Optimizing treatment approaches for patients with cutaneous melanoma by integrating clinical and pathologic features with the 31-gene expression profile test.

BACKGROUND: Many patients with low-stage cutaneous melanoma will experience tumor recurrence, metastasis, or death, and many higher staged patients will not. OBJECTIVE: To develop an algorithm by integrating the 31-gene expression profile test with clinicopathologic data for an optimized, personalized risk of recurrence (integrated 31 risk of recurrence [i31-ROR]) or death and use i31-ROR in conjunction with a previously validated algorithm for precise sentinel lymph node positivity risk estimates (i31-SLNB) for optimized treatment plan decisions. METHODS: Cox regression models for ROR were developed (n = 1581) and independently validated (n = 523) on a cohort with stage I-III melanoma. Using National Comprehensive Cancer Network cut points, i31-ROR performance was evaluated using the midpoint survival rates between patients with stage IIA and stage IIB disease as a risk threshold. RESULTS: Patients with a low-risk i31-ROR result had significantly higher 5-year recurrence-free survival (91% vs 45%, P < .001), distant metastasis-free survival (95% vs 53%, P < .001), and melanoma-specific survival (98% vs 73%, P < .001) than patients with a high-risk i31-ROR result. A combined i31-SLNB/ROR analysis identified 44% of patients who could forego sentinel lymph node biopsy while maintaining high survival rates (>98%) or were restratified as being at a higher or lower risk of recurrence or death. LIMITATIONS: Multicenter, retrospective study. CONCLUSION: Integrating clinicopathologic features with the 31-GEP optimizes patient risk stratification compared to clinicopathologic features alone.

The 31-gene expression profile stratifies recurrence and metastasis risk in patients with cutaneous melanoma.

Aim: Sentinel node biopsy is a prognostic indicator of melanoma recurrence. We hypothesized that adding the primary melanoma molecular signature from the 31-gene expression profile (31-GEP) test could refine the risk of recurrence prognosis for patients with stage I-III melanoma. Materials & methods: Four hundred thirty-eight patients with stage I-III melanoma consecutively tested with the 31-GEP were retrospectively analyzed. The 31-GEP stratified patients as low-risk (Class 1A), intermediate-risk (Class 1B/2A) or high risk (Class 2B) of recurrence or metastasis. Results: The 31-GEP significantly stratified patient risk for recurrence-free survival (p < 0.001), distant metastasis-free survival (p < 0.001) and melanoma-specific survival (p < 0.001) and was a significant, independent predictor of metastatic recurrence (hazard ratio: 5.38; p = 0.014). Conclusion: The 31-GEP improves prognostic accuracy in stage I-III melanoma.

Lay abstract Cutaneous melanoma is a type of skin tumor affecting 100,000 new patients each year. Even with the best tools available today, knowing which patients will die from their cancer can be challenging. Using individual tumors from over 400 patients, we analyzed the expression of 31 genes from each tumor. Doing this helped us split the patients into groups who are more or less likely to die from their tumor. By combining this technique with current medical practices and guidelines, we hope to help identify which patients may or may not benefit from more intense therapies.

A clinical impact study of dermatologists' use of diagnostic gene expression profile testing to guide patient management.

Aim: Cutaneous melanocytic neoplasms with diagnostic and/or clinical ambiguity pose patient management challenges. Methods: Six randomized case scenarios with diagnostic/clinical uncertainty were described with/without a benign or malignant diagnostic gene expression profile (GEP) result. Results: Clinical impact was assessed by reporting the mean increase/decrease of management changes normalized to baseline (n = 32 dermatologists). Benign GEP results prompted clinicians to decrease surgical margins (84.2%). Malignant GEP results escalated surgical excision recommendations (100%). A majority (72.2%) reduced and nearly all (98.9%) increased follow-up frequency for benign or malignant GEP results, respectively. There was an overall increase in management plan confidence with GEP results. Conclusion: Diagnostic GEP tests help guide clinical decision-making in a variety of diagnostically ambiguous or clinicopathologically discordant scenarios.

