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

New 4-(Benzotriazol-1-yl)-1,2,3-triazole derivatives

A new 4-(benzotriazol-1-yl)-1,2,3-triazole structure was obtained by the diazotization reaction of either of 1-(2-aminophenyl)-4-carboxamido-5-amino-1H-1,2,3-trizole (1c) or of the corresponding Dimroth isomer Id. It underwent some common reactions to evaluate its chemical behaviour and structure. An analogous reaction sequence was carried out from the 2-nitro-4-methylphenyl azide, to assign the structure to the nitro derivatives prepared. The structure of the new compounds prepared was confirmed by chemical and spectroscopic methods

1,2,3-Triazolodiazepine I. Preparation and Benzodiazepine Receptor Binding of 1-Benzyl and 1-Phenethyl-1,2,3-Triazolo[4,5-d][1,4]diazepines

Several new 1,2,3-triazolo[4,5-b][1,4]diazepines were prepared starting from 1-benzyl-1 and 1-phenethyl-4,5-diamino-1,2,3-triazole 2 (Scheme 1), by condensation reactions with β-diketones (Scheme 2), β-ketoesters (Scheme 3), and diethyl malonates (Scheme 4). In the first case we obtained compounds 3 and 4 with basic properties, while the ester function condensations gave cyclic amide derivatives 7, 8, 10, 12 and 13 with acid properties. Some N-methyl derivatives 11, 14 and 15 were obtained from the cyclic amide compounds. Most of compounds were tested for their ability to displace [3H]flunitrazepam from bovine brain membranes but no compound showed benzodiazepine receptor binding affinity

1,2,3-Triazole[4,5-d]pyridazines IV. Preparation and Adenosine Receptor Binding of New 4-and /or 7-Aminoderivatives

This paper reports the continuation of the studies on the 4-aminosubstituted 1,2,3-triazole[4,5-d]pyridazine derivatives which had shown binding affinity towards adenosine receptors. Biological results confirmed the greater activity of a benzyl substituent in the 1 position and the receptorial stereoselectivity related to the higher and more selective A1 affinity of the 4-D(+)-α-methylbenzylamino enantiomer 1b. The 4-phenylhydrazino substituent has shown an interesting binding activity about equipotent towards A1 and A2 receptorial sites. A surprisingly elevated A1 affinity (Ki = 7 nM), 440 fold higher than A2 affinity, is presented by compound 1d, bearing a m-toluidino substituent

1,2,3-Triazolo[1,5-a][1,3]benzodiazepine a new heterocyclic system: Synthesis, benzodiazepine receptor binding and theoretical calculations

This paper reports the synthesis of 1,2,3-triazolo[1,5-a][1,3] benzodiazepines, which represent a new heterocyclic system obtained by 1,3-dipolar cycloaddition reaction of ethyl 2-azidophenylacetate to methylenic compounds activated by a cyano group. The new derivatives were submitted to benzodiazepine receptor binding assays; only the 3-carboethoxy derivative 3c showed moderate receptorial affinity. However, on the basis of biological results, theoretical calculations were made, which suggested useful structural modifications

1,2,3-triazolo[1.5-a]quinazolines: synthesis, benzodiazepine receptor binding and theoretical calculations

This paper reports the synthesis of 3-substituted-1,2,3-triazolo[1,5-a]quinazolin-5-ones prepared by 1,3-dipolar cycloaddition reaction of 2-azidobenzoic acid to methylenic compounds activated by a cyano group. The new derivatives were submitted to benzodiazepine receptor binding assays: the results indicated an interesting receptorial affinity of the 1,2,3-triazolo[1,5-a]quinazoline ring. On the basis of the biological results, theoretical calculations were performed, which suggested useful structural modifications

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