PARP inhibitors affect growth, survival and radiation susceptibility of human alveolar and embryonal rhabdomyosarcoma cell lines

PARP inhibitors (PARPi) are used in a wide range of human solid tumours but a limited evidence is reported in rhabdomyosarcoma (RMS), the most frequent childhood soft-tissue sarcoma. The cellular and molecular effects of Olaparib, a specific PARP1/2 inhibitor, and AZD2461, a newly synthesized PARP1/2/3 inhibitor, were assessed in alveolar and embryonal RMS cells both as single-agent and in combination with ionizing radiation (IR)

Oral platelet gel supernatant plus supportive medical treatment versus supportive medical treatment in the management of radiation-induced oral mucositis: a matched explorative active control trial by propensity analysis

OBJECTIVES:: In this active control trial, the rate of radio-induced WHO grade 3/4 oral mucositis and the change in quality of life, assessed by OMWQ-HN, were measured in subjects with head and neck cancer treated by platelet gel supernatant (PGS) and supportive medical treatment versus subjects treated by supportive medical treatment alone. MATERIALS AND METHODS:: Eighty patients with nonmetastatic head and neck cancer underwent curative or adjuvant radiotherapy. All patients underwent supportive medical treatment and/or PGS at the beginning and during radiotherapy. Sixteen patients received PGS in association with supportive medical treatment. To obtain 2 groups virtually randomized for important clinical characteristics subjects were matched, by propensity analysis, with a group of subjects (64 patients) treated with supportive medical treatment alone. RESULTS:: Subjects treated with standard supportive treatment experienced significant higher WHO grade 3/4 toxicity (55%; 35/64) than subjects treated by PGS (13%; 3/16). The reduced toxicity found in PGS group paralleled with the evidence that they developed later symptoms with respect to controls. The Cox proportional hazard model indicated that patients treated with standard supportive medical treatment experienced 2.7-fold increase (hazard ratio=2.7; 95% confidence interval, 1.3-5.7) in the occurrence of WHO grade 3/4 toxicity. PGS group significantly experienced higher quality of life than control groups as measured by OMWQ-HN. A significant decrease in the opioid analgesics usage was found in the PGS group. CONCLUSIONS:: These preliminary data should be interpreted with caution and could serve as a framework around which to design future trials

Sulodexide counteracts endothelial dysfunction induced by metabolic or non-metabolic stresses through activation of the autophagic program

OBJECTIVE: Endothelial dysfunction (ED) predisposes to venous thrombosis (VT) and post-thrombotic syndrome (PTS), a long-term VT-related complication. Sulodexide (SDX) is a highly purified glycosaminoglycan with antithrombotic, pro-fibrinolytic and anti-inflammatory activity used in the treatment of chronic venous disease (CVD), including patients with PTS. SDX has recently obtained clinical evidence in the “extension therapy” after initial-standard anticoagulant treatment for the secondary prevention of recurrent deep vein thrombosis (DVT). Herein, we investigated how SDX counteracts ED. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVEC) were used. Metabolic and non metabolic-induced ED was induced by treating with methylglyoxal (MGO) or irradiation (IR), respectively. Bafilomycin A1 was used to inhibit autophagy. The production of reactive oxygen species (ROS), tetrazolium bromide (MTT) assay for cell viability, terminal de-oxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay for cell apoptosis, Real-time PCR and Western blot analysis for gene and protein expression were used. RESULTS: SDX protected HUVEC from MGO- or IR-induced apoptosis by counteracting the activation of the intrinsic and extrinsic caspase cascades. The cytoprotective effects of SDX resulted from a reduction in a) ROS production, b) neo-synthesis and release of pro-inflammatory cytokines (TNFα, IL1, IL6, IL8), c) DNA damage induced by MGO or IR. These effects were reduced when autophagy was inhibited. CONCLUSIONS: Data herein collected indicate the ability of SDX to counteract ED induced by metabolic or non-metabolic stresses by involving the intracellular autophagy pathway. Our experience significantly increases the knowledge of the mechanisms of action of SDX against ED and supports the use of SDX in the treatment of CVD, PTS and in the secondary prevention of recurrent DVT

Cyclin D1 silencing suppresses tumorigenicity, impairs DNA double strand break repair and thus radiosensitizes androgenindependent prostate cancer cells to DNA damage.

