Tissues tell the tale: Non-invasive optical technique detects cancer by looking under the skin

Sep. 24, 2012 — The trained eye of a dermatologist can identify many types of skin lesions, but human sight only goes so far. Now an international team of researchers has developed an advanced optics system to noninvasively map out the network of tiny blood vessels beneath the outer layer of patients' skin, potentially revealing telltale signs of disease. Such high resolution 3-D images could one day help doctors better diagnose, monitor, and treat skin cancer and other skin conditions.

The research was published September 24 in the Optical Society's (OSA) open-access journal Biomedical Optics Express.

Researchers from Medical University Vienna (MUW) in Austria and the Ludwig-Maximilians University in Munich, Germany, used a technique called optical coherence tomography (OCT) to "see" beneath the surface of skin. The researchers tested their system on a range of different skin conditions, including a healthy human palm, allergy-induced eczema on the forearm, dermatitis on the forehead, and two cases of basal cell carcinoma -- the most common type of skin cancer -- on the face. Compared to healthy skin, the network of vessels supplying blood to the tested lesions showed significantly altered patterns. "The condition of the vascular network carries important information on tissue health and its nutrition," says Rainer Leitgeb, a researcher at MUW and the study's principal investigator. "Currently, the value of this information is not utilized to its full extent."

Ophthalmologists have used OCT since the 1990s to image different parts of the eye and the technology has recently attracted increased interest from dermatologists. OCT has many advantages over other imaging techniques: It is non-invasive and provides high-resolution images at high speed. OCT is typically used to show tissue structure, but it can also reveal the pattern of blood vessels, which carry important clues about disease, by capitalizing on the unique optical properties of flowing blood cells.

The researchers at MUW are the first to use OCT to visualize the network of blood vessels in human skin that feed cancerous skin lesions. To maximize the quality of the images the team employed a high-tech laser light source developed by collaborators from the Ludwig-Maximilians University. The laser enabled unprecedented high-speed imaging and operated at a near-infrared wavelength that gave better penetration into skin tissue.

"High speed is of paramount importance in order to image lesions in vivo and in situ while minimizing the effect of involuntary patient motion," explains researcher Cedric Blatter of MUW. The device also shapes the light in a special way forming a Bessel beam, which can reform, or heal, its shape even if portions of it are blocked. The beam enabled the researchers to keep the images in focus across a depth range of approximately 1 millimeter.

The team's images of basal cell carcinoma showed a dense network of unorganized blood vessels, with large vessels abnormally close to the skin surface. The larger vessels branch into secondary vessels that supply blood to energy-hungry tumor regions. The images, together with information about blood flow rates and tissue structure, could yield important insights into the metabolic demands of tumors during different growth stages.

The imaging system shows the most promise for clinical application in the diagnosis and treatment of skin cancer, the researchers believe. "We hope that improved in-depth diagnosis of tissue alterations due to disease might help to reduce the number of biopsies by providing better guidance," says Leitgeb. The system could also be used by doctors to assess how quickly a tumor is likely to grow and spread, as well as to monitor the effectiveness of treatments such as topical chemotherapy. "Treatment monitoring may also be expanded toward inflammatory and auto-immune related dermatological conditions," Blatter notes.

Going forward, the researchers would like to increase the field of view of the device so that they can image the full lesion along with its border to healthy tissue. They are also working on speeding up the post-processing of the optical signal to enable live vasculature display, and improving the portability of the system, which currently occupies an area about half the size of an office desk. "We believe that in the future our method will help to simplify non-invasive dermatological in vivo diagnostics and allow for in-depth treatment monitoring," says Blatter.

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Cedric Blatter, Jessika Weingast, Aneesh Alex, Branislav Grajciar, Wolfgang Wieser, Wolfgang Drexler, Robert Huber, Rainer A. Leitgeb. In situ structural and microangiographic assessment of human skin lesions with high-speed OCT. Biomedical Optics Express, 2012; 3 (10): 2636 DOI: 10.1364/BOE.3.002636

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Melanoma manifests differently in children than in adults, study finds

Sep. 7, 2012 — Melanoma, newly diagnosed in more than 76,000 Americans in 2011, is the most common and dangerous form of skin cancer. Melanoma is rare in children, accounting for 1 to 4 percent of all melanoma cases and just 3 percent of pediatric cancers. Just as adult cases of melanoma are increasing, pediatric melanoma is rising at the rate of 1 to 4 percent per year.

