Melanoma

Janyana M.D. Deonizio, MD, and Joan Guitart, MD

The purpose of this review is to summarize the most important molecular techniques for the diagnosis of cutaneous lymphomas. When making a diagnosis, we are looking for the solid clinicopathological correlation. Molecular analysis includes immunophenotyping and clonality analysis, and is important for 2 principal reasons: (1) to confirm the diagnosis in cases where the clinical and/or pathological presentations are nondiagnostic, and (2) to further characterize the nature of the lymphoma. More specifically, we are trying to discern whether the lymphoma is primarily cutaneous or systemic with secondary skin involvement, and we are also attempting to subclassify the tumor. Recently, many techniques have provided a more accurate diagnosis of cutaneous lymphomas and some prognostic implications, including polymerase chain reaction, fluorescence in situ hybridization, and flow cytometry. Fluorescence in situ hybridization is not routinely used in the diagnosis of cutaneous lymphoma, but many studies have shown potential future applications in various areas. Other techniques, such as comparative genomic hybridization, are still confined to the research arena, but have added some insight into the molecular pathogenesis of cutaneous T-cell lymphoma.

*For a PDF of the full article, click on the link to the left of this introduction.

Janyana M.D. Deonizio, MD, and Joan Guitart, MD

The purpose of this review is to summarize the most important molecular techniques for the diagnosis of cutaneous lymphomas. When making a diagnosis, we are looking for the solid clinicopathological correlation. Molecular analysis includes immunophenotyping and clonality analysis, and is important for 2 principal reasons: (1) to confirm the diagnosis in cases where the clinical and/or pathological presentations are nondiagnostic, and (2) to further characterize the nature of the lymphoma. More specifically, we are trying to discern whether the lymphoma is primarily cutaneous or systemic with secondary skin involvement, and we are also attempting to subclassify the tumor. Recently, many techniques have provided a more accurate diagnosis of cutaneous lymphomas and some prognostic implications, including polymerase chain reaction, fluorescence in situ hybridization, and flow cytometry. Fluorescence in situ hybridization is not routinely used in the diagnosis of cutaneous lymphoma, but many studies have shown potential future applications in various areas. Other techniques, such as comparative genomic hybridization, are still confined to the research arena, but have added some insight into the molecular pathogenesis of cutaneous T-cell lymphoma.

*For a PDF of the full article, click on the link to the left of this introduction.

Janyana M.D. Deonizio, MD, and Joan Guitart, MD

The purpose of this review is to summarize the most important molecular techniques for the diagnosis of cutaneous lymphomas. When making a diagnosis, we are looking for the solid clinicopathological correlation. Molecular analysis includes immunophenotyping and clonality analysis, and is important for 2 principal reasons: (1) to confirm the diagnosis in cases where the clinical and/or pathological presentations are nondiagnostic, and (2) to further characterize the nature of the lymphoma. More specifically, we are trying to discern whether the lymphoma is primarily cutaneous or systemic with secondary skin involvement, and we are also attempting to subclassify the tumor. Recently, many techniques have provided a more accurate diagnosis of cutaneous lymphomas and some prognostic implications, including polymerase chain reaction, fluorescence in situ hybridization, and flow cytometry. Fluorescence in situ hybridization is not routinely used in the diagnosis of cutaneous lymphoma, but many studies have shown potential future applications in various areas. Other techniques, such as comparative genomic hybridization, are still confined to the research arena, but have added some insight into the molecular pathogenesis of cutaneous T-cell lymphoma.

*For a PDF of the full article, click on the link to the left of this introduction.

Melissa Pulitzer, MD

The association between viruses and skin cancer is increasingly recognized in a number of neoplasms, that is, cutaneous squamous cell carcinoma, Kaposi sarcoma, nasopharyngeal carcinoma, and Merkel cell carcinoma, as well as hematolymphoid malignancies such as adult T-cell leukemia/lymphoma and NK/T-cell lymphoma (nasal type) and post-transplant lymphoproliferative disorders. Molecular assays are increasingly used to diagnose and manage these diseases. In this review, molecular features of tumor viruses and related host responses are explored. The tests used to identify such features are summarized. Evaluation of the utility of these assays for diagnosis and/or management of specific tumor types is presented.

*For a PDF of the full article, click on the link to the left of this introduction.

Melissa Pulitzer, MD

The association between viruses and skin cancer is increasingly recognized in a number of neoplasms, that is, cutaneous squamous cell carcinoma, Kaposi sarcoma, nasopharyngeal carcinoma, and Merkel cell carcinoma, as well as hematolymphoid malignancies such as adult T-cell leukemia/lymphoma and NK/T-cell lymphoma (nasal type) and post-transplant lymphoproliferative disorders. Molecular assays are increasingly used to diagnose and manage these diseases. In this review, molecular features of tumor viruses and related host responses are explored. The tests used to identify such features are summarized. Evaluation of the utility of these assays for diagnosis and/or management of specific tumor types is presented.

*For a PDF of the full article, click on the link to the left of this introduction.

Melissa Pulitzer, MD

The association between viruses and skin cancer is increasingly recognized in a number of neoplasms, that is, cutaneous squamous cell carcinoma, Kaposi sarcoma, nasopharyngeal carcinoma, and Merkel cell carcinoma, as well as hematolymphoid malignancies such as adult T-cell leukemia/lymphoma and NK/T-cell lymphoma (nasal type) and post-transplant lymphoproliferative disorders. Molecular assays are increasingly used to diagnose and manage these diseases. In this review, molecular features of tumor viruses and related host responses are explored. The tests used to identify such features are summarized. Evaluation of the utility of these assays for diagnosis and/or management of specific tumor types is presented.

*For a PDF of the full article, click on the link to the left of this introduction.

Jonathan L. Curry, MD, Carlos A. Torres-Cabala, MD,Michael T. Tetzlaff, MD, PhD, Christopher Bowman, BS, MT(ASCP)SV, and Victor G. Prieto, MD, PhD

Metastatic melanoma (MM) is a deadly skin disease refractory to standard chemotherapy. Despite numerous clinical and pathological parameters derived to guide patient management, clinical outcomes in melanoma patients remain difficult to predict. There is a critical need to delineate the important biomarkers typical of this disease. These biomarkers will ideally illuminate those key biochemical pathways responsible for the aggressive behavior of melanoma and, in the process, unveil new opportunities for the design of rational therapeutic interventions in high-risk patients. The most common recurring mutation in cutaneous melanoma is the prooncogenic BRAF V600E mutation that drives melanoma cell proliferation. The development of RAF inhibitors targeted against BRAF V600E mutant melanoma cells has revolutionized the treatment of MM. Clinical trials with BRAF inhibitor vemurafenib have shown objective clinical response and improved survival in patients with MM; therefore, knowledge of the molecular signature of melanoma in patients will be important in directing management decisions. Several molecular platforms exist to analyze
the mutation status of melanoma. These include Sanger sequencing, pyrosequencing, allele-specific reverse transcriptase polymerase chain reaction, mass spectrometry base sequencing (Sequenom), high-resolution melting curve analysis, and next-generation sequencing methods using microfluidics technology. The Food and Drug Administration has approved the cobas BRAF V600 Mutation Test developed by Roche to analyze BRAF mutation status in formalin-fixed paraffin-embedded tumor samples. The cobas Mutation Test has been designed specifically to detect BRAF V600E mutations, and the analytic performance of this assay has demonstrated >99% sensitivity in the detection of BRAF V600E mutation when compared with the Sanger sequencing method and confirmed with the next-generation sequencing 454-pyrosequencing technology. The lower limit of detection of the percentage of mutant alleles in a tissue sample for the cobas test is less than 4%-5%. Some cross-reactivity with other variants of mutant BRAF was seen with the cobas V600 platform; however, this clinical test offers highly sensitive reproducible BRAF V600E mutation analysis in formalin-fixed paraffin-embedded tumor samples.

*For a PDF of the full article, click on the link to the left of this introduction.

