Synthesis and automated fluorine-18 radiolabeling of new PSMA-617 derivatives with a CuAAC radiosynthetic approach

In the last decade, the development of new radiopharmaceuticals for the imaging and therapy of prostate cancer has been a highly active and important area of research, especially focusing on the prostate-specific membrane antigen (PSMA), an antigen which is upregulated in prostate, as well as in other tumor cells. A large variety of PSMA ligands have been radiolabeled, to date. Among the various derivatives, PSMA-617 resulted to be one of the most interesting in terms of interaction with the antigen and clinical properties, and its lutetium-177 labeled version has recently been approved by regulatory agencies for therapeutic purposes. For this reasons, the radiolabeling with fluorine-18 of a PSMA-617 derivative might be of interest. Beside other methodologies to radiolabel macromolecules with fluorine-18, the “click-chemistry” approach resulted to be very useful, and the copper-catalyzed azide-alkyne cycloaddition (CuAAC) is considered one of most efficient and reliable. This paper proposes the synthesis of a suitable precursor for the radiolabeling with fluorine-18 of a new PSMA-617 derivative. The whole radiosynthetic procedure has been fully automated, and the final product, which proved to be stable in plasma, has been obtained with radiochemical yield and purity suitable for subsequent preclinical studies.     

Therapeutic strategies for gastroenteropancreatic neuroendocrine neoplasms: State-of-the-art and future perspectives

Although gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have always been considered rare tumors, their incidence has risen over the past few decades. They represent a highly heterogeneous group of neoplasms with several prognostic factors, including disease stage, proliferative index (Ki67), and tumor differentiation. Most of these neoplasms express somatostatin receptors on the cell surface, a feature that has important implications in terms of prognosis, diagnosis, and therapy. Although International Guidelines propose algorithms aimed at guiding therapeutic strategies, GEP-NEN patients are still very different from one another, and the need for personalized treatment continues to increase. Radical surgery is always the best option when feasible; however, up to 80% of cases are metastatic upon diagnosis. Regarding medical treatments, as GEP-NENs are characterized by relatively long overall survival, multiple therapy lines are adopted during the lifetime of these patients, but the optimum sequence to be followed has never been clearly defined. Furthermore, although new molecular markers aimed at predicting the response to therapy, as well as prognostic scores, are currently being studied, their application is still far from being part of daily clinical practice. As they represent a complex disease, with therapeutic protocols that are not completely standardized, GEP-NENs require a multidisciplinary approach. This review will provide an overview of the available therapeutic options for GEP-NENs and attempts to clarify the possible approaches for the management of these patients and to discuss future perspectives in this field.     

Effect of the NSAID flurbiprofen on remodelling after periodontal surgery

The aim of the present experiment was to assess the effect of the administration of the NSAID flurbiprofen (Froben®) on tissue healing after periodontal surgery. Sites from patients with the same treatment modality (modified Widman flap) but receiving a placebo drug and sites within each patient not exposed to surgery served as controls. Nineteen patients suffering from moderate to severe periodontal disease were recruited and they signed informed consent forms. These patients required periodontal surgery as assessed at the periodontal re-evaluation. The sites chosen for the study were all diagnosed with PPD ≥ 5 mm and were bleeding on probing. During the healing phase 10 patients received 50 mg Froben® 3 times per day for 30 d whereas 9 patients received a placebo drug. Two sites with PPD ≥ 5 mm after initial therapy and bleeding on probing served as surgical sites, whereas 2 similar sites were not exposed to surgery. The study design was set up double-blind. The radiographic examination consisted of 2–4 standardized vertical bitewings obtained at the periodontal re-evaluation (BL) at 1, 3 and 6 months post-surgically for digital subtraction and computer assisted densitometric image analysis (CADIA). The regions of interest analysed were mesial or distal crestal sites. Minimal remodelling activity was observed radiographically after periodontal surgery in both patient groups. There were no statistically significant differences between the four groups of sites regarding the mean changes in density when analysing the pairs of radiographs 0–1, 0–3, 0–6 months. A frequency analysis was performed to list the number of sites with different ranges of density change. No differences in the distributions of the numbers of sites were observed when comparing the 4 site groups (Kolmogorov-Smirnov, p > 0.05). A significant reduction of the probing pocket depth and a significant amount of clinical attachment gain was noted at the surgically treated sites irrespective of whether the patients had used flurbiprofen or placebo. Whereas the pathways leading to bone resorption in periodontally diseased sites have been shown, in other studies, to be influenced by NSAID, the results of the present study could not justify general administration of Froben® for the purpose of reduction of bone resorption after periodontal surgical procedures in patients with adult periodontitis.     

