One-Step Photochemical Green Synthesis of Water-Dispersible Ag, Au, and Au@Ag Core-Shell Nanoparticles.

A simple and green synthetic protocol for the rapid and effective preparation of Ag, Au and Au@Ag core-shell nanoparticles (NPs) is reported based on the light irradiation of a biocompatible, water-soluble dextran functionalized with benzophenone (BP) in the presence of AgNO3 , HAuCl4 , or both. Photoactivation of the BP moiety produces the highly reducing ketyl radicals through fast (<50 ns) intramolecular H-abstraction from the dextran scaffold, which, in turn, ensures excellent dispersibility of the obtained metal NPs in water. The antibacterial activity of the AgNPs and the photothermal action of the Au@Ag core-shell are also shown.

Stereotactic Ablative Radiotherapy Combined with Immune Checkpoint Inhibitors Reboots the Immune Response Assisted by Immunotherapy in Metastatic Lung Cancer: A Systematic Review.

Background: Immune checkpoint inhibitors (ICI) have represented a revolution in the treatment of non-small-cell lung cancer (NSCLC). To improve these results, combined approaches are being tested. The addition of stereotactic ablative radiotherapy (SABR) to ICI seems promising. A systematic review was performed in order to assess the safety and efficacy of SABR-ICI combination. Material and Methods: MEDLINE databases from 2009 to March 3, 2019 were reviewed to obtain English language studies reporting clinical outcomes of the combination of ICI-SABR in NSCLC. 18 out of the 429 initial results fulfilled the inclusion criteria and were selected for review. Results: Eighteen articles, including six prospective studies, describing 1736 patients treated with an ICI-SABR combination fulfilled the selection criteria. The reported mean rates for local control and distant/abscopal response rates were 71% and 41%, respectively. Eleven studies reported progression-free survival and overall survival, with a mean of 4.6 and 12.4 months, respectively. Toxicity rates were consistent with the ones attributable to ICI treatment alone. Conclusions: The ICI-SABR combination has a good safety profile and achieves high rates of local control and greater chances of obtaining abscopal responses than SABR alone, with a relevant impact on PFS. More studies are needed to improve patient selection for an optimal benefit from this approach.

Volumetric Modulated Arc Therapy (VMAT) make a difference in retro-orbital irradiation treatment of patients with bilateral Graves' ophthalmopathy. Comparative analysis of dosimetric parameters from different radiation techniques.

BACKGROUND: Graves' ophthalmopathy is the commonest extrathyroidal manifestation of Graves' disease. Treatment options include steroid therapy, corrective/decompressive surgery, radiation therapy or combination of these approaches. AIM: Our purpose was to investigate if retro-orbital irradiation with Volumetric Modulated Arc Therapy (VMAT) yielded better target coverage and dose sparing to adjacent normal structures compared to 3-Dimensional Conformal Radiotherapy (3DCRT) and Lateral Opposing Conformed Fields (LOCF). METHODS: Fourteen consecutive patients diagnosed with bilateral Graves' ophthalmopathy were prospectively recruited into this study from August 2012 until August 2014. An individual VMAT, 3DCRT and LOF plan was created for each patient. Conformity Index (CI), Homogeneity Index (HI) and other dosimetric parameters of the targets and organs-at-risk (OAR) were analyzed in all 28 orbits compared between the different techniques. RESULTS: CI generated by VMAT was superior to that produced by 3DCRT(p < .001) and LOF (p < .001). As expected, 3DCRT was also superior to LOF (p = .007). Regarding the OARs sparing dose (lens, globes, retina and lacrimal glands), VMAT showed a significant benefit when compared with 3DCRT and LOCF, with no differences between the two latter techniques. CONCLUSIONS: VMAT should be preferred over 3DCRT and LOF for bilateral Graves' ophthalmopathy treatment.

Improved and Highly Reproducible Synthesis of Methacrylated Hyaluronic Acid with Tailored Degrees of Substitution.

