Bullying Perpetration and Victimization in Youth: Associations with Irritability and Anxiety.

Prior work on has demonstrated that irritability and anxiety are associated with bullying perpetration and victimization, respectively. Even though symptoms of irritability and anxiety often occur concurrently, few studies have tested their interactive effects on perpetration or victimization. The current study recruited 131 youths from a broader program of research that examines the pathophysiology and treatment of pediatric irritability and anxiety. Two moderation tests were performed to examine concurrent irritability and anxiety symptoms and their relation to perpetration and victimization of bullying. More severe anxiety was associated with greater victimization. However, more severe irritability was associated with, not just greater perpetration, but also greater victimization. An irritability-by-anxiety interaction demonstrated that youths with more severe irritability and lower levels of anxiety engaged in more perpetration. Our findings suggest a more nuanced approach to understanding how the commonly comorbid symptoms of irritability and anxiety interact in relation to peer-directed behavior in youths.

"Could We Just Breathe for 30 Seconds?": Social Worker Experiences of Holistic Engagement Practice Training.

Given the still emerging evidence base about the effectiveness of practices, such as mindfulness, somatics, and integrative body-mind-spirit social work, there is a need to know more about the impacts that training in such areas can have on social workers and their professional work. This mixed-methods article reports on a pilot study that explored practitioners' perceptions regarding the impact of learning holistic engagement practice (HEP) skills on their service delivery and well-being. The research inquires into the perceptions of social workers who received the training, particularly in relation to their quality of presence and the therapeutic relationship; HEP as a form of self-care and a facilitator of compassion satisfaction; the impact it has on social work practice and settings; and the facilitators and barriers to using holistic engagement. Implications from the findings focus on the need for additional research, training, organizational change, and communities of practice to facilitate changes that could promote more effective social work practice, greater levels of empathy, and compassion satisfaction.

Developing AHRQ's Feasibility Assessment Criteria for Wide-Scale Implementation of Patient-Centered Outcomes Research Findings.

BACKGROUND: The Agency for Healthcare Research and Quality's (AHRQ) Patient-Centered Outcomes Research (PCOR) Dissemination and Implementation (D&I) Initiative identifies and prioritizes PCOR findings that could improve health care if widely implemented. To inform PCOR implementation investments, AHRQ sought to assess feasibility of widely implementing impactful PCOR findings with good strength of evidence in clinical practice. OBJECTIVE: To develop criteria to assess the feasibility of widely implementing nominated PCOR findings. METHODS: We reviewed literature and interviewed thirteen D&I experts to identify factors affecting feasibility of implementing PCOR findings. We grouped similar factors into themes. Fourteen technical expert panel (TEP) members discussed the face-validity and relative merits of the themes and additional factors, applied themes to fictional case studies, and prioritized themes for assessing feasibility. We developed criteria and guiding questions with a 3-point Likert scale. Seven D&I experts pilot-tested the criteria using sample nominations of PCOR findings. Experts represented diverse views of implementation from federal and state government agencies, research institutions, and quality improvement and advocacy organizations. KEY RESULTS: We developed a set of three essential criteria for AHRQ to assess feasibility of widely implementing PCOR findings to be widely implementable: (1) acceptability to the implementers; (2) generalizability, adaptability, and ease of implementing with fidelity; and (3) alignment with external policies and incentives. Two supplemental criteria, (1) the presence of a plan or toolkit supporting implementation, or (2) evidence supporting implementation outside the research setting, can enhance reviewers' confidence in the intervention's feasibility. Each criterion includes "guiding questions" to parse out specific components that could be more readily assessed. CONCLUSIONS: The criteria and guiding questions are a valuable tool for informing AHRQ's investment decisions regarding implementing PCOR findings. Although developed for AHRQ's needs, the criteria may help other funders and health care organizations determine the feasibility of implementing evidence-based practices.

Hereditary diffuse gastric cancer: updated clinical practice guidelines.

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.

