A Phase Ib Expansion Cohort Evaluating Aurora A Kinase Inhibitor Alisertib and Dual TORC1/2 Inhibitor Sapanisertib in Patients with Advanced Solid Tumors.

BACKGROUND: This study further evaluated the safety and efficacy of the combination of alisertib and sapanisertib in an expansion cohort of patients, including a subset of patients with refractory pancreatic adenocarcinoma, with further evaluation of the pharmacodynamic characteristics of combination therapy. METHODS: Twenty patients with refractory solid tumors and 11 patients with pancreatic adenocarcinoma were treated at the recommended phase 2 dose of alisertib and sapanisertib. Adverse events and disease response were assessed. Patients in the expansion cohort were treated with a 7-day lead-in of either alisertib or sapanisertib prior to combination therapy, with tumor tissue biopsy and serial functional imaging performed for correlative analysis. RESULTS: Toxicity across treatment groups was overall similar to prior studies. One partial response to treatment was observed in a patient with ER positive breast cancer, and a patient with pancreatic cancer experienced prolonged stable disease. In an additional cohort of pancreatic cancer patients, treatment response was modest. Correlative analysis revealed variability in markers of apoptosis and immune cell infiltrate according to lead-in therapy and response. CONCLUSIONS: Dual targeting of Aurora A kinase and mTOR resulted in marginal clinical benefit in a population of patients with refractory solid tumors, including pancreatic adenocarcinoma, though individual patients experienced significant response to therapy. Correlatives indicate apoptotic response and tumor immune cell infiltrate may affect clinical outcomes.

Pharmacokinetic study of capivasertib and the CYP3A4 substrate midazolam in patients with advanced solid tumors.

PURPOSE: Capivasertib, a potent, selective inhibitor of all three AKT serine/threonine kinase (AKT) isoforms, is being evaluated in phase 3 trials in advanced breast and prostate cancer. This study evaluated the drug-drug interaction risk of capivasertib with the cytochrome P450 3A substrate midazolam in previously treated adults with advanced solid tumors. METHODS: Patients received oral capivasertib 400 mg twice daily (BID) on an intermittent schedule (4 days on/3 days off) starting on day 2 of cycle 1 (29 days) and on day 1 of each 28-day cycle thereafter. In cycle 1 only, patients received oral midazolam (1 mg) on day 1 (alone), and days 8 and 12 (3rd day off and 4th day on capivasertib, respectively). Midazolam pharmacokinetics on days 8 and 12 were analyzed versus day 1. Capivasertib, with or without standard-of-care treatment, was continued in patients deemed likely to benefit. Safety and exploratory efficacy analyses were conducted. RESULTS: Capivasertib-midazolam coadministration increased midazolam exposure (n = 21): geometric mean ratio (90% confidence interval) AUCinf and Cmax was 1.13 (0.97-1.32) and 1.15 (0.99-1.33) for day 8 versus day 1, and 1.75 (1.50-2.05) and 1.25 (1.08-1.46) for day 12 versus day 1. The capivasertib safety profile was manageable when administered with or without midazolam. Two patients had partial responses to treatment. CONCLUSION: The up to 1.75-fold increase in midazolam exposure indicates capivasertib is a weak CYP3A inhibitor at 400 mg BID on an intermittent schedule. Capivasertib was well tolerated; exploratory efficacy analysis demonstrated evidence of clinical activity in this heavily pre-treated population. CLINICALTRIALS: gov: NCT04958226.

The emergence of targeted therapy for HER2-low triple-negative breast cancer: a review of fam-trastuzumab deruxtecan.

