Phase I and pharmacokinetic study of veliparib,a PARP inhibitor,and pegylated liposomal doxorubicin (PLD) in recurrent gynecologic cancer and triple negative breast cancer with long-term follow-up

Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents like doxorubicin. We sought to determine the recommended phase two dose (RP2D) of veliparib with pegylated liposomal doxorubicin (PLD) in breast and recurrent gynecologic cancer patients. Veliparib and PLD were administered in a standard phase 1, 3 + 3 dose-escalation design starting at 50 mg veliparib BID on days 1–14 with PLD 40 mg/mg2 on day 1 of a 28-day cycle. Dose escalation proceeded in two strata: A (prior PLD exposure) and B (no prior PLD exposure). Patients underwent limited pharmacokinetic (PK) sampling; an expansion PK cohort was added. 44 patients with recurrent ovarian or triple negative breast cancer were enrolled. Median age 56 years; 23 patients BRCA mutation carriers; median prior regimens four. Patients received a median of four cycles of veliparib/PLD. Grade 3/4 toxicities were observed in 10% of patients. Antitumor activity was observed in both sporadic and BRCA-deficient cancers. Two BRCA mutation carriers had complete responses. Two BRCA patients developed oral squamous cell cancers after completing this regimen. PLD exposure was observed to be higher when veliparib doses were > 200 mg BID. The RP2D is 200 mg veliparib BID on days 1–14 with 40 mg/m2 PLD on day 1 of a 28-day cycle. Anti-tumor activity was seen in both strata. However, given development of long-term squamous cell cancers and the PK interaction observed, efforts should focus on other targeted combinations to improve efficacy.     

Porocarcinoma coexisting at a site of Bowen disease in a 63‐year‐old woman

Porocarcinoma is an unusual, locally aggressive and potentially fatal neoplasm. Several cutaneous malignancies have been described in association with porocarcinoma, including squamous cell carcinoma, basal cell carcinoma and tricholemmal carcinoma. Previous reports have indicated that the occurrence of malignant tumours in combination with porocarcinoma is extremely rare, in particular with regard to Bowen disease (BD). We report an uncommon case of porocarcinoma occurring synchronously in a single BD lesion in a 63‐year‐old woman with multiple BD lesions. The clinical and histological findings confirmed this diagnosis.     

Reading the unique DNA methylation landscape of the brain: Non-CpG methylation,hydroxymethylation, and MeCP2

DNA methylation at CpG dinucleotides is an important epigenetic regulator common to virtually all mammalian cell types, but recent evidence indicates that during early postnatal development neuronal genomes also accumulate uniquely high levels of two alternative forms of methylation, non-CpG methylation and hydroxymethylation. Here we discuss the distinct landscape of DNA methylation in neurons, how it is established, and how it might affect the binding and function of protein readers of DNA methylation. We review studies of one critical reader of DNA methylation in the brain, the Rett syndrome protein methyl CpG-binding protein 2 (MeCP2), and discuss how differential binding affinity of MeCP2 for non-CpG and hydroxymethylation may affect the function of this methyl-binding protein in the nervous system.     

Dynamic LVOT Obstruction and Aortic Stenosis in the Same Patient: A Case of Challenging Doppler Hemodynamics

We present a patient with both dynamic left ventricular outflow tract obstruction and valvular aortic stenosis. The aortic valve was calcified, and velocities and gradients measured by continuous‐wave Doppler met standard criteria for severe aortic stenosis. The increased subvalvular velocities invalidated assumptions of the simplified Bernoulli equation; correction using the longer form of the Bernoulli equation suggested a lower but still significant gradient. The complex shape of the subvalvular spectral Doppler envelope indicated supranormal systolic function and dynamic left ventricular outflow obstruction. Left heart catheterization with an end‐hole catheter was required to determine the subvalvular and valvular components of the obstruction.