The physicians and staff at Moffitt Cancer Center have a special interest in melanoma and related conditions occurring in childhood, and recently published results of their experience with cases of pathologically confirmed childhood melanoma. They found evidence that the disease manifests differently in children than in adults, particularly with regard to the likelihood and significance of lymph node metastases. Metastases to the lymph nodes, particularly the sentinel nodes, were found more frequently in children with melanoma than would be expected in adults with the same stage of disease, yet with aggressive surgical and medical treatment, stage-for-stage the survival in children was better than expected for adults.

The study is published in the August issue of the Annals of Surgical Oncology.

"We really don't know why young children are getting melanoma, although for older children the risk factors -- fair skin, sun exposure and especially sunburns -- are similar to those in adults. Children with melanoma have higher rates of metastases to sentinel lymph nodes than adults, but they tend to do very well with aggressive treatment," said senior study author Vernon K. Sondak, M.D., chair of the Department of Cutaneous Oncology at Moffitt and an expert in the treatment of melanoma in children and adults. "There is suggestive evidence that the biology of melanoma in children, particularly young children, may be quite different than in adults. Importantly, the diagnosis of melanoma in children can be quite difficult, and consultation with an expert pathologist is often necessary to be sure that we are in fact dealing with melanoma and not some type of atypical mole. Our most recent study focused only on patients where our pathologist verified that melanoma was present, atypical tumors were excluded."

In this study, Moffitt researchers and colleagues at the University of South Florida and All Children's Hospital retrospectively reviewed 126 patients who were diagnosed with melanoma before age 21. One aspect of the study was to determine outcomes of childhood cases of melanoma where the patient had sentinel lymph nodes positive for metastases. The sentinel lymph node directly drains the skin where the primary tumor arose and is almost always the first node affected as a melanoma spreads. Primary tumor characteristics that may predict sentinel lymph node metastases in pediatric patients have not been extensively studied. Sentinel lymph node biopsies were performed in 62 cases, with 18 having a positive node. In the other 64 cases where a sentinel lymph node biopsy was not performed, the reasons were usually because the stage of the melanoma was not appropriate for the procedure.

"We observed a 29 percent positive sentinel lymph node rate," said Sondak, noting that the rate fell within the 25 to 40 percent rate found by other studies done in children, but higher than the 12 to 15 percent rate typically found in studies in adult melanoma. "We found that patients with positive SLN had significantly thicker melanomas when compared with SLN negative patients."

The researchers also found that pediatric melanoma patients with positive SLN had significantly worse recurrence-free survival and melanoma-specific survival rates. However, although lymph node metastases are seen at a higher rate in children, survival is comparable to -- or even better than -- what has been reported for adults with melanoma. According to Sondak, as the incidence of pediatric melanoma rises, it is important to gain a better understanding of the unique clinical characteristics of melanoma in children.

"We feel that most pediatric patients with clinically localized melanomas should be offered sentinel lymph node biopsies," concluded Sondak and his co-authors. "It is also noteworthy that a significant number of recurrences and melanoma-related deaths are seen more than five years after initial diagnosis. Thus, long-term follow-up is necessary as these children become young adults. Most of all, our study should remind people how important it is to protect children from the sun and from sunburn, starting from birth."

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The above story is reprinted from materials provided by H. Lee Moffitt Cancer Center & Research Institute.

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Dale Han, Jonathan S. Zager, Gang Han, Suroosh S. Marzban, Christopher A. Puleo, Amod A. Sarnaik, Damon Reed, Jane L. Messina, Vernon K. Sondak. The Unique Clinical Characteristics of Melanoma Diagnosed in Children. Annals of Surgical Oncology, 2012; DOI: 10.1245/s10434-012-2554-5

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Going viral to kill zits: Scientists uncover virus with potential to stop pimples in their tracks

Sep. 25, 2012 — Watch out, acne. Doctors soon may have a new weapon against zits: a harmless virus living on our skin that naturally seeks out and kills the bacteria that cause pimples.

The Sept. 25 online edition of the American Society for Microbiology's mBio publishes the findings by scientists at UCLA and the University of Pittsburgh.