INTRODUCTION: Metastatic triple-negative breast cancer (TNBC) is an aggressive sub-type of breast cancer. Despite recent advances, metastatic TNBC remains difficult to treat with limited targeted treatment options. Fam-trastuzumab deruxtecan (T-DXd), is a novel antibody-drug conjugate (ADC) targeting human epidermal growth factor receptor 2 (HER2) and is composed of a unique linker bound to the topoisomerase I inhibitor DXd. T-DXd has significant anti-tumor activity in patients with HER2-low TNBC. AREAS COVERED: This review reports on the mechanism, pre-clinical/clinical studies, efficacy, and tolerability of T-DXd. A literature search was conducted via PubMed using keywords such as 'fam-trastuzumab deruxtecan,' 'Enhertu,' and 'HER2-low cancers.' EXPERT OPINION: The Phase III Destiny-Breast04 Trial showed benefit in progression-free and overall survival in patients with HER2-low metastatic breast cancers treated with T-DXd compared to treatment of physician's choice chemotherapy. T-DXd is the first pharmaceutical to effectively target a HER2-low population with clinically meaningful efficacy in patients with HER2-low TNBC. Compared to chemotherapy, T-DXd has a similar safety profile, with the additional need for close monitoring for interstitial lung disease. Given the clinical activity of T-DXd in TNBC, it is likely there will be continued efforts to refine HER2-low diagnostics and to develop additional ADCs with other protein targets.

Uncertainty and the unmet informational needs of patients with cancer of unknown primary (CUP): a cross-sectional multi-site study.

OBJECTIVE: This study aimed to determine the healthcare experiences, quality of life, and psychosocial needs of patients with cancer of unknown primary (CUP) early after diagnosis; comparing their experiences to patients with advanced cancer of a known primary (non-CUP control patients) and published general population reference data where available. METHODS: This study was a cross-sectional, multi-site study comparing CUP patients (n = 139) compared to non-CUP controls (n = 45). Demographic, clinical information and patient-reported outcome questionnaire data were collected at baseline. RESULTS: Differences in healthcare experienced were found between CUP and non-CUP controls with CUP patients reporting higher scores for unmet medical communication/information needs compared with non-CUP control patients (p = 0.013) as well as greater uncertainty in illness (p = 0.042). Whilst no differences were found between CUP and non-CUP controls on the EORTC and PROMIS measures, of those that 'received written information about your cancer…' and asked '…how useful was it?' fewer CUP patients reported finding the information useful 40% vs 61%, and more were likely to not have received written information at all 59% vs 32%; (p = 0.002). Additionally, of those that found information about their cancer online, fewer patients with CUP reported finding it useful 32% vs 48% control patients (p = 0.005). CONCLUSIONS: CUP patients have unmet medical communication/information needs and greater uncertainty in illness but do not differ in health-related quality of life domains compared to patients with advanced cancer of a known primary.

Pharmacokinetics and safety of niraparib in patients with moderate hepatic impairment.

PURPOSE: The purpose of this study is to characterize niraparib pharmacokinetics (PK) and safety in patients with normal hepatic function (NHF) versus moderate hepatic impairment (MHI). METHODS: Patients with advanced solid tumors were stratified by NHF or MHI (National Cancer Institute-Organ Dysfunction Working Group criteria [bilirubin > 1.5-3 × upper limit of normal and any aspartate aminotransferase elevation]). In the PK phase, all patients received one 300 mg dose of niraparib. In the extension phase, patients with MHI received niraparib 200 mg daily; patients with NHF received 200 or 300 mg based on weight (< 77 kg, ≥ 77 kg)/platelets (< 150,000/µL, ≥ 150,000/µL). PK parameters included maximum concentration (Cmax), area under the curve to last measured concentration (AUClast) and extrapolated to infinity (AUCinf). Safety was assessed in both phases. Exposure-response (E-R) modeling was used to predict MHI effects on exposure and safety of niraparib doses ≤ 200 mg or 300/200 mg or 200/100 mg weight/platelet regimens. RESULTS: In the PK phase (NHF, n = 9; MHI, n = 8), mean niraparib Cmax was 7% lower in patients with MHI versus NHF. Mean exposure (AUClast, AUCinf) was increased by 45% and 56%, respectively, in patients with MHI without impacting tolerability. In the extension phase (NHF, n = 8; MHI, n = 7), the overall safety profile was consistent with previous trials. In patients with MHI, E-R modeling predicted niraparib 200 mg reduced Grade ≥ 3 thrombocytopenia incidence, whereas a 200/100 mg regimen yielded exposures below efficacy-associated levels in 15% of patients. CONCLUSION: These findings support adjusting the 300 mg niraparib starting dose to 200 mg QD in patients with MHI. TRIAL REGISTRATION: NCT03359850; registered December 2, 2017.