Dermatologists' use of diagnostic gene expression profiles for personalized patient care. When your doctor takes a piece of a mole, that mole is looked at under the microscope by a pathologist. The pathologist is responsible for figuring out if the mole is dangerous or not. Dangerous moles are removed with surgery to make sure all the dangerous tissue is gone. Moles without a health threat are left alone. Sometimes figuring out how dangerous a mole is is difficult. The pathologist may not provide the doctor with enough information for them to know how to treat your mole. There is a test that can provide information on whether your mole is unsafe. This test is called diagnostic gene expression profiling or GEP. In this study, GEP is used to help doctors figure out how to treat a mole and how often the patient should be seen in the office for skin checks. With GEP, important changes in patient treatment were identified. These include the need for an additional surgery, how much healthy tissue should be removed during surgery and how often the patient should be seen in the office. For suspicious moles where the pathology report is unclear, GEP can provide information that leads to more appropriate and personalized patient care.

Ancillary diagnostic gene expression profile testing for ambiguous cutaneous melanocytic lesions helps optimize dermatologist recommendations for excision margin and follow-up.

Efficacy and complication rates of full-thickness skin graft repair of lower extremity wounds after Mohs micrographic surgery.

BACKGROUND: Repair of below-the-knee lower extremity defects after Mohs micrographic surgery (MMS) that are not amenable to primary closure can be challenging given the high propensity for complications. No criterion standard exists for management of these wounds, but secondary-intention healing, partial- and full-thickness skin grafts (FTSGs), and various flaps are possible options to manage these wounds. Few data exist on the efficacy of FTSG repairs for lower extremity wounds. OBJECTIVES: Assess the efficacy and complications rates of FTSG repairs for lower extremity wounds after MMS. METHODS: This was a retrospective review of 80 FTSG repairs performed after MMS. Data were derived from 45 cases at Beth Israel Deaconess Medical Center and 35 cases at University of California, San Diego (UCSD) Medical Center. RESULTS: Seventy-two of 80 cases (90%) had full graft survival, six (7.5%) had partial failure, and two (2.5%) had complete failure. In the cases where grafts had failed, wounds healed by secondary intention without further complications. Other complications included infections in nine (11%) cases and hematoma formation in two (2.5%). CONCLUSION: FTSG is a consistent and safe reconstructive option for the management of lower extremity wounds after MMS.

A Physician's Guide to the Use of Gene Expression Profile Ancillary Diagnostic Testing for Cutaneous Melanocytic Neoplasms.

Objectives: Some melanocytic neoplasms suspicious for melanoma require additional workup to arrive at a final diagnosis. Within the last eight years, gene expression profiling (GEP) has become an important ancillary tool to aid in the diagnosis of melanocytic neoplasms with uncertain malignant potential. As the usage of two commercially available tests (23-GEP and 35-GEP) evolves, it is important to answer key questions about optimal utilization and their impact on patient care. Methods: Recent and relevant articles answering the following questions were included in the review. First, how do dermatopathologists synthesize the available literature, the latest guidelines, and their clinical experience to determine which cases would be most likely to benefit from GEP testing? Second, how best can a dermatologist convey to their dermatopathologist that the use of GEP in the diagnostic process could provide a more clearly defined result and thereby help empower the dermatologist to provide higher-quality patient care when making specific patient management decisions for otherwise pathologically ambiguous lesions? Results: When interpreted in the context of the clinical, pathologic, and laboratory information, GEP results can facilitate the rendering of timely, accurate, and definitive diagnoses for melanocytic lesions with otherwise uncertain malignant potential to inform personalized treatment and management plans. Limitations: This was a narrative review focused on clinical use of GEP compared to other ancillary diagnostic tests performed postbiopsy. Conclusion: Open communication between dermatopathologists and dermatologists, especially regarding GEP testing, can be a vital component to achieve appropriate clinicopathologic correlation for otherwise ambiguous melanocytic lesions.

A First in Human Clinical Trial Assessing the Safety and Immunogenicity of Two Intradermally Delivered Enterotoxigenic Escherichia coli CFA/I Fimbrial Tip Adhesin Antigens with and without Heat-Labile Enterotoxin with Mutation LT(R192G).