Synthesis and Antiangiogenic Properties of Tetrafluorophthalimido and Tetrafluorobenzamido Barbituric Acids.

The development of novel thalidomide derivatives as immunomodulatory and anti-angiogenic agents has revived over the last two decades. Herein we report the design and synthesis of three chemotypes of barbituric acids derived from the thalidomide structure: phthalimido-, tetrafluorophthalimido-, and tetrafluorobenzamidobarbituric acids. The latter were obtained by a new tandem reaction, including a ring opening and a decarboxylation of the fluorine-activated phthalamic acid intermediates. Thirty compounds of the three chemotypes were evaluated for their anti-angiogenic properties in an ex vivo assay by measuring the decrease in microvessel outgrowth in rat aortic ring explants. Tetrafluorination of the phthalimide moiety in tetrafluorophthalimidobarbituric acids was essential, as all of the nonfluorinated counterparts lost anti-angiogenic activity. An opening of the five-membered ring and the accompanying increased conformational freedom, in case of the corresponding tetrafluorobenzamidobarbituric acids, was well tolerated. Their activity was retained, although their molecular structures differ in torsional flexibility and possible hydrogen-bond networking, as revealed by comparative X-ray crystallographic analyses.

Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues.

Thalidomide has demonstrated clinical activity in various malignancies affecting immunomodulatory and angiogenic pathways. The development of novel thalidomide analogs with improved efficacy and decreased toxicity is an ongoing research effort. We recently designed and synthesized a new class of compounds, consisting of both tetrafluorinated thalidomide analogues (Gu973 and Gu998) and tetrafluorobenzamides (Gu1029 and Gu992). In this study, we demonstrate the antiangiogenic properties of these newly synthesized compounds. We examined the specific antiangiogenic characteristics in vitro using rat aortic rings with carboxyamidotriazole as a positive control. In addition, further in vitro efficacy was evaluated using human umbilical vein endothelial cells (HUVEC) and PC3 cells treated with 5 and 10 µmol/L doses of each compound. All compounds were seen to reduce microvessel outgrowth in rat aortic rings as well as to inhibit HUVECs to a greater extent, at lower concentrations than previously tested thalidomide analogs. The antiangiogenic properties of the compounds were also examined in vivo in fli1:EGFP zebrafish embryos, where all compounds were seen to inhibit the extent of outgrowth of newly developing blood vessels. In addition, Gu1029 and Gu973 reduced the anti-inflammatory response in mpo:GFP zebrafish embryos, whereas Gu998 and Gu992 showed no difference. The compounds' antitumor effects were also explored in vivo using the human prostate cancer PC3 xenograft model. All four compounds were also screened in vivo in chicken embryos to investigate their teratogenic potential. This study establishes these novel thalidomide analogues as a promising immunomodulatory class with anticancer effects that warrant further development to characterize their mechanisms of action.

A phase I trial of the HIV protease inhibitor nelfinavir in adults with solid tumors.

Nelfinavir is an HIV protease inhibitor being repurposed as an anti-cancer agent in preclinical models and in small oncology trials, yet the MTD of nelfinavir has not been determined. Therefore, we conducted a Phase Ia study to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of nelfinavir in subjects with advanced solid tumors. Adults with refractory cancers were given oral nelfinavir twice daily with pharmacokinetic and pharmacodynamic analyses. Twenty-eight subjects were enrolled. Nelfinavir was generally well tolerated. Common adverse events included diarrhea, anemia, and lymphopenia, which were mostly mild. The DLT was rapid-onset neutropenia that was reversible. The MTD was established at 3125 mg twice daily. In an expansion cohort at the MTD, one of 11 (9%) evaluable subjects had a confirmed partial response. This, plus two minor responses, occurred in subjects with neuroendocrine tumors of the midgut or pancreatic origin. Thirty-six percent of subjects had stable disease for more than 6 months. In peripheral blood mononuclear cells, Nelfinavir inhibited AKT and induced markers of ER stress. In summary, nelfinavir is well tolerated in cancer patients at doses 2.5 times the FDA-approved dose for HIV management and showed preliminary activity in tumors of neuroendocrine origin.