Patients with hormone-resistant prostate cancer (PCa) have higher biochemical failure rates following radiation therapy (RT). Cyclin D1 deregulated expression in PCa is associated with a more aggressive disease: however its role in radioresistance has not been determined. Cyclin D1 levels in the androgen-independent PC3 and 22Rv1 PCa cells were stably inhibited by infecting with cyclin D1-shRNA. Tumorigenicity and radiosensitivity were investigated using in vitro and in vivo experimental assays. Cyclin D1 silencing interfered with PCa oncogenic phenotype by inducing growth arrest in the G1 phase of cell cycle and reducing soft agar colony formation, migration, invasion in vitro and tumor formation and neo-angiogenesis in vivo. Depletion of cyclin D1 significantly radiosensitizes PCa cells by increasing the RT-induced DNA damages by affecting the NHEJ and HR pathways responsible of the DNA double-strand break repair. Following treatment of cells with RT the abundance of a biomarker of DNA damage, γ-H2AX, was dramatically increased in sh-cyclin D1 treated cells compared to shRNA control. Concordant with these observations DNA-PKcs-activation and RAD51-accumulation, part of the DNA double-strand break repair machinery, were reduced in shRNA-cyclin D1 treated cells compared to shRNA control. We further demonstrate the physical interaction between CCND1 with activated-ATM, -DNA-PKcs and RAD51 is enhanced by RT. Finally, siRNA-mediated silencing experiments indicated DNA-PKcs and RAD51 are downstream targets of CCND1-mediated PCa cells radioresistance. In summary, these observations suggest that CCND1 is a key mediator of PCa radioresistance and could represent a potential target for radioresistent hormone-resistant PCa

Magnetic resonance of rectal cancer response to therapy: an Image quality comparison between 3.0 and 1.5 Tesla

Purpose. To evaluate signal intensity (SI) differences between 3.0 T and 1.5 T on T2-weighted (T2w), diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) in rectal cancer pre-, during, and postneoadjuvant chemoradiotherapy (CRT). Materials and Methods. 22 patients with locally advanced rectal cancer were prospectively enrolled. All patients underwent T2w, DWI, and ADC pre-, during, and post-CRT on both 3.0 T MRI and 1.5 T MRI. A radiologist drew regions of interest (ROIs) of the tumor and obturator internus muscle on the selected slice to evaluate SI and relative SI (rSI). Additionally, a subanalysis evaluating the SI before and after-CRT (ΔSI pre-post) in complete responder patients (CR) and nonresponder patients (NR) on T2w, DWI, and ADC was performed. Results. Significant differences were observed for T2w and DWI on 3.0 T MRI compared to 1.5 T MRI pre-, during, and post-CRT (all P<0.001), whereas no significant differences were reported for ADC among all controls (all P>0.05). rSI showed no significant differences in all the examinations for all sequences (all P>0.05). ΔSI showed significant differences between 3.0 T and 1.5 T MRI for DWI-ΔSI in CR and NR (188.39±166.90 vs. 30.45±21.73 and 169.70±121.87 vs. 22.00±31.29, respectively, all P 0.02) and ADC-ΔSI for CR (-0.58±0.27 vs. -0.21±0.24P value 0.02), while no significant differences were observed for ADC-ΔSI in NR and both CR and NR for T2w-ΔSI. Conclusion. T2w-SI and DWI-SI showed significant differences for 3.0 T compared to 1.5 T in all three controls, while ADCSI showed no significant differences in all three controls on both field strengths. rSI was comparable for 3.0 T and 1.5 T MRI in rectal cancer patients; therefore, rectal cancer patients can be assessed both at 3.0 T MRI and 1.5 T MRI. However, a significant DWI-ΔSI and ADC-ΔSI on 3.0 T in CR might be interpreted as a better visual assessment in discriminating response to therapy compared to 1.5 T. Further investigations should be performed to confirm future possible clinical application

