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Newborn with a rapidly enlarging left flank tumor: A case of extrarenal clear cell sarcoma of the kidney
4908
5420
Neuropsychiatric adverse events in brodalumab psoriasis studies Mark Lebwohl, MD, Icahn School of Medicine at Mount Sinai; Kim A. Papp, MD, Probity Medical Research; Jashin Wu, MD, Kaiser Permanente Los Angeles Medical Center; Andrew Blauvelt, MD, Oregon Medical Research Center; Alan Menter, MD, Baylor University Medical Center; Shipra Rastogi, PhD, Valeant Pharmaceuticals North America LLC; Robert Israel, MD, Valeant Pharmaceuticals North America LLC
Newborn with a rapidly enlarging left flank tumor: A case of extrarenal clear cell sarcoma of the kidney Radhika Grandhi, MPH, University of Cincinnati College of Medicine; Kyle Owens, BS, ETSU Quillen College of Medicine; Bethany Rohr, MD, Geisinger Meidcal Center; Ryan Berry, MD, Geisinger Medical Center; Audrey Green, MD, Geisinger Medical Center; George Lin, MD, Geisinger Medical Center
Background: Patients with psoriasis are at increased risk for depression, and suicidal ideation and behavior (SIB). The efficacy and safety of brodalumab (140 or 210 mg q2w), an IL-17RA antagonist, were investigated in one phase 2 trial and in three phase 3, multicenter, randomized trials of patients with moderate-to-severe plaque psoriasis (AMAGINE-1/-2/-3). We analyzed psychiatric adverse events (AEs) in these trials, including SIB. Methods: The 12-week integrated safety data allowed direct randomized comparisons of brodalumab with placebo and ustekinumab. Data from the 52-week and long-term pools were summarized as follow-up time-adjusted or exposure-adjusted rates (events per 100 patient-years [py] and 95% confidence intervals [CIs]). Other assessments included HADS, DLQI, SF-36 mental component summary (MCS), and the incidence of psychiatric AEs. Results: The psoriasis studies included 4464 patients with a total of 9162 py of brodalumab exposure. Approximately 88% of patients were on brodalumab 210 mg by week 52. Of note, there were no exclusions in the brodalumab studies for mental health risk factors or a history of substance abuse. In AMAGINE-1, the prevalence of anxiety and depression at baseline were 36% and 27%, respectively. Mean HADS anxiety and depression scores, DLQI, and SF-36 MCS significantly improved with brodalumab compared with placebo by 12 weeks; improvements in HADS score with brodalumab were sustained through 52 weeks. In the psoriasis program (follow-up adjusted rate), there were 22 suicide ideations (0.24), 10 suicide attempts (0.11), 3 completed suicides (0.03), and 1 suicide adjudicated as indeterminate. Of the 3 completed suicides, all patients were receiving brodalumab 210 mg, had baseline risk factors, and had demonstrated clinical responses (PASI $73). Time-toevent from first dose ranged from 140 to 845 days. Follow-up time-adjusted SIB rates through week 52 were lower in the brodalumab group compared with the ustekinumab group, with overlapping CIs (0.20 [0.08, 0.41] vs 0.60 [0.12, 1.74]). Long-term rates of SIB with brodalumab were slightly higher (0.37 [0.26, 0.52]) compared with those through week 52, with no increase in the completed suicide rate (0.04 [0.01, 0.11] vs 0.06 [0.01, 0.20]). Rates of psychiatric AEs were comparable between treatments at week 52 and did not increase with long-term treatment. Conclusion: Controlled data did not suggest a causal relationship between brodalumab treatment and SIB.