Preformulation study of NSC-726796.

A stability-indicating high-performance liquid chromatography method to quantify 2-(2,4-difluorophenyl)-4,5,6,7-tetrafluoroisoindoline-1,3-dione (NSC-726796) and its three main degradation products was developed. This method was used to investigate its degradation kinetics and mechanism. The reaction follows first-order kinetics and appears to be base catalyzed with the maximum stability at pH 1. The products were identified as 2-(2,4-difluorophenylcarbamoyl)-3,4,5,6-tetrafluorobenzoic acid (NSC-749820), 2,4-difluoroaniline, and tetrafluorophthalic acid. The parent drug, NSC-726796, was also found to react with methanol and ethanol. NSC-726796 demonstrates antiangiogenic activity, however, when its degradant NSC749820 does not show antiangiogenic activity.

Sorafenib is an inhibitor of UGT1A1 but is metabolized by UGT1A9: implications of genetic variants on pharmacokinetics and hyperbilirubinemia.

PURPOSE: Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)(5/6/7) repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration. EXPERIMENTAL DESIGN: Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A1*28 and UGT1A9*3 genotypes were ascertained with fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients before receiving sorafenib (n = 41) and 19 to 30 days following treatment and were compared with UGT1A1*28 genotype. RESULTS: Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC(50) = 18 µmol/L; K(i) = 11.7 µmol/L) in vitro. Five patients carrying UGT1A1*28/*28 (n = 4) or UGT1A9*3/*3 (n = 1) genotypes had first dose, dose-normalized areas under the sorafenib plasma concentration versus time curve (AUC) that were in the 93rd percentile, whereas three patients carrying UGT1A1*28/*28 had AUCs in the bottom quartile of all genotyped patients. The Drug Metabolizing Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles (n = 12 and n = 5; R(2) = 0.38 and R(2) = 0.77; P = 0.032 and P = 0.051, respectively). UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure. CONCLUSIONS: This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib.

Antiangiogenic and antitumor activity of LP-261, a novel oral tubulin binding agent, alone and in combination with bevacizumab.

LP-261 is a novel tubulin targeting anticancer agent that binds at the colchicine site on tubulin, inducing G2/M arrest. Screening in the NCI60 cancer cell lines resulted in a mean GI50 of approximately 100 nM. Here, we report the results of testing in multiple mouse xenograft models and angiogenesis assays, along with bioavailability studies. To determine the antiangiogenic activity of LP-261, both in vitro and ex vivo experiments were performed. Human umbilical vein endothelial cells (HUVECs) were incubated with LP-261 at 50 nM to 10 µM. LP-261 was also tested in a rat aortic ring assay, from 20 nM to 10 µM. Multiple mouse xenograft studies were performed to assess in vivo antitumor activity. LP-261 was tested as a single agent in colon adenocarcinoma (SW620) and prostate cancer (LNCaP and PC3) xenografts, evaluating several different dosing schedules. LP-261 was also used in combination with bevacizumab in the SW620 xenograft model. LP-261 also exhibited high oral bioavailability and apparent lack of efflux by intestinal transporters such as ABCB1. LP-261 is a very potent inhibitor of angiogenesis, preventing microvessel outgrowth in the rat aortic ring assay and HUVEC cell proliferation at nanomolar concentrations. Complete inhibition of tumor growth was achieved in the PC3 xenograft model and shown to be schedule dependent. Excellent inhibition of tumor growth in the SW620 model was observed, comparable with paclitaxel. Combining oral, low dose LP-261 with bevacizumab led to significantly improved tumor inhibition. Oral LP-261 is very effective at inhibiting tumor growth in multiple mouse xenograft models and is well tolerated.

