Three vs. Four Cycles of Neoadjuvant Chemotherapy for Localized Muscle Invasive Bladder Cancer Undergoing Radical Cystectomy: A Retrospective Multi-Institutional Analysis.

BACKGROUND: Three or four cycles of cisplatin-based chemotherapy is the standard neoadjuvant treatment prior to cystectomy in patients with muscle-invasive bladder cancer. Although NCCN guidelines recommend 4 cycles of cisplatin-gemcitabine, three cycles are also commonly administered in clinical practice. In this multicenter retrospective study, we assessed a large and homogenous cohort of patients with urothelial bladder cancer (UBC) treated with three or four cycles of neoadjuvant cisplatin-gemcitabine followed by radical cystectomy, in order to explore whether three vs. four cycles were associated with different outcomes. METHODS: Patients with histologically confirmed muscle-invasive UBC included in this retrospective study had to be treated with either 3 (cohort A) or 4 (cohort B) cycles of cisplatin-gemcitabine as neoadjuvant therapy before undergoing radical cystectomy with lymphadenectomy. Outcomes including pathologic downstaging to non-muscle invasive disease, pathologic complete response (defined as absence of disease -ypT0), overall- and cancer-specific- survival as well as time to recurrence were compared between cohorts A vs. B. RESULTS: A total of 219 patients treated at 14 different high-volume Institutions were included in this retrospective study. Patients who received 3 (cohort A) vs. 4 (cohort B) cycles of neoadjuvant cisplatin-gemcitabine were 160 (73,1%) vs. 59 (26,9%).At univariate analysis, the number of neoadjuvant cycles was not associated with either pathologic complete response, pathologic downstaging, time to recurrence, cancer specific, and overall survival. Of note, patients in cohort B vs. A showed a worse non-cancer specific overall survival at univariate analysis (HR= 2.53; 95 CI= 1.05 - 6.10; p=0.046), although this finding was not confirmed at multivariate analysis. CONCLUSIONS: Our findings suggest that 3 cycles of cisplatin-gemcitabine may be equally effective, with less long-term toxicity, compared to 4 cycles in the neoadjuvant setting.

Optimization of a Low-Cost, Sensitive PNA Clamping PCR Method for JAK2 V617F Variant Detection.

BACKGROUND: The JAK2 V617F variant is diagnostic for myeloproliferative neoplasms, a group of clonal disorders of hematopoietic stem and progenitor cells. Although several approaches have been developed to detect the variant, a gold standard diagnostic method has not yet been defined. We describe a simple, fast, and cost-effective PCR-based approach that enhances test specificity and sensitivity by blocking the amplification of the large excess of wild-type DNA. METHODS: The method involves using an oligo peptide nucleic acid (PNA) perfectly matching its corresponding DNA sequence. The PCR protocol was optimized by collecting a detailed thermodynamic data set on PNA-DNA wild-type duplexes by circular dichroism melting experiments. The specificity and sensitivity of PNA clamping PCR were assessed by genotyping 50 patients with myeloproliferative neoplasm who carried the JAK2 V617F variant and 50 healthy donors. RESULTS: The optimized protocol enabled selective amplification of the variant alleles, achieving maximum sensitivity (100%) and specificity (100%). Analytical sensitivity was 0.05% of variant alleles as assessed by serial dilutions of DNA from the HEL cell line (which carries the JAK2 V617F variant) mixed to wild-type DNA from healthy donors. The JAK2 V617F variant test performed according to this method has better diagnostic performance than its 2 main PCR-based competitors, at much lower cost. CONCLUSIONS: High sensitivity and specificity and cost-effectiveness make PNA clamping PCR a useful testing platform for the detection of minor allele variants in small-scale diagnostic laboratories. It promises to improve patient care while enabling significant healthcare savings.

Overview of Current Targeted Anti-Cancer Drugs for Therapy in Onco-Hematology.