INTRODUCTION: Enterotoxigenic E. coli (ETEC) is a leading cause of diarrhea in travelers as well as for children living in low- to middle-income countries. ETEC adhere to intestinal epithelium via colonization factors (CFs). CFA/I, a common CF, is composed of a polymeric stalk and a tip-localized minor adhesive subunit, CfaE. Vaccine delivery by the transcutaneous immunization of dscCfaE was safe but was poorly immunogenic in a phase 1 trial when administered to volunteers with LTR(192G) and mLT. To potentially enhance the immunogenicity of CfaE while still delivering via a cutaneous route, we evaluated the safety and immunogenicity of two CfaE constructs administered intradermally (ID) with or without mLT. METHODS: CfaE was evaluated as a donor strand-complemented construct (dscCfaE) and as a chimeric construct (Chimera) in which dscCfaE replaces the A1 domain of the cholera toxin A subunit and assembles non-covalently with the pentamer of heat-labile toxin B (LTB). Subjects received three ID vaccinations three weeks apart with either dscCfaE (1, 5, and 25 µg) or Chimera (2.6 and 12.9 µg) with and without 0.1 µg of mLT. Subjects were monitored for local and systemic adverse events. Immunogenicity was evaluated by serum and antibody-secreting cell (ASC) responses. RESULTS: The vaccine was well-tolerated with predominantly mild and moderate local vaccine site reactions characterized by erythema, induration and post-inflammatory hyperpigmentation. High rates of serologic and ASC responses were seen across study groups with the most robust responses observed in subjects receiving 25 µg of dscCfaE with 0.1 mcg of LT(R192G). CONCLUSION: Both ETEC adhesin vaccine prototypes were safe and immunogenic when co-administered with mLT by the ID route. The observed immune responses induced with the high dose of dscCfaE and mLT warrant further assessment in a controlled human infection model.

Basal cell carcinoma on the ear is more likely to be of an aggressive phenotype in both men and women.

BACKGROUND: We observed that basal cell carcinoma (BCC) on the ear demonstrates a more aggressive phenotype compared with other body sites. OBJECTIVE: We sought to determine if it is statistically significant that BCC on the ear is more aggressive. METHODS: We queried our 2009 database for all BCCs biopsied from the ear. Multiple data points, including tumor subtype and risk level, were analyzed for 100 BCCs on the ear and 100 BCCs on the cheek. RESULTS: BCC on the ear was diagnosed 471 times. Of the first 100 occurrences of BCC on the ear, 57% were high risk compared with 38% on the cheek (odds ratio 2.16, 95% confidence interval 1.23-3.81, P = .01). Men were more likely to have BCC on the ear: 79% male on the ear and 53% male on the cheek (P < .001). However, BCC on the ear in women is also more likely to be aggressive (57%, 12 of 21). LIMITATIONS: The data were retrieved from a single year at our institution, and there could potentially be regional bias given that the population of data is from a single institution. Many of the specimens we evaluate are reviewed in consultation and may thus represent a selection bias. CONCLUSION: BCC on the ear presents as an aggressive phenotype in the majority of cases for both men and women, and it occurs much more frequently in men. Knowledge of this information can help guide physicians and ensure that these tumors are adequately biopsied and treated.

Expanded evidence that the 31-gene expression profile test provides clinical utility for melanoma management in a multicenter study.