Jonathan L. Curry, MD, Carlos A. Torres-Cabala, MD,Michael T. Tetzlaff, MD, PhD, Christopher Bowman, BS, MT(ASCP)SV, and Victor G. Prieto, MD, PhD

Metastatic melanoma (MM) is a deadly skin disease refractory to standard chemotherapy. Despite numerous clinical and pathological parameters derived to guide patient management, clinical outcomes in melanoma patients remain difficult to predict. There is a critical need to delineate the important biomarkers typical of this disease. These biomarkers will ideally illuminate those key biochemical pathways responsible for the aggressive behavior of melanoma and, in the process, unveil new opportunities for the design of rational therapeutic interventions in high-risk patients. The most common recurring mutation in cutaneous melanoma is the prooncogenic BRAF V600E mutation that drives melanoma cell proliferation. The development of RAF inhibitors targeted against BRAF V600E mutant melanoma cells has revolutionized the treatment of MM. Clinical trials with BRAF inhibitor vemurafenib have shown objective clinical response and improved survival in patients with MM; therefore, knowledge of the molecular signature of melanoma in patients will be important in directing management decisions. Several molecular platforms exist to analyze
the mutation status of melanoma. These include Sanger sequencing, pyrosequencing, allele-specific reverse transcriptase polymerase chain reaction, mass spectrometry base sequencing (Sequenom), high-resolution melting curve analysis, and next-generation sequencing methods using microfluidics technology. The Food and Drug Administration has approved the cobas BRAF V600 Mutation Test developed by Roche to analyze BRAF mutation status in formalin-fixed paraffin-embedded tumor samples. The cobas Mutation Test has been designed specifically to detect BRAF V600E mutations, and the analytic performance of this assay has demonstrated >99% sensitivity in the detection of BRAF V600E mutation when compared with the Sanger sequencing method and confirmed with the next-generation sequencing 454-pyrosequencing technology. The lower limit of detection of the percentage of mutant alleles in a tissue sample for the cobas test is less than 4%-5%. Some cross-reactivity with other variants of mutant BRAF was seen with the cobas V600 platform; however, this clinical test offers highly sensitive reproducible BRAF V600E mutation analysis in formalin-fixed paraffin-embedded tumor samples.

*For a PDF of the full article, click on the link to the left of this introduction.

Jonathan L. Curry, MD, Carlos A. Torres-Cabala, MD,Michael T. Tetzlaff, MD, PhD, Christopher Bowman, BS, MT(ASCP)SV, and Victor G. Prieto, MD, PhD

Metastatic melanoma (MM) is a deadly skin disease refractory to standard chemotherapy. Despite numerous clinical and pathological parameters derived to guide patient management, clinical outcomes in melanoma patients remain difficult to predict. There is a critical need to delineate the important biomarkers typical of this disease. These biomarkers will ideally illuminate those key biochemical pathways responsible for the aggressive behavior of melanoma and, in the process, unveil new opportunities for the design of rational therapeutic interventions in high-risk patients. The most common recurring mutation in cutaneous melanoma is the prooncogenic BRAF V600E mutation that drives melanoma cell proliferation. The development of RAF inhibitors targeted against BRAF V600E mutant melanoma cells has revolutionized the treatment of MM. Clinical trials with BRAF inhibitor vemurafenib have shown objective clinical response and improved survival in patients with MM; therefore, knowledge of the molecular signature of melanoma in patients will be important in directing management decisions. Several molecular platforms exist to analyze
the mutation status of melanoma. These include Sanger sequencing, pyrosequencing, allele-specific reverse transcriptase polymerase chain reaction, mass spectrometry base sequencing (Sequenom), high-resolution melting curve analysis, and next-generation sequencing methods using microfluidics technology. The Food and Drug Administration has approved the cobas BRAF V600 Mutation Test developed by Roche to analyze BRAF mutation status in formalin-fixed paraffin-embedded tumor samples. The cobas Mutation Test has been designed specifically to detect BRAF V600E mutations, and the analytic performance of this assay has demonstrated >99% sensitivity in the detection of BRAF V600E mutation when compared with the Sanger sequencing method and confirmed with the next-generation sequencing 454-pyrosequencing technology. The lower limit of detection of the percentage of mutant alleles in a tissue sample for the cobas test is less than 4%-5%. Some cross-reactivity with other variants of mutant BRAF was seen with the cobas V600 platform; however, this clinical test offers highly sensitive reproducible BRAF V600E mutation analysis in formalin-fixed paraffin-embedded tumor samples.

*For a PDF of the full article, click on the link to the left of this introduction.

Hilmy Shahbain, BS, Chelsea Cooper, BA, and Pedram Gerami, MD

Certain subsets of melanocytic neoplasms are difficult to classify because of conflicting histologic features and the existence of a poorly defined intermediate grade of melanocytic tumors. The integration of molecular diagnostic information with a histologic impression may contribute significantly toward improving classification. This review discusses the development of and advances in molecular techniques, including comparative genomic hybridization and fluorescence in situ hybridization (FISH) as diagnostic and prognostic tools for melanocytic neoplasms. Further, we discuss how specific molecular aberrations identified via FISH correlate with certain morphologies in melanocytic neoplasms. We also examine the prognostic value of FISH in intermediate-grade melanocytic tumors, particularly atypical Spitz tumors.

*For a PDF of the full article, click on the link to the left of this introduction.

Hilmy Shahbain, BS, Chelsea Cooper, BA, and Pedram Gerami, MD

Certain subsets of melanocytic neoplasms are difficult to classify because of conflicting histologic features and the existence of a poorly defined intermediate grade of melanocytic tumors. The integration of molecular diagnostic information with a histologic impression may contribute significantly toward improving classification. This review discusses the development of and advances in molecular techniques, including comparative genomic hybridization and fluorescence in situ hybridization (FISH) as diagnostic and prognostic tools for melanocytic neoplasms. Further, we discuss how specific molecular aberrations identified via FISH correlate with certain morphologies in melanocytic neoplasms. We also examine the prognostic value of FISH in intermediate-grade melanocytic tumors, particularly atypical Spitz tumors.

*For a PDF of the full article, click on the link to the left of this introduction.

Hilmy Shahbain, BS, Chelsea Cooper, BA, and Pedram Gerami, MD

Certain subsets of melanocytic neoplasms are difficult to classify because of conflicting histologic features and the existence of a poorly defined intermediate grade of melanocytic tumors. The integration of molecular diagnostic information with a histologic impression may contribute significantly toward improving classification. This review discusses the development of and advances in molecular techniques, including comparative genomic hybridization and fluorescence in situ hybridization (FISH) as diagnostic and prognostic tools for melanocytic neoplasms. Further, we discuss how specific molecular aberrations identified via FISH correlate with certain morphologies in melanocytic neoplasms. We also examine the prognostic value of FISH in intermediate-grade melanocytic tumors, particularly atypical Spitz tumors.

*For a PDF of the full article, click on the link to the left of this introduction.

SAN DIEGO – If you’re thinking about adding Mohs surgery to your dermatology practice, Dr. Edward Yob recommended that you consider the following question: "Am I willing to commit the time and resources necessary to developing a Mohs practice and do it right?"

Ultimately, your decision "will be based on your experience, how efficient you are, and how interested you are in Mohs surgery," he said at the meeting sponsored by the American Society for Mohs Surgery. "There’s no dabbling in Mohs; you either do it, or you don’t."

He offered the following tips on incorporating Mohs surgery into your existing practice:

• Start small. Allow extra time, be careful in your patient selection, and avoid distractions. "You don’t want to do your first few Mohs cases when you have a very busy general dermatology clinic," advised Dr. Yob, who practices dermatology and Mohs surgery in Tulsa, Okla. "Attention to detail is the key to Mohs surgery."

• Consider the impact on your practice environment. Do you plan to generate Mohs patients from your practice, or will the cases be generated from other referring physicians? What’s your population base, what are the community practice patterns, and what’s the competition like? "Do you have a Mohs surgeon on every other block?" Dr. Yob asked. "And what’s your surgical experience and that of your team? Are you in an area where managed care is going to reimburse you?"

• Be mindful of referral sources. In 1990, when Dr. Yob moved to Oklahoma from Washington, D.C., where he served as an Air Force dermatologist, "there was not a Mohs surgeon on the Eastern side of the state," he recalled. "Primary care physicians are an enormous referral source, especially those who do simple excisions. If they know you’re there to take care of those patients, you’ll build a bond and you’ll have a steady stream of patients to care for."

Dr. Yob emphasized the importance of keeping referring physicians in the loop about the patients they send you. "If another dermatologist sends me a patient and that patient says, ‘While I’m here, do you think you could check out this spot?’ I’ll check with the referring physician first," he explained. "Some of them will say, ‘Take care of whatever the patient needs while they’re there,’ while others will say, ‘Send them back and let me do the biopsy,’ or whatever the case may be. You have to respect that. Ultimately good communication is the key."

