RESUMO
BACKGROUND: Mohs surgeons routinely encounter squamous cell carcinoma at surgical margins and often base the decision to take another layer on the severity of atypia observed. Currently, no criteria exists for distinguishing borderline histological patterns that could be interpreted differently as actinic keratosis (AK), squamous cell carcinoma in situ (SCCIS), or AK with focal SCCIS. OBJECTIVE: To assess interrater concordance amongst Mohs surgeons in distinguishing AK from SCCIS when evaluating Mohs frozen sections. METHODS: Seventeen slides were selected and converted into digitally formatted cases. They were compiled into an electronic survey and distributed to the American College of Mohs Surgery. RESULTS: Overall κ was 0.26 corresponding to weak agreement between raters compared to the standard, with κ of 0.34 for AK and 0.37 for SCCIS. CONCLUSION: There exists notable variability among Mohs surgeons who interpret the spectrum of in situ carcinoma differently. Ongoing learning and consensus building among Mohs surgeons and trainees can aid in quality patient care, even if there may not be agreement on every case. J Drugs Dermatol. 2023;22(2):199-194. doi:10.36849/JDD.7084.
Assuntos
Carcinoma de Células Escamosas , Ceratose Actínica , Neoplasias Cutâneas , Humanos , Ceratose Actínica/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/cirurgia , Neoplasias Cutâneas/patologia , Secções Congeladas , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/patologia , Cirurgia de MohsRESUMO
Atypical fibroxanthoma is a rare cutaneous malignancy that usually presents as a rapidly growing red papule on the head and neck in elderly white males. Several variants have been described. We report a patient who presented with a slowly enlarging pigmented lesion on his left ear that was clinically worrisome for malignant melanoma. Histopathologic evaluation with immunohistochemistry revealed an unusual case of hemosiderotic pigmented atypical fibroxanthoma. The tumor was successfully extirpated with Mohs micrographic surgery, with no recurrence at 6-month follow-up.
Assuntos
Hemocromatose , Melanoma , Neoplasias Cutâneas , Masculino , Humanos , Idoso , Neoplasias Cutâneas/patologia , Melanoma/patologia , Imuno-Histoquímica , Melanoma Maligno CutâneoRESUMO
Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of ß-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of ß-amyloid peptides; one of which, Aß42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aß42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aß42 production in mice.
Assuntos
Amidas/síntese química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/química , Piperidinas/química , Doença de Alzheimer/tratamento farmacológico , Amidas/farmacologia , Peptídeos beta-Amiloides/biossíntese , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Camundongos , Fragmentos de Peptídeos/biossínteseRESUMO
We have developed a series of potent and selective factor VIIa inhibitors based on the 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-biphenyl-3-yl]-succinic acid scaffold. These amidine-containing compounds have low oral bioavailability. Herein, we describe our efforts to improve the oral bioavailability of the parent amidine via a prodrug strategy where the amidine basicity and polarity were reduced with either an alkoxy-amidine or a carbamate prodrug.
Assuntos
Amidinas/química , Carbamatos/química , Fator VIIa/antagonistas & inibidores , Pró-Fármacos/farmacocinética , Administração Oral , Amidinas/farmacologia , Animais , Disponibilidade Biológica , Carbamatos/farmacologia , Masculino , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Structure-activity relationships and binding mode of novel heterocyclic factor VIIa inhibitors will be described. In these inhibitors, a highly basic 5-amidinoindole moiety has been successfully replaced with a less basic 5-aminopyrrolo[3,2-b]pyridine scaffold.
Assuntos
Aminopiridinas/química , Fator VIIa/antagonistas & inibidores , Fibrinolíticos/síntese química , Compostos Heterocíclicos/síntese química , Tromboplastina/antagonistas & inibidores , Aminopiridinas/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Fibrinolíticos/farmacologia , Compostos Heterocíclicos/farmacologia , Humanos , Relação Estrutura-AtividadeRESUMO
Within the trypsin family of coagulation proteases, obtaining highly selective inhibitors of factor VIIa has been challenging. We report a series of factor VIIa (fVIIa) inhibitors based on the 5-amidino-2-(2-hydroxy-biphenyl-3-yl)-benzimidazole (1) scaffold with potency for fVIIa and high selectivity against factors IIa, Xa, and trypsin. With this scaffold class, we propose that a unique hydrogen bond interaction between a hydroxyl on the distal ring of the biaryl system and the backbone carbonyl of fVIIa lysine-192 provides a basis for enhanced selectivity and potency for fVIIa.