Population pharmacokinetic analysis of sorafenib in patients with solid tumours.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Sorafenib is a multikinase inhibitor with activity against B-raf, C-raf, VEGFR2, PDGFRß and FGFR1. Sorafenib is clinically approved for the treatment of renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). The pharmacokinetics (PK) of sorafenib are highly variable between subjects. Sorafenib exposure increases less than dose proportionally (likely due to limited solubility). Sorafenib undergoes enterohepatic recycling (EHC). WHAT THIS STUDY ADDS: This is the first study to characterize the PK of sorafenib using a model based on sorafenib's known disposition characteristics such as delayed/solubility-limited GI absorption and EHC. The parameterization of the EHC model used a square wave function to describe the gall bladder emptying. This study evaluated the effect of baseline bodyweight, BSA, age, gender, liver function parameters, kidney function parameters and genotype with respect to CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5 on sorafenib PK. No clinically important covariates were identified. This model can be used to simulate and explore alternative dosing regimens and to develop exposure-response relationships for sorafenib. AIMS: To characterize the pharmacokinetics (PK) of sorafenib in patients with solid tumours and to evaluate the possible effects of demographic, clinical and pharmacogenetic (CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5) covariates on the disposition of sorafenib. METHODS: PK were assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphisms in metabolic enzymes for sorafenib. Population PK analysis was performed by using nonlinear mixed effects modelling (NONMEM). The final model was validated using visual predictive checks and nonparametric bootstrap analysis. RESULTS: A one compartment model with four transit absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline bodyweight was a statistically significant covariate for distributional volume, accounting for 4% of inter-individual variability (IIV). PK model parameter estimates (range) for an 80 kg patient were clearance 8.13 l h(-1) (3.6-22.3 l h(-1) ), volume 213 l (50-1000 l), mean absorption transit time 1.98 h (0.5-13 h), fraction undergoing EHC 50% and average time to gall bladder emptying 6.13 h. CONCLUSIONS: Overall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified.

A pharmacodynamic study of docetaxel in combination with the P-glycoprotein antagonist tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer.

PURPOSE: P-glycoprotein (Pgp) antagonists have been difficult to develop because of complex pharmacokinetic interactions and a failure to show meaningful results. Here we report the results of a pharmacokinetic and pharmacodynamic trial using a third-generation, potent, noncompetitive inhibitor of Pgp, tariquidar (XR9576), in combination with docetaxel. EXPERIMENTAL DESIGN: In the first treatment cycle, the pharmacokinetics of docetaxel (40 mg/m(2)) were evaluated after day 1 and day 8 doses, which were administered with or without tariquidar (150 mg). (99m)Tc-sestamibi scanning and CD56(+) mononuclear cell rhodamine efflux assays were conducted to assess Pgp inhibition. In subsequent cycles, 75 mg/m(2) docetaxel was administered with 150 mg tariquidar every 3 weeks. RESULTS: Forty-eight patients were enrolled onto the trial. Nonhematologic grade 3/4 toxicities in 235 cycles were minimal. Tariquidar inhibited Pgp-mediated rhodamine efflux from CD56(+) cells and reduced (99m)Tc-sestamibi clearance from the liver. There was striking variability in basal sestamibi uptake; a 12% to 24% increase in visible lesions was noted in 8 of 10 patients with lung cancer. No significant difference in docetaxel disposition was observed in pairwise comparison with and without tariquidar. Four partial responses (PR) were seen (4/48); 3 in the non-small cell lung cancer (NSCLC) cohort, measuring 40%, 57%, and 67% by RECIST, and 1 PR in a patient with ovarian cancer. CONCLUSIONS: Tariquidar is well tolerated, with less observed systemic pharmacokinetic interaction than previous Pgp antagonists. Variable effects of tariquidar on retention of sestamibi in imageable lung cancers suggest that follow-up studies assessing tumor drug uptake in this patient population would be worthwhile.

Impact of ABCB1 allelic variants on QTc interval prolongation.

