Mario Di Staso

MEK/ERK Inhibitor U0126 Increases the Radiosensitivity of Rhabdomyosarcoma Cells In vitro and In vivo by Downregulating Growth and DNA Repair Signals

Multimodal treatment has improved the outcome of many solid tumors, and in some cases the use of radiosensitizers has significantly contributed to this gain. Activation of the extracellular signaling kinase pathway (MEK/ERK) generally results in stimulation of cell growth and confers a survival advantage playing the major role in human cancer. The potential involvement of this pathway in cellular radiosensitivity remains unclear. We previously reported that the disruption of c-Myc through MEK/ERK inhibition blocks the expression of the transformed phenotype; affects in vitro and in vivo growth and angiogenic signaling; and induces myogenic differentiation in the embryonal rhabdomyosarcoma (ERMS) cell lines (RD). This study was designed to examine whether the ERK pathway affects intrinsic radiosensitivity of rhabdomyosarcoma cancer cells. Exponentially growing human ERMS, RD, xenograft-derived RD-M1, and TE671 cell lines were used. The specific MEK/ERK inhibitor, U0126, reduced the clonogenic potential of the three cell lines, and was affected by radiation. U0126 inhibited phospho-active ERK1/2 and reduced DNA protein kinase catalytic subunit (DNA-PKcs) suggesting that ERKs and DNA-PKcs cooperate in radioprotection of rhabdomyosarcoma cells. The TE671 cell line xenotransplanted in mice showed a reduction in tumor mass and increase in the time of tumor progression with U0126 treatment associated with reduced DNA-PKcs, an effect enhanced by radiotherapy. Thus, our results show that MEK/ERK inhibition enhances radiosensitivity of rhabdomyosarcoma cells suggesting a rational approach in combination with radiotherapy. Mol Cancer Ther; 10(1); 159–68. ©2011 AACR.

5‐azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors

Epigenetic modifications play a key role in the in prostate cancer (Pca) progression to a hormone refractory state (HRPC) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research. In this regard, 5‐Azacitine (5‐Aza) represents a promising epigenetic modulator. This study tested the hypothesis that 5‐Aza may restore and enhance the responsiveness of HRPC cells to anti‐hormonal therapy on Androgen receptor (AR) expressing (22rv1) and AR‐deficient (PC3) cells.

Hypofractionated radical radiotherapy in elderly patients with medically inoperable stage I-II non-small-cell lung cancer

We described the results of a hypofractionated regimen (HFRT) in a cohort of elderly patients (36 subjects) with stage I-II non-small-cell-lung cancer (NSCLC), tumor size> or =3 cm and ineligible for surgery. HFRT was delivered in 20 daily fractions of 3 Gy per fraction with a total dose of 60 Gy. The median PTV was 145 cm(3). The primary purpose of study was to estimate the local tumor control at 2 years as well as the modifications in the lung function parameters at 6 and 12 months. The local tumor control was 63.9% at 2 years. The incidence of distant recurrence rate at 2 years was 50%. The overall-survival (OS), the cause-specific-survival (CSS) and the disease-free-survival (DSF) at 2 years were 55.6, 57.1, and 38.9%, respectively. The median OS, CSS, and DFS was 25.4 (CI 95% 21.7-32.9), 26.7 (CI 95% 22.5-33.5) and 23.4 months (CI 95% 18.6-30.1), respectively. The two clinical parameters with a positive influence on OS were a KPS> or =90 (HR 1.16; p=0.013) and tumor size< or =4 cm (HR 0.763; p=0.011). No grade 3-4 acute toxicity was reported. No significant change in lung function parameters was measured at 6 and 12 months. For patients with larger or centrally located tumors as well as for subjects with lymph nodes involvement SBRT may be of limited valiance. Although the performances of our regimen were lower than the ones achieved by SBRT, our therapeutic option may offer a lower incidence of complications against a satisfactory local tumor control.

