Azacitidine favorably modulates PSA kinetics correlating with plasma DNA LINE-1 hypomethylation in men with chemonaïve castration-resistant prostate cancer

Background

Azacitidine is a hypomethylating agent that activates genes repressed by promoter methylation. Preclinically, demethylating agents reverse resistance of prostate cancer to androgen ablation. A phase II trial evaluated azacitidine for men with castration-resistant prostate cancer (CRPC) progressing on combined androgen blockade (CAB).

Methods

Chemonaïve patients with CRPC on CAB and PSA-doubling time (DT) < 3 months were eligible. The primary endpoint was prolongation of PSA-DT to ≥3 months. Correlation of biologic activity (fetal hemoglobin, plasma DNA LINE-1 methylation) with prolongation of PSA-DT was tested. CAB was continued and azacitidine 75 mg/m² was administered subcutaneously on days 1–5 of each 28-day cycle up to 12 cycles or until clinical progression/intolerable toxicities.

Results

Thirty-six patients were enrolled, 80.6% had metastatic disease, and 34 were evaluable. A PSA-DT ≥ 3 months was attained in 19 patients (55.8%). Overall median PSA-DT was significantly prolonged compared to baseline (2.8 vs. 1.5 months, P < 0.01). Fourteen patients had some PSA decline during therapy and 1 patient had a ≥30% decline compared with baseline. The median clinical progression-free survival was 12.4 weeks. Grade 3 toxicities included fatigue (12%), and neutropenia (6%), with 4 patients discontinuing due to toxicities. A trend in decreasing plasma DNA LINE-1 methylation was seen with longer treatment duration (P = 0.06), which significantly correlated with prolongation of PSA-DT (P = 0.02).

Conclusions

Azacitidine favorably modulates PSA kinetics in chemonaïve CRPC that correlates with decreasing plasma DNA LINE-1 methylation. Given the excellent tolerability, further development of azacitidine for CRPC may be warranted, with exploration of combination regimens.     

Myocardial myocyte remodeling and fibrosis in the cardiometabolic syndrome

Myocardial cellular and extracellular matrix remodeling are important in the development of left ventricular hypertrophy and are essential for the adaptive and maladaptive changes associated with the cardiometabolic syndrome. This brief review of myocyte remodeling also presents preliminary observational findings regarding myocardial adaptive hypertrophy remodeling, including an increase in mitochondria and capillaries, convolutions and lengthening of intercalated discs, the addition of sarcomeres, thickened Z lines, and the novel presence of pericapillary fibrosis (in addition to perivascular arteriolar fibrosis). The 11-week-old TG(mREN-2)27 transgene rat model of tissue angiotensin II overexpression, which develops hypertension and insulin resistance, was chosen to examine both myocyte hypertrophy and extracellular matrix fibrosis. This review and the preliminary observational findings may provide the clinician and researcher a better understanding of remodeling changes in the myocardium and ultimately foster earlier recognition and therapeutic interventions.     

Perioperative chemotherapy for bladder cancer

The presence of occult micrometastases at the time of radical cystectomy leads to both distant and local failure in patients with locally advanced transitional cell carcinoma of the bladder. Cisplatin-based chemotherapy produces responses in 40-60% of patients with metastatic bladder cancer. Perioperative administration of chemotherapy in bladder cancer patients theoretically can impart the same survival benefits demonstrated in patients with breast, lung and colon cancer. Both neoadjuvant and adjuvant therapy have been evaluated in patients with locally advanced bladder cancer. Studies evaluating adjuvant chemotherapy have been limited by inadequate statistical power to detect meaningful clinical answers, as well as experimental arms utilizing inadequate chemotherapy. Two randomized clinical trials have demonstrated a survival benefit for neoadjvuant CMV (Cisplatin, Methotrexate, Vinblastine) or MVAC (methotrexate, vinblastine, adriamycin, cisplatin). The aggregate of available evidence suggests that neoadjuvant cisplatin-based combination chemotherapy should be considered a standard of care for patients with muscle-invasive/locally advanced operable bladder cancer. However, some physicians prefer to defer chemotherapy until after surgery, when pathologic stage is defined, as well as the risk of relapse. In patients who are either unfit for or refuse radical cystectomy, neoadjuvant chemotherapy with or without radiation can render bladder preservation possible in patients who attain pathologic major response.     

Bladder cancer update. Current evaluation methods and standard of care

Urinary bladder cancer arises in the transitional cell epithelium of the bladder. In the United States, it is the fourth most common tumor in men and the eighth most common tumor in women. Here, Dr Sonpavde reviews the risk factors for bladder cancer, its diagnosis, the latest concepts of its molecular characteristics and metastatic potential, and current strategies to treat this common disease. He focuses in particular on management of transitional cell carcinoma, which is responsible for about 95% of cases.     