"Acne affects millions of people, yet we have few treatments that are both safe and effective," said principal investigator Dr. Robert Modlin, chief of dermatology and professor of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA. "Harnessing a virus that naturally preys on the bacteria that causes pimples could offer a promising new tool against the physical and emotional scars of severe acne."

The scientists looked at two little microbes that share a big name: Propionibacterium acnes, a bacterium thriving in our pores that can trigger acne; and P. acnes phages, a family of viruses that live on human skin. The viruses are harmless to humans, but programmed to infect and kill the aforementioned P. acnes bacteria.

When P. acnes bacteria aggravate the immune system, it causes the swollen, red bumps associated with acne. Most effective treatments work by reducing the number of P. acnes bacteria on the skin.

"We know that sex hormones, facial oil and the immune system play a role in causing acne, however, a lot of research implicates P. acnes as an important trigger," explained first author Laura Marinelli, a UCLA postdoctoral researcher in Modlin's laboratory. "Sometimes they set off an inflammatory response that contributes to the development of acne."

Using over-the-counter pore cleansing strips from the drugstore, the researchers lifted acne bacteria and the P. acnes viruses from the noses of both pimply and clear-skinned volunteers.

When the team sequenced the bacteriophages' genomes, they discovered that the viruses possess multiple features -- such as small size, limited diversity and the broad ability to kill their hosts -- that make them ideal candidates for the development of a new anti-acne therapy.

"Our findings provide valuable insights into acne and the bacterium that causes it," observed corresponding author Graham Hatfull, Eberly Family Professor of Biotechnology, professor of biological sciences at the University of Pittsburgh and a Howard Hughes Medical Institute researcher. "The lack of genetic diversity among the phages that attack the acne bacterium implies that viral-based strategies may help control this distressing skin disorder."

"Phages are programmed to target and kill specific bacteria, so P. acnes phages will attack only P. acnes bacteria, but not others like E. coli," added Marinelli. "This trait suggests that they offer strong potential for targeted therapeutic use."

Acne affects nearly 90 percent of Americans at some point in their lives, yet scientists know little about what causes the disorder and have made narrow progress in developing new strategies for treating it. Dermatologists' arsenal of anti-acne tools -- benzoyl peroxide, antibiotics and Accutane -- hasn't expanded in decades.

"Antibiotics such as tetracycline are so widely used that many acne strains have developed resistance, and drugs like Accutane, while effective, can produce risky side effects, limiting their use," explained coauthor Dr. Jenny Kim, director of the UCLA Clinic for Acne, Rosacea and Aesthetics. "Acne can dramatically disfigure people and undermine their self-esteem, especially in teens. We can change patients' lives with treatment. It's time we identified a new way to safely treat the common disorder."

The research team plans to isolate the active protein from the P. acnes virus and test whether it is as effective as the whole virus in killing acne bacteria. If laboratory testing proves successful, the researchers will study the compound's safety and effectiveness in combating acne in people.

The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR060382, R01 AR053542 and F32AR060655) at the National Institutes of Health in Bethesda, Md.

Additional coauthors included Sorel Fitz-Gibbon, Megan Inkeles, Shawn Cokus, Matteo Pellegrini and Jeffrey F. Miller, all of UCLA; former UCLA researchers Clarmyra Hayes and Anya Loncaric, now of the California Institute of Technology and Solta Medical, respectively; and Charles Bowman, Daniel Russell and Deborah Jacobs-Sera of the University of Pittsburgh.

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The above story is reprinted from materials provided by University of California, Los Angeles (UCLA), Health Sciences.

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Laura J. Marinelli, Sorel Fitz-Gibbon, Clarmyra Hayes, Charles Bowman, Megan Inkeles, Anya Loncaric, Daniel A. Russell, Deborah Jacobs-Sera, Shawn Cokus, Matteo Pellegrini, Jenny Kim, Jeff F. Miller, Graham F. Hatfull, and Robert L. Modlin. Propionibacterium acnes Bacteriophages Display Limited Genetic Diversity and Broad Killing Activity against Bacterial Skin Isolates. mBio, 2012 DOI: 10.1128/mBio.00279-12

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Happy face tattoo does serious work

Dec. 3, 2012 — A medical sensor that attaches to the skin like a temporary tattoo could make it easier for doctors to detect metabolic problems in patients and for coaches to fine-tune athletes' training routines. And the entire sensor comes in a thin, flexible package shaped like a smiley face.