Treatment of Solitary Painful Osseous Metastases with Radiotherapy, Cryoablation or Combined Therapy: Propensity Matching Analysis in 175 Patients

Purpose aim of this study was to identify outcomes in pain relief and quality of life in patients with a solitary painful osseous metastasis treated by radiotherapy, cryoablation or the combination using a propensity score matching study design. Materials and Methods 175 patients with painful bone metastases were included in the study. Twenty-five of them underwent a radiation course (20 Gy in five daily fractions) 15 days after the cryoablation. These subjects were retrospectively matched by propensity analysis with a group of subjects treated by radiotherapy (125 subjects) and with a group treated byCryoablation (25 subjects). The pain relief in terms of complete response, rate of subjects requiring analgesics after treatments and the changes in self-rated quality of life were measured. Informed consent was obtained from the subject and the study was approved by the local Ethical Committee. Results An higher proportion of subjects treated by cryoablation (32%) or cryoablation followed by RT (72%;) experienced a complete response compared with patients treated by radiotherapy alone (11.2%). After Bonferroni correction strategy, the addition of radiotherapy to cryoablation significantly improved the rate of complete response compared with cryoablation alone (p = 0.011) and this paralleled with an improved self-rated quality of life. Seventeen subjects (13.6%) of patients in the radiotherapy group, 9 (36%) in the cryoablation group, and 19 (76)% in the cryoablation- radiotherapy group did not require narcotic medications. Conclusions The addition of radiotherapy to cryoablation favorably impacts on perceived pain, with a favorable toxicity profile. However, our data should be interpreted with caution and could serve as a framework around which to design future trials.

Late morbidity and oncological outcome after radical hypofractionated radiotherapy in men with prostate cancer

Study Type – Therapy (case control)
Level of Evidence 3b

Maintenance Immunotherapy in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

The purpose of this study was to determine the efficacy and safety of a maintenance immunotherapy regimen administered to patients with recurrent/metastatic squamous cell carcinoma of the head and neck (RMHN) who showed clinical benefit from docetaxel, ifosfamide, and cisplatin chemotherapy (DIP). Every 4 weeks, patients with RMHN received 60 mg/m2 docetaxel on day 1, and 1200 mg/m2 ifosfamide and 20 mg/m2 cisplatin on days 1 to 4. Low-dose subcutaneous interleukin-2 and oral 13-cis-retinoic acid were administered as maintenance immunotherapy to patients who showed a clinical benefit (complete or partial response, disease stability). The primary end point was response; secondary end points were progression-free survival, overall survival, toxicity, and evaluations of lymphocytes, natural killer cells, and serum vascular endothelial growth factor (VEGF). After a median follow-up of 22 months, 263 courses of chemotherapy were administered to the 54 patients. The overall response rate was 59%. Forty-two patients (78%) had a clinical benefit and received 185 courses of maintenance immunotherapy. Median progression-free survival and overall survival were 11.1 and 21.8 months, respectively. Statistically significant, progressive increases in lymphocytes and natural killer cells and a decrease in VEGF were observed in patients treated with maintenance immunotherapy. The toxicity was relatively well tolerated and caused no death. Outpatient administration of DIP, followed by low-dose interleukin-2 and 13-cis-retinoic acid, was generally well tolerated and showed promising activity against RMHN. Longitudinal changes in lymphocytes, natural killer cells, and VEGF might be useful biomarkers for response and survival.

Advances in imaging and in non-surgical salvage treatments after radiorecurrence in prostate cancer: what does the oncologist, radiotherapist and radiologist need to know?

ObjectivesIn this article the state of art the of prostate cancer (Pca) imaging and non-surgical salvage treatments (STs) is surveyed in order to explore the impact of imaging findings on the identification of radiorecurrent Pca after external beam radiotherapy (EBRT).MethodsA computerised search was performed to identify all relevant studies in Medline up to 2012. Additional articles were extracted based on recommendations from an expert panel of authors.ResultsDefinitive EBRT for Pca is increasingly used as treatment. After radiorecurrent Pca, non-surgical STs are emerging and shifting from investigational status to more established therapeutic options. Therefore, several scientific societies have published guidelines including clinical and imaging recommendations, even if the timing, efficacy and long-term toxicity of these STs have to be established. In some measure, accurately delineating the location and the extent of cancer is critical in selecting target lesions and in identifying patients who are candidates for STs. However, there is increasing awareness that anatomical approaches based on measurements of tumour size have substantial limitations, especially for tumours of unknown activity that persist or recur following irradiationConclusionsTo date, the main focus for innovations in imaging is the combination of excellence in anatomical resolution with specific biological correlates that depict metabolic processes and hallmarks at the tumour level. The emergence of new molecular markers could favour the development of methods that directly determine their presence, thereby improving tumour detection.Key Points• Imaging may influence therapeutic decisions during non-surgical STs.• MRI findings correlate with parametric maps derived from multiple functional techniques.• Non-surgical salvage treatments allow local tumour control in patients with radiorecurrent PCa.