Other potential referral sources include colleagues who specialize in the ear, nose, and throat; plastic surgery; general surgery; and ophthalmology. You can also spread the word about your practice by offering to give Mohs-specific lectures to hospital staff or to meetings of church groups or civic groups. In those cases, "emphasize the advantage of Mohs in terms of its high cure rate, the fact that it spares tissue, and the fact that it involves an immediate repair," he said.

• What will your backup support be? If a case becomes troublesome beyond your scope of expertise, can you send the patient to the hospital right away and know that he or she will be taken care of? "What about specialty backup in the form of other Mohs surgeons, or experts in pathology, ENT, plastics, radiation oncology, general surgery, neurosurgery, and urology?" he asked. "You need to be able to take advice from your backups."

• Will you use an in-house tech or a contracted tech? "If you’re only doing Mohs on a limited basis, a contracted tech works pretty well," Dr. Yob said. "How experienced is your tech? How fast are they? Are they eager to learn?"

• Be conservative with patient scheduling. Scheduling patients depends on your volume, how many rooms you have dedicated to Mohs, your surgical experience, and the experience of your team. "If you think one Mohs case will take an hour, schedule the time for 2 hours," Dr. Yob recommended. He takes a complexity-based approach to scheduling in which "1" is a minimally complex case, "2" is a moderately complex case, and "3" is a highly complex case "that is going to take you some time and is going to be tough."

Dr. Yob said that he had no relevant financial conflicts to disclose.

SAN DIEGO – If you’re thinking about adding Mohs surgery to your dermatology practice, Dr. Edward Yob recommended that you consider the following question: "Am I willing to commit the time and resources necessary to developing a Mohs practice and do it right?"

Ultimately, your decision "will be based on your experience, how efficient you are, and how interested you are in Mohs surgery," he said at the meeting sponsored by the American Society for Mohs Surgery. "There’s no dabbling in Mohs; you either do it, or you don’t."

He offered the following tips on incorporating Mohs surgery into your existing practice:

• Start small. Allow extra time, be careful in your patient selection, and avoid distractions. "You don’t want to do your first few Mohs cases when you have a very busy general dermatology clinic," advised Dr. Yob, who practices dermatology and Mohs surgery in Tulsa, Okla. "Attention to detail is the key to Mohs surgery."

• Consider the impact on your practice environment. Do you plan to generate Mohs patients from your practice, or will the cases be generated from other referring physicians? What’s your population base, what are the community practice patterns, and what’s the competition like? "Do you have a Mohs surgeon on every other block?" Dr. Yob asked. "And what’s your surgical experience and that of your team? Are you in an area where managed care is going to reimburse you?"

• Be mindful of referral sources. In 1990, when Dr. Yob moved to Oklahoma from Washington, D.C., where he served as an Air Force dermatologist, "there was not a Mohs surgeon on the Eastern side of the state," he recalled. "Primary care physicians are an enormous referral source, especially those who do simple excisions. If they know you’re there to take care of those patients, you’ll build a bond and you’ll have a steady stream of patients to care for."

Dr. Yob emphasized the importance of keeping referring physicians in the loop about the patients they send you. "If another dermatologist sends me a patient and that patient says, ‘While I’m here, do you think you could check out this spot?’ I’ll check with the referring physician first," he explained. "Some of them will say, ‘Take care of whatever the patient needs while they’re there,’ while others will say, ‘Send them back and let me do the biopsy,’ or whatever the case may be. You have to respect that. Ultimately good communication is the key."

Other potential referral sources include colleagues who specialize in the ear, nose, and throat; plastic surgery; general surgery; and ophthalmology. You can also spread the word about your practice by offering to give Mohs-specific lectures to hospital staff or to meetings of church groups or civic groups. In those cases, "emphasize the advantage of Mohs in terms of its high cure rate, the fact that it spares tissue, and the fact that it involves an immediate repair," he said.

• What will your backup support be? If a case becomes troublesome beyond your scope of expertise, can you send the patient to the hospital right away and know that he or she will be taken care of? "What about specialty backup in the form of other Mohs surgeons, or experts in pathology, ENT, plastics, radiation oncology, general surgery, neurosurgery, and urology?" he asked. "You need to be able to take advice from your backups."

• Will you use an in-house tech or a contracted tech? "If you’re only doing Mohs on a limited basis, a contracted tech works pretty well," Dr. Yob said. "How experienced is your tech? How fast are they? Are they eager to learn?"

• Be conservative with patient scheduling. Scheduling patients depends on your volume, how many rooms you have dedicated to Mohs, your surgical experience, and the experience of your team. "If you think one Mohs case will take an hour, schedule the time for 2 hours," Dr. Yob recommended. He takes a complexity-based approach to scheduling in which "1" is a minimally complex case, "2" is a moderately complex case, and "3" is a highly complex case "that is going to take you some time and is going to be tough."

Dr. Yob said that he had no relevant financial conflicts to disclose.

SAN DIEGO – If you’re thinking about adding Mohs surgery to your dermatology practice, Dr. Edward Yob recommended that you consider the following question: "Am I willing to commit the time and resources necessary to developing a Mohs practice and do it right?"

Ultimately, your decision "will be based on your experience, how efficient you are, and how interested you are in Mohs surgery," he said at the meeting sponsored by the American Society for Mohs Surgery. "There’s no dabbling in Mohs; you either do it, or you don’t."

He offered the following tips on incorporating Mohs surgery into your existing practice:

• Start small. Allow extra time, be careful in your patient selection, and avoid distractions. "You don’t want to do your first few Mohs cases when you have a very busy general dermatology clinic," advised Dr. Yob, who practices dermatology and Mohs surgery in Tulsa, Okla. "Attention to detail is the key to Mohs surgery."

• Consider the impact on your practice environment. Do you plan to generate Mohs patients from your practice, or will the cases be generated from other referring physicians? What’s your population base, what are the community practice patterns, and what’s the competition like? "Do you have a Mohs surgeon on every other block?" Dr. Yob asked. "And what’s your surgical experience and that of your team? Are you in an area where managed care is going to reimburse you?"

• Be mindful of referral sources. In 1990, when Dr. Yob moved to Oklahoma from Washington, D.C., where he served as an Air Force dermatologist, "there was not a Mohs surgeon on the Eastern side of the state," he recalled. "Primary care physicians are an enormous referral source, especially those who do simple excisions. If they know you’re there to take care of those patients, you’ll build a bond and you’ll have a steady stream of patients to care for."

Dr. Yob emphasized the importance of keeping referring physicians in the loop about the patients they send you. "If another dermatologist sends me a patient and that patient says, ‘While I’m here, do you think you could check out this spot?’ I’ll check with the referring physician first," he explained. "Some of them will say, ‘Take care of whatever the patient needs while they’re there,’ while others will say, ‘Send them back and let me do the biopsy,’ or whatever the case may be. You have to respect that. Ultimately good communication is the key."

Other potential referral sources include colleagues who specialize in the ear, nose, and throat; plastic surgery; general surgery; and ophthalmology. You can also spread the word about your practice by offering to give Mohs-specific lectures to hospital staff or to meetings of church groups or civic groups. In those cases, "emphasize the advantage of Mohs in terms of its high cure rate, the fact that it spares tissue, and the fact that it involves an immediate repair," he said.

• What will your backup support be? If a case becomes troublesome beyond your scope of expertise, can you send the patient to the hospital right away and know that he or she will be taken care of? "What about specialty backup in the form of other Mohs surgeons, or experts in pathology, ENT, plastics, radiation oncology, general surgery, neurosurgery, and urology?" he asked. "You need to be able to take advice from your backups."

• Will you use an in-house tech or a contracted tech? "If you’re only doing Mohs on a limited basis, a contracted tech works pretty well," Dr. Yob said. "How experienced is your tech? How fast are they? Are they eager to learn?"

• Be conservative with patient scheduling. Scheduling patients depends on your volume, how many rooms you have dedicated to Mohs, your surgical experience, and the experience of your team. "If you think one Mohs case will take an hour, schedule the time for 2 hours," Dr. Yob recommended. He takes a complexity-based approach to scheduling in which "1" is a minimally complex case, "2" is a moderately complex case, and "3" is a highly complex case "that is going to take you some time and is going to be tough."