PURPOSE: Although the ABCB1 (P-glycoprotein) drug transporter is a constituent of several blood-tissue barriers (i.e., blood-brain and blood-nerve), its participation in a putative blood-heart barrier has been poorly explored. ABCB1 could decrease the intracardiac concentrations of drugs that cause QT prolongation and cardiotoxicity. EXPERIMENTAL DESIGN: ABCB1-related romidepsin transport kinetics were explored in LLC-PK1 cells transfected with different ABCB1 genetic variants. ABCB1 plasma and intracardiac concentrations were determined in Abcb1a/1b (-/-) mice and wild-type FVB controls. These same mice were used to evaluate romidepsin-induced heart rate-corrected QT interval (QTc) prolongation over time. Finally, a cohort of 83 individuals with available QTcB and ABCB1 genotyping data were used to compare allelic variation in ABCB1 versus QTc-prolongation phenotype. RESULTS: Here, we show that mice lacking the ABCB1-type P-glycoprotein have higher intracardiac concentrations of a model ABCB1 substrate, romidepsin, that correspond to changes in QT prolongation from baseline (ΔQTc) over time. Consistent with this observation, we also show that patients carrying genetic variants that could raise ABCB1 expression in the cardiac endothelium have lower ΔQTc following a single dose of romidepsin. CONCLUSIONS: To our knowledge, this is the first evidence that Abcb1-type P-glycoprotein can limit intracardiac exposure to a drug that mediates QT prolongation and suggests that certain commonly inherited polymorphisms in ABCB1 may serve as markers for QT prolongation following the administration of ABCB1-substrate drugs.

Delayed treatment and continued growth of nonmelanoma skin cancer.

BACKGROUND: Patients may delay treatment for skin cancer for various reasons. Prior research on treatment delay has focused on melanoma rather than nonmelanoma skin cancer (NMSC), which is much more common. OBJECTIVE: We sought to clarify the reasons for delay in the presentation for diagnosis and treatment of NMSC. METHODS: This was a prospective cohort study in a Mohs micrographic surgery private practice in an urban setting. Eligible subjects were 982 consecutive patients presenting for Mohs micrographic surgery for NMSC between March and December 2005. No enrolled subjects were withdrawn for adverse effects. The survey was a 4-page written self-administered questionnaire, eliciting patient medical history, skin cancer history, demographic information, initial and subsequent lesion size, and reasons for delay in presentation for evaluation and management. Outcome analyses addressed the: (1) frequency of specific reasons for delayed presentation, as provided by self-report; (2) association between reasons for delay with demographic or other patient-specific factors; and (3) change in lesion diameter from the time of detection by the patient to the time of presentation to the doctor. RESULTS: Among the reasons for waiting, denial (including: thought it would go away, thought it wasn't important, too busy, thought they could self-treat, afraid it might be something dangerous) was the most frequent, accounting for 71% of cases; difficulty scheduling was associated with 10% of the instances of delay. Older patients (age >64 years) were more likely to wait to seek care than younger patients (odd ratio [OR] = 0.5; 95% confidence interval [CI] 0.4-0.7). Patients with a prior skin cancer were more likely to wait (OR = 1.4; 95% CI 1.1-2.0), as were patients with major life problems (OR = 2.6; 95% CI 1.6-4.3) and patients with a history of any cancer (OR = 1.8; 95% CI 1.3-2.4). Weighted kappa analysis comparing tumor size at the two time points yielded a kappa of 0.72 (SE = .02; 95% CI 0.68-0.77). When the data were separated into two groups, one including those tumors that had decreased in size or remained the same (698 patients), and those that had increased in size (120 patients), the median delay-to-presentation intervals associated with these two groups (2.5 vs 6.0 months, respectively) were found to be significantly different (P < .0001). LIMITATIONS: This study may have limited generalizability to the extent that it reflects the characteristics only of the subpopulation of patients with skin cancer who eventually received treatment at a referral-based, urban, dermatology private practice. Overall, these patients may have been better insured and be more affluent than the general population. CONCLUSIONS: Denial is the most common patient-specific factor accounting for delayed presentation for NMSC diagnosis and treatment. Patients younger than 65 years, with a skin cancer history, with major life problems, and with a history of any cancer were most likely to wait to see a doctor. There was a significant increase in tumor size from the time when tumors were noticed by patients to the time when patients presented to a physician. Increased delay was associated with increased tumor growth.

