Leras Blog

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.

The finding, reported online and in the August edition of Antimicrobial Agents and Chemotherapy, is particularly important for those living in societies plagued by obesity, said Dr. Tawanda Gumbo, associate professor of internal medicine at UT Southwestern and the study’s lead author.

"What really drives the variability of this particular drug is patient weight and gender, so in our simulations we took that into account," Dr. Gumbo said. "What we found is that we’re really using doses for very skinny people – 105 to 110 pounds. I haven’t met many adults who are at that weight."

About one-third of the world’s population is infected with Mycobacterium tuberculosis, the bacterium that causes TB, and as many as 2 million people die from the disease each year. TB, which is the leading cause of death among people infected with HIV/AIDS, kills more people than any other disease caused by a single infectious agent, according to the National Institutes of Health. Treatment usually lasts six to 12 months and includes a combination of antibiotics such as Pyrazinamide, the drug examined in this study.

Because treatment typically includes multiple drugs, introducing new ones to existing regimens has made it harder to identify which, if any, of the drugs are working at the current dosage levels. Researchers also have struggled to identify the needed dosage as well as exactly where in the body these drugs work to combat the bacterium.

The new model developed at UT Southwestern uses cultured cells to gauge the effectiveness and proper dosage of anti-tuberculosis drugs.

"With this model, we can directly test molecules that have the potential to shorten therapy and go straight to coming up with the doses that you would use in patients," Dr. Gumbo said. "What that means is that if you have a molecule that could cure TB in one month in this model, it stands a good chance that it would do the same in patients."

For this study, the researchers gave patients Pyrazinamide – an older drug generally used in combination with other drugs – daily for one month. The researchers then used the data collected to calculate how much bacteria the drug killed before resistance emerged. They opted to focus on Pyrazinamide because physicians once used it alone to treat the disease, so there are many studies documenting precisely how the drug behaves in patients – something that is unclear for some newer drugs.

When the UT Southwestern researchers began testing Pyrazinamide in the lab, they found that the concentration of the drug declined at a rate that matches the rate seen in patients.

"In patients, unlike in test tubes, it’s not a constant concentration. A patient given multiple drugs degrades each of them at different rates," he said. "Using this model, we can actually copy this concentration profile of the drugs to human-like exposures."

Dr. Gumbo said his team’s finding that the doses traditionally given to tuberculosis patients are much too low suggests that different doses are probably needed in different countries. "Most of the patients we see here in Dallas are not 110 pounds unless they have some other severe disease," he added.

The next step, Dr. Gumbo said, is to continue researching drug combinations in order to devise the optimum treatment regimen for tuberculosis patients.

"We’ve rationally and scientifically come up with a dose that depends not just on the kinetics or the concentration time profile of patients, but also how the bug itself responds to that particular drug," he said. "So, instead of using the average patient or a mean patient, we can now project how a drug combination will fare in actual patients. With this model, researchers can use these simulations to determine the duration of therapy, which could shorten from years to months."

Also involved in the study were UT Southwestern’s Dr. Wasana Siyambalapitiyage, a research associate in internal medicine, and researchers from Texas Tech University Health Sciences Center’s School of Pharmacy, DFW campus.

Surgeons and audiologists from Penn are the first in Pennsylvania to implant this device and are participating in current clinical trials assessing the benefits of the new capabilities of the CII Bionic Ear. The Bionic Ear is marketed by Advanced Bionics Corporation under the trade name CLARION® CII Bionic Ear®. It can deliver sound information directly to the hearing nerve up to 1 million times a second– significantly faster than conventional cochlear implant technology– which delivers sound information under 20,000 times each second.

“The Bionic Ear is a great advance in cochlear implant technology,” said Douglas C. Bigelow, MD, senior neurotologist at Penn who, along with neurotologist Michael Ruckenstein, MD, has implanted over 100 profoundly deaf adults with cochlear implants. Dr. Bigelow serves as Principal Investigator in the proposed clinical study of the CII Bionic Ear. “The new advanced speech processing strategies used in this implant have the potential to help people with severe to profound hearing loss regain much of their hearing. The improvement in quality-of-life that this technology offers can be quite dramatic.”

Conventional cochlear implants do not have internal electronic memory banks and control electronics to store hearing programs directly in the implant. Therefore, they rely on the external sound processor to continuously transmit all hearing program instruction to the implant electronics.