Dr. Yob said that he had no relevant financial conflicts to disclose.

One of the main reasons patients with darker skin don't apply sunscreen is because they believe they are at low or no risk for ultraviolet damage, according to the results of a survey that I conducted with Dr. Brooke Jackson and Dr. Chikoti Mibenge.

Our findings were presented in a poster at the American Academy of Dermatology's Summer Academy Meeting in Boston.

The study, conducted by surveying 105 patients in Chicago, revealed that 60% of black patients do not wear sunscreen regularly. Additionally, many darker skinned patients reported not liking the whitish or chalky appearance that sunscreens often leave.

However, sunscreen manufacturers are making more elegant formulations of both chemical and physical blockers that do not leave a whitish hue on darker skin.

Sun protective clothing, hats, parasols or umbrellas, avoiding peak hours of sun intensity, and avoiding tanning are all common methods we recommend to patients to protect themselves. Lesser known methods that we can also recommend to our patients include:

Heliocare

Heliocare tablets contain Polypodium leucotomos extract, a fern native to Central and South America rich in antioxidants which protect against formation of free radicals from UV exposure, particularly UVA. The science is based off of the fact that the fern, which was once aquatic, adapted to life on land and created its own protection from UV rays. The recommended dose is 1 tablet each morning or 2 tablets before intense sun exposure. The effect begins 30 minutes after consumption and is still active 2.5 hours after consumption. Total elimination is estimated to be about 8 hours, but pharmacokinetics for elimination have not been published. Numerous published studies have reported its benefits with regards to UV protection. A head-to-head study of UV protection from heliocare versus other powerful antioxidant supplements would be interesting.

Algae and Coral

At King's College in London, research is being done on the photoprotective effect of coral. In a press release last year, Dr. Paul Long reported that algae living within coral produces a sunscreen-like compound that not only protects the algae and coral from UV damage, but also the fish that feed on the coral. The part the algae play is thought to be part of the shikimate pathway found only in microbes and plants. A sunscreen tablet with this ingredient for human use is in the works.

Strawberries

thinkstockphotos.com

Strawberries, as well as other darker colored berries, are known to contain polyphenols, which are antioxidants. Researchers in Italy and Spain tested a strawberry extract on cultured human fibroblasts to see if there was a photoprotective effect. They added strawberry extract in different concentrations to all but the control group. They then exposed the samples to a dose of UV light "equivalent to 90 minutes of midday summer sun in the French Riviera," said lead investigator Maurizio Battino. The results demonstrated that strawberry extract, especially at a concentration of 0.5 mg/ml, provided UVA protection. It not only boosted cell survival and viability, but also minimized DNA damage when compared with control cells.

Perhaps there will be topical sunscreens that contain strawberry extract in the future. Other foods high in antioxidants that may have sun protective benefits include:

1. Colored peppers and yellow squash (high in carotenoids).

2. Tomatoes and watermelon (high in lycopene).

3. Dark berries, such as blueberries, acai, blackberries, cranberries (rich in anthocyanin).

4. Turmeric root (curcumin).

5. Pomegranate (ellegic acid).

6. Green and black tea (catechins).

7. Dark cocoa (flavanols).

8. Green leafy vegetables, such as spinach and kale (xanthophylls, oxygenated carotenoids).

9. Fish, such as mackerel, salmon, trout, herring, and sardines (omega 3 fatty acids).

These are not a replacement for the more common methods of sun protection, but they may certainly provide an added benefit.

- Naissan Wesley, M.D.

Do you have questions about treating patients with darker skin? If so, send them to [email protected].

One of the main reasons patients with darker skin don't apply sunscreen is because they believe they are at low or no risk for ultraviolet damage, according to the results of a survey that I conducted with Dr. Brooke Jackson and Dr. Chikoti Mibenge.

Our findings were presented in a poster at the American Academy of Dermatology's Summer Academy Meeting in Boston.

The study, conducted by surveying 105 patients in Chicago, revealed that 60% of black patients do not wear sunscreen regularly. Additionally, many darker skinned patients reported not liking the whitish or chalky appearance that sunscreens often leave.

However, sunscreen manufacturers are making more elegant formulations of both chemical and physical blockers that do not leave a whitish hue on darker skin.

Sun protective clothing, hats, parasols or umbrellas, avoiding peak hours of sun intensity, and avoiding tanning are all common methods we recommend to patients to protect themselves. Lesser known methods that we can also recommend to our patients include:

Heliocare

Heliocare tablets contain Polypodium leucotomos extract, a fern native to Central and South America rich in antioxidants which protect against formation of free radicals from UV exposure, particularly UVA. The science is based off of the fact that the fern, which was once aquatic, adapted to life on land and created its own protection from UV rays. The recommended dose is 1 tablet each morning or 2 tablets before intense sun exposure. The effect begins 30 minutes after consumption and is still active 2.5 hours after consumption. Total elimination is estimated to be about 8 hours, but pharmacokinetics for elimination have not been published. Numerous published studies have reported its benefits with regards to UV protection. A head-to-head study of UV protection from heliocare versus other powerful antioxidant supplements would be interesting.

Algae and Coral

At King's College in London, research is being done on the photoprotective effect of coral. In a press release last year, Dr. Paul Long reported that algae living within coral produces a sunscreen-like compound that not only protects the algae and coral from UV damage, but also the fish that feed on the coral. The part the algae play is thought to be part of the shikimate pathway found only in microbes and plants. A sunscreen tablet with this ingredient for human use is in the works.

Strawberries

thinkstockphotos.com

Strawberries, as well as other darker colored berries, are known to contain polyphenols, which are antioxidants. Researchers in Italy and Spain tested a strawberry extract on cultured human fibroblasts to see if there was a photoprotective effect. They added strawberry extract in different concentrations to all but the control group. They then exposed the samples to a dose of UV light "equivalent to 90 minutes of midday summer sun in the French Riviera," said lead investigator Maurizio Battino. The results demonstrated that strawberry extract, especially at a concentration of 0.5 mg/ml, provided UVA protection. It not only boosted cell survival and viability, but also minimized DNA damage when compared with control cells.

Perhaps there will be topical sunscreens that contain strawberry extract in the future. Other foods high in antioxidants that may have sun protective benefits include:

1. Colored peppers and yellow squash (high in carotenoids).

2. Tomatoes and watermelon (high in lycopene).

3. Dark berries, such as blueberries, acai, blackberries, cranberries (rich in anthocyanin).

4. Turmeric root (curcumin).

5. Pomegranate (ellegic acid).

6. Green and black tea (catechins).

7. Dark cocoa (flavanols).

8. Green leafy vegetables, such as spinach and kale (xanthophylls, oxygenated carotenoids).

9. Fish, such as mackerel, salmon, trout, herring, and sardines (omega 3 fatty acids).

These are not a replacement for the more common methods of sun protection, but they may certainly provide an added benefit.

- Naissan Wesley, M.D.

Do you have questions about treating patients with darker skin? If so, send them to [email protected].

One of the main reasons patients with darker skin don't apply sunscreen is because they believe they are at low or no risk for ultraviolet damage, according to the results of a survey that I conducted with Dr. Brooke Jackson and Dr. Chikoti Mibenge.

Our findings were presented in a poster at the American Academy of Dermatology's Summer Academy Meeting in Boston.

The study, conducted by surveying 105 patients in Chicago, revealed that 60% of black patients do not wear sunscreen regularly. Additionally, many darker skinned patients reported not liking the whitish or chalky appearance that sunscreens often leave.

However, sunscreen manufacturers are making more elegant formulations of both chemical and physical blockers that do not leave a whitish hue on darker skin.

Sun protective clothing, hats, parasols or umbrellas, avoiding peak hours of sun intensity, and avoiding tanning are all common methods we recommend to patients to protect themselves. Lesser known methods that we can also recommend to our patients include:

Heliocare

Heliocare tablets contain Polypodium leucotomos extract, a fern native to Central and South America rich in antioxidants which protect against formation of free radicals from UV exposure, particularly UVA. The science is based off of the fact that the fern, which was once aquatic, adapted to life on land and created its own protection from UV rays. The recommended dose is 1 tablet each morning or 2 tablets before intense sun exposure. The effect begins 30 minutes after consumption and is still active 2.5 hours after consumption. Total elimination is estimated to be about 8 hours, but pharmacokinetics for elimination have not been published. Numerous published studies have reported its benefits with regards to UV protection. A head-to-head study of UV protection from heliocare versus other powerful antioxidant supplements would be interesting.