Methacrylated hyaluronic acid (HAMA) is a versatile material that has gained significant attention in various pharmaceutical and biomedical applications. This biocompatible material can be photo-cross-linked in the presence of Irgacure 2959 (I2959) to produce hydrogels. Controlling the degree of methacrylation (DM) is crucial since it plays a pivotal role in determining the properties and thus the potential applications of the gels. We report herein a new green approach for the highly controlled and tailored modification of hyaluronic acid (HA) with methacrylic anhydride (MA). The reaction conditions of previously reported procedures were optimized, leading to a decreased reaction time (3 h instead of 24 h) and consumption of fewer equivalents of MA (5 equiv instead of 20) and water as the sole solvent. By changing the amount of base added, HAMA with three different DMs was obtained: 19, 35, and 60%. The influence of the molecular weight of HA, degree of substitution, and concentration of the HAMA solution prior to photo-cross-linking on the rheological, swelling, and degradation properties of HAMA hydrogels was also studied in this work.

Ten-Year Results of Accelerated Partial-Breast Irradiation with Interstitial Multicatheter Brachytherapy after Breast-Conserving Surgery for Low-Risk Early Breast Cancer.

Patients with an early carcinoma of the breast are commonly treated by breast-conserving surgery (BCS) and postoperative radiotherapy. Partial-breast irradiation has gained acceptance in the last few years. Between December 2008 and December 2017, 182 low-risk breast cancer patients treated by BCS in the four university hospitals of the province of Las Palmas and treated with APBI using interstitial multicatheter brachytherapy were included in this study. After a mean follow-up for survivors of 10 years, the treatment was shown to be safe, as no severe acute/late toxicity (grade ≥ 3) was observed. The 10-year IBTR was 1.7% (95%CI: 0.7-2.7%), and the cause-specific survival was 94.9% (95%CI: 93.2-96.6%). We suggest that multicatheter brachytherapy after BCS is safe and effective in early breast cancer patients.

Promises of anionic calix[n]arenes in life science: State of the art in 2023.

Because they hold together molecules by means of non-covalent interactions - relatively weak and thus, potentially reversible - the anionic calixarenes have become an interesting tool for efficiently binding a large range of ligands - from gases to large organic molecules. Being highly water soluble and conveniently biocompatible, they showed growing interest for many interdisciplinary fields, particularly in biology and medicine. Thanks to their intrinsic conical shape, they provide suitable platforms, from vesicles to bilayers. This is a valuable characteristic, as so they mimic the biologically functional architectures. The anionic calixarenes propose efficient alternatives for overcoming the limitations linked to drug delivery and bioavailability, as well as drug resistance along with limiting the undesirable side effects. Moreover, the dynamic non-covalent binding with the drugs enables predictable and on demand drug release, controlled by the stimuli present in the targeted environment. This particular feature instigated the use of these versatile, stimuli-responsive compounds for sensing biomarkers of diverse pathologies. The present review describes the recent achievements of the anionic calixarenes in the field of life science, from drug carriers to biomedical engineering, with a particular outlook on their applications for the diagnosis and treatment of different pathologies.

High-throughput genotyping system as a robust and useful tool in oncology: experience from a single institution.

BACKGROUND AND AIM: Single nucleotide polymorphisms (SNPs) are substitutions of one base for another in the gene sequence and conforms the basis for pharmacogenetics and the development of personalized medicine. Many methods have been developed for SNP genotyping. The aim of the present study was to validate the use of a novel high-throughput genotyping system. METHODS: Five SNPs (rs25487, rs25489, rs1799782, rs13181, and rs11615) were genotyped in 118 cancer patients using the classical method PCR restriction fragment length polymorphism (RFLP) and the high-throughput, automated assay Biotrove OpenArray(®) NT Cycler, trying to explore the feasibility and reproducibility of the OpenArray system in the context of oncology. RESULTS: The call rates obtained ranged from 95.7 to 100% for both techniques. The percentage of overlapping ranged from 96.2 to 100% among both assays, showing a high reproducibility between the techniques. CONCLUSION: These findings, together with the low-cost and the simple and fast work flow, suggest that the OpenArray system is a robust and easy methodology for genotyping in the field of oncology.

