- Email: [email protected]
Role of microRNAs in the pathogenesis of melanoma
4857
4352
Risk factors and predictors of outcome of nodular melanoma Erin Wei, MD, Brigham and Women’s Hospital, Harvard Medical School; Lucy Chen, MD, University of Miami Department of Dermatology and Cutaneous Surgery; Fangchao Ma, PhD, Independent Consultant; Jonette Keri, MD, University of Miami Department of Dermatology and Cutaneous Surgery; Shasa Hu, MD, University of Miami Department of Dermatology and Cutaneous Surgery
Risk of malignancy associated with biologic therapy and methotrexate (MTX) in the Psoriasis Longitudinal Assessment and Registry (PSOLAR) David Fiorentino, MD, Stanford University School of Medicine; Vincent Ho, MD, University of British Columbia; Mark Lebwohl, MD, Icahn School of Medicine at Mount Sinai; Luiz Leite, MD, Clınica Laser De Belem Lda; Lori Hopkins, PharmD, Janssen Scientific Affairs, LLC; Claudia Galindo, MD, Janssen Scientific Affairs, LLC; Wayne Langholff, PhD, Janssen Research & Development, LLC; Bhaskar Srivastava, MD, Janssen Scientific Affairs, LLC; Richard Langley, MD, Dalhousie University
Nodular melanoma (NM) accounts for 14% of all melanomas in incidence, but is responsible for approximately 40% of the melanoma-related deaths. Studies show that only 3% of NMs are detected at the early stage of less than 0.8 mm. This is partially due to a lack of understanding of the population at risk for NM development and NM-specific clinical features. This retrospective review of melanomas diagnosed among veterans investigates risk factors for NM and the predictors of survival. All cases with histologic confirmation of melanoma from September 1996 through December 2015 were reviewed. Melanoma in situ, acrolentiginous, mucosal, ocular, amelanotic, recurrent, and metastatic melanomas were excluded. Of melanoma with histologic confirmation, 265 cases were non-nodular melanoma (non-NM) and 60 cases were NM. The Breslow thickness of non-NM differed significantly from NM (mean of 0.76 mm at diagnosis for non-NM vs 3.9 mm for NM, P ¼.006). There was no significant change in the secondary prevention of NM over the past 19 years (mean NM Breslow thickness of 3.8 mm in 1996 vs 4.3 mm in 2015, P ¼ .84); in contrast, the detection for superficial spreading melanomas (SSMs) had improved significantly (mean SSM Breslow thickness of 0.8 mm in 1996 vs 0.3 mm in 2015, P ¼ .01). Veterans diagnosed with NM were older (mean age of 66 for non-NM vs 70 for NM, P ¼ .03), less likely have been seen by a VA dermatologist in the previous 6 months (34% for non-NM vs 20% for NM, P ¼ .04), and less likely to have other markers of health-care utilization, such as age-appropriate colonoscopy screening (73% for non-NM vs 47% for NM, P \.05). Comparing to non-NMs, NMs were more likely to be found on the neck, chest, and shoulder area (P ¼ .02). Younger age at diagnosis less than 65 was associated with improved survival (P ¼.02); dermoscopy use (P ¼.10) and shorter duration between dermatology visits (P ¼.27) also trended with improved survival. The lack of improvement in secondary prevention of NM over the past 19-years suggests that more effort needs to be dedicated into identifying individuals at risk for NMs. The trend of improved outcome of patient with more frequent dermatology visits suggests that regular skin exams may be an invaluable tool in this effort. In addition, based on these results, lower threshold for biopsy of new lesions on the neck, shoulder and chest region of older adults may be warranted. Commercial support: None identified.