Algae and Coral

At King's College in London, research is being done on the photoprotective effect of coral. In a press release last year, Dr. Paul Long reported that algae living within coral produces a sunscreen-like compound that not only protects the algae and coral from UV damage, but also the fish that feed on the coral. The part the algae play is thought to be part of the shikimate pathway found only in microbes and plants. A sunscreen tablet with this ingredient for human use is in the works.

Strawberries

thinkstockphotos.com

Strawberries, as well as other darker colored berries, are known to contain polyphenols, which are antioxidants. Researchers in Italy and Spain tested a strawberry extract on cultured human fibroblasts to see if there was a photoprotective effect. They added strawberry extract in different concentrations to all but the control group. They then exposed the samples to a dose of UV light "equivalent to 90 minutes of midday summer sun in the French Riviera," said lead investigator Maurizio Battino. The results demonstrated that strawberry extract, especially at a concentration of 0.5 mg/ml, provided UVA protection. It not only boosted cell survival and viability, but also minimized DNA damage when compared with control cells.

Perhaps there will be topical sunscreens that contain strawberry extract in the future. Other foods high in antioxidants that may have sun protective benefits include:

1. Colored peppers and yellow squash (high in carotenoids).

2. Tomatoes and watermelon (high in lycopene).

3. Dark berries, such as blueberries, acai, blackberries, cranberries (rich in anthocyanin).

4. Turmeric root (curcumin).

5. Pomegranate (ellegic acid).

6. Green and black tea (catechins).

7. Dark cocoa (flavanols).

8. Green leafy vegetables, such as spinach and kale (xanthophylls, oxygenated carotenoids).

9. Fish, such as mackerel, salmon, trout, herring, and sardines (omega 3 fatty acids).

These are not a replacement for the more common methods of sun protection, but they may certainly provide an added benefit.

- Naissan Wesley, M.D.

Do you have questions about treating patients with darker skin? If so, send them to [email protected].

Treatment with vemurafenib, a RAF inhibitor, triggered proliferation of leukemia cells in a patient receiving therapy for metastatic melanoma, according to a case report published Nov. 7 in the New England Journal of Medicine.

Increased use of RAF inhibitors such as vemurafenib (Zelboraf) and the still-experimental dabrafenib are likely to stimulate additional cases of leukemia and other cancers in patients with coincidental RAS mutations, warn Dr. Paul D. Chapman of Memorial Sloan-Kettering Cancer Center in New York, and his coauthors.

Patients being treated with RAF inhibitors should be closely monitored, the authors advise, and any rapid rise in white-cell count "should be investigated promptly and the drug withheld until the cause of the rise in white cells is clarified." For now, they recommend that adjuvant treatment with RAF inhibitors should only be offered in the context of a clinical trial (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1208958]).

The patient in the case report, a 76-year-old man with stage IV melanoma, experienced improved breathing but also developed "new, profound fatigue" after starting vemurafenib, according to the report. Clinicians determined that he had marked elevations in his white blood count, along with increases in monocytes and neutrophils.

Vemurafenib was stopped, after which white cell and monocyte counts decreased. As the patient responded to treatment, he is again taking vemurafenib, but with clinicians adjusting the dose based on changes in white-cell counts.

Investigation of the case led the authors to hypothesize that vemurafenib was hyperactivating the ERK pathway and stimulating growth of chronic myelomonocytic leukemia cells carrying a preexisting NRAS mutation. They were able to verify this in vitro, and also came up with another hypothesis – that MEK inhibitors might weaken ERK signaling and suppress the proliferation of leukemic cells indirectly caused by vemurafenib.

As of publication, however, the authors were unable obtain a MEK inhibitor to test this hypothesis in a patient, as none are approved by the Food and Drug Administration. MEK inhibitors are being studied in combination with RAF inhibitors and have been shown to improve progression-free survival (N. Engl. J. Med. 2012;367:1694-703 [doi: 10.1056/NEJMoa1210093]).

About half of metastatic melanomas carry BRAF mutations, and about half of patients with BRAF mutations have been found to respond to vemurafenib. This led the FDA to approve vemurafenib in 2011 for treatment of inoperable or metastatic melanoma carrying the BRAF^V600E mutation. One side effect of vemurafenib treatment has been an increase in cutaneous skin conditions in about a quarter of patients.

"This case report shows that paradoxical ERK activation by RAF inhibitors is not restricted to proliferations such as squamous cell carcinomas and keratoacanthomas. It is clear that paradoxical activation can be seen in other premalignant lesions in which there are RAS mutations or other genetic changes that result in upstream activation of this pathway," Dr. Chapman and his coauthors wrote.

Dr. Chapman disclosed financial relationships with Roche/Genentech and GlaxoSmithKline and a pending institutional patent title Methods of Using BRAF Inhibitors for Cancer Screening and Imaging.

Treatment with vemurafenib, a RAF inhibitor, triggered proliferation of leukemia cells in a patient receiving therapy for metastatic melanoma, according to a case report published Nov. 7 in the New England Journal of Medicine.

Increased use of RAF inhibitors such as vemurafenib (Zelboraf) and the still-experimental dabrafenib are likely to stimulate additional cases of leukemia and other cancers in patients with coincidental RAS mutations, warn Dr. Paul D. Chapman of Memorial Sloan-Kettering Cancer Center in New York, and his coauthors.

Patients being treated with RAF inhibitors should be closely monitored, the authors advise, and any rapid rise in white-cell count "should be investigated promptly and the drug withheld until the cause of the rise in white cells is clarified." For now, they recommend that adjuvant treatment with RAF inhibitors should only be offered in the context of a clinical trial (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1208958]).

The patient in the case report, a 76-year-old man with stage IV melanoma, experienced improved breathing but also developed "new, profound fatigue" after starting vemurafenib, according to the report. Clinicians determined that he had marked elevations in his white blood count, along with increases in monocytes and neutrophils.

Vemurafenib was stopped, after which white cell and monocyte counts decreased. As the patient responded to treatment, he is again taking vemurafenib, but with clinicians adjusting the dose based on changes in white-cell counts.

Investigation of the case led the authors to hypothesize that vemurafenib was hyperactivating the ERK pathway and stimulating growth of chronic myelomonocytic leukemia cells carrying a preexisting NRAS mutation. They were able to verify this in vitro, and also came up with another hypothesis – that MEK inhibitors might weaken ERK signaling and suppress the proliferation of leukemic cells indirectly caused by vemurafenib.

As of publication, however, the authors were unable obtain a MEK inhibitor to test this hypothesis in a patient, as none are approved by the Food and Drug Administration. MEK inhibitors are being studied in combination with RAF inhibitors and have been shown to improve progression-free survival (N. Engl. J. Med. 2012;367:1694-703 [doi: 10.1056/NEJMoa1210093]).

About half of metastatic melanomas carry BRAF mutations, and about half of patients with BRAF mutations have been found to respond to vemurafenib. This led the FDA to approve vemurafenib in 2011 for treatment of inoperable or metastatic melanoma carrying the BRAF^V600E mutation. One side effect of vemurafenib treatment has been an increase in cutaneous skin conditions in about a quarter of patients.

"This case report shows that paradoxical ERK activation by RAF inhibitors is not restricted to proliferations such as squamous cell carcinomas and keratoacanthomas. It is clear that paradoxical activation can be seen in other premalignant lesions in which there are RAS mutations or other genetic changes that result in upstream activation of this pathway," Dr. Chapman and his coauthors wrote.

Dr. Chapman disclosed financial relationships with Roche/Genentech and GlaxoSmithKline and a pending institutional patent title Methods of Using BRAF Inhibitors for Cancer Screening and Imaging.

Treatment with vemurafenib, a RAF inhibitor, triggered proliferation of leukemia cells in a patient receiving therapy for metastatic melanoma, according to a case report published Nov. 7 in the New England Journal of Medicine.

Increased use of RAF inhibitors such as vemurafenib (Zelboraf) and the still-experimental dabrafenib are likely to stimulate additional cases of leukemia and other cancers in patients with coincidental RAS mutations, warn Dr. Paul D. Chapman of Memorial Sloan-Kettering Cancer Center in New York, and his coauthors.