Comparative Pre-clinical Efficacy of Chinese and Indian Cultivars of Bitter Melon (Momordica charantia) against Pancreatic Cancer.

Given the high rates of incidence and mortality associated with pancreatic cancer (PanC), there is a need to develop alternative strategies to target PanC. Recent studies have demonstrated that fruits of bitter melon (Momordica charantia) exhibit strong anticancer efficacy against PanC. However, the comparative effects of different bitter melon varieties have not been investigated. This has important implications, given that several bitter melon cultivars are geographically available but their differential effects are not known; and that on a global level, individuals could consume different bitter melon varieties sourced from different cultivars for anti-PanC benefits. Considering these shortcomings, in the present study, comparative pre-clinical anti-PanC studies have been conducted using lyophilized-juice and aqueous-methanolic extracts of the two most widely consumed but geographically diverse bitter melon varieties (Chinese [bitter melon juice; BMJ] and Indian [bitter melon extract; BME] variants). We observed that both BMJ and BME possess comparable efficacy against PanC growth and progression; specifically, these preparations have the potential to (a) inhibit PanC cell proliferation and induce cell death; (b) suppress PanC tumor growth, proliferation, and induce apoptosis; (c) restrict capillary tube formation by human umbilical vein endothelial cells, and decrease angiogenesis in PanC tumor xenografts. Thus, given the comparable pre-clinical anti-PanC efficacy of bitter melon cultivars, the geographical non-availability of a certain cultivar should not be a limiting factor in selecting a variant for moving forward for future clinical use/clinical trials either as a preventive or a therapeutic alternative for targeting PanC.

Preclinical and Dose-Finding Phase I Trial Results of Combined Treatment with a TORC1/2 Inhibitor (TAK-228) and Aurora A Kinase Inhibitor (Alisertib) in Solid Tumors.

PURPOSE: The purpose of this study was to evaluate the rational combination of TORC1/2 inhibitor TAK-228 and Aurora A kinase inhibitor alisertib in preclinical models of triple-negative breast cancer (TNBC) and to conduct a phase I dose escalation trial in patients with advanced solid tumors. EXPERIMENTAL DESIGN: TNBC cell lines and patient-derived xenograft (PDX) models were treated with alisertib, TAK-228, or the combination and evaluated for changes in proliferation, cell cycle, mTOR pathway modulation, and terminal cellular fate, including apoptosis and senescence. A phase I clinical trial was conducted in patients with advanced solid tumors treated with escalating doses of alisertib and TAK-228 using a 3+3 design to determine the maximum tolerated dose (MTD). RESULTS: The combination of TAK-228 and alisertib resulted in decreased proliferation and cell-cycle arrest in TNBC cell lines. Treatment of TNBC PDX models resulted in significant tumor growth inhibition and increased apoptosis with the combination. In the phase I dose escalation study, 18 patients with refractory solid tumors were enrolled. The MTD was alisertib 30 mg b.i.d. days 1 to 7 of a 21-day cycle and TAK-228 2 mg daily, continuous dosing. The most common treatment-related adverse events were neutropenia, fatigue, nausea, rash, mucositis, and alopecia. CONCLUSIONS: The addition of TAK-228 to alisertib potentiates the antitumor activity of alisertib in vivo, resulting in increased cell death and apoptosis. The combination is tolerable in patients with advanced solid tumors and should be evaluated further in expansion cohorts with additional pharmacodynamic assessment.

Time-dependent changes in kidney injury biomarkers in patients receiving multiple cycles of cisplatin chemotherapy.

