Purpose:This study tested the feasibility and efficacy of using a text-based intervention to increase initiation, decrease discontinuation, and improve adherence as prescribed to adjuvant hormone therapy (AHT) among hyphenate post-menopausal breast cancer survivors.Methods:The 3-month intervention consisted of daily text message reminders to take medication, coupled with a dynamic (eg, feedback on progress) tailored intervention using weekly interactive surveys delivered by a smartphone app. Five clinic sites within the Alliance for Clinical Trials in Oncology participated. Hormone levels were measured prior to AHT initiation and at study exit.Results:Of the 39 patients recruited to the pilot study, 27 (69.2%) completed all study requirements (completed both the baseline and the exit surveys, both blood draws, and did not miss more than 2 weekly surveys). Significant improvements were observed pre- to postintervention for self-reported medication adherence (P = .015), mental health functioning (P = .007), and perceived stress (P = .04). Significant decreases in estradiol, estrogen, and estrone hormone levels were observed from baseline to study exit (P < .001), indicating the accuracy of self-reported AHT adherence. Participants (91.9%) and physicians (100%) agreed that participant participation in the intervention was beneficial.Conclusions:The results of this pilot study established the general feasibility and efficacy of an app-based intervention to support patient AHT adherence. Larger controlled, randomized trials are needed to examine the effectiveness of the app-based intervention in improving AHT and quality of life among breast cancer survivors.
Renal tubular epithelial cells (RTECs) perform the essential function of maintaining the constancy of body fluid composition and volume. Toxic, inflammatory, or hypoxic-insults to RTECs can cause systemic fluid imbalance, electrolyte abnormalities and metabolic waste accumulation-manifesting as acute kidney injury (AKI), a common disorder associated with adverse long-term sequelae and high mortality. Here we report the results of a kinome-wide RNAi screen for cellular pathways involved in AKI-associated RTEC-dysfunction and cell death. Our screen and validation studies reveal an essential role of Cdkl5-kinase in RTEC cell death. In mouse models, genetic or pharmacological Cdkl5 inhibition mitigates nephrotoxic and ischemia-associated AKI. We propose that Cdkl5 is a stress-responsive kinase that promotes renal injury in part through phosphorylation-dependent suppression of pro-survival transcription regulator Sox9. These findings reveal a surprising non-neuronal function of Cdkl5, identify a pathogenic Cdkl5-Sox9 axis in epithelial cell-death, and support CDKL5 antagonism as a therapeutic approach for AKI.
High dose melphalan followed by autologous stem cell transplantation remains standard of care for eligible patients with multiple myeloma, but disease response and toxicity, including severe mucositis, varies among patients. Our randomized trial investigated duration of cryotherapy (2 and 6 hours) for reduction of mucositis prevalence and severity and explored factors associated with variability in pharmacokinetics and outcomes from melphalan therapy. The results demonstrate 2-hour is at least as effective as 6-hour cryotherapy in decreasing severe mucositis. From a population pharmacokinetic model, we identified fat free mass, hematocrit, and creatinine clearance were significant covariates, as had been reported previously. Furthermore, we observed the rs4240803 SLC7A5 polymorphism was significantly associated with pharmacokinetic variability, and pharmacokinetics was associated with both mucositis and neutropenia. However, melphalan exposure was not associated with progression-free or overall survival in our dataset. These findings contribute to ongoing efforts to personalize melphalan dosing in transplant patients.
Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells and overproduction of monoclonal immunoglobins. Treatment with melphalan is currently standard of care for younger and fit patients when followed by hematopoietic stem cell transplantation (HSCT), and in transplant ineligible patients when used in combination regimens. It has been previously shown that changes in the p53 pathway are associated with melphalan efficacy, but the regulatory role of the p14ARF-MDM2-p53 axis has yet to be fully explored. Recently, a non-coding RNA, ANRIL (antisense non-coding RNA in the INK4-ARF locus) has been shown to negatively regulate the transcription of the entire INK4-ARF locus and simultaneously modulate the p53 and pRb pathways. Moreover, some single nucleotide polymorphisms (SNPs) in ANRIL have previously been associated with susceptibility to several malignancies. Here we investigated select ANRIL SNPs in DNA from patient-derived peripheral blood mononuclear cells obtained from 108 MM patients treated with high-dose melphalan followed by HSCT. Our results show that the rs2151280 (CàT) SNP in ANRIL was associated with worse progression-free survival (TC/CC vs TT: HR = 0.53, 95%CI, [0.26, 1.07], P = 0.07; adjusted HR = 0.39, 95%CI, [0.18, 0.84], P = 0.016), and the TT variant had higher ANRIL expression and lower p15, p14ARF, and p16 expression compared to the TC/CC variants. Our results indicate that ANRIL may be involved in melphalan-mediated apoptosis via down-regulating p14ARF and subsequent p53, and that the rs2151280 polymorphism may be a potential prognostic biomarker for relapse in melphalan-treated MM patients.
Histone deacetylase inhibitors (HDACi) have proven activity in hematologic malignancies, and their FDA approval in multiple myeloma (MM) and T-cell lymphoma highlights the need for further development of this drug class. We investigated AR-42, an oral pan-HDACi, in a first-in-man phase 1 dose escalation clinical trial. Overall, treatment was well tolerated, no DLTs were evident, and the MTD was defined as 40 mg dosed three times weekly for three weeks of a 28-day cycle. One patient each with MM and mantle cell lymphoma demonstrated disease control for 19 and 27 months (ongoing), respectively. Treatment was associated with reduction of serum CD44, a transmembrane glycoprotein associated with steroid and immunomodulatory drug resistance in MM. Our findings indicate that AR-42 is safe and that further investigation of AR-42 in combination regimens for the treatment of patients with lymphoma and MM is warranted. Trial registration: http://clinicaltrials.gov/ct2/show/NCT01129193
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