Patients being treated with RAF inhibitors should be closely monitored, the authors advise, and any rapid rise in white-cell count "should be investigated promptly and the drug withheld until the cause of the rise in white cells is clarified." For now, they recommend that adjuvant treatment with RAF inhibitors should only be offered in the context of a clinical trial (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1208958]).

The patient in the case report, a 76-year-old man with stage IV melanoma, experienced improved breathing but also developed "new, profound fatigue" after starting vemurafenib, according to the report. Clinicians determined that he had marked elevations in his white blood count, along with increases in monocytes and neutrophils.

Vemurafenib was stopped, after which white cell and monocyte counts decreased. As the patient responded to treatment, he is again taking vemurafenib, but with clinicians adjusting the dose based on changes in white-cell counts.

Investigation of the case led the authors to hypothesize that vemurafenib was hyperactivating the ERK pathway and stimulating growth of chronic myelomonocytic leukemia cells carrying a preexisting NRAS mutation. They were able to verify this in vitro, and also came up with another hypothesis – that MEK inhibitors might weaken ERK signaling and suppress the proliferation of leukemic cells indirectly caused by vemurafenib.

As of publication, however, the authors were unable obtain a MEK inhibitor to test this hypothesis in a patient, as none are approved by the Food and Drug Administration. MEK inhibitors are being studied in combination with RAF inhibitors and have been shown to improve progression-free survival (N. Engl. J. Med. 2012;367:1694-703 [doi: 10.1056/NEJMoa1210093]).

About half of metastatic melanomas carry BRAF mutations, and about half of patients with BRAF mutations have been found to respond to vemurafenib. This led the FDA to approve vemurafenib in 2011 for treatment of inoperable or metastatic melanoma carrying the BRAF^V600E mutation. One side effect of vemurafenib treatment has been an increase in cutaneous skin conditions in about a quarter of patients.

"This case report shows that paradoxical ERK activation by RAF inhibitors is not restricted to proliferations such as squamous cell carcinomas and keratoacanthomas. It is clear that paradoxical activation can be seen in other premalignant lesions in which there are RAS mutations or other genetic changes that result in upstream activation of this pathway," Dr. Chapman and his coauthors wrote.

Dr. Chapman disclosed financial relationships with Roche/Genentech and GlaxoSmithKline and a pending institutional patent title Methods of Using BRAF Inhibitors for Cancer Screening and Imaging.

PRAGUE – Add Merkel cell carcinoma to the seemingly ever-growing list of malignancies linked to vitamin D deficiency.

A multicenter French study involving 89 patients with histologically confirmed Merkel cell carcinoma indicates that individuals with this rare and often aggressive neuroendocrine skin malignancy have an increased prevalence of vitamin D deficiency. Moreover, the vitamin D–deficient subgroup had a greater mean tumor size at diagnosis and sharply worse outcomes, Dr. Mahtab Samimi reported at the annual congress of the European Academy of Dermatology and Venereology.

© Kaspri/Fotolia.com

Fifty-eight of the 89 (65%) Merkel cell carcinoma patients were vitamin D deficient as defined by a serum level below 50 nmol/L. During follow-up, 33 patients developed nodal and/or distant metastases and 19 died of Merkel cell carcinoma. The 4-year Merkel cell carcinoma–free survival rate was 40% in the vitamin D deficient group and more than 90% in patients with normal-range vitamin D. The metastasis-free survival rate at 4 years was 20% in vitamin D–deficient patients and 70% in those without serum vitamin D deficiency.

In a multivariate regression analysis, low vitamin D was independently associated with an adjusted 2.89-fold increased risk of developing nodal and/or distant metastases and a 5.28-fold increased risk for death from their malignancy, reported Dr. Samimi of Francois Rabelais University in Tours, France.

The multivariate analysis was adjusted for age, gender, immune status, tumor location, time of year of the serum vitamin D measurement, and Merkel cell polyomavirus DNA levels.

It’s biologically plausible that a patient’s vitamin D status influences Merkel cell carcinoma behavior, according to Dr. Samimi. She and her coworkers analyzed 19 primary tumor specimens and 9 nodal metastases and found every single one strongly expressed the vitamin D receptor.

"The active metabolites of vitamin D bind to the vitamin D receptor, which is able to regulate genes involved in cell cycle control and others that have anti-inflammatory effects," the dermatologist explained.

Other investigators have shown that melanoma, too, is affected by a patient’s vitamin D status. Vitamin D deficiency is associated with thicker melanomas at diagnosis and reduced survival, she noted.

Dr. Samimi stressed that the newly shown association that she and her coworkers have found between vitamin D deficiency and worse-prognosis Merkel cell carcinoma must be considered hypothesis-generating rather than proof of causality. Serum vitamin D wasn’t measured until an average of 3 months after cancer diagnosis.

Asked by the audience if she screens her patients with Merkel cell carcinoma or melanoma for vitamin D deficiency, Dr. Samimi replied affirmatively. And if they’re deficient, as is so often the case, she puts them on vitamin D supplementation.

"The protective role of doing this in terms of cancer prognosis is not proven, but at the very least the supplementation has beneficial effects on skeletal and muscle health, so it’s a good thing," she said.

In a separate study, Dr. Nicolas Kluger of the University of Helsinki presented national Finnish data showing a predisposition of Merkel cell carcinoma for the left side of affected patients.

The comprehensive Finnish Cancer Registry is thought to have captured all 177 Finns diagnosed with Merkel cell carcinoma in a recent 20-year period. Fifty-six percent of the tumors were on the left, 37% on the right, and 7% occurred on the midline.

Tumors located on the trunk were equally likely to be left or right sided, but tumors on the head and neck were 3.2-fold more likely to be on the left side. Merkel cell carcinomas arising on the forearm or hand were fourfold more likely to occur on the left than the right side. On the leg and foot, the left-sided excess was 2.4-fold. Tumors located on the face were 1.5-fold more likely to occur on the left side.

These Finnish data confirm an earlier U.S. study involving a much larger patient population: 2,384 individuals with Merkel cell carcinoma included the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database, Dr. Kluger noted. In the U.S. study, 52.7% of the cancers occurred on the left side. On the arm it was 55%, while on the face it was 52%, but there was no difference in lateral distribution of the tumors on the legs (J. Am. Acad. Dermatol. 2011;65:35-9).

The same large U.S. study also showed an excess of left-sidedness in the distribution of melanomas among 82,587 affected patients in the SEER registry.

Since ultraviolet light exposure figures in the pathogenesis of both of these serious skin cancers, one leading theory regarding the explanation for the left-sided predominance of Merkel cell carcinoma and melanoma involves increased driver-side UV exposure while operating motor vehicles. Dr. Kluger finds this explanation unlikely. Although steering wheels are placed on the left side of vehicles in Finland, as in the United States, left-side predominance of these skin cancers also has been reported in countries such as Scotland, where drivers stick to the left side of the road and the steering wheel is on the right, he noted.

In Finland, there was a significant excess of Merkel cell carcinomas on the left side in nearly every year of the 20-year study. That means if the skewed lateral distribution of the tumors is due to some as-yet-unidentified environmental factor, it’s a factor that hasn’t changed in 20 years, Dr. Kluger observed.

"For now it’s an interesting curiosity," he commented.

Both Dr. Kluger and Dr. Samimi reported having no financial conflicts.

PRAGUE – Add Merkel cell carcinoma to the seemingly ever-growing list of malignancies linked to vitamin D deficiency.

A multicenter French study involving 89 patients with histologically confirmed Merkel cell carcinoma indicates that individuals with this rare and often aggressive neuroendocrine skin malignancy have an increased prevalence of vitamin D deficiency. Moreover, the vitamin D–deficient subgroup had a greater mean tumor size at diagnosis and sharply worse outcomes, Dr. Mahtab Samimi reported at the annual congress of the European Academy of Dermatology and Venereology.

© Kaspri/Fotolia.com

Fifty-eight of the 89 (65%) Merkel cell carcinoma patients were vitamin D deficient as defined by a serum level below 50 nmol/L. During follow-up, 33 patients developed nodal and/or distant metastases and 19 died of Merkel cell carcinoma. The 4-year Merkel cell carcinoma–free survival rate was 40% in the vitamin D deficient group and more than 90% in patients with normal-range vitamin D. The metastasis-free survival rate at 4 years was 20% in vitamin D–deficient patients and 70% in those without serum vitamin D deficiency.