Combination of SABR With Anti-PD-1 in Oligoprogressive Non-Small Cell Lung Cancer and Melanoma: Results of a Prospective Multicenter Observational Study.

PURPOSE: The percentage of patients with metastatic non-small cell lung cancer (NSCLC) and melanoma who benefit from anti-programmed cell death protein 1 (anti-PD-1) is low owing to resistance mechanisms. SABR has a role in oligoprogressive disease and can improve responses to anti-PD-1. This multicenter prospective observational study aimed to determine whether concomitant anti-PD-1 and SABR to oligoprogressive sites enhance tumor response in metastatic NSCLC and melanoma. METHODS AND MATERIALS: Patients with metastatic NSCLC or melanoma in progression to anti-PD-1 but continuing the same line owing to clinical benefit were referred for palliative SABR. All patients received concomitant pembrolizumab or nivolumab and SABR to 1 to 5 lesions, maintaining anti-PD-1 until further progression, unacceptable toxicity, or medical/patient decision. Objective response rate-complete responses and partial responses-was evaluated during all follow-up according to Response Evaluation Criteria in Solid Tumors 1.1. The abscopal response was evaluated 8 weeks after SABR as a ≥30% reduction in 1 to 2 predefined nonirradiated lesions. RESULTS: Of the 61 patients enrolled, 50 could be analyzed. With a median follow-up of 32.8 months, objective response rate was 42% (30% complete responses and 12% partial responses). Median progression-free survival was 14.2 months (95% confidence interval, 6.9-29 months). Median overall survival since SABR was 37.4 months (95% confidence interval, 22.9 months-not reached). Abscopal response was 65%, evaluated in 40 patients who fulfilled the criteria. CONCLUSIONS: Combined anti-PD-1 and SABR in oligoprogressive metastatic NSCLC or melanoma can achieve high rates of response and extend the clinical benefit of immunotherapy by delaying further progression and a new systemic therapy. This approach should be assessed in larger randomized trials.

BCL-2, in combination with MVP and IGF-1R expression, improves prediction of clinical outcome in complete response cervical carcinoma patients treated by radiochemotherapy.

OBJECTIVES: To investigate whether BCL-2 expression would improve MVP/IGF-1R prediction of clinical outcome in cervix carcinoma patients treated by radiochemotherapy, and suggest possible mechanisms behind this effect. METHODS: Fifty consecutive patients, who achieved complete response to treatment, from a whole series of 60 cases suffering from non-metastatic localized cervical carcinoma, were prospectively included in this study from July 1999 to December 2003. Follow-up was closed in January 2011. All patients received pelvic radiation (45-64.80 Gy in 1.8-2 Gy fractions) with concomitant cisplatin at 40 mg/m2/week doses followed by brachytherapy. Oncoprotein expression was studied by immunohistochemistry in paraffin-embedded tumour tissue. RESULTS: No relation was found between BCL-2 and clinicopathological variables. High MVP/IGF-1R/BCL-2 tumour expression was strongly related to poor local and regional disease-free survival (P<0.0001), distant disease-free survival (P=0.010), disease-free survival (P<0.0001), and cause-specific survival (P<0.0001). NHEJ repair protein Ku70/80 expression was significantly repressed in tumours overexpressing all three oncoproteins (P=0.047). No differences were observed in proliferation (Ki67 expression) or P53 alteration. CONCLUSIONS: BCL-2, MVP, and IGF-1R overexpression were related to poorer clinical outcome in cervical cancer patients who achieved clinical complete response to radiochemotherapy. The NHEJ repair protein Ku70/80 expression could be involved in the regulation of these oncoproteins.

Pretreatment inflammatory indices predict Bevacizumab response in recurrent Glioma.