"We wanted a design that could conceal the electrodes," says Vinci Hung, a PhD candidate in the Department of Physical & Environmental Sciences at UTSC, who helped create the new sensor. "We also wanted to showcase the variety of designs that can be accomplished with this fabrication technique."

The new tattoo-based solid-contact ion-selective electrode (ISE) is made using standard screen printing techniques and commercially available transfer tattoo paper, the same kind of paper that usually carries tattoos of Spiderman or Disney princesses. In the case of the sensor, the "eyes" function as the working and reference electrodes, and the "ears" are contacts for a measurement device to connect to.

Hung contributed to the work while in the lab of Joseph Wang, a distinguished professor at the University of California San Diego. She worked there for six months earlier this year under the Michael Smith Foreign Study supplement from NSERC.

"It was a wonderful opportunity," Hung said. She worked directly with Wang, who is well-known for his innovations in the field of nanoengineering and is a pioneer in biosensor technology.

The sensor she helped make can detect changes in the skin's pH levels in response to metabolic stress from exertion. Similar devices, called ion-selective electrodes (ISEs), are already used by medical researchers and athletic trainers. They can give clues to underlying metabolic diseases such as Addison's disease, or simply signal whether an athlete is fatigued or dehydrated during training. The devices are also useful in the cosmetics industry for monitoring skin secretions.

But existing devices can be bulky, or hard to keep adhered to sweating skin. The new tattoo-based sensor stayed in place during tests, and continued to work even when the people wearing them were exercising and sweating extensively. The tattoos were applied in a similar way to regular transfer tattoos, right down to using a paper towel soaked in warm water to remove the base paper.

To make the sensors, Hung and her colleagues used a standard screen printer to lay down consecutive layers of silver, carbon fiber-modified carbon and insulator inks, followed by electropolymerization of aniline to complete the sensing surface.

By using different sensing materials, the tattoos can also be modified to detect other components of sweat, such as sodium, potassium or magnesium, all of which are of potential interest to researchers in medicine and cosmetology.

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Amay J. Bandodkar, Vinci W. S. Hung, Wenzhao Jia, Gabriela Valdés-Ramírez, Joshua R. Windmiller, Alexandra G. Martinez, Julian Ramírez, Garrett Chan, Kagan Kerman, Joseph Wang. Tattoo-based potentiometric ion-selective sensors for epidermal pH monitoring. The Analyst, 2013; 138 (1): 123 DOI: 10.1039/C2AN36422K

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First appropriate use criteria in dermatology released

Sep. 7, 2012 — A new manuscript co-published in the Journal of the American Academy of Dermatology (JAAD) and Dermatologic Surgery outlines Appropriate Use Criteria (AUC) for Mohs surgery -- the first AUC for any test or treatment within the field of dermatology.

The Mohs AUC represents a collaborative initiative by the American Academy of Dermatology (Academy), American College of Mohs Surgery (ACMS), the American Society for Dermatologic Surgery Association (ASDSA), and the American Society for Mohs Surgery (ASMS).

"These Appropriate Use Criteria for Mohs surgery embody a unique effort to develop criteria to support the efficient use of medical resources while providing the highest quality care for the patients who will benefit the most," said board-certified dermatologist Suzanne M. Connolly, MD, FAAD, chair, Ad Hoc Task Force on the Development of Appropriate Use Criteria for Mohs Surgery. "The goal of the AUC is to provide evidence-based guidance on which types of skin cancer cases are most appropriate for this specialized surgery."

Statistics and facts:

More than 3.5 million skin cancer cases affecting 2 million people are diagnosed annually.Current estimates are that one in five Americans will be diagnosed with skin cancer in their lifetime.

About Mohs Surgery

Mohs surgery is a specialized skin cancer surgery in which a dermatologist who has completed additional training in Mohs surgery is able to remove skin cancer layer by layer until the entire tumor has been removed. The Mohs surgeon uses a microscope to examine each tissue layer to look for cancer cells until no further ones are found at any spot around any edges of the tumor. This technique allows the Mohs surgeon to preserve as much healthy tissue as possible, yet remove the entire cancer.