OBJECTIVE: National Comprehensive Cancer Network (NCCN) guidelines for cutaneous melanoma (CM) recommend physicians consider increased surveillance for patients who typically have lower melanoma survival rates (stages IIB-IV as determined by the American Joint Committee on Cancer (AJCC), 8th edition). However, up to 15% of patients identified as having a low recurrence risk (stages I-IIA) experience disease recurrence, and some patients identified as having a high recurrence risk will not experience any recurrence. The 31-gene expression profile test (31-GEP) stratifies patient recurrence risk into low (Class 1) and high (Class 2) and has demonstrated risk-appropriate impact on disease management and clinical decisions. METHODS: Five-year plans for lab work, frequency of clinical visits, and imaging pre- and post-31-GEP test results were assessed for a cohort of 509 stage I-III patients following an interim subset analysis of 247 patients. RESULTS: After receiving 31-GEP results, 50.6% of patients had a change in management plans in at least one of the following categories-clinical visits, lab work, or surveillance imaging. The changes aligned with the risk predicted by the 31-GEP for 76.1% of patients with a Class 1 result and 78.7% of patients with a Class 2 result. A Class 1 31-GEP result was associated with changes toward low-intensity management recommendations, while a Class 2 result was associated with changes toward high-intensity management recommendations. CONCLUSION: The 31-GEP can stratify patient recurrence risk in patients with CM, and clinicians understand and apply the prognostic ability of the 31-GEP test to alter patient management in risk-appropriate directions.

When caught early, cancer of the skin can usually be removed, and patients have excellent chances of survival. However, some patients will have their cancer come back or spread to a new location in their body.The 31-gene expression profile (GEP) test measures the expression levels of 31 genes from an individual patient's tumor. A proprietary formula uses this information to identify the risk of recurrence or spread as low risk (Class 1) or high risk (Class 2). Cancers with low-risk 31-GEP scores have a lower chance of cancer recurrence or spread than patients with a high-risk score.In this study, we wanted to determine if doctors treated patients with low-risk scores differently from patients with high-risk scores. We found that doctors changed approximately half of patient treatment plans (doctor visits, lab work, or imaging to see if the cancer has come back) after learning the 31-GEP test results. Doctors usually planned less frequent follow-up visits for Class 1 results and more frequent follow up for Class 2 results.This study found doctors understand and make changes to their treatment plans based on the patient's 31-GEP test result.

Pulsed dye laser as a novel non-surgical treatment for basal cell carcinomas: response and follow up 12-21 months after treatment.

BACKGROUND AND OBJECTIVE: We showed previously that pulsed dye laser (PDL) is a potentially effective therapy for BCCs <15 mm on trunk and extremities. To follow-up, we conducted a study based on optimized parameters and expanded the duration of the study to at least 1 year after treatment. MATERIALS AND METHODS: Fourteen patients with 20 biopsy-proven BCCs on trunk and extremities, 8-35 mm in diameter, were treated. Each BCC received four consecutive PDL treatments at 3-4 week intervals. A 4 mm margin of clinically normal skin was also treated. Standardized photography was performed prior to each treatment and follow up visit. Patients were asked to consent for standard excision or at least scouting biopsies after treatment completion. RESULTS: Complete clinical response was seen with 19 of 20 treated BCCs, regardless of size and histologic subtype. One did not respond completely to therapy. All remaining 19 BCCs were followed between 12 and 21 months (median = 18 months) after the last PDL treatment. Of these 19 BCCs, only one recurred at 17 months follow up. The remaining 18 BCCs did not show any clinical signs of residual or recurrent tumor at 12-21 months follow-up. Overall, 90% (18/20 tumors) of treated BCCs in this study showed no clinical or histologic evidence of BCC more than 12 months after PDL treatment. Additionally, 18/19 (95%) BCCs less than or equal to 17 mm showed no evidence of residual or recurrent tumor clinically or on histology 12-21 months post-laser treatment. CONCLUSIONS: PDL treatment of BCC represents a novel, quick, and relatively non-painful treatment that does not usually produce scar and may represent an alternative treatment for certain types of BCC in the appropriate clinical setting. This study confirms prior findings regarding the efficacy of PDL in the treatment of BCC, with longer follow-up period.

Gnathostomiasis in a patient who frequently consumes sushi.