Continuous transmission of hearing program parameters occupies much of the data and information pipeline to the implant and leaves limited room for the transmission of detailed sound signal. As a result, conventional cochlear implants can deliver only a small, custom subset of full sound signals to the hearing nerve, and must discard many of the important fine details of speech and sound.

The high resolution CI Bionic Ear can directly store all hearing program parameters in the internal electronic memory banks, leaving the data and information pipeline open for the fine details of sound. This advance design allows the miniature sound processor to be dedicated to transmitting the full broadband signal to the powerful electronics of the Bionic Ear, resulting in more and better sound information delivered to the hearing nerve in much greater detail.

“Today, more and more patients achieve higher levels of speech understanding in shorter periods of time. The CII Bionic Ear System can offer patients fuller sound signals at faster speeds,” said Michelle Montes, MS, coordinator of cochlear implant services in Penn’s department of Audiology. “These advancements have the potential to provide more detailed speech and sound information with improved fidelity. The CII technology will undoubtedly contribute to growth in patient benefit and provide an invaluable platform for future cochlear implant improvements. It’s exciting to be a part of this process.”

Candidates for the new Bionic Ear include children who are born deaf and adults who have lost their hearing. Most health insurance carriers, including Medicare, cover the cost of the implanted device and surgery. The surgery, which takes between two and four hours, does require follow-up treatment. Patients will need multiple outpatient appointments with an audiologist.

Olga Modlich
and colleagues, from the University of Düsseldorf and Bayer HealthCare
AG in Germany, analysed samples of breast tissue from five healthy
individuals and tumour tissue from fifty-six breast cancer patients
treated with preoperative systemic chemotherapy (PST) with a
combination of the anti-cancer drugs epirubicin and cyclophosphamide.
The genes present in the samples were analysed using a DNA microarray -
a collection of microscopic DNA spots attached to a solid surface used
to measure the expression levels of large numbers of genes
simultaneously.

From the DNA microarray analysis the authors were
able to identify a total of fifty-seven ‘predictor’ genes active in
tumours: thirty-one genes associated with a favourable response and
twenty-six genes associated with a poor response. The authors then
tested the ability of these genes to predict the response of
twenty-seven breast cancer patients, who were then treated with PST.

The
predictor genes could be used to correctly predict the outcome of PST
in all cases of partial remission and nearly 75% of cases of complete
remission of primary tumours. According to the authors the use of
microarray technology to identify genes that can predict response to
chemotherapy could represent a powerful tool to identify patients for
whom PST is the most appropriate, and would be the most successful form
of treatment.

Currently, decisions about whether to use
chemotherapy as a breast cancer treatment are based on factors such as
patients’ age and type and size of tumour. These factors do not provide
sufficient information to tailor treatment to the individual patient.
Nearly all breast cancer patients receive standard chemotherapy
treatment, despite the potential for a poor response to therapy,
adverse side effects and excess healthcare costs. According to the
authors “the identification of molecular markers predictive of
patients’ responsiveness to treatment is becoming a central focus of
research”. The ability to predict a patient’s response to chemotherapy
for breast cancer would be of benefit to doctors and patients, shifting
the focus away from a standard treatment for all patients and towards
treatment based on predictions made from patients’ genetic background.

Huntington’s disease was first identified more than 125 years ago, and often inhibits speech, movement, reasoning and memory. The result of an abnormal Huntington gene, the hereditary disorder is estimated to affect one out of every 10,000 people. Though some current pharmacological treatments do address symptoms, scientists have been unable to stop the disease’s progression.

However, scientists at Emory are making headway in the search for a cure. The findings that appear in the May 31 issue of the Journal of Neuroscience are the latest of more than a decade of Huntington’s disease-related discoveries led by Xiao-Jiang Li, PhD, professor of human genetics at Emory University School of Medicine.

Juan Rong, doctoral student in the neuroscience graduate program at the Emory University School of Medicine, is the lead author of the article. The senior author, Dr. Li, first discovered the protein HAP1 as a postdoctoral fellow in 1995. In previous articles, he has identified the importance of HAP1 to the normal functioning of the hypothalamus, a region of the brain that acts as a central switchboard to regulate feeding and other body functions. Earlier this year, Dr. Li’s group published an article identifying HAP1′s role connecting insulin to the hypothalamus in the journal Nature Medicine.