Proteins secreted into urine following tubular injury are being increasingly used as biomarkers of clinical and subclinical nephrotoxicity. In the present study, we sought to characterize the time-dependent urinary excretion of three promising biomarkers, kidney injury molecule-1 (KIM-1), calbindin, and trefoil factor 3 (TFF3), during two different chemotherapy cycles in 27 patients with solid tumors prescribed the anticancer drug cisplatin (≥25 mg/m2). Urinary biomarkers were evaluated at Days 3 and 10 during an initial and a subsequent cycle of cisplatin chemotherapy. Longitudinal analyses compared the mean difference estimations for biomarker concentrations during and across the initial and subsequent cycles of cisplatin treatment. Traditional biomarkers including serum creatinine, estimated glomerular filtration rate, and blood urea nitrogen were unchanged during and across both cycles of cisplatin therapy. In response to the initial cycle, urinary KIM-1 concentrations increased from baseline and remained elevated through a subsequent cycle of cisplatin chemotherapy. By comparison, urinary levels of calbindin were elevated 10 days after the initial cisplatin treatment, but largely unchanged by cisplatin exposure in a subsequent cycle. Early elevations in urinary TFF3 at 3 days after cisplatin administration were observed consistently in both the initial and subsequent cycle of cisplatin treatment. In conclusion, the longitudinal assessment of biomarker performance in the same cohort of oncology patients reveals different patterns of urinary excretion between initial and subsequent cycles of cisplatin-containing chemotherapy. These data add novel cycle-dependent insight to the growing literature addressing the ability of urinary biomarkers to detect subclinical renal injury in patients receiving cisplatin.

Evaluation of fosaprepitant-associated hypersensitivity reactions at a National Cancer Center.

INTRODUCTION: At our institution, an increased incidence of hypersensitivity reactions was reported following standardization of fosaprepitant as the preferred agent for the prophylaxis of chemotherapy induced nausea and vomiting (CINV) caused by highly emetogenic therapies. The purpose of this evaluation was to assess the incidence of systemic hypersensitivity reactions (HSRs) to fosaprepitant infusions compared to available literature. METHODS: This evaluation is a retrospective review of electronic health records of adult patients who received their first dose of fosaprepitant for CINV prophylaxis beginning January 1, 2017 through June 30, 2017 at the University of Colorado Cancer Center outpatient infusion center. Subjects were identified using medication administration reports. Individual chart reviews were performed for all patients who received fosaprepitant during the specified timeframe and had a reaction reported on the same date. RESULTS: A total of 868 patients received fosaprepitant in the outpatient infusion center during the study time period. Four patients (0.461%) had a systemic HSR attributed to fosaprepitant. Two of the reactions were reported as HSRs in the adverse reaction reporting system and two were found in provider notes during chart review. Due to the small sample size, risk factors for HSRs to fosaprepitant were not able to be determined. CONCLUSION: The incidence of HSRs to fosaprepitant at our institution was found to be consistent with the <1% incidence currently noted in literature. Based on these findings, opportunities have been identified for education on fosaprepitant-associated HSRs, proper documentation and patient-specific precautions.

A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction.

AIMS: The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic. METHODS: We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of belinostat in patients with advanced cancer and varying degrees of liver dysfunction. RESULTS: Seventy-two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m2 /day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of belinostat was 661 mL/min/m2 in patients with normal liver function, compared to 542, 505 and 444 mL/min/m2 in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease. CONCLUSION: While a statistically significant difference in clearance indicates increased belinostat exposure with worsening liver function, no relationship was observed between belinostat exposure and toxicity. An assessment of belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population.

Pharmacokinetic determinants of cisplatin-induced subclinical kidney injury in oncology patients.

PURPOSE: The ability to predict and detect clinical and subclinical nephrotoxicity early in the course of therapy has the potential to improve long-term outcomes in cancer patients receiving cisplatin chemotherapy. Pharmacokinetic parameters could serve as predictors of cisplatin-induced nephrotoxicity. METHODS: Participants [n = 13] were treated with a 1-h cisplatin infusion [30-75 mg/m2]. Blood was collected pre-dose and up to 6 h post-dose. Urinary biomarkers [KIM-1, calbindin, clusterin, GST-pi, ß2M, albumin, NGAL, osteopontin, clusterin, MCP-1, cystatin C, and TFF3] were measured at baseline, days 3 and 10. Total and unbound platinum concentrations were measured using ICP/MS. Noncompartmental analysis was performed, and correlation and regression analyses evaluated the relationships between platinum pharmacokinetics and nephrotoxicity. RESULTS: Peak platinum urinary concentrations correlated with urinary levels of KIM-1, calbindin, clusterin, GST-pi, ß2M, albumin, NGAL, osteopontin, clusterin, cystatin C, and TFF3 at day 10. Unbound platinum plasma concentrations at 2 h also correlated with urinary clusterin, ß2M, cystatin C, NGAL, osteopontin, and TFF3 at day 3. Regression analyses suggested 2-h total plasma platinum concentrations greater than 2000 ng/ml, and peak urinary platinum concentrations above 24,000 ng/ml may serve as potential approximations for elevated risk of nephrotoxicity. Platinum area under the plasma concentration time curve was associated with serum creatinine and estimated glomerular filtration rate. CONCLUSIONS: Peak plasma and urinary platinum concentrations and pharmacokinetic parameters were associated with risk of subclinical cisplatin-induced kidney injury as assessed using novel urinary biomarkers. Future studies will examine these relationships in larger clinical populations of cisplatin-induced acute kidney injury.