A 45-year-old woman presented for evaluation of a solitary pruritic nodule on the abdomen that suddenly appeared 3 weeks before. She was healthy without a significant medical history, travel history, exposures, medications, or pets. She reported that she consumed sushi at least weekly in the city of San Francisco. A punch biopsy revealed a superficial and deep perivascular and interstitial infiltrates consisting of lymphocytes, plasma cells, and many eosinophils. Most notably, there was a parasite centered in the reticular dermis with prominent lateral chords, a well-developed muscular esophagus, and an intestine that contained a brush border and multinucleate cells. Evaluation of these histological sections by the Centers for Disease Control and Prevention determined the parasite to be a nematode of the genus Gnathostoma. The patient underwent a systemic work-up for gnathostomiasis, including imaging, and no other abnormalities were found. She completed a 3-week course of albendazole and has remained asymptomatic since the biopsy of her abdominal lesion. Although gnathostomiasis is often a systemic illness, this patient did well with apparently only localized cutaneous disease. Gnathostomiasis should be considered in patients who present with nonspecific papules and nodules, especially when there is a history of frequent consumption of raw fish.

Infectious granulomatous dermatitis associated with Rothia mucilaginosa bacteremia: A case report.

Infections with rare pathogens are being recognized with increasing frequency in severely immunocompromised patients. As a result of these patients' underlying compromised defenses and susceptibility to atypical organisms, tissue biopsies from patients within this population may demonstrate nonclassical histopathological findings. Here, we describe an unusual granulomatous reaction to gram-positive cocci in the skin of a 52-year-old man undergoing salvage chemotherapy for acute myeloid leukemia. The patient presented with a papular eruption on the arms, trunk, and face and fever; concomitant blood cultures were positive for Rothia mucilaginosa and Streptococcus salivarius. Histologic evaluation revealed a granulomatous dermatitis associated with numerous small, round, predominantly intracellular bacteria. Classically, cutaneous infiltrates associated with coccoid bacterial infections are suppurative and not granulomatous. The intracellular organisms stained positive for Gram, periodic acid-Schiff, and Grocott methenamine silver stains, suggestive of R. mucilaginosa. Rothia mucilaginosa, a component of the oral flora, was first reported as a human pathogen in 1978. Although the majority of cases in the literature have described R. mucilaginosa bacteremia, other reported manifestations include meningitis, endocarditis, pneumonia, osteomyelitis, and peritonitis. To our knowledge, however, only 1 prior report has described a cutaneous manifestation of R. mucilaginosa septicemia, which occurred in a patient with neutropenia. This is the second reported case of an infectious granulomatous dermatitis associated with R. mucilaginosa bacteremia and raises awareness of this unusual histopathological presentation in the setting of a bacterial infection affecting the skin.

A grading system for local skin reactions developed for clinical trials of an intradermal and transcutaneous ETEC vaccine.

BACKGROUND: Trials assessing the safety of novel vaccine candidates are essential in the evaluation and development of candidate vaccines. Immunogenicity and dose-sparing features of vaccination approaches which target skin and associated tissues have garnered increased interest; for enteric vaccines, cutaneous vaccination has been of particular interest. Cutaneous vaccine site reactions are among the most common and visible vaccine related adverse events (AEs) when skin routes are used. Regulatory guidelines governing classification of severity focus on functional impact but are insufficient to characterize a spectrum of skin reaction and allow for comparisons of routes, doses and products with similar local cutaneous AEs. OBJECTIVES: Our group developed a grading scale to evaluate and compare cutaneous vaccine site reactions ahead of early-phase clinical trials of intradermal (ID) and transcutaneous immunization (TCI) with enterotoxigenic E.coli (ETEC) vaccine candidates (adhesin-based vaccine co-administered with LTR192G). We reviewed existing methods for characterizing the appearance and severity of local vaccine site reactions following TCI and ID vaccination and devised a standardized vaccine site appearance grading scale (VSAGS) for use in the clinical development of novel ETEC vaccine candidates which focused on pathophysiologic manifestation of skin findings. RESULTS: Available data from published reports revealed erythematous papules and pruritus were the most common local AEs associated with TCI. Frequency of reactions varied notably across studies as did TCI vaccination methodologies and products. ID vaccination commonly results in erythema and induration at the vaccine site as well as pigmentation changes. There was no published methodology to characterize the spectrum of dermatologic findings. CONCLUSION: ID and TCI vaccination are associated with a largely predictable range of cutaneous AEs. A grading scale focused on the appearance of cutaneous changes was useful in comparing cutaneous AEs. A standardized grading scale will facilitate documentation and comparison of cutaneous AEs.