Background: Clear cell sarcoma of the kidney (CCSK) is a rare, high-grade sarcoma occurring in children with a peak incidence between 12 and 36 months of age. Few cases of extra-renal CCSK have been reported to date and only 3 cases in the literature show extra-renal CCSK with YWHAE-NUTM2B/E fusion. Case Description: A one-week-old female, born at 33-weeks and 4 days, presented for evaluation of a rapidly enlarging mass. The prenatal course was significant for a twin gestation. Examination showed a 4 centimeter, dome-shaped, firm, non-mobile violaceous tumor on the left flank. MRI with contrast revealed a mass within the subcutaneous tissue with no communication to or involvement of the kidney. The patient underwent wide local excision. H&E sections showed atypical spindled-toround appearing cells with variably myxoid and fibrous stroma, admixed small vessels, and intervening fibrous septae. Genetic analysis revealed an abnormal karyotype 46,XX,add(17)(p13). FISH failed to show rearrangement of EWSR1 or ETV6. Further molecular analysis revealed an isolated YWHAE-NUTM2 fusion. These findings with the histopathologic features determined the diagnosis of extra-renal CCSK. At three months of age, the patient had evidence of recurrence with two palpable masses; one located at the original site and another in the left axilla. She underwent wide resection of the primary site and partial excision of the left axillary mass, which showed metastatic CCSK in a lymph node. Due to metastatic disease and early recurrence, chemotherapy with etoposide, cyclophosphamide, and carboplatin was initiated. Discussion: With only 20 new cases per year in the United States, CCSK is reported to make up 4% of all renal sarcomas, and an extrarenal location is extremely rare. CCSK is a highly malignant neoplasm with an aggressive clinical course. Due to overlapping features of other pediatric sarcomas, genetic markers have been developed. Recent studies have identified recurrent genetic abnormalities in CCSK alterations in exon 16 of BCOR occurring in the majority of cases, or t(10;17) resulting in fusion of YWHAE-NUTM2 in 12%. Conclusion: We present a case of extrarenal CCSK harboring a Y2HAE-NUTM2 fusion in a newborn. To our knowledge, this is only the fourth reported case of extrarenal CCSK in an infant shown to harbor this mutation. This case reviews the clinical presentation and histopathology of extrarenal CCSK and importance of genetic markers in diagnosing this rare sarcoma. Commercial support: None identified.
Commercial support: This study was sponsored by Valeant Pharmaceuticals North America LLC. Medical writing support was provided by MedThink SciCom and funded by Valeant Pharmaceuticals North America LLC.
4534
4955 Neutrophilic dermatosis of the dorsal hands Jewell Gaulding, MD, Henry Ford Health System; Laurie Kohen, MD, Henry Ford Health System We report a case of a 78-year-old white gentleman who presented with a three to four week history of lesions on the dorsal aspect of his bilateral hands. The areas were associated with edema, pruritus and pain. Physical exam revealed edematous hemorrhagic plaques with focal areas of ulceration, predominantly on bilateral dorsal hands. Punch biopsy of a plaque on his left dorsal hand showed a diffuse neutrophilic infiltrate with areas of leukocytoclasis. In addition, there was hemorrhage and endothelial swelling with neutrophils noted within vessel walls. Tissue culture was obtained with a negative gram stain. Fungal culture was also negative and acid-fast bacilli were not present. The patient was treated with prednisone 80 mg daily, approximately 1 mg/kg with substantial improvement in edema, pruritus and pain. Neutrophilic dermatosis of the dorsal hands (NDDH) is a rare, localized variant of Sweet’s syndrome first described in 1996. This condition has been observed in patients with myelodysplasia, leukemia, inflammatory bowel disease, sarcoidosis, lymphoma and hepatitis C. Presentation of this condition varies greatly including, but not limited to, violaceous edematous or ulcerated plaques with bullous or hemorrhagic lesions also being described. Fever, neutrophilic leukocytosis and elevated sedimentation rate have been reported in one-third of patients. Treatment is similar to Sweet’s syndrome with first line therapy considered to be systemic corticosteroids. Dapsone, colchicine, azathioprine, tetracyclines, and cyclosporine have also been reported as treatment options.