Determination of PF-04928473 in human plasma using liquid chromatography with tandem mass spectrometry.

A simple, rapid and sensitive liquid chromatography/tandem mass spectrometric (LC/MS/MS) analytical method was developed for quantification of Hsp90 inhibitor PF-04928473 in human plasma, following administration of its prodrug, PF-04929113. Sample processing involved protein precipitation by addition of 0.4 mL of methanol containing internal standard (PF-04972487) to 50 µL volume of plasma sample. Chromatographic separation of PF-04928473 and PF-04972487 was achieved on a Phenomenex®) Luna C18(2) (2.0 mm x 50 mm, 5 µm) column using a gradient elution method with mobile phase solvents: methanol containing 0.1% formic acid and 0.1% formic acid at a flow rate of 0.25 mL/min. Detection was performed in electrospray positive ionization mode, monitoring the ion transitions from m/z 465.1→350.1 (PF-04928473) and m/z 447.0→329.1 (PF-04972487). The retention times for PF-04928473 and PF-04972487 were 1.86 and 2.85 min, respectively. Calibration curves were generated in the range of 2-2000 ng/mL. The accuracy and precision ranged from 94.1 to 99.0% and 86.7 to 97.6%, respectively, which were calculated using quality control samples of three different concentrations analyzed in quintuplicate on four different days.

Romidepsin: a new therapy for cutaneous T-cell lymphoma and a potential therapy for solid tumors.

Romidepsin is a histone deacetylase inhibitor (HDI), approved by the US FDA for the treatment of cutaneous T-cell lymphoma (CTCL). Although various mechanisms have been proposed for the activity of HDIs, including induction of genes controlling cell cycle, acetylation of cytoplasmic proteins and direct induction of apoptosis, the mechanism underlying activity of romidepsin and other HDIs in CTCL is not known. Romidepsin induces long-lasting responses. The side-effect profile is similar to that of other HDIs, causing fatigue, nausea and thrombocytopenia. Management of the CTCL population requires vigilence to prevent infection with skin contaminants, and monitoring of potassium and magnesium, electrolytes found to be low in a large proportion of patients. Electrocardiographic (ECG) changes are common but are not associated with myocardial damage. When molecular end points were evaluated in 61 patients enrolled on a Phase II trial with romidepsin, response was associated with persistence of acetylated histone H3, suggesting that drug exposure is important in effective therapy with romidepsin. Future studies will endeavor to identify combination strategies to increase the efficacy both in resistant CTCL and in solid tumors and to identify biomarkers of response that will allow selection of patients most likely to benefit from the therapy.

Bioluminescent imaging study: FAK inhibitor, PF-562,271, preclinical study in PC3M-luc-C6 local implant and metastasis xenograft models.

Focal adhesion kinase (FAK) is essential in regulating integrin signaling pathways responsible for cell survival and proliferation, as well as motility, making FAK a distinctive target in the field of anticancer drug development, especially with regards to metastatic disease.(1) Our objective was to demonstrate tumor growth inhibition by PF-562,271, a selective inhibitor of FAK and FAK2, or Pyk2,(2) in mouse xenograft models, both subcutaneous and metastatic, employing the human prostate cancer cell line PC3M-luc-C6, a modified PC3M cell line that expresses luciferase. After 2 weeks of treatment with PF-562,271, 25 mg/kg PO BID 5x/wk, the subcutaneous model showed a 62% tumor growth inhibition compared to control based on tumor measurements (p < 0.05), with a 88% vs. a 490% increase in bioluminescent signal for treatment and control respectively (p < 0.05). In the metastasis model, the percent change from baseline, after 18 days of treatment, of the treatment group was 2,854 vs. 14,190% for the vehicle (p < 0.01). These results show that PF-562,271 has a potent effect on metastatic prostate cancer growth in vivo.