Prognostic role of sarcopenia in metastatic colorectal cancer patients during first-line chemotherapy: A retrospective study

BACKGROUNDSarcopenia is a condition characterized by decreased skeletal muscle mass due to physiological ageing or to a concomitant disease such as neoplasia. In cancer patients, a low lean body mass is suggested to be a negative prognostic factor for survival and for the development of dose-limiting chemotherapy toxicities irrespective of disease stage. AIMTo evaluate the prognostic role of sarcopenia in patients with metastatic colorectal cancer (mCRC) undergoing first-line chemotherapy.METHODSOur retrospective analysis included 56 mCRC patients who received first-line chemotherapy from 2014 to 2017 at the Medical Oncology Unit of our hospital. Computerized scans were performed before starting chemotherapy and at the first disease reassessment. Sarcopenia was assessed using the skeletal mass index = muscle area in cm²/(height in m²) calculated at the L3 vertebra. Overall survival and objective response rate were evaluated. Toxicities were analyzed during the first four cycles of therapy and graded according to Common Terminology Criteria for Adverse Events version 4.0. A loss of skeletal muscle mass ≥ 5% was considered indicative of deterioration in muscle condition.RESULTSMedian age was 67 years and 35.7% of patients were ≥ 70 years old. Fourteen patients (25%) were sarcopenic at baseline computed tomography (CT) scan (7/33 men; 7/23 women); 5/14 sarcopenic patients were ≥ 70 years old. Median follow-up was 26.8 mo (3.8-66.8 mo) and median overall survival was 27.2 mo (95%CI: 23.3-37.3). Sarcopenia was not correlated to overall survival (P = 0.362), to higher toxicities reported during the first 4 cycles of chemotherapy (P = 1.0) or to response to treatment (P = 0.221). At the first disease reassessment, a skeletal muscle loss (SML) ≥ 5% was found in 17 patients (30.3%) 3 of whom were already sarcopenic at baseline CT scan, while 7 patients became sarcopenic. SML was not correlated to overall survival (P = 0.961). No statistically significant correlation was found between baseline sarcopenia and age (P = 1.0), body mass index (P = 0.728), stage at diagnosis (P = 0.355) or neutrophil/lymphocyte ratio (P = 0.751).CONCLUSIONNeither baseline sarcopenia nor SML affected survival. In addition, baseline sarcopenia was not related to worse treatment toxicity. However, these results must be interpreted with caution due to the limited sample size.     

Role of concomitant therapy for Helicobacter pylori eradication: A technical note

We read with interest the recent meta-analysis by Lin et al who evaluated the effectiveness of concomitant regimen for Helicobacter pylori (H. pylori) in Chinese regions. They found that 7-d concomitant regimen is undoubtedly superior to 7-d triple therapy (91.2% vs 77.9%, P < 0.0001). However, it is a common belief that a triple therapy lasting 7 d should be definitively removed from the clinical practice for its ineffectiveness. Only its prolongation to 14 d may give satisfactory success rate. Thus, the assessment of an old and outdated treatment versus a more recent and successful one does not seem to bring novel and useful information. Moreover, a 7-d duration has not been ascertained for concomitant regimen, as main guidelines recommend a 10-d schedule for this scheme. Therefore, only studies comparing 10-d concomitant versus 14-d triple seem to be appropriate according to current Guidelines and would clarify which regimen is the most suitable worldwide. Additionally, in this meta-analysis concomitant and sequential therapy showed similar performances, despite it is common opinion that sequential is more prone than concomitant therapy to fail when metronidazole resistance occurs, and China is characterized by high rate of resistance to this antibiotic. None of the included studies evaluated a priori antibiotic resistances, and the lack of this detail hampers the unveiling of this apparent contradiction. In conclusion, the lack of the evaluation of the quality of included trials as well as their high heterogeneity constitute a burdensome limit to draw solid conclusions in this meta-analysis. On the bases of these considerations and the low number of examined trials, we believe that further studies and the knowledge of antibiotic resistances will support with high quality evidence which is the best regimen and its optimal duration.