NF-kB inhibition is associated with OPN/MMP-9 down-regulation in cutaneous melanoma Claudio Guarneri, MD, Department of Clinical Experimental Medicine, Section of Dermatology, University of Messina; Valentina Bevelacqua, MD, 2Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy; Pietro Gangemi, PhD, Pathology Unit, University Hospital Policlinico-Vittorio Emanuele, Catania, Italy; Jerry Polesel, PhD, 4Unit of Cancer Epidemiology, National Cancer Institute, IRCCS, CRO-Aviano, Aviano, Italy; Kazou Umezawa, PhD, Department of Molecular Target Medicine, Aichi Medical University School of Medicine, Nagakute, Aic; Serafinella Patrizia Cannav o, MD, Department of Clinical Experimental Medicine, Section of Dermatology, University of Messina; Massimo Libra, MD, 2Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy Cutaneous melanoma development is influenced by genetic factors, including B-Raf mutations and environmental factors, such as ultraviolet exposure. Its expansion has been also associated with the involvement of several tumor microenvironmental molecules. Among these, NF-kB has been indicated as a key player of osteopontin (OPN) and matrix metalloproteinase-9 (MMP-9) activation. However, if NF-kB plays a role on OPN/MMP-9 axis in melanoma development and progression according to BRAFV600E mutation status has not been deeply investigated. On these bases, 148 melanoma patients and 53 healthy donors were recruited for the analysis of OPN, MMP-9 and NF-kB. Significant higher circulating levels of OPN, and MMP-9 were observed in melanoma patients when compared to healthy donors. Similar data were obtained for NF-kBp65 activity. OPN levels were not statistically different between melanomas with and without B-RAFV600E mutation. While, significant differences were observed for NF-kB and MMP-9. To demonstrate if NF-kB inhibition is associated with the decrease of OPN and MMP-9 levels, peripheral blood mononuclear cells (PBMCs) from 29 melanoma patients were treated with NF-kB inhibitor dehydroxymethylepoxyquinomycin (DHMEQ) in association or not with OPN. As expected, the inhibition of NF-kB induced a strong decrease of both OPN and MMP-9 levels. Furthermore, the decrease of MMP-9 was higher among melanomas harboring B-RAFV600E mutation. Overall, our data suggest that the activation of MMP-9 is associated with B-RAFV600E mutation. Furthermore, such activation is mediated by NF-kB suggesting its role as therapeutic target for melanoma patients. Commercial support: None identified.
Commercial support: None identified.
AB178
J AM ACAD DERMATOL
JUNE 2017
5420
Neuropsychiatric adverse events in brodalumab psoriasis studies Mark Lebwohl, MD, Icahn School of Medicine at Mount Sinai; Kim A. Papp, MD, Probity Medical Research; Jashin Wu, MD, Kaiser Permanente Los Angeles Medical Center; Andrew Blauvelt, MD, Oregon Medical Research Center; Alan Menter, MD, Baylor University Medical Center; Shipra Rastogi, PhD, Valeant Pharmaceuticals North America LLC; Robert Israel, MD, Valeant Pharmaceuticals North America LLC
Newborn with a rapidly enlarging left flank tumor: A case of extrarenal clear cell sarcoma of the kidney Radhika Grandhi, MPH, University of Cincinnati College of Medicine; Kyle Owens, BS, ETSU Quillen College of Medicine; Bethany Rohr, MD, Geisinger Meidcal Center; Ryan Berry, MD, Geisinger Medical Center; Audrey Green, MD, Geisinger Medical Center; George Lin, MD, Geisinger Medical Center
Background: Patients with psoriasis are at increased risk for depression, and suicidal ideation and behavior (SIB). The efficacy and safety of brodalumab (140 or 210 mg q2w), an IL-17RA antagonist, were investigated in one phase 2 trial and in three phase 3, multicenter, randomized trials of patients with moderate-to-severe plaque psoriasis (AMAGINE-1/-2/-3). We analyzed psychiatric adverse events (AEs) in these trials, including SIB. Methods: The 12-week integrated safety data allowed direct randomized comparisons of brodalumab with placebo and ustekinumab. Data from the 52-week and long-term pools were summarized as follow-up time-adjusted or exposure-adjusted rates (events per 100 patient-years [py] and 95% confidence intervals [CIs]). Other assessments included HADS, DLQI, SF-36 mental component summary (MCS), and the incidence of psychiatric AEs. Results: The psoriasis