evaluation for pharyngitis. Of students receiving oral antibiotic treatment, 11.3 percent reported pharyngitis. Conversely, pharyngitis was reported by 3.3 percent of students not receiving oral antibiotics. Additionally, no association with pharyngitis was noted for those who used a topical antibiotic for acne, and the authors found that less than 1 percent of participants were colonized by GAS, indicating that it is not associated with pharyngitis.

“Our studies show that the odds of developing self-reported pharyngitis is more than three times baseline in patients receiving oral antibiotics for acne vs. the odds for those who are not receiving oral antibiotics,” the authors conclude. “The true clinical importance of these findings needs to be evaluated further by prospective studies.”

“Anecdotally, many researchers have observed that HDL levels may be lower in states of inflammation, such as rheumatoid arthritis, psoriasis and even obesity,” said lead study author Nehal Mehta, MD, MSCE, director of Inflammatory Risk in Preventive Cardiology at Penn. “However, these new findings suggest that in addition to lower levels, chronic inflammation associated with conditions like psoriasis may change the composition and decrease the function of HDL as well.”

In the current studies, researchers enrolled 78 patients with psoriasis and 84 control subjects. In the first study, the authors measured fasting lipid levels and examined the number and size of cholesterol particles using nuclear magnetic resonance (NMR) spectroscopy. This analysis revealed that patients with psoriasis had a higher number of smaller LDL particles, or “bad” cholesterol, which was independent of traditional risk factors and obesity. “It was striking that the NMR profiles from patients with psoriasis resembled those seen in patients with diabetes, and that these patients with psoriasis had otherwise normal traditional lipid panels” Dr. Mehta added.

In the second study, the researchers measured HDL efflux, which is the ability of a patient’s HDL to remove cholesterol from cells involved in atherosclerosis. This process, known as ‘reverse cholesterol transport’, is why HDL may have protective properties. In a previous study, researchers at Penn have demonstrated that measuring HDL efflux capacity may be a more effective barometer of protection from heart disease than measuring HDL levels alone.

In this same group of patients who had normal cholesterol levels compared to controls, patients with psoriasis demonstrated dramatically reduced HDL efflux capacity compared to control patients. This negative association observed between psoriasis and HDL efflux persisted after adjusting for traditional lipid levels and other traditional risk factors, including body mass index (BMI).

“Patients with psoriasis had an approximate 25 percent reduction in the HDL efflux capacity than the controls, despite their relatively normal overall lipid profiles which leads to the question of whether function is more important than concentration in chronic inflammatory states” Dr. Mehta noted.

The new findings may provide a critical clue to the link between psoriasis and heart disease, but the researchers say larger studies are needed to validate their findings. Joel M. Gefland, MD, MSCE, assistant professor of Dermatology and Epidemiology, and a senior author on the studies, said “We’ve been able to show that psoriasis is an important risk factor for vascular disease, and now we may finally be able to identify and ultimately treat the pathways by which psoriasis increases these risks.”

Zoltán Takáts and colleagues point out that cancer can recur if tumor cells remain in the body after surgery. As a precaution, surgeons typically remove extra tissue surrounding a breast, prostate and other tumors in the body. But neurosurgeons face severe limitations because removing extra tissue can impair the patient’s memory, mobility and other vital functions. Neurosurgeons thus strive to precisely identify the tumor margins during brain surgery. Current methods take too long and are unreliable. To overcome these challenges, the researchers developed a new tool that can identify the margin between cancerous and healthy tissue in half the time previously needed.

They describe linking a mainstay surgical tool termed an ultrasonic aspirator — used to break up and suction tissue — to a modified version of a standard laboratory tool called a mass spectrometer. Their tests proved successful on human brain samples. “Besides brain surgery, the method has application potential in the field of the surgery of organs including liver, pancreas or kidney,” say the researchers.

The success of this vaccine, CSIC’s patent, is based on the capability of human’s immune system to learn how to react over time against virus particles and infected cells. “MVA-B vaccine has proven to be as powerful as any other vaccine currently being studied, or even more”, says Mariano Esteban, head researcher from CSIC’s National Biotech Centre.

In 2008, MVA-B already showed very high efficiency in mice as well as macaque monkeys against Simian’s immunodeficiency virus (SIV). Due to it’s high immunological response in humans, Phase I clinic trials will be conducted with HIV infected volunteers, to test its efficiency as a therapeutic vaccine.