Background: Studies on potential association between systemic psoriasis therapies and malignancy are limited. Objective: Determine the effect of selected therapies (ustekinumab [UST] tumornecrosis-factor inhibitors [TNFi]) and MTX) on malignancy risk (excluding nonmelanoma skin cancer) in patients with moderate-to-severe psoriasis. Methods: PSOLAR is a prospective psoriasis registry that evaluated long-term safety for patients eligible to receive systemic treatment. Patients with a history of malignancy or with recurrence/2nd malignancy after a 1st malignancy were excluded from this analysis. The incidence of 1) overall malignancy and 2) the five most frequent malignancies were calculated per 100 pt-yr. A nested case-control analysis was performed to assess the risk of overall malignancy in patients treated with biologics and/or MTX compared with matched controls. Duration of exposure was defined as none (0 or\3 months), short-term (3-12 months) and long-term ([12 months). Followup began on therapy start date and ended 12 months after therapy discontinuation. Results: Overall incidence of malignancy was 0.55/100 pt-yr (95% CI: 0.48, 0.62). Rates/100 pt-yr of the most common malignancies were: breast (0.09), prostate (0.08), lung (0.06), melanoma (0.06), and lymphoma (0.03). For the case-control analysis, 252 patients with malignancy were included, and matched for age, gender, and geographic region in a 1:4 ratio to 1008 controls. Compared with no exposure, neither short- or long-term UST exposure (ORs [95%CIs]: 1.14 [0.64-2.04]) and 0.97 [0.63-1.50], respectively) nor MTX exposure (1.01 [0.45-2.29] and 0.97 [0.62-1.52], respectively) increased overall malignancy risk. Long-term TNFi exposure (1.47 [1.06-2.04]), but not short-term exposure (1.10 [0.61-1.99]) increased malignancy risk (P ¼.021). Limitations: Some patients were exposed to concomitant medications or switched therapy on registry; thus exposure time and malignancies for such patients were counted for more than one treatment group. Data on some malignancy risk factors are not collected in the registry. Findings are based on median follow-up of \5 yr. Conclusions: Of psoriasis therapies evaluated, only TNFi exposure $12 months was associated with increased risk of overall malignancy. Additional studies are needed to investigate these associations. Commercial support: Janssen Research & Development, LLC supported this study 100%.
4594 Risk of completed suicide in psoriasis patients using biologics: Results from the US FDA Adverse Event Reporting System (FAERS) Madhulika A. Gupta, MD, University of Western Ontario, London, Ontario; Branka Vujcic, BS, University of Western Ontario; Aditya K. Gupta, MD, Department of Medicine, University of Toronto Background: Psoriasis, especially more severe disease, is associated with a high prevalence suicidal ideation and suicide attempts, which may be associated with an increased risk of completed suicide (CS). Using biologics for the treatment of severe psoriasis can therefore pose a clinical dilemma, as there are case reports of suicidal behaviors and CS with biologics. To our knowledge there are no population based studies that have examined the risk of CS with biologics in psoriasis patients. Objective: Examine the FAERS database (Jan 2004-Sep 2015) for all adverse event reports of CS in psoriasis patients who were treated with FDA-approved biologics (alefacept, adalimumab, etanercept, infliximab, efalizumab, and ustekinumab) for psoriasis. Methods: Medical Dictionary for Regulatory Activities preferred terms were searched to account for individual safety reports (ISR) which specified psoriasis as the indication for which the biologics were the documented primary suspect responsible for the adverse event reaction of CS. Reporting odds ratios (ROR) with 95% CI were calculated to assess baseline risk of CS with the use of biologics. Results: There were 284,758 ISR when biologics were used for the indication of psoriasis. There were 36 CS (average age 48.74 years 6 10.23 years, 91.67% males). Adalimumab was implicated in 33.3%, etanercept in 30.6%, ustekinumab in 19.4%, infliximab in 13.9% and alefacept in 2.8% of ISR. The risk of CS with biologics was not significantly different than the risk of CS with all other medications (including drugs used to treat severe psoriasis eg, acitretin, cyclosporine, methotrexate) used in psoriasis with ROR ¼ 1.99 (95% CI 0.78-5.08). However, the risk of CS when biologics were used for psoriasis was greater than when biologics were used for any other indication: ROR ¼ 1.47 (95% CI 1.03-2.11). Comment: CS was not more frequent in psoriasis patients using biologics versus other psoriasis therapies, however CS was about 1.5 times more frequent in psoriasis patients using biologics versus all other conditions where biologics were used. Our results suggest that the risk of CS was greater when biologics were used to treat psoriasis versus other disorders for which biologics are indicated. These findings suggest that CS as a side effect of biologics in psoriasis may be a complex phenomenon as there may be an interaction between the diagnosis of psoriasis and CS as a side effect. Commercial support: None identified.