studies included 4464 patients with a total of 9162 py of brodalumab exposure. Approximately 88% of patients were on brodalumab 210 mg by week 52. Of note, there were no exclusions in the brodalumab studies for mental health risk factors or a history of substance abuse. In AMAGINE-1, the prevalence of anxiety and depression at baseline were 36% and 27%, respectively. Mean HADS anxiety and depression scores, DLQI, and SF-36 MCS significantly improved with brodalumab compared with placebo by 12 weeks; improvements in HADS score with brodalumab were sustained through 52 weeks. In the psoriasis program (follow-up adjusted rate), there were 22 suicide ideations (0.24), 10 suicide attempts (0.11), 3 completed suicides (0.03), and 1 suicide adjudicated as indeterminate. Of the 3 completed suicides, all patients were receiving brodalumab 210 mg, had baseline risk factors, and had demonstrated clinical responses (PASI $73). Time-toevent from first dose ranged from 140 to 845 days. Follow-up time-adjusted SIB rates through week 52 were lower in the brodalumab group compared with the ustekinumab group, with overlapping CIs (0.20 [0.08, 0.41] vs 0.60 [0.12, 1.74]). Long-term rates of SIB with brodalumab were slightly higher (0.37 [0.26, 0.52]) compared with those through week 52, with no increase in the completed suicide rate (0.04 [0.01, 0.11] vs 0.06 [0.01, 0.20]). Rates of psychiatric AEs were comparable between treatments at week 52 and did not increase with long-term treatment. Conclusion: Controlled data did not suggest a causal relationship between brodalumab treatment and SIB.
Background: Clear cell sarcoma of the kidney (CCSK) is a rare, high-grade sarcoma occurring in children with a peak incidence between 12 and 36 months of age. Few cases of extra-renal CCSK have been reported to date and only 3 cases in the literature show extra-renal CCSK with YWHAE-NUTM2B/E fusion. Case Description: A one-week-old female, born at 33-weeks and 4 days, presented for evaluation of a rapidly enlarging mass. The prenatal course was significant for a twin gestation. Examination showed a 4 centimeter, dome-shaped, firm, non-mobile violaceous tumor on the left flank. MRI with contrast revealed a mass within the subcutaneous tissue with no communication to or involvement of the kidney. The patient underwent wide local excision. H&E sections showed atypical spindled-toround appearing cells with variably myxoid and fibrous stroma, admixed small vessels, and intervening fibrous septae. Genetic analysis revealed an abnormal karyotype 46,XX,add(17)(p13). FISH failed to show rearrangement of EWSR1 or ETV6. Further molecular analysis revealed an isolated YWHAE-NUTM2 fusion. These findings with the histopathologic features determined the diagnosis of extra-renal CCSK. At three months of age, the patient had evidence of recurrence with two palpable masses; one located at the original site and another in the left axilla. She underwent wide resection of the primary site and partial excision of the left axillary mass, which showed metastatic CCSK in a lymph node. Due to metastatic disease and early recurrence, chemotherapy with etoposide, cyclophosphamide, and carboplatin was initiated. Discussion: With only 20 new cases per year in the United States, CCSK is reported to make up 4% of all renal sarcomas, and an extrarenal location is extremely rare. CCSK is a highly malignant neoplasm with an aggressive clinical course. Due to overlapping features of other pediatric sarcomas, genetic markers have been developed. Recent studies have identified recurrent genetic abnormalities in CCSK alterations in exon 16 of BCOR occurring in the majority of cases, or t(10;17) resulting in fusion of YWHAE-NUTM2 in 12%. Conclusion: We present a case of extrarenal CCSK harboring a Y2HAE-NUTM2 fusion in a newborn. To our knowledge, this is only the fourth reported case of extrarenal CCSK in an infant shown to harbor this mutation. This case reviews the clinical presentation and histopathology of extrarenal CCSK and importance of genetic markers in diagnosing this rare sarcoma. Commercial support: None identified.
Commercial support: This study was sponsored by Valeant Pharmaceuticals North America LLC. Medical writing support was provided by MedThink SciCom and funded by Valeant Pharmaceuticals North America LLC.
