Toxicity after moderately hypofractionated versus conventionally fractionated prostate radiotherapy: A systematic review and meta-analysis of the current literature

Background: Moderately hypofractionated radiotherapy (RT) currently represents the standard RT approach for all prostate cancer (PCa) risk categories. We performed a systematic review and meta-analysis of available literature, focusing on acute and late genitourinary (GU) and gastrointestinal (GI) adverse events (AEs) of moderate hypofractionation for localized PCa. Materials and methods: Literature search was performed and two independent reviewers selected the records according to the following Population (P) Intervention (I) Comparator (C) and Outcomes (O) (PICO) question: “In patients affected by localized PCa (P), moderately hypofractionated RT (defined as a treatment schedule providing a single dose per fraction of 3–4.5 Gy) (I) can be considered equivalent to conventionally fractionated RT (C) in terms of G > 2 GI and GU acute and late adverse events (O)?”. Bias assessment was performed using Cochrane Cochrane Collaboration's Tool for Assessing Risk of Bias. Results: Thirteen records were identified and a meta-analysis was performed. Risk of acute GI and GU > 2 adverse events in the moderately hypofractionated arm was increased by 9.8 % (95 %CI 4.8 %–14.7 %; I2 = 57 %) and 1.5 % (95 % CI -1.5 %-4.4 %; I2 = 0%), respectively. Discussion: Overall, majority of trials included in our meta-analysis suggested that moderately hypofractionated RT is equivalent, in terms of GI and GU adverse events, to conventional fractionation. Pooled analysis showed a trend to increased GI toxicity after hypofractionated treatment, but this might be related to dose escalation rather than hypofractionation

Dexketoprofen/tramadol: randomised double-blind trial and confirmation of empirical theory of combination analgesics in acute pain

Background: Combination analgesics are effective in acute pain, and a theoretical framework predicts efficacy for combinations. The combination of dexketoprofen and tramadol is untested, but predicted to be highly effective. Methods: This was a randomised, double-blind, double-dummy, parallel-group, placebo-controlled, single-dose trial in patients with moderate or severe pain following third molar extraction. There were ten treatment arms, including dexketoprofen trometamol (12.5 mg and 25 mg) and tramadol hydrochloride (37.5 mg and 75 mg), given as four different fixed combinations and single components, with ibuprofen 400 mg as active control as well as a placebo control. The study objective was to evaluate the superior analgesic efficacy and safety of each combination and each single agent versus placebo. The primary outcome was the proportion of patients with at least 50 % max TOTPAR over six hours. Results: 606 patients were randomised and provided at least one post-dose assessment. All combinations were significantly better than placebo. The highest percentage of responders (72 %) was achieved in the dexketoprofen trometamol 25 mg plus tramadol hydrochloride 75 mg group (NNT 1.6, 95 % confidence interval 1.3 to 2.1). Addition of tramadol to dexketoprofen resulted in greater peak pain relief and greater pain relief over the longer term, particularly at times longer than six hours (median duration of 8.1 h). Adverse events were unremarkable. Conclusions: Dexketoprofen trometamol 25 mg combined with tramadol hydrochloride 75 mg provided good analgesia with rapid onset and long duration in a model of moderate to severe pain. The results of the dose finding study are consistent with pre-trial calculations based on empirical formulae