Predictive role of diffusion-weighted MRI in the assessment of response to total neoadjuvant therapy in locally advanced rectal cancer

Objective To investigate the predictive role of diffusion-weighted magnetic resonance imaging (DW-MRI) in the assessment of response to total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer (LARC). Methods In this single-center retrospective study, patients with LARC who underwent staging MRI and TNT were enrolled. MRI-based staging, tumor volume, and DWI-ADC values were analyzed. Patients were classified as complete responders (pCR) and non-complete responders (non-pCR), according to post-surgical outcome. Pre-treatment ADC values were compared to pathological outcome, post-treatment downstaging, and reduction of tumor volume. The diagnostic accuracy of DWI-ADC in differentiating between pCR and non-pCR groups was calculated with receiver operating characteristic (ROC) analysis. Results A total of 36 patients were evaluated (pCR, n = 20; non-pCR, n = 16). Pre-treatment ADC values were significantly different between the two groups (p = 0.034), while no association was found between pre-TNT tumor volume and pathological response. ADC values showed significant correlations with loco-regional downstaging after therapy (r = -0.537, p = 0.022), and with the reduction of tumor volume (r = -0.480, p = 0.044). ADC values were able to differentiate pCR from non-pCR patients with a sensitivity of 75% and specificity of 70%. Conclusions ADC values on pre-treatment MRI were strongly associated with the outcome in patients with LARC, both in terms of pathological response and in loco-regional downstaging after TNT, suggesting the use of DW-MRI as a potential predictive tool of response to therapy

Otx015 epi‐drug exerts antitumor effects in ovarian cancer cells by blocking gnl3‐mediated radioresistance mechanisms: Cellular, molecular and computational evidence

Ovarian cancer (OC) is the most aggressive gynecological tumor worldwide and, notwithstanding the increment in conventional treatments, many resistance mechanisms arise, this leading to cure failure and patient death. So, the use of novel adjuvant drugs able to counteract these pathways is urgently needed to improve patient overall survival. A growing interest is focused on epigenetic drugs for cancer therapy, such as Bromodomain and Extra‐Terminal motif inhibitors (BETi). Here, we investigate the antitumor effects of OTX015, a novel BETi, as a single agent or in combination with ionizing radiation (IR) in OC cellular models. OTX015 treatment significantly reduced tumor cell proliferation by triggering cell cycle arrest and apoptosis that were linked to nucleolar stress and DNA damage. OTX015 impaired migration capacity and potentiated IR effects by reducing the expression of different drivers of cancer resistance mechanisms, including GNL3 gene, whose expression was found to be significantly higher in OC biopsies than in normal ovarian tissues. Gene specific knocking down and computational network analysis confirmed the centrality of GNL3 in OTX015‐mediated OC antitumor effects. Altogether, our findings suggest OTX015 as an effective option to improve therapeutic strategies and overcome the development of resistant cancer cells in patients with OC

COVID-19 in patients with hematologic disorders undergoing therapy: perspective of a large referral hematology center in Rome