A first in human clinical trial assessing the safety and immunogenicity of transcutaneously delivered enterotoxigenic Escherichia coli fimbrial tip adhesin with heat-labile enterotoxin with mutation R192G.

Enterotoxigenic Escherichia coli (ETEC) is a leading cause of diarrhea among travelers and pediatric populations worldwide. The tip-localized adhesin of colonization factor antigen (CFA)/I fimbriae was engineered as a donor strand complemented variant (dscCfaE) and delivered via transcutaneous immunization. Preclinical vaccine testing demonstrated safety, immunogenicity and efficacy. A series of open-label dose-escalating phase 1 studies evaluated a 3-dose (days 0, 21, 42) regimen via a transcutaneous skin patch. A total of forty-six subjects were enrolled into one of four vaccine dose levels (10, 50, 250, or 1250 µg) co-administered with single-mutant heat-labile enterotoxin (LTR(192G)). At the 50 µg dose level, ten subjects received the dscCfaE vaccine without LT(R192G). The vaccine was well tolerated with mild local vaccine site reactions characterized by an erythematous papular rash and pruritus, which were less frequent and reactive in the group not receiving LT(R192G). The frequency of responses to dscCfaE were moderate, whereas anti-toxin responses (serum IgA/IgG) ranged from 75 to 100% across groups that received LT(R192G). Antigen-specific antibody-secreting cell responses were elicited at all dose levels, but were generally low. Follow-on studies will optimize construct and route of delivery and assess efficacy in an ETEC challenge study.

Lues maligna in early HIV infection case report and review of the literature.

BACKGROUND: Lues maligna (also known as malignant syphilis or ulceronodular syphilis) is a rare dermatologic manifestation of syphilis more commonly seen in patients with HIV infection. The classic lesion of lues maligna is an oval, papulopustular skin lesion with well demarcated borders sometimes covered with a lamellar crust, but myriad clinical presentations of this disease also exist. GOALS: To report a presentation of lues maligna in a patient with probable early HIV infection, emphasizing the diagnostic criteria and clinical manifestations of lues maligna. STUDY DESIGN: Case report of lues maligna in a patient with probable early HIV infection. CONCLUSIONS: As syphilis becomes more common in many developed regions, it is important to recognize even atypical presentations of this clinical entity, especially among individuals who have unrecognized or early HIV infection.

Uncombable hair syndrome.

A 4-year-old boy was noted to have unruly, spangled hair, which could not be combed flat. His mother reported that his hair had always had that texture and that it seemed to grow slowly. A hair pull test demonstrated that hairs could not be easily extracted, and light microscopic examination of the hair revealed pathognomonic characteristics of uncombable hair syndrome, including a triangular cross-sectional shape and canal-like longitudinal depressions.

Lupus erythematosus tumidus of the scalp masquerading as alopecia areata.

Lupus erythematosus tumidus (LET) is a unique subset of chronic cutaneous lupus erythematosus (CCLE) that generally presents as urticarialike papules and plaques with induration and erythema on the face, trunk, and upper extremities. Lesions rarely present on the scalp or below the waist. We report a unique case of LET on the scalp of a woman that presented clinically as alopecia areata. Resistance to the standard treatment for alopecia areata prompted a biopsy that proved the diagnosis.

PET/CT imaging of squamoid eccrine ductal carcinoma.

Squamoid eccrine ductal carcinoma is an extremely uncommon type of eccrine carcinoma (EC). An important distinguishing feature of EC is potential for metastasis. Eccrine carcinoma has been reported to metastasize in up to 50% of cases. Despite tumor aggressivity, no recommendations for staging exist. We present the case of a 91-year-old woman with a lesion involving the left index finger confirmed to be squamoid eccrine ductal carcinoma by dermatopathologic evaluation. 18F-FDG PET/CT images revealed widespread multifocal FDG-avid metastatic disease. Although rare, staging of EC with 18F-FDG PET/CT imaging of the entire body is indicated.