Background

The AUC process was based on the well-established, credible method developed by the RAND Corporation/UCLA more than 30 years ago. AUC have been shown to improve patient selection, clinical outcomes and health-related quality of life while reducing overall cost and resource utilization. The Mohs AUC are the first AUC developed for any test or treatment option within the scope of dermatology.

Study details

The AUC process combines evidence-based medicine, clinical practice experience, and expert judgment.Nearly 80 dermatologists, both Mohs surgeons and non-Mohs dermatologists, contributed to the development of this first AUC for the specialty, including a 17-member ratings panel that was balanced by expertise, society representation, type of practice, and geographic location. To manage potential conflict of interest, the majority of the Ratings Panel members were not Mohs surgeons.The collaboration of dermatologists involved in this process developed AUC for 270 scenarios for which Mohs surgery is frequently considered based on tumor and patient characteristics.The Mohs AUC outline highly specific skin cancer patient scenarios that dermatologists encounter in daily clinical practice and classify the use of Mohs into one of three categories: appropriate, uncertain, or inappropriate.At the conclusion of the rating process, consensus was reached for all 270 scenarios (100 percent) by the ratings panel, with 200 (74.07 percent) deemed as appropriate, 24 (8.89 percent) as uncertain and 46 (17.04 percent) as inappropriate. With few exceptions, all scenarios involving the head, neck, hands, feet and genitalia are rated appropriate. An appropriate rating solely means that Mohs is an acceptable approach for that clinical scenario and patient; other approaches also may be considered based on physician assessment.The benefits of these AUC are expected to be numerous and include: Clinical decision supportFacilitation of discussions with referring physicians and patientsSupport for researchEducational and quality improvement toolsThe Mohs AUC is a living document and intended to be modified as new clinical information is published or encountered in the practice setting. This new evidence may lead to future revisions to ratings as well as the clinical scenarios to more precisely define patient selection for Mohs surgery.

"As the incidence of skin cancer continues to climb and the practice of Mohs surgery advances in the future, Mohs surgeons, dermatologists, primary care providers and the health care community in general will need to understand how to best utilize Mohs surgery in the treatment of skin cancer -- and the AUC we initiated is an important first step in that direction," said Dr. Connolly.

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Ultrasound gel and infections: Researchers propose guidelines to reduce risk

Nov. 12, 2012 — In the December issue of Infection Control and Hospital Epidemiology, the journal of the Society for Healthcare Epidemiology of America, guidelines have been proposed by epidemiologists from Beaumont Health System to reduce the risk of infection from contaminated gels. The recommendations are based on the authors' own experiences with an outbreak traced to contaminated ultrasound transmission gel.

In December 2011, researchers uncovered an unusual cluster of Pseudomonas aeruginosa in a cardiovascular surgery intensive care unit during routine infection control surveillance. The outbreak was found to have stemmed from bottles of ultrasound transmission gel that were contaminated during the manufacturing process and that were being used for intraoperative transesophageal echocardiography. This information ultimately led to a national recall of the product.

These gels contain parabens or methyl benzoate that inhibit, but not kill, the growth of bacteria. However, past studies have demonstrated that ultrasound gels do not have antimicrobial properties and could serve as a medium for bacterial growth. Contaminated gels have been found to be the source of other outbreaks of infection in the last two decades.

"After our investigation of the Pseudomonas outbreak last year linked the source of the outbreak to contaminated ultrasound gel, we were surprised to find that very little guidance is available on appropriate uses for different ultrasound gel products," said Susan Oleszkowicz, MPH, lead author of the paper.

In their article the authors outline initial guidelines for recommended uses of ultrasound transmission gels, calling on manufacturers of ultrasound gel and professional societies to take an active role in developing recommendations for appropriate and intended use of products.

Suggestions include: 1) the need for sterile, single-dose ultrasound gel in any invasive procedure or procedures involving non-intact skin or fresh surgical wounds; 2) sterile, single-dose ultrasound gel should be used with newborns or critically ill children; 3) multi-dose, non-sterile gel can still be used on intact skin, but containers should be sealed appropriately when not in use, and replaced when empty, rather than refilled.