Aim: It remains unclear what the best therapeutic option for recurrent glioma patients after Stupp treatment is. Bevacizumab (BVZ) is commonly administered in progression, but it appears that only some patients benefit. It would be useful to find biomarkers that determine beforehand who these patients are. Methods: The protocol included 31 high-risk progressing glioma patients after Stupp treatment who received BVZ 5-10 mg/kg every 14 days and temozolomide (3-19 cycles, 150-200 mg five days each 28-day cycle) during a mean of eight cycles of BVZ or until tumor progression or unacceptable toxicity. We analyzed the clinical outcome values of inflammatory indices measured before BVZ administration. Results: Lymphocyte level before BVZ administration was the best independent predictor of overall survival (HR = 0.34; 95%CI: 0.145-0.81; P = 0.015). The area under the receiver operating characteristic (ROC) curve was 0.823, with 1.645 being the optimal cut-off value, and 0.80 and 0.85 the sensitivity and specificity values, respectively. Responder and non-responder survival curves were also significantly different, considering the first and second tertiles as cut-off points. The number of BVZ cycles was not related to lymphopenia. Pretreatment neutrophil, platelet levels, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) did not have independent predictive value. Inflammatory variables were not correlated with each other. However, patients with high NLR and PLR simultaneously (double positive PLR-NLR) showed a worse clinical outcome than the rest (P = 0.043). Conclusion: Pretreatment lymphocyte levels and double positive PLR-NLR could be used as non-invasive hematological prognostic markers for recurrent gliomas treated with bevacizumab. A close relationship emerged between inflammation and angiogenesis.

Stereotactic ablative radiotherapy for oligometastatic breast cancer in elderly patients.

Breast cancer (BC) is the principal cause of cancer-related death in women. Metastatic patients are usually treated with a systemic therapy, but clinical results are limited. Oligometastatic subjects can benefit from high-precision radiotherapy techniques to potentially achieve a complete response. Currently, there is limited evidence of stereotactic ablative radiotherapy (SABR) treatments in elderly oligometastatic cancer patients. A review of the medical literature was performed in PubMed database to assess the current role of SABR in the treatment of breast oligometastases in elderly patients. SABR represents a feasible and safe therapeutic approach in oligometastatic elderly BC patients. Further studies are required to establish the optimum patient selection and treatment scheme.

Accelerated partial breast irradiation with interstitial multicatheter brachytherapy after breast-conserving surgery for low-risk early breast cancer.

Patients with low-risk invasive ductal carcinoma treated with breast-conserving surgery (BCS) were included in a multicatheter brachytherapy APBI protocol. The primary endpoint was ipsilateral breast recurrence. Between December 2008-December 2017, 186 low-risk breast cancer patients were treated with APBI using interstitial multicatheter brachytherapy and followed prospectively. At 5-years of follow-up, cumulative local recurrence (LR) and cause-specific survival was 1.1% (95% CI 0.3-1.9) and 98.3% (95% CI 97.3-99.3%) respectively. No grade 3 adverse effects were observed. Postoperative APBI using multicatheter brachytherapy after BCS in early breast cancer patients have excellent rates of local control and survival, without significant toxicity.

Modification of glucose metabolism in radiation-induced brain injury areas using cervical spinal cord stimulation.

PURPOSE: Radiation-induced brain injury (RBI) is an insidious side-effect of radiotherapy mediated by vascular alterations, inflammation and ischaemia. In previous studies we had shown potential increases in loco-regional blood flow and glucose metabolism in brain tumours by using electrical cervical spinal cord stimulation (SCS). In this preliminary report we demonstrate the effect of cervical SCS on RBI-tissue metabolism, as assessed using [(18)F]fluorodeoxyglucose-positron emission tomography (FDG-PET). METHODS: SCS devices were inserted in eight patients with diagnosis of potential RBI in previously irradiated areas. While the SCS device was deactivated, each patient underwent an initial FDG-PET study to evaluate the clinical status. A second FDG-PET study was performed later the same day while the SCS device was activated in order to evaluate the effect of cervical SCS on glucose metabolism. RESULTS: Basal glucose metabolism in RBI areas was 31% lower than peri-RBI areas (p = 0.009) and 32% lower than healthy contra-lateral areas (p = 0.020). There was a significant increase in glucose uptake during SCS in both the RBI (p = 0.005) and the peri-RBI (p = 0.004) areas, with measured increases of 38 and 42%, respectively. The estimated potential maximal residual activity of the first FDG dose's contribution to the activity on the second scan was

Hypoxia downregulates Ku70/80 expression in cervical carcinoma tumors.