"This protein is very important," says Dr. Li. "When an animal does not have HAP1 it dies after birth. Certainly, it’s essential for differentiation and survival of some neurons in the brain."

In this latest paper, Dr. Li, Ms. Rong, and their colleagues used cellular models to show that HAP1 normally links to transport proteins, including the growth factor receptor tyrosine kinase (TrkA), in growing neurites. HAP1 protects TrkA from degrading, ensuring the neurites continue to develop. This trafficking function is regulated by the addition of phosphate and oxygen to the HAP1 protein, a process known as phosphorylation.

However, when mutant huntingtin is present, the Emory researchers have found that this disease protein stops HAP1 from fulfilling its trafficking function. HAP1 cannot prevent the degradation of TrkA. The insufficient amount of TrkA cannot maintain the normal function of nerve terminals.

Although the discovery that HAP1 works as a transporter and plays a crucial role in neuronal function was obtained from cell models, it will assist scientists as they continue to look for a cure for Huntington’s disease. Dr. Li’s current experiments involve selective HAP1 deletions from neurons in animal models, and his results are sure to offer relevant clues to the mechanisms behind Huntington’s disease.

Says Dr. Li, "If we can find the pathogenesis for Huntington’s disease, or if we know how the mutant huntingtin affects the transporting inside cells, maybe then we can find some effective treatment to prevent this kind of defect."

Research into other neurodegenerative disorders may also benefit from a thorough understanding of HAP1. "This work also has implications for understanding the normal physiological processing for neuronal functioning," says Dr. Li.

The research was supported by the National Institutes of Health.

Epidemiologists found that evidence pointed to the ground beef as the problem taco ingredient. A strain of E coli, which can cause people to suffer bloody diarrhea and renal problems, occurs in the manure of some healt hy cattle; any meat that comes into contact with that manure in slaughterhouses can become contaminated. In this study, a slaughterhouse in Idaho was the source of beef that was distributed to several Mexican-style restaurants in California and Nevada. The single Arizona restaurant affected by the outbreak may have been supplied with meat transferred from Nevada.

E coli can be killed by cooking ground meat to at least 160º F. When inspectors examined the restaurants’ self-monitored temperature data after being notified of the potential exposure to E coli, the documents showed a flaw in only one of the restaurants’ meat handling. However, that doesn’t necessarily mean the other restaurants did everything correctly.

"The reality is that by time the illnesses are diagnosed, the reports are submitted to the health department, and the epidemiological study is completed, it could be weeks since the actual exposure to the contaminated food," said Dr. Michele Jay of the California Department of Health Services and lead author of the study. "Additionally, investigators are depending on written records from the food facilities that may be incomplete."

There are, however, potential solutions on the horizon to help combat E coli outbreaks. The U.S. Department of Agriculture’s Animal and Plant Health Inspection Service plans to phase in a tracking system over the next five years that would enable the tracing of meat products back to their sources. Such a system would also allow epidemiologists to compare distribution of human illness cases with distribution of the food in question.

In the meantime, doctors need to watch patients for symptoms of E coli and other foodborne illness, which may include bloody or prolonged diarrhea, weight loss, fever, and vomiting, said Dr. Jay. Very old, very young, and immunocompromised patients are more susceptible to E coli, and physicians should be sure to ask about activities that could have put patients at risk for the infection, such as eating raw or undercooked food, drinking unpasteurized milk, coming into contact with farm animals, or visiting a farm.

"Early melanoma detection is the cornerstone of effective treatment, but guidelines remain sparse regarding appropriate screening procedures for both the general population as well as high-risk patients," the authors write as background information in the article. "While it is known that screening identifies melanomas at an earlier stage than would be found otherwise and that physicians detect melanomas with less tumor thickness, the U.S. Preventive Services Task Force states that current evidence is insufficient to recommend for or against routine screening. The population seen in skin cancer screenings differs markedly from that seen in a dermatology practice with a high-risk patient population."

Jonathan Kantor, M.D., M.S.C.E., and Deborah E. Kantor, M.S.N., C.R.N.P., of North Florida Dermatology Associates, Jacksonville, analyzed 126 cases of melanoma diagnosed at the practice between July 2005 and October 2008. Of these, 51 cases were invasive (had spread to deeper layers of the skin) and 75 were in situ.