The upgraded knowledge of tumor biology and microenviroment provides information on differences in neoplastic and normal cells. Thus, the need to target these differences led to the development of novel molecules (targeted therapy) active against the neoplastic cells' inner workings. There are several types of targeted agents, including Small Molecules Inhibitors (SMIs), monoclonal antibodies (mAbs), interfering RNA (iRNA) molecules and microRNA. In the clinical practice, these new medicines generate a multilayered step in pharmacokinetics (PK), which encompasses a broad individual PK variability, and unpredictable outcomes according to the pharmacogenetics (PG) profile of the patient (e.g., cytochrome P450 enzyme), and to patient characteristics such as adherence to treatment and environmental factors. This review focuses on the use of targeted agents in-human phase I/II/III clinical trials in cancer-hematology. Thus, it outlines the up-to-date anticancer drugs suitable for targeted therapies and the most recent finding in pharmacogenomics related to drug response. Besides, a summary assessment of the genotyping costs has been discussed. Targeted therapy seems to be an effective and less toxic therapeutic approach in onco-hematology. The identification of individual PG profile should be a new resource for oncologists to make treatment decisions for the patients to minimize the toxicity and or inefficacy of therapy. This could allow the clinicians to evaluate benefits and restrictions, regarding costs and applicability, of the most suitable pharmacological approach for performing a tailor-made therapy.

Assessment of Pharmacogenomic Panel Assay for Prediction of Taxane Toxicities: Preliminary Results.

Backbone: Paclitaxel and docetaxel are the primary taxane anticancer drugs regularly used to treat, breast, gastric, ovarian, head/neck, lung, and genitourinary neoplasm. Suspension of taxane treatments compromising patient benefits is more frequently caused by peripheral neuropathy and allergy, than to tumor progression. Several strategies for preventing toxicity have been investigated so far. Recently, findings on the genetic variants associated with toxicity and resistance to taxane-based chemotherapy have been reported. Methods: An extensive panel of five polymorphisms on four candidate genes (ABCB1, CYP2C8*3, CYP3A4*1B, XRCC3), previously validated as significant markers related to paclitaxel and Docetaxel toxicity, are analyzed and discussed. We genotyped 76 cancer patients, and 35 of them received paclitaxel or docetaxel-based therapy. What is more, an early outline evaluation of the genotyping costs and benefit was assessed. Results: Out of 35 patients treated with a taxane, six (17.1%) had adverse neuropathy events. Pharmacogenomics analysis showed no correlation between candidate gene polymorphisms and toxicity, except for the XRCC3 AG+GG allele [OR 2.61 (95% CI: 0.91-7.61)] which showed a weak significant trend of risk of neurotoxicities vs. the AG allele [OR 1.52 (95% CI: 0.51-4.91)] P = 0.03. Summary: Based on our experimental results and data from the literature, we propose a useful and low-cost genotyping panel assay for the prevention of toxicity in patients undergoing taxane-based therapy. With the individual pharmacogenomics profile, clinicians will have additional information to plan the better treatment for their patients to minimize toxicity and maximize benefits, including determining cost-effectiveness for national healthcare sustainability.

Drug-Drug Interactions Based on Pharmacogenetic Profile between Highly Active Antiretroviral Therapy and Antiblastic Chemotherapy in Cancer Patients with HIV Infection.

The introduction of Highly Active Antiretroviral Therapy (HAART) into clinical practice has dramatically changed the natural approach of HIV-related cancers. Several studies have shown that intensive antiblastic chemotherapy (AC) is feasible in HIV-infected patients with cancer, and that the outcome is similar to that of HIV-negative patients receiving the same AC regimens. However, the concomitant use of HAART and AC can result in drug accumulation or possible toxicity with consequent decreased efficacy of one or both classes of drugs. In fact, many AC agents are preferentially metabolized by CYP450 and drug-drug interactions (DDIs) with HAART are common. Therefore, it is important that HIV patients with cancer in HAART receiving AC treatment at the same time receive an individualized cancer management plan based on their liver and renal functions, their level of bone marrow suppression, their mitochondrial dysfunction, and their genotype profile. The rationale of this review is to summarize the existing data on the impact of HAART on the clinical management of cancer patients with HIV/AIDS and DDIs between antiretrovirals and AC. In addition, in order to maximize the efficacy of antiblastic therapy and minimize the risk of drug-drug interaction, a useful list of pharmacogenomic markers is provided.