In a multivariate regression analysis, low vitamin D was independently associated with an adjusted 2.89-fold increased risk of developing nodal and/or distant metastases and a 5.28-fold increased risk for death from their malignancy, reported Dr. Samimi of Francois Rabelais University in Tours, France.

The multivariate analysis was adjusted for age, gender, immune status, tumor location, time of year of the serum vitamin D measurement, and Merkel cell polyomavirus DNA levels.

It’s biologically plausible that a patient’s vitamin D status influences Merkel cell carcinoma behavior, according to Dr. Samimi. She and her coworkers analyzed 19 primary tumor specimens and 9 nodal metastases and found every single one strongly expressed the vitamin D receptor.

"The active metabolites of vitamin D bind to the vitamin D receptor, which is able to regulate genes involved in cell cycle control and others that have anti-inflammatory effects," the dermatologist explained.

Other investigators have shown that melanoma, too, is affected by a patient’s vitamin D status. Vitamin D deficiency is associated with thicker melanomas at diagnosis and reduced survival, she noted.

Dr. Samimi stressed that the newly shown association that she and her coworkers have found between vitamin D deficiency and worse-prognosis Merkel cell carcinoma must be considered hypothesis-generating rather than proof of causality. Serum vitamin D wasn’t measured until an average of 3 months after cancer diagnosis.

Asked by the audience if she screens her patients with Merkel cell carcinoma or melanoma for vitamin D deficiency, Dr. Samimi replied affirmatively. And if they’re deficient, as is so often the case, she puts them on vitamin D supplementation.

"The protective role of doing this in terms of cancer prognosis is not proven, but at the very least the supplementation has beneficial effects on skeletal and muscle health, so it’s a good thing," she said.

In a separate study, Dr. Nicolas Kluger of the University of Helsinki presented national Finnish data showing a predisposition of Merkel cell carcinoma for the left side of affected patients.

The comprehensive Finnish Cancer Registry is thought to have captured all 177 Finns diagnosed with Merkel cell carcinoma in a recent 20-year period. Fifty-six percent of the tumors were on the left, 37% on the right, and 7% occurred on the midline.

Tumors located on the trunk were equally likely to be left or right sided, but tumors on the head and neck were 3.2-fold more likely to be on the left side. Merkel cell carcinomas arising on the forearm or hand were fourfold more likely to occur on the left than the right side. On the leg and foot, the left-sided excess was 2.4-fold. Tumors located on the face were 1.5-fold more likely to occur on the left side.

These Finnish data confirm an earlier U.S. study involving a much larger patient population: 2,384 individuals with Merkel cell carcinoma included the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database, Dr. Kluger noted. In the U.S. study, 52.7% of the cancers occurred on the left side. On the arm it was 55%, while on the face it was 52%, but there was no difference in lateral distribution of the tumors on the legs (J. Am. Acad. Dermatol. 2011;65:35-9).

The same large U.S. study also showed an excess of left-sidedness in the distribution of melanomas among 82,587 affected patients in the SEER registry.

Since ultraviolet light exposure figures in the pathogenesis of both of these serious skin cancers, one leading theory regarding the explanation for the left-sided predominance of Merkel cell carcinoma and melanoma involves increased driver-side UV exposure while operating motor vehicles. Dr. Kluger finds this explanation unlikely. Although steering wheels are placed on the left side of vehicles in Finland, as in the United States, left-side predominance of these skin cancers also has been reported in countries such as Scotland, where drivers stick to the left side of the road and the steering wheel is on the right, he noted.

In Finland, there was a significant excess of Merkel cell carcinomas on the left side in nearly every year of the 20-year study. That means if the skewed lateral distribution of the tumors is due to some as-yet-unidentified environmental factor, it’s a factor that hasn’t changed in 20 years, Dr. Kluger observed.

"For now it’s an interesting curiosity," he commented.

Both Dr. Kluger and Dr. Samimi reported having no financial conflicts.

PRAGUE – Add Merkel cell carcinoma to the seemingly ever-growing list of malignancies linked to vitamin D deficiency.

A multicenter French study involving 89 patients with histologically confirmed Merkel cell carcinoma indicates that individuals with this rare and often aggressive neuroendocrine skin malignancy have an increased prevalence of vitamin D deficiency. Moreover, the vitamin D–deficient subgroup had a greater mean tumor size at diagnosis and sharply worse outcomes, Dr. Mahtab Samimi reported at the annual congress of the European Academy of Dermatology and Venereology.

© Kaspri/Fotolia.com

Fifty-eight of the 89 (65%) Merkel cell carcinoma patients were vitamin D deficient as defined by a serum level below 50 nmol/L. During follow-up, 33 patients developed nodal and/or distant metastases and 19 died of Merkel cell carcinoma. The 4-year Merkel cell carcinoma–free survival rate was 40% in the vitamin D deficient group and more than 90% in patients with normal-range vitamin D. The metastasis-free survival rate at 4 years was 20% in vitamin D–deficient patients and 70% in those without serum vitamin D deficiency.

In a multivariate regression analysis, low vitamin D was independently associated with an adjusted 2.89-fold increased risk of developing nodal and/or distant metastases and a 5.28-fold increased risk for death from their malignancy, reported Dr. Samimi of Francois Rabelais University in Tours, France.

The multivariate analysis was adjusted for age, gender, immune status, tumor location, time of year of the serum vitamin D measurement, and Merkel cell polyomavirus DNA levels.

It’s biologically plausible that a patient’s vitamin D status influences Merkel cell carcinoma behavior, according to Dr. Samimi. She and her coworkers analyzed 19 primary tumor specimens and 9 nodal metastases and found every single one strongly expressed the vitamin D receptor.

"The active metabolites of vitamin D bind to the vitamin D receptor, which is able to regulate genes involved in cell cycle control and others that have anti-inflammatory effects," the dermatologist explained.

Other investigators have shown that melanoma, too, is affected by a patient’s vitamin D status. Vitamin D deficiency is associated with thicker melanomas at diagnosis and reduced survival, she noted.

Dr. Samimi stressed that the newly shown association that she and her coworkers have found between vitamin D deficiency and worse-prognosis Merkel cell carcinoma must be considered hypothesis-generating rather than proof of causality. Serum vitamin D wasn’t measured until an average of 3 months after cancer diagnosis.

Asked by the audience if she screens her patients with Merkel cell carcinoma or melanoma for vitamin D deficiency, Dr. Samimi replied affirmatively. And if they’re deficient, as is so often the case, she puts them on vitamin D supplementation.

"The protective role of doing this in terms of cancer prognosis is not proven, but at the very least the supplementation has beneficial effects on skeletal and muscle health, so it’s a good thing," she said.

In a separate study, Dr. Nicolas Kluger of the University of Helsinki presented national Finnish data showing a predisposition of Merkel cell carcinoma for the left side of affected patients.

The comprehensive Finnish Cancer Registry is thought to have captured all 177 Finns diagnosed with Merkel cell carcinoma in a recent 20-year period. Fifty-six percent of the tumors were on the left, 37% on the right, and 7% occurred on the midline.

Tumors located on the trunk were equally likely to be left or right sided, but tumors on the head and neck were 3.2-fold more likely to be on the left side. Merkel cell carcinomas arising on the forearm or hand were fourfold more likely to occur on the left than the right side. On the leg and foot, the left-sided excess was 2.4-fold. Tumors located on the face were 1.5-fold more likely to occur on the left side.

These Finnish data confirm an earlier U.S. study involving a much larger patient population: 2,384 individuals with Merkel cell carcinoma included the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database, Dr. Kluger noted. In the U.S. study, 52.7% of the cancers occurred on the left side. On the arm it was 55%, while on the face it was 52%, but there was no difference in lateral distribution of the tumors on the legs (J. Am. Acad. Dermatol. 2011;65:35-9).

The same large U.S. study also showed an excess of left-sidedness in the distribution of melanomas among 82,587 affected patients in the SEER registry.

Since ultraviolet light exposure figures in the pathogenesis of both of these serious skin cancers, one leading theory regarding the explanation for the left-sided predominance of Merkel cell carcinoma and melanoma involves increased driver-side UV exposure while operating motor vehicles. Dr. Kluger finds this explanation unlikely. Although steering wheels are placed on the left side of vehicles in Finland, as in the United States, left-side predominance of these skin cancers also has been reported in countries such as Scotland, where drivers stick to the left side of the road and the steering wheel is on the right, he noted.