Bone targeted therapy for preventing skeletal-related events in metastatic breast cancer

Cancer cells can alter physiological mechanisms within bone resulting in high bone turnover, and consequently in skeletal-related events (SREs), causing severe morbidity in affected patients. The goals of bone targeted therapy, as bisphosphonates and denosumab, are the reduction of incidence and the delay in occurrence of the SREs, to improve quality of life and pain control. The toxicity profile is similar between bisphosphonates and denosumab, even if pyrexia, bone pain, arthralgia, renal failure and hypercalcemia are more common with bisphosphonates, while hypocalcemia and toothache are more frequently reported with denosumab. Osteonecrosis of the jaw (ONJ) occurred infrequently without statistically significant difference. The present review aims to provide an assessment on bone targeted therapies for preventing the occurrence of SREs in bone metastatic breast cancer patients, critically analyzing the evidence available so far on their effectiveness, in light of the different mechanisms of action. Thus, we try to provide tools for the most fitting treatment of bone metastatic breast cancer patients. We also provide an overview on the usefulness of bone turnover markers in clinical practice and new molecules currently under study for the treatment of bone metastatic disease.

Strategies for Imaging Androgen Receptor Signaling Pathway in Prostate Cancer: Implications for Hormonal Manipulation and Radiation Treatment

Prostate cancer (Pca) is a heterogeneous disease; its etiology appears to be related to genetic and epigenetic factors. Radiotherapy and hormone manipulation are effective treatments, but many tumors will progress despite these treatments. Molecular imaging provides novel opportunities for image-guided optimization and management of these treatment modalities. Here we reviewed the advances in targeted imaging of key biomarkers of androgen receptor signaling pathways. A computerized search was performed to identify all relevant studies in Medline up to 2013. There are well-known limitations and inaccuracies of current imaging approaches for monitoring biological changes governing tumor progression. The close integration of molecular biology and clinical imaging could ease the development of new molecular imaging agents providing novel tools to monitor a number of biological events that, until a few years ago, were studied by conventional molecular assays. Advances in translational research may represent the next step in improving the oncological outcome of men with Pca who remain at high risk for systemic failure. This aim may be obtained by combining the anatomical properties of conventional imaging modalities with biological information to better predict tumor response to conventional treatments.

Diagnostic accuracy of proton magnetic resonance spectroscopy and perfusion-weighted imaging in brain gliomas follow-up: a single institutional experience

Objectives The objective of this study was to evaluate whether proton magnetic resonance spectroscopy and perfusion magnetic resonance imaging (MRI) are able to increase diagnostic accuracy in the follow-up of brain gliomas, identifying the progression of disease before it becomes evident in the standard MRI; also to evaluate which of the two techniques has the best diagnostic accuracy. Methods Eighty-three patients with cerebral glioma (50 high-grade gliomas (HGGs), 33 low-grade gliomas (LGGs)) were retrospectively enrolled. All patients underwent standard MRI, H spectroscopic and perfusion echo-planar imaging MRI. For spectroscopy variations of choline/creatine, choline/N-acetyl-aspartate ratio, and lipids and lactates peak were considered. For perfusion 2.0 was considered the cerebral blood volume cut-off for progression. The combination of functional parameters gave a multiparametric score (0–2) to predict outcome. Diagnostic performance was determined by the receiver operating characteristic curve, with sensitivity, specificity, positive predictive and negative predictive values. Results In patients with LGGs a combined score of at least 1 was the best predictor for progression (odds ratio (OR) 3.91) with 8.4 months median anticipation of diagnosis compared to standard MRI. The individual advanced magnetic resonance technique did not show a diagnostic accuracy comparable to the combination of the two. Overall diagnostic accuracy area under the curve (AUC) was 0.881. In patients with HGGs the multiparametric score did not improve diagnostic accuracy significantly. Perfusion MRI was the best predictor of progression (OR 3.65), with 6.7 months median anticipation of diagnosis. Overall diagnostic accuracy AUC was 0.897. Then spectroscopy and perfusion MRI are able to identify tumour progression during follow-up earlier than standard MRI. Conclusion In patients with LGGs the combination of the functional parameters seems to be the best method for diagnosis of progression. In patients with HGGs perfusion is the best diagnostic method.