Evaluation of hepatic impairment on pharmacokinetics and safety of crizotinib in patients with advanced cancer.

PURPOSE: This phase 1 study evaluated the effect of hepatic impairment on pharmacokinetics and safety of crizotinib in patients with advanced cancer. METHODS: Patients were dosed according to hepatic function classified by modified National Cancer Institute Organ Dysfunction Working Group criteria and group assignment [normal (A1 and A2), mild (B), moderate (C1 and C2), or severe (D)]. Primary pharmacokinetic endpoints included area under the concentration-time curve as daily exposure (AUCdaily) and maximum plasma concentration (Cmax) at steady state. Safety endpoints included types, incidence, seriousness, and relationship to crizotinib of adverse events. RESULTS: The AUCdaily and Cmax in patients with normal liver function were 7107 ng h/mL and 375.1 ng/mL (A1) and 5422 ng h/mL and 283.9 ng/mL (A2), respectively. The AUCdaily and Cmax ratios of adjusted geometric means for Groups B, C2, and D versus Group A1 were 91.12 and 91.20, 114.08 and 108.87, and 64.47 and 72.63, respectively. Any grade treatment-related adverse events (TRAEs) occurred in 75% of patients; grade 3/4 TRAEs occurred in 25%, including fatigue (6%), hyponatremia (5%), and hyperbilirubinemia (3%). CONCLUSIONS: No adjustment to the approved 250 mg twice daily (BID) dose of crizotinib is recommended for patients with mild hepatic impairment. The recommended dose is 200 mg BID for patients with moderate hepatic impairment, and the dose should not exceed 250 mg daily for patients with severe hepatic impairment. Adverse events appeared consistent among the hepatic impairment groups. CLINICAL TRIAL REGISTRATION NO: NCT01576406.

Phase I Study of Enavatuzumab, a First-in-Class Humanized Monoclonal Antibody Targeting the TWEAK Receptor, in Patients with Advanced Solid Tumors.

This phase I study evaluates the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary anticancer activity of enavatuzumab, a humanized IgG1 antibody to the TWEAK receptor, in patients with advanced solid malignancies. Patients received escalating doses of enavatuzumab given intravenously over 60 minutes every 2 weeks. Blood was obtained for PK and biomarker assessment. Three patients were enrolled per dose level in a standard 3+3 design with response assessment by RECIST version 1.0, every 8 weeks. Thirty patients were enrolled at 6 dose levels ranging from 0.1 to 1.5 mg/kg. Dose-limiting toxicities included grade 4 (G4) lipase, G3 bilirubin, and G4 amylase elevations. There was no apparent correlation of liver or pancreatic enzyme elevation with drug exposure or the presence of liver metastases. Enavatuzumab exhibited a two-compartment linear PK model. Estimated systemic clearance was 23 to 33 mL/h with an elimination half-life of 7 to 18 days. The predicted target efficacious peak and trough concentrations occurred at 1.0 mg/kg following the second dose. There were no objective responses; 4 patients had stable disease. The MTD of enavatuzumab is 1.0 mg/kg i.v. every 2 weeks. Higher doses were not tolerated due to hepatopancreatic lab abnormalities. Further evaluation of the mechanisms of the liver and pancreatic enzyme toxicities is needed before embarking on further single-agent or combination strategies. Mol Cancer Ther; 17(1); 215-21. ©2017 AACR.

Implementation of a pharmacist-managed clinic for patients with chronic nonmalignant pain.