Weapon’s origins

Back in 1999, Esteban’s research team began to work in the development and preclinical studies of MVA-B, which name comes from its composition, based in Modified Ankara Vaccinia virus. MVA-B is an attenuated virus, which has already been used in the past to eradicate smallpox, and also as a model in the research of many other vaccines. The “B” stands for the HIV subtype it is meant to work against, the most common in Europe.

Development of MVA-B is based in the insertion of four HIV genes (Gag, Pol, Nef & Env) in Vaccina’s genetic sequence. A healthy immunitary system is able to react against MVA.

On the other hand, the inserted HIV genes in its DNA are not able to self-replicate, which guarantees the safety of the clinical trial.

30 healthy volunteers participated in this clinical trial. 24 of them were treated with MVA-B, while the other 6 were treated with a placebo, following a double-blind testing method. 3 doses of the vaccine were given via intramuscular route in weeks 0, 4 and 16. The effects were studied in peripheral blood until the trial ended on week 48.

Combat battalion

Inoculating the vaccine in a healthy volunteer is intended to train it’s immune system to detect and learn how to combat those virus components. According to Esteban ” it is like showing a picture of the HIV so that it is able to recognise it if it sees it again in the future”.

Lymphocytes T and B are the main cells in this experiment, the soldiers in charge of detecting the foreign substances in the body and sending the right coordinates to destroy them.

“Our body is full of lymphocytes, each of them programmed to fight against a different pathogen” says Esteban. For that reason “Training is needed when it involves a pathogen, like the HIV one, which cannot be naturally defeated”.

Lymphocytes B are responsible for the humoral immune response, producing antibodies which attack the HIV particles before they penetrate and infect the cell, anchoring themselves to the external structure and blocking it. 48th week blood tests reveal 72,7% of the treated volunteers hold specific antibodies against HIV.

On the other side, lymphocytes T control cell’s immune response, in charge of detecting and destroying HIV infected cells. In order to verify their defence response to the vaccine, production of interferon gamma immunitary protein was measured.

Tests performed on the 48th week, 32 weeks after the last inoculation of the vaccine, show the production of lymphocytes T CD4+ and CD8+ of the vaccinated group is 38,5% and 69,2%, respectively, while it stays at 0% in the control group.

Action in several fronts

Besides interferon gamma, other immune proteins (cytokines and chemokines) are produced by the body when the presence of a pathogen is detected. Each of these proteins tends to attack a different enemy front. When T lymphocytes’ defence action is able to generate several of these proteins it is called a polyfunctional action. CSIC’s researcher adds “The importance of polyfunctionality has to do with the capability of pathogens to develop resistance to the immune systems attacks. The higher the polyfunctionality, the lower the resistance”.

The defence spectrum of T lymphocytes in vaccinated subjects was measured based on the production of 3 other immunitary proteins. Tests indicate the vaccine generates up to 15 types of lymphocyte T CD4+ and CD8+ populations. 25% of CD4+ type and 45% of CD8+ type are able to produce two or more different proteins, proving their polyfunctionality.

War veterans

For a vaccine to become really effective, besides its immune system’s defence capability, generating a long lasting response against future attacks is the key. For this purpose, the body needs to be able to keep a basic level of memory T lymphocytes. These lymphocytes, generated after a first pathogen attack, are veteran soldiers, which can circulate the body for years, prepared to respond to a new enemy’s incursion.

48th week blood tests ran on vaccinated subjects show over 50% of CD4+ and CD8+ lymphocytes were memory T lymphocytes in the 85% of the patients who kept an immune response at this point of the trials.

In Esteban’s opinión “MVA-B immune profile meets, initially, the requirements for a promising HIV vaccine”. MVA-B is not capable of removing the virus from the body as once a cell is infected, virus’ genetic data is integrated and replicated with the cell. However, the immune response induced by the vaccine could keep the virus under control, “if the virus enters the body and tries to develop in a cell, the immune system is ready to inactivate the virus and destroy the infected cell”.

According to CSIC’s researcher: “If this genetic cocktail passes Phase II and Phase III future clinic trials, and makes it into production, in the future HIV could be compared to herpes virus nowadays”. Virus would not cause a disease anymore and would become a minor chronic infection, which would only show its effects in a low defence scenario, with a much lower contagious profile.