PROTON THERAPY RE-IRRADIATION OF RECURRENT HIGH-GRADE GLIOMAS: ANALYSIS OF RADIATION-INDUCED EDEMA

Aims: During and after re-irradiation of relapsed high-grade gliomas (rHGG) variation of edema (ED) is a common event and may translate into neurological symptoms, clinical deterioration and steroid use modi- fication. In magnetic resonance imaging (MRI), ED is usually evaluated with T2 or fluid-attenuated inversion recovery (FLAIR) sequences. Aim of the study was to report a quantitative analysis of radiation-induced ED during and after proton therapy (PT) re-irradiation of rHGG.ty-one patients (pts) with rHGG were re-irradiated with PT at our institution. 22 pts underwent MRI early before, during, at the end as well as 1 month after the treatment and were included in the analysis. All pts received 36 GyRBE in 18 fractions. ED was evaluated and contoured on 88 MRI scans using T2 and FLAIR sequences (5 mm thickness). ED volume (in cc) was Gross Tumor Volume. We analyzed the temporal change of ED.Results: Eighteen pts were treated for recurrent glioblastoma and 4 for anaplastic gliomas. Median (Med) CTV was 78,48 cc (range, 12-259 cc). Med ED volume at the baseline, mid-therapy, at the end, and 1 month after treatment was 63 cc (range, 7-265), 83 (range, 9-242), 85 (range 10-194), 69 (range 9-200), respectively. During treatment ED increased in 16 pts (72%) and decreased in 6 (27%). Such increase of ED volume was associated with mild symptoms only in 8 pts (50%) and was controlled with modification of steroids dose. One month after treatment ED decreased in 10 pts (45%), increased in 7 (32%) and was stable in 5 (23%). Six out of 7 pts (86%) with increased ED needed modification of steroids dose. During follow up 2 pts (9%) developed radionecrosis (RN - diagnosed at imaging) with mild symptoms controlled with steroids. In pts who presented RN, ED volume increased of 130% during treatment. In pts who registered increased ED without RN, the mean ED volume increase during the treatment was of 82%. Pts who presented RN had a mean CTV volume of 67.39 cc. ciated with increase of ED volume during treat- ment. Such variation often does not need modification of steroid use. ED volume seems to decrease after the end of the treatment. ED volume during treatment sig- nificantly increase in pts who experience RN after re- irradiation and could predict the development of RN. CTV volume does not seems to predict the development of RN

Synthesis, biological activity and molecular modelling of new trisubstituted 8-azaadenines with high affinity for A(1) adenosine receptors

We describe here the synthesis and biological activity of new 8-azaadenines bearing both a phenyl group on C(2) and a 9-benzyl group substituted in the ortho position with a Cl or a F atom or a CF3 group, to verify the synergistic effect of a combination of these substitution patterns on binding with the A1 adenosine receptors. In position N6 aliphatic and cycloaliphatic substituents were chosen which had been shown to bind well with the A1 receptors. Because of the high lipophilicity of these kinds of molecules, we also introduced a hydroxyalkyl substituent in the same position. The compounds obtained generally showed a very good affinity and selectivity for A1 receptors. Some of the compounds showed Ki in the nanomolar range, one even in the subnanomolar range (0.6 nM). Molecular docking calculations were performed in order to evaluate the interaction energies between the bovine A1 receptor model and the selected ligands, and then to correlate these energies with biological activities of the ligands as obtained from the experiments. Molecular docking analysis suggests different binding modes towards A1 receptors that are plausible for these ligands

Consolidative active scanning proton therapy for mediastinal lymphoma: selection criteria, treatment implementation and clinical feasibility

aims proton therapy (PT) represents an advanced form of radiotherapy with unique physical properties which could be of great advantage in reducing long-term radiation morbidity for cancer survivors. here, we aim to describe the whole process leading to the clinical implementation of consolidative active scanning proton therapy treatment (PT) for mediastinal lymphoma. methods the process included administrative, technical and clinical issues. authorization of PT is required in all cases as mediastinal lymphoma is currently not on the list of diseases reimbursable by the Italian national health service. technically, active scanning PT treatment for mediastinal lymphoma is complex, due to the interaction between actively scanned protons and the usually irregular and large volumes to be irradiated, the nearby healthy tissues and the target motion caused by breathing. a road map to implement the technical procedures was prepared. the clinical selection of patients was of utmost importance and took into account both patient and tumor characteristics. results the first mediastinal lymphoma was treated at our PT center in 2018, four years after the start of the clinical activities. The treatment technique implementation included mechanical deep inspiration breath-hold simulation computed tomography (CT), clinical target volume (CTV)-based multifield optimization planning and plan robustness analysis. the ultimate authorization rate was 93%. In 4 cases a proton-photon plan comparison was required. between may 2018 and february, 2021, 14 patients were treated with consolidative PT. The main clinical reasons for choosing PT over photons was a bulky disease in 8 patients (57%), patient's age in 11 patients (78%) and the proximity of the lymphoma to cardiac structures in 10 patients (71%). With a median follow-up of 15 months (range, 1-33 months) all patients but one (out-of-field relapse) are without evidence of disease, all are alive and no late toxicities were observed during the follow-up period. conclusions the clinical implementation of consolidative active scanning PT for mediastinal lymphoma required specific technical procedures and a prolonged experience with PT treatments. an accurate selection of patients for which PT could be of advantage in comparison with photons is mandatory