PURPOSE: A pharmacist-managed chronic pain clinic (PMCPC) in a primary care setting is described. SUMMARY: As primary care providers (PCPs) may be unprepared or lack time to manage high-risk patients receiving opioids for chronic nonmalignant pain, alternative models of care are needed. The University of Colorado PMCPC is integrated into an internal medicine outpatient clinic. The PMCPC is staffed by 1 clinical pharmacist, with pharmacy students and residents also performing clinic duties. The pharmacy team reviews health records to determine eligibility for PMCPC services and documents referral requests in the electronic health record (EHR); on PCP acceptance of a referral, the pharmacy team assumes primary responsibility for the patient's pain management under a collaborative practice agreement. Using a collaborative drug therapy management (CDTM) protocol, the pharmacy team conducts patient assessments, including an assessment for signs of aberrant drug-taking behaviors; provides initial and ongoing counseling and education; and makes recommendations to the PCP for opioid dosage adjustments and regimen additions and discontinuations. Experience at the clinic to date indicates that the PMCPC model is feasible and accepted by PCPs and patients. CONCLUSION: A PMCPC based in a primary care setting was established to improve the care of patients with chronic nonmalignant pain who are prescribed opioid therapy for a period of 3 months or longer. Clinic patients are referred to the clinic through the EHR and managed by a pharmacist under a CDTM protocol.

Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin.

Nephrotoxicity is a dose limiting side effect associated with the use of cisplatin in the treatment of solid tumors. The degree of nephrotoxicity is dictated by the selective accumulation of cisplatin in renal tubule cells due to: (1) uptake by organic cation transporter 2 (OCT2) and copper transporter 1 (CTR1); (2) metabolism by glutathione S-transferases (GSTs) and γ-glutamyltransferase 1 (GGT1); and (3) efflux by multidrug resistance-associated protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1). The purpose of this study was to determine the significance of single nucleotide polymorphisms that regulate the expression and function of transporters and metabolism genes implicated in development of acute kidney injury (AKI) in cisplatin treated patients. Changes in the kidney function were assessed using novel urinary protein biomarkers and traditional markers. Genotyping was conducted by the QuantStudio 12K Flex Real-Time PCR System using a custom open array chip with metabolism, transport, and transcription factor polymorphisms of interest to cisplatin disposition and toxicity. Traditional and novel biomarker assays for kidney toxicity were assessed for differences according to genotype by ANOVA. Allele and genotype frequencies were determined based on Caucasian population frequencies. The polymorphisms rs596881 (SLC22A2/OCT2), and rs12686377 and rs7851395 (SLC31A1/CTR1) were associated with renoprotection and maintenance of estimated glomerular filtration rate (eGFR). Polymorphisms in SLC22A2/OCT2, SLC31A1/CTRI, SLC47A1/MATE1, ABCC2/MRP2, and GSTP1 were significantly associated with increases in the urinary excretion of novel AKI biomarkers: KIM-1, TFF3, MCP1, NGAL, clusterin, cystatin C, and calbindin. Knowledge concerning which genotypes in drug transporters are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding cisplatin altogether, in order to prevent AKI.

Silibinin Treatment Inhibits the Growth of Hedgehog Inhibitor-Resistant Basal Cell Carcinoma Cells via Targeting EGFR-MAPK-Akt and Hedgehog Signaling.

Basal cell carcinoma (BCC) is the most common skin malignancy. Deregulated hedgehog signaling plays a central role in BCC development; therefore, hedgehog inhibitors have been approved to treat locally advanced or metastatic BCC. However, the development of resistance to hedgehog inhibitors is the major challenge in effective treatment of this disease. Herein, we evaluated the efficacy of a natural agent silibinin to overcome resistance with hedgehog inhibitors (Sant-1 and GDC-0449) in BCC cells. Silibinin (25-100 µm) treatment for 48 h strongly inhibited growth and induced death in ASZ001, Sant-1-resistant (ASZ001-Sant-1) and GDC-0449-resistant (ASZ001-GDC-0449) BCC cells. Furthermore, colony-forming ability of ASZ001, ASZ001-Sant-1 and ASZ001-GDC-0449 cells was completely inhibited by silibinin treatment. Molecular analysis showed that silibinin treatment decreased the level of phosphorylated EGFR (Tyrosine 1173) and total EGFR in ASZ001-Sant-1 cells, key signaling molecules responsible for BCC resistance toward hedgehog inhibitors. Further, silibinin treatment decreased the phosphorylated Akt (Serine 473), phosphorylated ERK1/2 (Threonine 202/Tyrosine 204), cyclin D1 and Gli-1 level but increased the SUFU expression in ASZ001-Sant-1-resistant cells. Silibinin treatment of ASZ001-Sant-1-resistant cells also decreased bcl-2 but increased cleaved caspase 3 and PARP cleavage, suggesting induction of apoptosis. Together, these results support silibinin use to target hedgehog inhibitor-resistant BCC cells.