Hypoxia may inhibits the NHEJ DNA repair through downregulating Ku70/80 expression and combined with an increased angiogenesis and altered p53 expression would be responsible for tumor progression in cervical carcinoma.

MVP expression is related to IGF1-R in cervical carcinoma patients treated by radiochemotherapy.

OBJECTIVE: To assess the expression of MVP in cervix carcinoma patients treated by radiochemotherapy, its relation to clinical and pathologic prognostic factors and its role in predicting clinical outcome. In addition the relation to IGF-1R expression in this cohort of patients will be explored. MATERIALS AND METHODS: Sixty consecutive patients suffering from localized cervix carcinoma were prospectively included in this study from July 1999 to December 2003. Follow-up was closed in November 2007. Patients were staged following the TNM classification. All patients received pelvic radiation (45-64.80 Gy in 1.8-2 Gy fractions) followed brachytherapy and concomitant cisplatin at 40 mg/m(2)/week doses. MVP expression was studied by immunohistochemistry in paraffin-embedded tumour tissue. RESULTS: MVP was expressed in 58 patients (96.7%) and no relation was found with clinicopathological variables. High MVP expression was related to high IGF1-R expression (p=0.023). Complete response after treatment was observed in 50 patients (83.3%). Clinical stage of the disease and clinical response to radiochemotherapy were the most important prognostic factors related to survival. High MVP and IGF-1R tumour expression was strongly related to poor local and regional disease-free survival (p=0.006), distant disease-free survival (p=0.050), disease-free survival (p=0.006), and cause-specific survival (p=0.007) in patients achieving a complete response. CONCLUSION: MVP and IGF-1R expression were related in clinical cervical tumours and confer reduced long-term local control in patients who achieved clinical complete response to radiochemotherapy.

GEORCC recommendations on target volumes in radiotherapy for Head Neck Cancer of Unkown Primary.

Head Neck Cancer of Unknown Primary (HNCUP) is a rare condition, representing approximately 5-10% of all head neck cancers. Radiotherapy, adjuvant or radical, is usually employed in the treatment of those patients. To date, no specific guidelines for the optimal definition of the target volume to be irradiated have been published. In recent years, there have been advances in the knowledge of the molecular biology of HNCUP, its diagnostic imaging and the implementation of sophisticated radiotherapy techniques with enhanced precision in target localization and treatment delivery. These progresses have provided valuable information about the natural history of HNCUP that will allow for establishment of the best treatment for each patient, including standardized, consistent and reproducible target volumes definitions. Several recommendations regarding how to choose volumes when contouring HNCUP in clinical practice are reported, in order to achieve a high rate of loco-regional control while avoiding unnecessary toxicity.

Radiation-induced DNA damage as a predictor of long-term toxicity in locally advanced breast cancer patients treated with high-dose hyperfractionated radical radiotherapy.

