ABSTRACT
Merkel Cell Carcinoma (MCC) is a rare neuroendocrine skin cancer. In our previous work, we decoded genes specifically deregulated by MCPyV early genes as opposed to other polyomaviruses and established functional importance of NDRG1 in inhibiting cellular proliferation and migration in MCC. In the present work, we found the SET protein, (I2PP2A, intrinsic inhibitor of PP2A) upstream of NDRG1 which was modulated by MCPyV early genes, both in hTERT-HK-MCPyV and MCPyV-positive (+) MCC cell lines. Additionally, MCC dermal tumour nodule tissues showed strong SET expression. Inhibition of the SET-PP2A interaction in hTERT-HK-MCPyV using the small molecule inhibitor, FTY720, increased NDRG1 expression and inhibited cell cycle regulators, cyclinD1 and CDK2. SET inhibition by shRNA and FTY720 also decreased cell proliferation and colony formation in MCPyV(+) MCC cells. Overall, these results pave a path for use of drugs targeting SET protein for the treatment of MCC.
Subject(s)
Carcinoma, Merkel Cell , Cell Movement , Cell Proliferation , Merkel cell polyomavirus , Protein Phosphatase 2 , Humans , Merkel cell polyomavirus/physiology , Merkel cell polyomavirus/genetics , Protein Phosphatase 2/metabolism , Protein Phosphatase 2/genetics , Carcinoma, Merkel Cell/virology , Carcinoma, Merkel Cell/metabolism , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Fingolimod Hydrochloride/pharmacology , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Cell Line, Tumor , Histone Chaperones/metabolism , Histone Chaperones/genetics , Polyomavirus Infections/virology , Skin Neoplasms/virology , Skin Neoplasms/pathology , Skin Neoplasms/metabolism , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase 2/geneticsABSTRACT
BACKGROUND: Pre-/perioperative chemotherapy is well-established for management of locoregional gastric cancer (LRGC). The American Joint Committee on Cancer advocates histopathologic assessment of tumor regression grade (TRG) but does not endorse a specific schema. We sought to examine the prognostic value of the recently revised National Comprehensive Cancer Network (NCCN) definition of TRG specifying TRG0 as no disease in primary tumor or lymph nodes. PATIENTS AND METHODS: Patients with clinical-stage T2+/N+/M0 LRGC receiving preoperative chemotherapy and curative-intent gastrectomy were identified (2000-2020). TRG using the current NCCN definition was retrospectively assigned. Factors associated with TRG were examined using ordinal logistic regression and overall survival (OS) was assessed using the Kaplan-Meier method and Cox regression. RESULTS: Among 117 patients, the most common chemotherapy regimen was epirubicin, cisplatin, plus fluorouracil or capecitabine (ECF/ECX) (n = 48, 41%), followed by folinic acid, fluorouracil, and oxaliplatin (FOLFOX) (n = 30, 26%), and fluorouracil, leucovorin, oxaliplatin, plus docetaxel (FLOT) (n = 13, 11%). TRG3 was the most common histopathologic response (n = 68, 58%), followed by TRG2 (n = 25, 21%), TRG1 (n = 18, 15%), and, lastly, TRG0 (n = 6, 5.1%). The only preoperative factor independently associated with lower TRG was gastroesophageal junction tumor location (OR 0.24, p = 0.012). Higher TRG was independently associated with worse OS in a stepwise fashion (HR 1.49, p = 0.026). Posttreatment pathologic lymph node status was the strongest prognostic factor (HR 1.93, p = 0.026). Independent prognostic value of TRG and ypT stage could not be shown due to substantial overlap. CONCLUSIONS: TRG using the contemporary NCCN definition is associated with OS in LRGC. TRG0 is uncommon but with excellent prognosis. ypN status is the strongest prognostic factor and the revised NCCN definition acknowledging this is appropriate.
Subject(s)
Stomach Neoplasms , Humans , Stomach Neoplasms/drug therapy , Stomach Neoplasms/surgery , Oxaliplatin/therapeutic use , Retrospective Studies , Fluorouracil/therapeutic use , Prognosis , Neoadjuvant Therapy , Gastrectomy , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
Bullous pemphigoid (BP) is a rare autoimmune blistering condition that predominantly affects the elderly population. Typical treatment regimens target the immune system and inflammatory response. We present a case of BP in a 78-year-old male patient that occurred following the coronavirus disease 2019 (COVID-19) vaccination. This case was refractory to topical steroids and immunosuppressants. However, it responded to treatment with dupilumab, a monoclonal antibody therapy. Dupilumab is classically indicated for the treatment of asthma, eosinophilic esophagitis, atopic dermatitis, and chronic rhinosinusitis with nasal polyposis. We highlight the importance of considering the off-label use of dupilumab and its success in treating BP.