In Finland, there was a significant excess of Merkel cell carcinomas on the left side in nearly every year of the 20-year study. That means if the skewed lateral distribution of the tumors is due to some as-yet-unidentified environmental factor, it’s a factor that hasn’t changed in 20 years, Dr. Kluger observed.

"For now it’s an interesting curiosity," he commented.

Both Dr. Kluger and Dr. Samimi reported having no financial conflicts.

PRAGUE – Everolimus significantly improved the skin lesions of tuberous sclerosis complex in two phase-III clinical trials, Dr. Sergiusz Jozwiak reported at the annual congress of the European Academy of Dermatology and Venereology.

Tuberous sclerosis is a genetic disorder characterized by the growth of numerous nonmalignant tumors in various organs including the brain, kidneys, heart, and skin.

The most devastating skin lesions associated with tuberous sclerosis complex are facial angiofibromas. Hypopigmented spots are also common, said Dr. Jozwiak, a pediatric neurologist at the Children’s Memorial Health Institute of Warsaw.

In the first study, Examining Everolimus in a Study of Tuberous Sclerosis Complex (EXIST-1), about 100 patients with subependymal giant cell astrocytoma (SEGA) were randomized 2:1 to receive everolimus or placebo. In EXIST-2, approximately 100 patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis were randomized to receive either everolimus or placebo. EXIST-1 participants averaged about 8 years of age; those in EXIST-2 had an average age of 30 years.

Both studies met their primary end points, with favorable effects documented in patients with SEGA and renal angiomyolipoma. This led the Food and Drug Administration to approve everolimus (Afinitor), an oral inhibitor of the mammalian target of rapamycin (mTOR), for the treatment of both conditions.

Dr. Jozwiak reported on the skin lesion response to everolimus, a prespecified secondary end point in EXIST-1 and -2.

Close to 95% of all participants – 224 subjects in the two trials – had skin lesions at baseline. Of those on everolimus, 42% in EXIST-1 and 26% in EXIST-2 had significant improvements in their skin lesions, compared with 11% and 0%, respectively, of those on placebo.

The skin response was partial in all cases as judged on a 7-point scale, but the response, when it occurred, was durable: All patients with a partial response to everolimus maintained that response at last follow-up, ranging from 2 to 20 months. Thus, the median duration of skin response has yet to be determined, Dr. Jozwiak noted.

Mouth ulcers were the most common and troublesome everolimus side effect, seen intermittently in 70% of the patients in the two phase-III trials. The side effect was managed by temporary reductions in dosing or suspension of therapy for a week.

"We were able to reinstitute full-dose therapy in all patients," he said.

There were no other serious treatment-related adverse events. The incidence of infections was similar in the everolimus and placebo arms of the studies.

Everolimus was dosed starting at 4.5 mg/m² per day, with a target trough level of 5-15 ng/mL in EXIST-1. In EXIST-2, which was limited to an adult patient population, the drug was dosed at 10 mg/day.

The EXIST trials were sponsored by Novartis. Dr. Jozwiak is a consultant to the company.

PRAGUE – Everolimus significantly improved the skin lesions of tuberous sclerosis complex in two phase-III clinical trials, Dr. Sergiusz Jozwiak reported at the annual congress of the European Academy of Dermatology and Venereology.

Tuberous sclerosis is a genetic disorder characterized by the growth of numerous nonmalignant tumors in various organs including the brain, kidneys, heart, and skin.

The most devastating skin lesions associated with tuberous sclerosis complex are facial angiofibromas. Hypopigmented spots are also common, said Dr. Jozwiak, a pediatric neurologist at the Children’s Memorial Health Institute of Warsaw.

In the first study, Examining Everolimus in a Study of Tuberous Sclerosis Complex (EXIST-1), about 100 patients with subependymal giant cell astrocytoma (SEGA) were randomized 2:1 to receive everolimus or placebo. In EXIST-2, approximately 100 patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis were randomized to receive either everolimus or placebo. EXIST-1 participants averaged about 8 years of age; those in EXIST-2 had an average age of 30 years.

Both studies met their primary end points, with favorable effects documented in patients with SEGA and renal angiomyolipoma. This led the Food and Drug Administration to approve everolimus (Afinitor), an oral inhibitor of the mammalian target of rapamycin (mTOR), for the treatment of both conditions.

Dr. Jozwiak reported on the skin lesion response to everolimus, a prespecified secondary end point in EXIST-1 and -2.

Close to 95% of all participants – 224 subjects in the two trials – had skin lesions at baseline. Of those on everolimus, 42% in EXIST-1 and 26% in EXIST-2 had significant improvements in their skin lesions, compared with 11% and 0%, respectively, of those on placebo.

The skin response was partial in all cases as judged on a 7-point scale, but the response, when it occurred, was durable: All patients with a partial response to everolimus maintained that response at last follow-up, ranging from 2 to 20 months. Thus, the median duration of skin response has yet to be determined, Dr. Jozwiak noted.

Mouth ulcers were the most common and troublesome everolimus side effect, seen intermittently in 70% of the patients in the two phase-III trials. The side effect was managed by temporary reductions in dosing or suspension of therapy for a week.

"We were able to reinstitute full-dose therapy in all patients," he said.

There were no other serious treatment-related adverse events. The incidence of infections was similar in the everolimus and placebo arms of the studies.

Everolimus was dosed starting at 4.5 mg/m² per day, with a target trough level of 5-15 ng/mL in EXIST-1. In EXIST-2, which was limited to an adult patient population, the drug was dosed at 10 mg/day.

The EXIST trials were sponsored by Novartis. Dr. Jozwiak is a consultant to the company.

PRAGUE – Everolimus significantly improved the skin lesions of tuberous sclerosis complex in two phase-III clinical trials, Dr. Sergiusz Jozwiak reported at the annual congress of the European Academy of Dermatology and Venereology.

Tuberous sclerosis is a genetic disorder characterized by the growth of numerous nonmalignant tumors in various organs including the brain, kidneys, heart, and skin.

The most devastating skin lesions associated with tuberous sclerosis complex are facial angiofibromas. Hypopigmented spots are also common, said Dr. Jozwiak, a pediatric neurologist at the Children’s Memorial Health Institute of Warsaw.

In the first study, Examining Everolimus in a Study of Tuberous Sclerosis Complex (EXIST-1), about 100 patients with subependymal giant cell astrocytoma (SEGA) were randomized 2:1 to receive everolimus or placebo. In EXIST-2, approximately 100 patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis were randomized to receive either everolimus or placebo. EXIST-1 participants averaged about 8 years of age; those in EXIST-2 had an average age of 30 years.

Both studies met their primary end points, with favorable effects documented in patients with SEGA and renal angiomyolipoma. This led the Food and Drug Administration to approve everolimus (Afinitor), an oral inhibitor of the mammalian target of rapamycin (mTOR), for the treatment of both conditions.

Dr. Jozwiak reported on the skin lesion response to everolimus, a prespecified secondary end point in EXIST-1 and -2.

Close to 95% of all participants – 224 subjects in the two trials – had skin lesions at baseline. Of those on everolimus, 42% in EXIST-1 and 26% in EXIST-2 had significant improvements in their skin lesions, compared with 11% and 0%, respectively, of those on placebo.

The skin response was partial in all cases as judged on a 7-point scale, but the response, when it occurred, was durable: All patients with a partial response to everolimus maintained that response at last follow-up, ranging from 2 to 20 months. Thus, the median duration of skin response has yet to be determined, Dr. Jozwiak noted.

Mouth ulcers were the most common and troublesome everolimus side effect, seen intermittently in 70% of the patients in the two phase-III trials. The side effect was managed by temporary reductions in dosing or suspension of therapy for a week.

"We were able to reinstitute full-dose therapy in all patients," he said.

There were no other serious treatment-related adverse events. The incidence of infections was similar in the everolimus and placebo arms of the studies.

Everolimus was dosed starting at 4.5 mg/m² per day, with a target trough level of 5-15 ng/mL in EXIST-1. In EXIST-2, which was limited to an adult patient population, the drug was dosed at 10 mg/day.

The EXIST trials were sponsored by Novartis. Dr. Jozwiak is a consultant to the company.