Overall, 56.3 percent of all melanomas and 60 percent of melanomas in situ were detected by the dermatologists and were not among the reasons the patient had visited the clinic. "A greater proportion of melanomas in the physician-detected group (mean [average], 63.4 percent) than in the patient-detected group (mean, 54.5 percent) were in situ," the authors write.

Dermatologist detection was also associated with thinner melanomas. "Including only invasive melanomas, the median [midpoint] melanoma depth for the physician-detected group was 0.33 millimeters, and for the patient-detected group the median depth was 0.55 millimeters," they continue. Patients whose melanoma was detected by a clinician were significantly more likely to have cancers thinner than 1 millimeter.

"These data suggest that minimizing the substantial public health and financial impact of melanoma may be aided by a full-body skin examination. While self-examination plays a critical role in early detection, prior studies have suggested that physicians, and dermatologists in particular, may be better able to detect melanomas with lesser tumor thickness. Because increasing tumor thickness is closely correlated with decreasing survival, it follows that complete examination plays an important role, particularly in high-risk populations," the authors write.

"Further research in this area, and in the cost-effectiveness of screening, may lead to important changes in practice that could potentially reduce melanoma mortality and improve patient outcomes," they conclude.

Editorial: Findings Add to Body of Evidence for Screenings

"In this issue of the Archives, Kantor and Kantor provide new data on the topic of melanoma screening," write Daniel G. Federman, M.D., of VA Connecticut Health Care, West Haven, and colleagues in an accompanying editorial.

"Does this report, along with similar reports, provide convincing evidence that screening with full-body skin examination decreases melanoma-related mortality? The results, although provocative, are not definitive."

"At this time, we see the metaphorical glass with respect to screening for skin cancer as ‘half full’," the editorial authors conclude. "Findings from suitable reports, such as the article by Kantor and Kantor, contribute information that adds incrementally to our understanding of the issues involved. Perhaps we can sip from the glass (i.e., consider full-body skin examination to be a reasonable approach), assuming that future studies will eventually fill the remaining half with fine wine."

Growth pattern refers to the tumor growth in relation to normal lung tissue and blood vessels within the tumor; tumors need these blood vessels to survive and scientists have been studying these patterns in an effort to individualize therapy.

In data presented at the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer, researchers classified tumors into three growth patterns: destructive, alveolar and papillary. In destructive patterns, the tumor makes its own microenvironment for further growth. In the alveolar pattern, the tumor uses the microenvironment of the lung to grow, and in the papillary pattern the normal lung tissue is preserved in the presence of a new microenvironment.

Peyman Sardari Nia, M.D., Ph.D., a postdoctoral fellow at the University of Antwerp in Belgium, and colleagues tested this classification to see if they had prognostic value in patients with non-small cell lung cancer.

"The current management, treatment and prognosis of lung cancer is treatment based on tumor-node-metastasis staging," said Sardari Nia. "Unfortunately, tumor node metastasis does not account for survival differences in the same stage and does not provide information about the biology of the tumor."

For this study, Sardari Nia and colleagues enrolled 432 patients who had a complete resection for primary non-small cell lung cancer. The researchers followed the patients for about 50 months. According to the classifications outlined, 71.1 percent had a destructive growth pattern, 13.9 percent had a papillary growth pattern and 15 percent had an alveolar growth pattern. These growth patterns were independent predictors for overall survival, disease-specific survival and disease-free survival.

Patients with an alveolar growth pattern had a 52 percent greater chance of a poor prognosis for overall survival and a nearly two-fold increased risk for poorer disease-specific survival and for disease-free survival.

"This biological classification provides explanations for survival differences at the same disease stage," said Sardari Nia. "Additionally, these growth patterns represent distinct biologic subtypes implying that different growth patterns might respond differently to the pallet of treatment modalities, paving the way for individualization of the patient’s treatment."

HCV affects up to 170,000 million individuals worldwide and is a leading cause of chronic liver disease and a primary indication for liver transplantation according to the World Health Organization (WHO). The Centers for Disease Control and Prevention (CDC) estimates that 2.7 to 3.9 million Americans are living with chronic HCV with roughly 12,000 deaths reported each year. WHO has reported up to 20% of HCV patients develop cirrhosis and 1% to 5% die from cirrhosis or liver cancer.

"Fibrosis progression can be highly unpredictable and accurate classification of the stage of fibrosis is extremely important," said Dr. Jérôme Boursier from Centre Hospitalier Universitaire d’Angers in France. "A diagnostic algorithm that provides similar accuracy as successive classifications without the need of liver biopsy to determine the extent of fibrosis is highly beneficial to patients."