4534
4955 Neutrophilic dermatosis of the dorsal hands Jewell Gaulding, MD, Henry Ford Health System; Laurie Kohen, MD, Henry Ford Health System We report a case of a 78-year-old white gentleman who presented with a three to four week history of lesions on the dorsal aspect of his bilateral hands. The areas were associated with edema, pruritus and pain. Physical exam revealed edematous hemorrhagic plaques with focal areas of ulceration, predominantly on bilateral dorsal hands. Punch biopsy of a plaque on his left dorsal hand showed a diffuse neutrophilic infiltrate with areas of leukocytoclasis. In addition, there was hemorrhage and endothelial swelling with neutrophils noted within vessel walls. Tissue culture was obtained with a negative gram stain. Fungal culture was also negative and acid-fast bacilli were not present. The patient was treated with prednisone 80 mg daily, approximately 1 mg/kg with substantial improvement in edema, pruritus and pain. Neutrophilic dermatosis of the dorsal hands (NDDH) is a rare, localized variant of Sweet’s syndrome first described in 1996. This condition has been observed in patients with myelodysplasia, leukemia, inflammatory bowel disease, sarcoidosis, lymphoma and hepatitis C. Presentation of this condition varies greatly including, but not limited to, violaceous edematous or ulcerated plaques with bullous or hemorrhagic lesions also being described. Fever, neutrophilic leukocytosis and elevated sedimentation rate have been reported in one-third of patients. Treatment is similar to Sweet’s syndrome with first line therapy considered to be systemic corticosteroids. Dapsone, colchicine, azathioprine, tetracyclines, and cyclosporine have also been reported as treatment options.
NF-kB inhibition is associated with OPN/MMP-9 down-regulation in cutaneous melanoma Claudio Guarneri, MD, Department of Clinical Experimental Medicine, Section of Dermatology, University of Messina; Valentina Bevelacqua, MD, 2Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy; Pietro Gangemi, PhD, Pathology Unit, University Hospital Policlinico-Vittorio Emanuele, Catania, Italy; Jerry Polesel, PhD, 4Unit of Cancer Epidemiology, National Cancer Institute, IRCCS, CRO-Aviano, Aviano, Italy; Kazou Umezawa, PhD, Department of Molecular Target Medicine, Aichi Medical University School of Medicine, Nagakute, Aic; Serafinella Patrizia Cannav o, MD, Department of Clinical Experimental Medicine, Section of Dermatology, University of Messina; Massimo Libra, MD, 2Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy Cutaneous melanoma development is influenced by genetic factors, including B-Raf mutations and environmental factors, such as ultraviolet exposure. Its expansion has been also associated with the involvement of several tumor microenvironmental molecules. Among these, NF-kB has been indicated as a key player of osteopontin (OPN) and matrix metalloproteinase-9 (MMP-9) activation. However, if NF-kB plays a role on OPN/MMP-9 axis in melanoma development and progression according to BRAFV600E mutation status has not been deeply investigated. On these bases, 148 melanoma patients and 53 healthy donors were recruited for the analysis of OPN, MMP-9 and NF-kB. Significant higher circulating levels of OPN, and MMP-9 were observed in melanoma patients when compared to healthy donors. Similar data were obtained for NF-kBp65 activity. OPN levels were not statistically different between melanomas with and without B-RAFV600E mutation. While, significant differences were observed for NF-kB and MMP-9. To demonstrate if NF-kB inhibition is associated with the decrease of OPN and MMP-9 levels, peripheral blood mononuclear cells (PBMCs) from 29 melanoma patients were treated with NF-kB inhibitor dehydroxymethylepoxyquinomycin (DHMEQ) in association or not with OPN. As expected, the inhibition of NF-kB induced a strong decrease of both OPN and MMP-9 levels. Furthermore, the decrease of MMP-9 was higher among melanomas harboring B-RAFV600E mutation. Overall, our data suggest that the activation of MMP-9 is associated with B-RAFV600E mutation. Furthermore, such activation is mediated by NF-kB suggesting its role as therapeutic target for melanoma patients. Commercial support: None identified.
Commercial support: None identified.
AB178
J AM ACAD DERMATOL
JUNE 2017