A phase I trial of UCN-01 and prednisone in patients with refractory solid tumors and lymphomas.

PURPOSE: UCN-01 potently inhibits protein kinase C, phosphatidylinositide-dependent kinase-1, and checkpoint kinase 1, which are involved in regulating cell cycle progression. We designed a phase I study to determine the maximum tolerated dose (MTD) of UCN-01 with prednisone in patients with advanced malignancies. METHODS: UCN-01 was administered as a continuous intravenous infusion over 72 h in cycle 1 and 36 h in subsequent cycles. Prednisone was given orally at 60 mg/m(2) per day for five consecutive days within each 28-day cycle. Standard dose escalation was employed, and MTD was defined as the dose at which no more than one of six patients experienced a dose-limiting toxicity (DLT). Plasma pharmacokinetics of UCN-01 were assessed. RESULTS: Fifteen patients received a total of 55 courses of treatment. The MTD and the recommended phase II dose of UCN-01 in this combination is 72 mg/m(2) total dose over 72 h for cycle 1 followed by 36 mg/m(2) per cycle over 36 h. All patients experienced hyperglycemia but responded to insulin treatment. Hypophosphatemia was a DLT in two patients. There were no cumulative toxicities. No objective responses were observed, but five patients had stable disease, including two patients with lymphoid malignancies who had prolonged disease stabilizations. UCN-01 has a long terminal half-life and low clearance; there was wide inter-patient variability in peak concentrations. CONCLUSION: UCN-01 can be safely administered in combination with prednisone without unacceptable toxicity. The prolonged stable disease in two patients with lymphoid malignancies is a proof of principle for the evaluation of cyclin-dependent kinase inhibitors in oncology.

Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies.

PURPOSE: Phase I dose-escalation study to determine the toxicity and maximum tolerated dose (MTD) of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, administered on a twice weekly schedule in patients with advanced cancer. EXPERIMENTAL DESIGN: 17-DMAG was administered as a 1- to 2-h infusion twice weekly in 4-week cycles. An accelerated titration design was followed until toxicity was observed, at which point standard dose-escalation proceeded. MTD was defined as the dose at which no more than one of the six patients experienced a dose-limiting toxicity (DLT). Pharmacokinetics were assessed, and Hsp70 mRNA, whose gene product is a chaperone previously shown to be upregulated following the inhibition of Hsp90, was measured in peripheral blood mononuclear cells (PBMCs). RESULTS: A total of 31 patients received 92 courses of treatment. The MTD was 21mg/m(2)/d; 20 patients were enrolled at this dose level. Nine patients had stable disease for a median of 4 (range 2-22) months. Both C(max) and AUC increased proportionally with dose. The most common toxicities were grade 1 or 2 fatigue, anorexia, nausea, blurred vision and musculoskeletal pain. DLTs were peripheral neuropathy and renal dysfunction. Expression of Hsp70 mRNA in PBMCs was highly variable. CONCLUSION: Twice-weekly i.v. infusion of 17-DMAG is well tolerated, and combination phase I studies are warranted.

Pharmacogenetics of membrane transporters: an update on current approaches.

This review provides an overview of the pharmacogenetics of membrane transporters including selected ABC transporters (ABCB1, ABCC1, ABCC2, and ABCG2) and OATPs (OATP1B1 and OATP1B3). Membrane transporters are heavily involved in drug clearance and alters drug disposition by actively transporting substrate drugs between organs and tissues. As such, polymorphisms in the genes encoding these proteins may have significant effects on the absorption, distribution, metabolism and excretion of compounds, and may alter pharmacodynamics of many agents. This review discusses the techniques used to identify substrates and inhibitors of these proteins and subsequently to assess the effect of genetic mutation on transport, both in vitro and in vivo. A comprehensive list of substrates for the major drug transporters is included. Finally, studies linking transporter genotype with clinical outcomes are discussed.