Profiling of Kidney Injury Biomarkers in Patients Receiving Cisplatin: Time-dependent Changes in the Absence of Clinical Nephrotoxicity.

The success of cisplatin-containing regimens to treat solid tumors is limited, in part, by nephrotoxicity. In rodents, several urinary proteins have emerged that are sensitive indicators of cisplatin-induced kidney injury. We sought to characterize time-dependent changes in the urinary concentrations of 12 proteins, including kidney injury molecule-1 (KIM-1), calbindin, beta 2-microglobulin (ß2M), and trefoil factor 3 (TFF3) after cisplatin therapy. Urine was collected at baseline, 3 days (range, 2-5 days), and 10 days (range, 9-11 days) from 57 patients with solid tumors receiving outpatient cisplatin therapy (≥25 mg/m2 ). Serum creatinine was largely unchanged after cisplatin infusion. However, compared with baseline values, several novel biomarkers were significantly increased in the urine, including ß2M, which was threefold higher by day 3 (P < 0.0001). Urinary KIM-1 and TFF3 were elevated twofold by day 10 (P = 0.002 and P = 0.002, respectively), whereas calbindin levels were increased eightfold (P < 0.0001). We report novel time-dependent changes in the urinary excretion of noninvasive markers of subclinical kidney injury after cisplatin treatment.

Drugs That May Cause or Exacerbate Heart Failure: A Scientific Statement From the American Heart Association.

Heart failure is a common, costly, and debilitating syndrome that is associated with a highly complex drug regimen, a large number of comorbidities, and a large and often disparate number of healthcare providers. All of these factors conspire to increase the risk of heart failure exacerbation by direct myocardial toxicity, drug-drug interactions, or both. This scientific statement is designed to serve as a comprehensive and accessible source of drugs that may cause or exacerbate heart failure to assist healthcare providers in improving the quality of care for these patients.

Board-Certified Oncology Pharmacists: Their Potential Contribution to Reducing a Shortfall in Oncology Patient Visits.

PURPOSE: With an aging US population, the number of patients who need cancer treatment will increase significantly by 2020. On the basis of a predicted shortage of oncology physicians, nonphysician health care practitioners will need to fill the shortfall in oncology patient visits, and nurse practitioners and physician assistants have already been identified for this purpose. This study proposes that appropriately trained oncology pharmacists can also contribute. The purpose of this study is to estimate the supply of Board of Pharmacy Specialties-certified oncology pharmacists (BCOPs) and their potential contribution to the care of patients with cancer through 2020. METHODS: Data regarding accredited oncology pharmacy residencies, new BCOPs, and total BCOPs were used to estimate oncology residencies, new BCOPs, and total BCOPs through 2020. A Delphi panel process was used to estimate patient visits, identify patient care services that BCOPs could provide, and study limitations. RESULTS: By 2020, there will be an estimated 3,639 BCOPs, and approximately 62% of BCOPs will have completed accredited oncology pharmacy residencies. Delphi panelists came to consensus (at least 80% agreement) on eight patient care services that BCOPs could provide. Although the estimates given by our model indicate that BCOPs could provide 5 to 7 million 30-minute patient visits annually, sensitivity analysis, based on factors that could reduce potential visit availability resulted in 2.5 to 3.5 million visits by 2020 with the addition of BCOPs to the health care team. CONCLUSION: BCOPs can contribute to a projected shortfall in needed patient visits for cancer treatment. BCOPs, along with nurse practitioners and physician assistants could substantially reduce, but likely not eliminate, the shortfall of providers needed for oncology patient visits.