Comparative Assessment of In Vitro Release Kinetics of Calcitonin Polypeptide from Biodegradable Microspheres

The objective of our study was to compare the in vitro release kinetics of a sustained-release injectable microsphere formulation of the polypeptide drug, calcitonin (CT), to optimize the characteristics of drug release from poly-(lactide-co-glycolide) (PLGA) copolymer biodegradable microspheres. A modified solvent evaporation and double emulsion technique was used to prepare the microspheres. Release kinetic studies were carried out in silanized tubes and dialysis bags, whereby microspheres were suspended and incubated in phosphate buffered saline, sampled at fixed intervals, and analyzed for drug content using a modified Lowry protein assay procedure. An initial burst was observed whereby about 50% of the total dose of the drug was released from the microspheres within 24 hr and 75% within 3 days. This was followed by a period of slow release over a period of 3 weeks in which another 10-15% of drug was released. Drug release from the dialysis bags was more gradual, and 50% CT was released only after 4 days and 75% after 12 days of release. Scanning electron micrographs revealed spherical particles with channel-like structures and a porous surface after being suspended in an aqueous solution for 5 days. Differential scanning calorimetric studies revealed that CT was present as a mix of amorphous and crystalline forms within the microspheres. Overall, these studies demonstrated that sustained release of CT from PLGA microspheres over a 3-week period is feasible and that release of drug from dialysis bags was more predictable than from tubes.     

Challenges and Regulatory Considerations in the Acoustic Measurement of High‐Frequency (>20 MHz) Ultrasound

This article examines the challenges associated with making acoustic output measurements at high ultrasound frequencies (>20 MHz) in the context of regulatory considerations contained in the US Food and Drug Administration industry guidance document for diagnostic ultrasound devices. Error sources in the acoustic measurement, including hydrophone calibration and spatial averaging, nonlinear distortion, and mechanical alignment, are evaluated, and the limitations of currently available acoustic measurement instruments are discussed. An uncertainty analysis of acoustic intensity and power measurements is presented, and an example uncertainty calculation is done on a hypothetical 30‐MHz high‐frequency ultrasound system. This analysis concludes that the estimated measurement uncertainty of the acoustic intensity is +73%/?86%, and the uncertainty in the mechanical index is +37%/?43%. These values exceed the respective levels in the Food and Drug Administration guidance document of 30% and 15%, respectively, which are more representative of the measurement uncertainty associated with characterizing lower‐frequency ultrasound systems. Recommendations made for minimizing the measurement uncertainty include implementing a mechanical positioning system that has sufficient repeatability and precision, reconstructing the time‐pressure waveform via deconvolution using the hydrophone frequency response, and correcting for hydrophone spatial averaging.     

Role of ICOS pathway in autoimmune and alloimmune responses in NOD mice

Islet allografts are subject to alloimmune and autoimmune destruction when transplanted into autoimmune prone animals or humans. The ICOS-B7h pathway plays a role in alloimmune responses, but its function in autoimmunity against islet cells is controversial. We investigated the role of ICOS signaling in autoimmune and alloimmune responses in NOD mice. ICOS blockade prevents development of spontaneous disease in pre-diabetic NOD mice. Furthermore, while ICOS blockade prolongs graft survival in a fully mismatched non-autoimmune islet allograft model in C57BL/6 recipients, it has no beneficial effect in reversing diabetes in models of islet transplantation in NOD mice involving autoimmunity alone or both allo- and autoimmunity. Interestingly, ICOS blockade is effective in prolonging heart allograft (not subject to tissue-specific autoimmunity) survival in NOD mice. We conclude that in islet transplantation and autoimmune diabetes, ICOS blockade can be effective in inhibiting alloimmunity and preventing autoimmunity but is ineffective in inhibiting recurrence of autoimmunity.     

Synthesis, pharmacological evaluation and docking studies of coumarin derivatives

We synthesized coumarin derivatives using various aromatic and heterocyclic amines, and tested the target compound for its analgesic, anti-inflammatory, antimicrobial activities. Compounds 3l, 3m and 3n showed significant anti-inflammatory, analgesic and antimicrobial activities. The synthesized compounds, then docked on COX-2 to predict the binding affinity and orientation at the active site of the receptor. It was found that the active compounds 3l, 3m and 3n intact mainly with Arg 44 amino acid, which may be involved in COX-2 inhibition. The compounds which bind with Arg 44 have significant anti-inflammatory activity. This could be due to the formation of more effective hydrogen bond with the receptor. Comparing pharmacological activity and docking results, we conclude that heterocyclic derivatives linked with nitrogen at 7-position of coumarin seem to be potentially active drug.     

Recent advances in immunotherapy for the treatment of prostate cancer

INTRODUCTION: Prostate cancer vaccines attempt to induce cancer-specific systemic immune responses and represent a new class of targeted therapies, many of which are non-toxic. Several vaccine technologies are in development. AREAS COVERED: An autologous antigen presenting cell vaccine loaded with prostate acid phosphatase conjugated with GM-CSF, sipuleucel-T confers a survival advantage in men with metastatic castration-resistant prostate cancer (CRPC) and is now FDA approved based on the IMPACT trial. A poxvirus-based vaccine, PROSTVAC-VF TRICOM targeting prostate-specific antigen (PSA), has demonstrated improved survival in a randomized Phase II trial of patients with metastatic CRPC. Novel T lymphocyte checkpoint inhibitors of cytotoxic T lymphocyte antigen 4 and programmed death-1 are also emerging. Recognition of improved survival without an earlier clinical signal of activity by conventional criteria has led to new guidelines to evaluate immunotherapeutic agents. The clinical benefit of combining vaccines with chemotherapy, radiotherapy and other immunotherapeutic and biologic agents is being evaluated in the context of disappointing results of combination GVAX vaccine and docetaxel chemotherapy. EXPERT OPINION: To build on the success of early phase trials, efforts must be made to optimize vaccine approaches and patient selection.