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Susan C. Oleszkowicz, Paul Chittick, Victoria Russo, Paula Keller, Matthew Sims, Jeffrey Band. Infections Associated with Use of Ultrasound Transmission Gel: Proposed Guidelines to Minimize Risk. Infection Control and Hospital Epidemiology, 2012; 33 (12): 1235 DOI: 10.1086/668430

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Kids with psoriasis likely to be obese or overweight

Nov. 19, 2012 — The largest study of physician-treated children with psoriasis around the world shows children with the skin disease are about twice as likely to be overweight or obese as children who don't have the disease, according to new Northwestern Medicine research.

And US children with psoriasis have much higher odds than psoriatic children in other countries of being obese or overweight.

In the US, children with psoriasis had four times the odds of being overweight or obese as healthy controls. Within this US population, Hispanics and African American children had significantly greater rates of being obese and overweight than whites and Asians. The odds ratio of being obese were particularly high for U.S. children with more severe psoriasis (7.6).

"There has been increasing attention to the association of psoriasis and metabolic risks in adults, but this study shows that the association of being overweight or obese and having psoriasis may be even higher in affected children than in adults," said Amy Paller, M.D., chair of dermatology at Northwestern University Feinberg School of Medicine and lead author of the study. She also is a pediatric dermatologist at the Ann and Robert H. Lurie Children's Hospital of Chicago.

The paper was published Nov. 19 in Archives of Dermatology.

"This is incredibly significant," Paller said. "It tells us these children are at increased risk of health complications (cardiac risk and insulin resistance) and need to be watched closely and treated."

The study included 614 children five to 17 years old from nine countries in the Americas, Europe and Asia.

Previous studies showing an association between psoriasis and obesity were largely based on registry data, which is less precise and may under identify cases because of the reliance on diagnosis codes rather than a direct examination and measurements to calculate Body Mass Index.

In this study, about 30 percent of the affected children had an immediate family member with psoriasis, suggesting a strong genetic component. However, the reported family history of obesity was not higher in children with psoriasis than in control children.

"Perhaps our U.S. environment of eating more calories and getting less exercise along with a strong genetic component for the disease hikes the risk," Paller said.

"There is something in the genetic makeup of these kids that predisposes them to these metabolic issues and positions psoriasis as a metabolic disorder," noted Paller, also the Walter J. Hamlin Professor of Dermatology at the Feinberg School. "Psoriasis is driven by many of the same cytokines (proteins) that drive insulin resistance and being overweight."

Psoriasis is characterized by red, often itchy scaling lesions that can be localized (especially to the scalp, knees and elbows) or cover the entire body. The disease affects 2.5 to 3.5 percent of the global population with up to 33 percent of the cases starting in childhood, particularly during adolescence.

"It's a highly visible disease which can be devastating during the all-important years of psychosocial development of childhood and adolescence," Paller said. "It affects their social life and even their ability to participate in sports. Psoriasis has a profound effect on children's quality of life."

The study also looked beyond the commonly used Body Mass Index (BMI) to investigate psoriasis' link to central adiposity (fat around the waist) and the waist-to-height ratio, both of which are believed to have a higher correlation with metabolic risk. Internationally, the odds ratio of having a high waist-to-height ratio that imparted a high level of cardiac risk was 3.1 for all children with psoriasis and 4.1 for those with severe psoriasis.

"The bottom line is these kids need lifestyle intervention," Paller said. "You can't just treat psoriasis. You've got to work with these kids to increase exercise and decrease their caloric intake to reduce their risk for metabolic diseases. Perhaps losing weight could help their psoriasis as well." Previous studies in adults have suggested that weight loss can result in less severe symptoms.

A question not yet answered is which comes first, the psoriasis or the excess fat? Is a high BMI the precursor of psoriasis in children or does the disease lead to an increased BMI through chronic cytokine release from psoriatic tissues, compounded by a lifestyle that may contribute to excess fat? Paller is currently investigating that question.

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The above story is reprinted from materials provided by Northwestern University. The original article was written by Marla Paul.

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Amy S. Paller et al. Association of Pediatric Psoriasis Severity With Excess and Central AdiposityAn International Cross-Sectional StudyPediatric Psoriasis Severity and Excess Adiposity. Archives of Dermatology, 2012; : 1 DOI: 10.1001/jamadermatol.2013.1078

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