Introduction: Patients with cancer may be more susceptible to and have higher morbidity and mortality rates from COVID-19 than the general population, while epidemiologic data specifically addressed to hematologic patients are limited. To investigate whether patients with hematologic diseases undergoing therapy are at increased risk for acquiring SARS CoV-2 infection compared to the general population, a retrospective study was carried out at a referral hematologic center in Rome, Italy, during the period of the greatest epidemic spread (March 8 to May 14, 2020). Methods: All adult and pediatric patients with a diagnosis of a neoplastic or a nonneoplastic hematologic disease who underwent treatment (chemotherapy or immunosuppressive or supportive therapy) during the study period or in the previous 6 months were considered. The prevalence of COVID-19 in the overall outpatient and inpatient population undergoing hematologic treatment compared to that of the general population was analyzed. The measures taken to manage patients during the epidemic period are described. Results: Overall, 2,513 patients with hematological diseases were considered. Out of 243 (9.7%) patients who were screened for SARS CoV-2, three of 119 (2.5%) outpatients with fever or respiratory symptoms and none of 124 asymptomatic patients were diagnosed with COVID-19. Three further patients were diagnosed with COVID-19 and managed in other hospitals in Rome. As of May 14, 2020, the prevalence of COVID-19 in our hematologic population accounted for 0.24% (95% CI 0.23-0.25; 6 of 2,513 patients: 1 case in every 419 patients) as compared to 0.12% (7,280 of 5,879,082 residents; 1 case in every 807 residents) in the general population (p = 0.14). Three of 6 patients diagnosed with COVID-19 required critical care and 2 died while still positive for SARS CoV-2. Out of 225 healthcare providers on duty at our Institution during the study period, 2 (0.9%) symptomatic cases were diagnosed with COVID-19. Conclusion: In our experience, the prevalence of COVID-19 in hematologic patients, mainly affected by malignancies, was not significantly higher compared to that of the general population. Definition of adapted strategies for healthcare services, while continuing to administer the standard hematologic treatments, represents the crucial challenge for the management of hematologic diseases in the COVID-19 era

FDG uptake by prosthetic arterial grafts in large vessel vasculitis Is not specific for active disease

OBJECTIVES: This study investigated the incidence and clinical significance of arterial graft-associated uptake of fluorodeoxyglucose in large-vessel vasculitis (LVV). BACKGROUND: The role of (18)F-labeled fluorodeoxyglucose-positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) in the management of LVV remains to be defined. Although [(18)F]FDG uptake at arterial graft sites raises concerns regarding active arteritis or infection, its clinical significance in LVV has never been formally studied. METHODS: An observational prospective study sought to identify patients with Takayasu arteritis (TA) undergoing [(18)F]FDG-PET/CT more than 6 months after graft surgery from a large cohort of patients from 2 tertiary referral centers. [(18)F]FDG uptake by the graft and native arteries was scored on a scale of 0 to 3 relative to hepatic uptake, and periprosthetic maximum standardized uptake value (SUVmax) was calculated. Periprosthetic [(18)F]FDG uptake in active disease was compared with that in inactive disease, and arterial progression was assessed by prospective magnetic resonance angiography (MRA). RESULTS: Twenty-six subjects with TA were enrolled. All were afebrile with negative blood culture. Periprosthetic uptake was significant in 23 of 26 patients, and the mean SUVmax was 4.21 ± 1.46. Median periprosthetic [(18)F]FDG uptake score (3; interquartile range [IQR]: 3 to 3) was higher than in native aorta (1; IQR: 0 to 1; p < 0.001). Graft-specific [(18)F]FDG uptake was unrelated to disease activity. Despite the high frequency of graft-associated [(18)F]FDG uptake, sequential MRAs did not reveal arterial progression in 25 of 26 patients; the 1 remaining case showed minor progression limited to native arteries. Nine patients underwent repeated PET/CT scanning without showing changes in graft-specific uptake, despite increased treatment. CONCLUSIONS: Significant [(18)F]FDG uptake that is confined to arterial graft sites in patients with LVV does not reflect clinically relevant disease activity or progression. To minimize exposure to immunosuppression and in the face of negative blood culture, clinically quiescent arteritis, normal or stably raised C-reactive protein levels, we elected not to escalate treatment and monitor progression with MRA