JUNE 2017
5065 Role of microRNAs in the pathogenesis of melanoma Rosa Murria, PhD, University Hospital La Fe; Blanca De Unamuno, MD, University Hospital La Fe; Gema Perez, BS, University Hospital La Fe; Eva Barragan, PhD, University Hospital La Fe; Marta Llop, PhD, University Hospital La Fe; Mercedes Rodriguez, PhD, University Hospital La Fe; Sarai Palanca, PhD, University Hospital La Fe; Rafael Botella, PhD, University Hospital La Fe Background: Several studies have focused on identifying microRNAs (miRs) involved in the pathogenesis of melanoma. However, its association with clinicopathological features (Breslow index, growth rate, presence of ulceration, mitosis or regression) has been scarcely addressed. Objective: We aimed to identify miRs associated with the most relevant clinicopathological characteristics in the melanoma prognosis. Methods: We studied miR expression profiles in 22 melanomas employing miRNA gene chip arrays (v4.0, Affymetrix). Expression results were analyzed using the Partek Genomic Suite software (6.6v). The subsequent validation, conducted in a wider series of 114 new melanomas, was performed by qRT-PCR employing miScript II Reverse Transcription Kit, miScript Primer Assay y miScript SYBR Green PCR kit (Quiagen) on the 7500 Real Time PCR System platform (Applied Biosystems). The association between clinicopathological characteristics and miR expression was evaluated by ANOVA test (P \.05, SPSS v21). Results Expression studies selected four miRs (miR30b-5p, miR-34a-5p, miR-130b-3p y miR-138-5p) candidates in the pathogenesis of melanoma. Tumors with greater Breslow index overexpressed miR-138-5p and miR130b-3p (P \.001 and P ¼.003, respectively), these miRs were also overexpressed in melanomas with mitosis and ulceration (P ¼ .004 and P \ .001, respectively). Overexpression of miR-30b-5p (P ¼.04) and miR-138-5p (P ¼.05) was associated with fast-growing melanomas; and melanomas carrying TERT promoter mutations overexpressed miR-138-5p and miR-130b-3p (P ¼.001 and P ¼.03, respectively). There was no miR whose expression was associated with the regression phenomenon. Conclusion: The miR expression signature here found is associated with previously identified clinicopathological features of poor prognosis in melanoma. The expression of these miRs may in the future be used as a prognosis biomarker. However functional studies are needed to establish the right role of these miRs in the melanoma pathogenesis. Acknowledgements: We thank Carlos III Health Institute for having granted the project PIE13/00046. We also thank to the Health Research Institute La Fe for having granted Blanca de Unamuno (04/2014) and Rosa Murria (18/2015) which made possible their participation in the study. Commercial support: None identified.
J AM ACAD DERMATOL
AB221
4352
Risk factors and predictors of outcome of nodular melanoma Erin Wei, MD, Brigham and Women’s Hospital, Harvard Medical School; Lucy Chen, MD, University of Miami Department of Dermatology and Cutaneous Surgery; Fangchao Ma, PhD, Independent Consultant; Jonette Keri, MD, University of Miami Department of Dermatology and Cutaneous Surgery; Shasa Hu, MD, University of Miami Department of Dermatology and Cutaneous Surgery
Risk of malignancy associated with biologic therapy and methotrexate (MTX) in the Psoriasis Longitudinal Assessment and Registry (PSOLAR) David Fiorentino, MD, Stanford University School of Medicine; Vincent Ho, MD, University of British Columbia; Mark Lebwohl, MD, Icahn School of Medicine at Mount Sinai; Luiz Leite, MD, Clınica Laser De Belem Lda; Lori Hopkins, PharmD, Janssen Scientific Affairs, LLC; Claudia Galindo, MD, Janssen Scientific Affairs, LLC; Wayne Langholff, PhD, Janssen Research & Development, LLC; Bhaskar Srivastava, MD, Janssen Scientific Affairs, LLC; Richard Langley, MD, Dalhousie University