This 14-year-long study makes a novel contribution to the debate on the relationship between the in vitro radiosensitivity of peripheral blood lymphocytes and normal tissue reactions after radiation therapy. The aims were (1) to prospectively assess the degree and time of onset of skin side effects in 40 prospectively recruited consecutive patients with locally advanced breast cancer treated with a hyperfractionated dose-escalation radiotherapy schedule and (2) to assess whether initial radiation-induced DNA damage in peripheral blood lymphocytes of these patients could be used to determine their likelihood of suffering severe late damage to normal tissue. Initial radiation-induced DNA double-strand breaks (DSBs) were assessed in peripheral blood lymphocytes of these patients by pulsed-field electrophoresis. Acute and late cutaneous and subcutaneous toxicity was evaluated using the Radiation Therapy Oncology Group morbidity score. A wide interindividual variation was observed in toxicity grades and in radiation-induced DNA DSBs in peripheral blood lymphocytes (mean 1.61 +/- 0.76 DSBs/Gy per 200 MBp, range 0.63- 4.08), which were not correlated. Multivariate analysis showed a correlation (P < 0.008) between late toxicity and higher prescribed protocol dose (81.6 Gy). Analysis of the 29 patients referred to 81.6 Gy revealed significantly (P < 0.031) more frequent late subcutaneous toxicity in those with intrinsic sensitivity to radiation-induced DNA DSBs of >1.69 DSBs/Gy per DNA unit. Our demonstration of a relationship between the sensitivity of in vitro-irradiated peripheral blood lymphocytes and the risk of developing late toxic effects opens up the possibility of predicting normal tissue response to radiation in individual patients, at least in high-dose non-conventional radiation therapy regimens.

A multifunctional ß-cyclodextrin-conjugate photodelivering nitric oxide with fluorescence reporting.

This contribution reports the design, synthesis and photochemical properties of a novel cationic, water soluble, ß-cyclodextrin (ßCD) conjugate integrating an anthracene moiety and a nitroaniline derivative within the primary side of the ßCD scaffold. Photoinduced energy transfer between the anthracene and the nitroaniline chromophores effectively suppresses the fluorescence of the anthracene unit. Excitation with visible light triggers the release of nitric oxide (NO) from the nitroaniline chromophore, accompanied to the concomitant revival of the anthracene fluorescence, which acts as an optical reporter for detecting the amount of the NO released. Furthermore, the anthracene moiety photogenerates singlet oxygen (1O2) sequentially to NO release. The conjugate is also able to accommodate hydrophobic guests within the ßCD cavity, as proven by using naphthalene as a model compound. In view of the key role NO and 1O2 play as anticancer and antibacterial species, the present ßCD derivative represents an intriguing candidate for further studies in biopharmaceutical research addressed to multimodal therapeutic applications.

Photo-antimicrobial polymeric films releasing nitric oxide with fluorescence reporting under visible light.

A novel photoresponsive molecular hybrid has been embedded in poly(lactic-co-glycolic acid) (PLGA) to give an antibacterial polymeric film generating nitric oxide (NO) under visible light, with concomitant fluorescence reporting of NO release. The molecular hybrid integrates a nitroaniline NO photodonor and a coumarin latent fluorophore in the same molecular skeleton and results in quite homogeneous distribution in the polymer matrix where it preserves well the photobehavior exhibited in solution. The doped PLGA film shows an excellent optical transparency and can be excited by visible light leading to the production of NO and the parallel fluorescence revival of the coumarin fluorophore, which acts as an optical NO reporter. Photogenerated NO diffuses out of the polymer film, can be transferred to a biological milieu and induces remarkable antibacterial activity against Escherichia coli.

Graphene oxide nanohybrid that photoreleases nitric oxide.

We report herein a photoresponsive nanoplatform that delivers nitric oxide (NO) on demand, achieved by the covalent functionalization of graphene oxide (GO) with an amino-terminated nitric oxide (NO) photodonor (NOP1). The resulting GO-NOP1 hybrid nanomaterial is dispersible in water, is very stable in the dark and has been thoroughly characterized by SEM, TEM, AFM, XRD, FTIR and UV-Vis absorption spectroscopy. Photolysis experiments demonstrate that the photodecomposition of the NO photoreleaser integrated into the GO scaffold occurs with an efficiency similar to that observed for a free model compound, ruling out any significant quenching effect (i.e. photoinduced energy/electron transfer) and accounting for the excellent preservation of its photochemical properties upon grafting. A combination of direct amperometric detection and indirect measurements based on a fluorometric assay prove that the remote-controlled release of NO from the GO-NOP1 nanoplatform is exclusively regulated by visible light stimuli.