Dr. Boursier and colleagues evaluated the Sequential Algorithm for Fibrosis Evaluation (SAFE) and Bordeaux algorithm (BA), compared to a more detailed classification for determining fibrosis severity. The team used data for 1785 patients with chronic HCV who were enrolled in 3 previous study populations (SNIFF, VINDIAG, and FIBROSTAR), representing a total of 31 centers throughout France. Data included liver biopsy, blood fibrosis test, and Fibroscan — an ultrasound technology used to assess liver fibrosis (stiffness).

The team found that successive SAFE diagnostic accuracy was 87% — significantly lower than the individual SAFE devoted for the diagnosis of significant fibrosis (F≥2) at 95% or for cirrhosis (F4) at 90%. The number of liver biopsies required with successive SAFE was significantly higher than individual SAFE for F≥2 or SAFE for F4 at 71% compared to 64% and 6%, respectively. Researchers also reported similar results with successive BA diagnostic accuracy at 85% compared to individual BA at 88% (F≥2) and 94% (F4). More biopsies were required for successive versus individual BA at 50% compared to 35% and 25%, respectively.

"Our findings show that SAFE and BA diagnostic testing are highly accurate in determining fibrosis or cirrhosis in patients with HCV," said Dr. Boursier. However, a high percentage of patients also required liver biopsy to confirm the diagnosis. The authors creation of a new classification which synchronously combines two fibrosis tests (FibroMeter + Fibroscan) was as accurate as successive SAFE or BA at 87%, and did not require any liver biopsy. "The new non-invasive classification of fibrosis is as accurate as successive SAFE or BA, but is more precise with six fibrosis classes and entirely non-invasive with no liver biopsy required," concludes Dr. Boursier.

Dr Alyssa Barry from the Walter and Eliza Hall Institute’s Infection and Immunity division is using ‘protein microarray’ technology to screen human blood serum samples for immunity to proteins produced by the malaria-causing Plasmodium falciparum parasite. Her research, which determines a person’s immunity to hundreds of proteins simultaneously, has been published in the journal Molecular and Cellular Proteomics this month.

Malaria is a mosquito-borne disease that affects more than 500 million people each year. It causes more than one million deaths, mostly in children under five years of age.

Dr Barry is investigating how humans living in countries where malaria is prevalent, such as Papua New Guinea, establish immunity that protects them from developing malaria.

The malaria parasite has evolved many ways to evade the immune system, Dr Barry said. "We know that one protein, called PfEMP1, that is particularly important for the host immune response can be produced in many different varieties, and these can be altered by the parasite to avoid detection by the immune system."

Dr Barry and colleagues at the Queensland Institute of Medical Research, the Papua New Guinea Institute of Medical Research and the University of California Irvine adapted existing protein microarray technology to allow small samples of human serum (less than one hundredth of a millilitre) to be tested simultaneously against hundreds of variants of PfEMP1 to determine to which variants the person was immune.

Dr Barry said the testing revealed that in a small region of Papua New Guinea where malaria is endemic, children under the age of two are immune to only a few specific variants of PfEMP1 while older children and adults show immunity to an increasing range of PfEMP1 variants.

"Young children are the most vulnerable to malaria," she said. "Our studies show that this is partly because they have not developed immunity to the many different malaria variants to which they are exposed. As people get older, they become immune to a wider spectrum of malaria parasites, and so when they are infected they develop milder disease and eventually do not develop disease at all, although they can still be infected."

The research team is now undertaking a larger study that will screen more people from other regions of Papua New Guinea, and will screen a wider variety of Plasmodium protein variants.

Dr Barry said she hoped the research would lead to the development of a diagnostic test for susceptibility to malaria, and also determine which proteins might be the best to use as the basis for a malaria vaccine. "We currently do not know how people become immune to malaria," she said. "Our protein microarray technology could assist in monitoring malaria control and elimination programs, by showing when a population becomes more susceptible to the disease as a result of waning immunity."

The research was supported by the National Health and Medical Research Council, the National Institutes of Health (US), the Wellcome Trust (UK), the Victorian Endowment for Science Knowledge and Innovation (VESKI), Pfizer Australia, and the Victorian Government. The research was conducted while Dr Barry was employed by the Burnet Institute.