Nodular melanoma (NM) accounts for 14% of all melanomas in incidence, but is responsible for approximately 40% of the melanoma-related deaths. Studies show that only 3% of NMs are detected at the early stage of less than 0.8 mm. This is partially due to a lack of understanding of the population at risk for NM development and NM-specific clinical features. This retrospective review of melanomas diagnosed among veterans investigates risk factors for NM and the predictors of survival. All cases with histologic confirmation of melanoma from September 1996 through December 2015 were reviewed. Melanoma in situ, acrolentiginous, mucosal, ocular, amelanotic, recurrent, and metastatic melanomas were excluded. Of melanoma with histologic confirmation, 265 cases were non-nodular melanoma (non-NM) and 60 cases were NM. The Breslow thickness of non-NM differed significantly from NM (mean of 0.76 mm at diagnosis for non-NM vs 3.9 mm for NM, P ¼.006). There was no significant change in the secondary prevention of NM over the past 19 years (mean NM Breslow thickness of 3.8 mm in 1996 vs 4.3 mm in 2015, P ¼ .84); in contrast, the detection for superficial spreading melanomas (SSMs) had improved significantly (mean SSM Breslow thickness of 0.8 mm in 1996 vs 0.3 mm in 2015, P ¼ .01). Veterans diagnosed with NM were older (mean age of 66 for non-NM vs 70 for NM, P ¼ .03), less likely have been seen by a VA dermatologist in the previous 6 months (34% for non-NM vs 20% for NM, P ¼ .04), and less likely to have other markers of health-care utilization, such as age-appropriate colonoscopy screening (73% for non-NM vs 47% for NM, P \.05). Comparing to non-NMs, NMs were more likely to be found on the neck, chest, and shoulder area (P ¼ .02). Younger age at diagnosis less than 65 was associated with improved survival (P ¼.02); dermoscopy use (P ¼.10) and shorter duration between dermatology visits (P ¼.27) also trended with improved survival. The lack of improvement in secondary prevention of NM over the past 19-years suggests that more effort needs to be dedicated into identifying individuals at risk for NMs. The trend of improved outcome of patient with more frequent dermatology visits suggests that regular skin exams may be an invaluable tool in this effort. In addition, based on these results, lower threshold for biopsy of new lesions on the neck, shoulder and chest region of older adults may be warranted. Commercial support: None identified.
Background: Studies on potential association between systemic psoriasis therapies and malignancy are limited. Objective: Determine the effect of selected therapies (ustekinumab [UST] tumornecrosis-factor inhibitors [TNFi]) and MTX) on malignancy risk (excluding nonmelanoma skin cancer) in patients with moderate-to-severe psoriasis. Methods: PSOLAR is a prospective psoriasis registry that evaluated long-term safety for patients eligible to receive systemic treatment. Patients with a history of malignancy or with recurrence/2nd malignancy after a 1st malignancy were excluded from this analysis. The incidence of 1) overall malignancy and 2) the five most frequent malignancies were calculated per 100 pt-yr. A nested case-control analysis was performed to assess the risk of overall malignancy in patients treated with biologics and/or MTX compared with matched controls. Duration of exposure was defined as none (0 or\3 months), short-term (3-12 months) and long-term ([12 months). Followup began on therapy start date and ended 12 months after therapy discontinuation. Results: Overall incidence of malignancy was 0.55/100 pt-yr (95% CI: 0.48, 0.62). Rates/100 pt-yr of the most common malignancies were: breast (0.09), prostate (0.08), lung (0.06), melanoma (0.06), and lymphoma (0.03). For the case-control analysis, 252 patients with malignancy were included, and matched for age, gender, and geographic region in a 1:4 ratio to 1008 controls. Compared with no exposure, neither short- or long-term UST exposure (ORs [95%CIs]: 1.14 [0.64-2.04]) and 0.97 [0.63-1.50], respectively) nor MTX exposure (1.01 [0.45-2.29] and 0.97 [0.62-1.52], respectively) increased overall malignancy risk. Long-term TNFi exposure (1.47 [1.06-2.04]), but not short-term exposure (1.10 [0.61-1.99]) increased malignancy risk (P ¼.021). Limitations: Some patients were exposed to concomitant medications or switched therapy on registry; thus exposure time and malignancies for such patients were counted for more than one treatment group. Data on some malignancy risk factors are not collected in the registry. Findings are based on median follow-up of \5 yr. Conclusions: Of psoriasis therapies evaluated, only TNFi exposure $12 months was associated with increased risk of overall malignancy. Additional studies are needed to investigate these associations. Commercial support: Janssen Research & Development, LLC supported this study 100%.
