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Background: Efficient treatment of patients with multiple synchronous nonmelanoma skin cancers represents a therapeutic challenge.Objective: To study the safety and efficacy of photodynamic therapy (PDT) with verteporfin and red light in the treatment of multiple nonmelanoma skin cancers.Design: Open-label, randomized, multicenter, doseranging phase 2 study conducted at 4 North American university-based dermatology clinics.Patients: Fifty-four patients with 421 multiple nonmelanoma skin cancers including superficial and nodular basal cell carcinoma and squamous cell carcinoma in situ (Bowen disease).Methods: A single intravenous infusion of 14 mg/m 2 of verteporfin followed 1 to 3 hours later by exposure of tumors to 60, 120, or 180 J/cm 2 of red light (688±10 nm) from a light-emitting diode panel.Main Outcome Measures: Pathologic response of treated sites was assessed at 6 months. Clinical and cosmetic responses were assessed and graded at 6 weeks, 3 months, and 6 months after verteporfin PDT, with optional follow-up visits at 12, 18, and 24 months. Results:The histopathologic response, defined as absence of tumor on biopsy specimens 6 months after verteporfin PDT, ranged from 69% at 60 J/cm 2 to 93% at 180 J/cm 2 . At 24 months of follow-up (276 tumors in 31 patients), the clinical complete response rate ranged from 51% at 60 J/cm 2 to 95% at 180 J/cm 2 . No significant systemic adverse events were observed; most events occurred at the treated tumor sites and included events such as pain. Overall, 65% (95% confidence interval, 58%-71%) of tumors were judged to have good to excellent cosmesis at 24 months. Conclusion:A single course of verteporfin PDT showed treatment benefit for patients with multiple nonmelanoma skin cancers.

Purpose: This first-inhuman , phase 1 study evaluated ASTX660, an oral, smallmolecule antagonist of cellular/X-linked inhibitors of apoptosis proteins in patients with advanced solid tumors or lymphoma. Experimental Design: ASTX660 was administered orally once daily on a 7-day-on/7day-off schedule in a 28-day cycle. Dose escalation followed a standard 3+3 design to determine the maximum tolerated dose and recommended phase 2 dose (RP2D). Dose expansion was conducted at the RP2D. Results: Forty-five patients received ASTX660 (range 15-270 mg/d). Dose-limiting toxicity of grade 3 increased lipase with or without increased amylase occurred in 3 patients at 270 mg/d and 1 patient at 210 mg/d. The maximum tolerated dose was determined to be 210 mg/d and the RP2D 180 mg/d. Common treatment-related adverse events included fatigue (33%), vomiting (31%), and nausea (27%). Grade ≥3 treatment-related adverse events occurred in 7 patients, most commonly anemia (13%), increased lipase (11%), and lymphopenia (9%). ASTX660 was rapidly absorbed, with maximum concentration achieved at ~0.5-1.0 hour. An ~2-fold accumulation in area under the curve exposures was observed on day 7 vs 1. ASTX660 suppressed cellular inhibitor of apoptosis protein-1 in peripheral blood mononuclear cells, which was maintained into the second cycle beyond the off-therapy week at the 180-mg/d RP2D and above. Clinical activity was seen in a patient with cutaneous T-cell lymphoma. Conclusions: ASTX660 demonstrated a manageable safety profile, and exhibited evidence of pharmacodynamic and preliminary clinical activity at the 180-mg/d RP2D.

Inflammation and proliferation of vascular smooth muscle cells (VSMCs) are the key events in intimal hyperplasia. This study aimed to explore the mechanism by which long non-coding RNA (lncRNA) KCNQ1OT1 affects VSMC inflammation and proliferation in this context. A vein graft (VG) model was established in mice to introduce intimal hyperplasia. Isolated normal VSMCs were induced with platelet-derived growth factor type BB (PDGF-BB), and the cell proliferation, migration, and secretion of inflammatory factors were determined. The results showed that KCNQ1OT1 was downregulated in the VSMCs from mice with intimal hyperplasia and in the PDGF-BB-treated VSMCs, and such downregulation of KCNQ1OT1 resulted from the increased methylation level in the KCNQ1OT1 promoter. Overexpressing KCNQ1OT1 suppressed PDFG-BB-induced VSMC proliferation, migration, and secretion of inflammatory factors. In VSMCs, KCNQ1OT1 bound to the nuclear transcription factor kappa Ba (IkBa) protein and increased the cellular IkBa level by reducing phosphorylation and promoting ubiquitination of the IkBa protein. Meanwhile, KCNQ1OT1 promoted the expression of IkBa by sponging miR-221. The effects of KCNQ1OT1 knockdown on promoting VSMC proliferation, migration, and secretion of inflammatory factors were abolished by IkBa overexpression. The roles of KCNQ1OT1 in reducing the intimal area and inhibiting IkBa expression were proved in the VG mouse model after KCNQ1OT1 overexpression. In conclusion, KCNQ1OT1 attenuated intimal hyperplasia by suppressing the inflammation and proliferation of VSMCs, in which the mechanism upregulated IkBa expression by binding to the IkBa protein and sponging miR-221.

Background Guadecitabine is a novel DNA methyltransferase (DNMT) inhibitor with improved pharmacokinetics and clinical activity in a subset of patients with relapsed/refractory acute myeloid leukemia (r/r AML), but identification of this subset remains difficult. Methods To search for biomarkers of response, we measured genome-wide DNA methylation, mutations of 54 genes, and expression of a panel of 7 genes in pre-treatment samples from 128 patients treated at therapeutic doses in a phase I/II study. Results Response rate to guadecitabine was 17% (2 complete remission (CR), 3 CR with incomplete blood count recovery (CRi), or CR with incomplete platelets recovery (CRp)) in the phase I component and 23% (14 CR, 9 CRi/CRp) in phase II. There were no strong mutation or methylation predictors of response. Gene expression clustering defined a subset of patients (~ 20%) that had (i) high DNMT3B and low CDKN2B, CTCF, and CDA expression; (ii) enrichment for KRAS/NRAS mutations; (iii) frequent CpG island hypermethylation; (iv) low long interspersed nuclear element 1 (LINE-1) hypomethylation after treatment; and (v) resistance to guadecitabine in both phase I (response rate 0% vs. 33%, p = 0.07) and phase II components of the study (response rate 5% vs. 30%, p = 0.02). Multivariate analysis identified peripheral blood (PB) blasts and hemoglobin as predictors of response and cytogenetics, gene expression, RAS mutations, and hemoglobin as predictors of survival. Conclusions A subset of patients (~ 20%) with r/r AML is unlikely to benefit from guadecitabine as a single agent. In the remaining 80%, guadecitabine is a viable option with a median survival of 8 months and a 2-year survival rate of 21%. Trial registration NCT01261312 . Electronic supplementary material The online version of this article (10.1186/s13148-019-0704-3) contains supplementary material, which is available to authorized users.