4594 Risk of completed suicide in psoriasis patients using biologics: Results from the US FDA Adverse Event Reporting System (FAERS) Madhulika A. Gupta, MD, University of Western Ontario, London, Ontario; Branka Vujcic, BS, University of Western Ontario; Aditya K. Gupta, MD, Department of Medicine, University of Toronto Background: Psoriasis, especially more severe disease, is associated with a high prevalence suicidal ideation and suicide attempts, which may be associated with an increased risk of completed suicide (CS). Using biologics for the treatment of severe psoriasis can therefore pose a clinical dilemma, as there are case reports of suicidal behaviors and CS with biologics. To our knowledge there are no population based studies that have examined the risk of CS with biologics in psoriasis patients. Objective: Examine the FAERS database (Jan 2004-Sep 2015) for all adverse event reports of CS in psoriasis patients who were treated with FDA-approved biologics (alefacept, adalimumab, etanercept, infliximab, efalizumab, and ustekinumab) for psoriasis. Methods: Medical Dictionary for Regulatory Activities preferred terms were searched to account for individual safety reports (ISR) which specified psoriasis as the indication for which the biologics were the documented primary suspect responsible for the adverse event reaction of CS. Reporting odds ratios (ROR) with 95% CI were calculated to assess baseline risk of CS with the use of biologics. Results: There were 284,758 ISR when biologics were used for the indication of psoriasis. There were 36 CS (average age 48.74 years 6 10.23 years, 91.67% males). Adalimumab was implicated in 33.3%, etanercept in 30.6%, ustekinumab in 19.4%, infliximab in 13.9% and alefacept in 2.8% of ISR. The risk of CS with biologics was not significantly different than the risk of CS with all other medications (including drugs used to treat severe psoriasis eg, acitretin, cyclosporine, methotrexate) used in psoriasis with ROR ¼ 1.99 (95% CI 0.78-5.08). However, the risk of CS when biologics were used for psoriasis was greater than when biologics were used for any other indication: ROR ¼ 1.47 (95% CI 1.03-2.11). Comment: CS was not more frequent in psoriasis patients using biologics versus other psoriasis therapies, however CS was about 1.5 times more frequent in psoriasis patients using biologics versus all other conditions where biologics were used. Our results suggest that the risk of CS was greater when biologics were used to treat psoriasis versus other disorders for which biologics are indicated. These findings suggest that CS as a side effect of biologics in psoriasis may be a complex phenomenon as there may be an interaction between the diagnosis of psoriasis and CS as a side effect. Commercial support: None identified.
JUNE 2017
5065 Role of microRNAs in the pathogenesis of melanoma Rosa Murria, PhD, University Hospital La Fe; Blanca De Unamuno, MD, University Hospital La Fe; Gema Perez, BS, University Hospital La Fe; Eva Barragan, PhD, University Hospital La Fe; Marta Llop, PhD, University Hospital La Fe; Mercedes Rodriguez, PhD, University Hospital La Fe; Sarai Palanca, PhD, University Hospital La Fe; Rafael Botella, PhD, University Hospital La Fe Background: Several studies have focused on identifying microRNAs (miRs) involved in the pathogenesis of melanoma. However, its association with clinicopathological features (Breslow index, growth rate, presence of ulceration, mitosis or regression) has been scarcely addressed. Objective: We aimed to identify miRs associated with the most relevant clinicopathological characteristics in the melanoma prognosis. Methods: We studied miR expression profiles in 22 melanomas employing miRNA gene chip arrays (v4.0, Affymetrix). Expression results were analyzed using the Partek Genomic Suite software (6.6v). The subsequent validation, conducted in a wider series of 114 new melanomas, was performed by qRT-PCR employing miScript II Reverse Transcription Kit, miScript Primer Assay y miScript SYBR Green PCR kit (Quiagen) on the 7500 Real Time PCR System platform (Applied Biosystems). The association between clinicopathological characteristics and miR expression was evaluated by ANOVA test (P \.05, SPSS v21). Results Expression studies selected four miRs (miR30b-5p, miR-34a-5p, miR-130b-3p y miR-138-5p) candidates in the pathogenesis of melanoma. Tumors with greater Breslow index overexpressed miR-138-5p and miR130b-3p (P \.001 and P ¼.003, respectively), these miRs were also overexpressed in melanomas with mitosis and ulceration (P ¼ .004 and P \ .001, respectively). Overexpression of miR-30b-5p (P ¼.04) and miR-138-5p (P ¼.05) was associated with fast-growing melanomas; and melanomas carrying TERT promoter mutations overexpressed miR-138-5p and miR-130b-3p (P ¼.001 and P ¼.03, respectively). There was no miR whose expression was associated with the regression phenomenon. Conclusion: The miR expression signature here found is associated with previously identified clinicopathological features of poor prognosis in melanoma. The expression of these miRs may in the future be used as a prognosis biomarker. However functional studies are needed to establish the right role of these miRs in the melanoma pathogenesis. Acknowledgements: We thank Carlos III Health Institute for having granted the project PIE13/00046. We also thank to the Health Research Institute La Fe for having granted Blanca de Unamuno (04/2014) and Rosa Murria (18/2015) which made possible their participation in the study. Commercial support: None identified.
J AM ACAD DERMATOL
AB221