Breast conserving treatment for ductal carcinoma in situ in the elderly: Can radiation therapy be avoided? Our experience

AbstractIntroduction: Ductal Carcinoma In Situ (DCIS) is a heterogeneous, pre-malignant disease accounting for 15–20% of all new breast cancers. If appropriately managed, DCIS has a small chance of impacting on patient life expectancy. Despite the possibility of a further recurrence or of a development in an invasive form, we are unable to select treatment of choice especially in the elderly. In particularly we risk an overtreatment of women at low risk of progression to invasive breast cancer. The aim of this study was to retrospectively evaluate the outcome of elderly patients affected by DCIS not undergoing Radiation Therapy (RT) after Breast Conserving Surgery (BCS). Material and methods: We reviewed our prospectively-maintained database from 1998 to 2013, selecting all women over 65 years old diagnosed with DCIS who did not receive RT for personal choice. We considered two groups, according to the risk of local recurrence (Low Risk (Group 1) vs. High Risk (Group 2)). Results: We identified 44 cases of DCIS treated with surgery alone or with surgery followed by adjuvant tamoxifen. 24 patients presented low risk of local recurrence (Group 1) and 20 had characteristics associated to high risk of local recurrence (Group 2). At a median follow-up of 66.3 months, no local recurrences have been described in group 1. No patients presented distant metastases, while 4 patients died for other causes. At a median follow-up of 72 months we observed 5 local recurrences in the second group (p < 0.05). Conclusion: Our results suggest that radiation therapy can be safely avoided in a selected group of elderly patients affected by DCIS

DESIGN AND PRECLINICAL DEVELOMENT OF CP86, A NEW POTENT IN VIVO ANTIEPILEPTIC AGENT

Kv7.2/7.3 potassium channels represent an attractive pharmacological targets for the treatment of different neurological disorders, in particular epilepsy. During 2011 the Kv7.2/7.3 agonist retigabine has been approved as add-on treatment for drug-resistant partial onset seizures with or without secondary generalization. However, the clinical use of retigabine has been declining over the years, leading to its market withdrawal in 2017,1 due to several drawbacks and side effects. The resulting limitation in therapeutic options led to extensive efforts, both from academia and industry, in the search for new Kv7.2/7.3 agonists. These efforts were largely frustrated by a substantial lack of knowledge concerning retigabine binding site.1 This is why, starting from our previously published results,1 we have performed in-silico studies to shed light on the chemical space at the retigabine binding site. A structure-based approach was used to verify the in-silico hypotheses synthesizing a focused library of 25 compounds, which were tested by an HTS fluorometric assay. Results obtained further expanded the structure-activity relationship clues for the rational design of Kv7.2/7.3 channels agonists, confirming the pivotal importance of a wide, lipophilic pocket in correspondence of the pore region for the modulation of Kv7.2/7.3 agonists potency and efficacy. Nevertheless, as assessed by photostability testing, synthesized compounds were unable to overcome one of the main retigabine drawback: light-induced instability. Thus, taking advantage form the previously obtained SAR clues, a photostability-driven design was performed, generating a second set of 16 molecules. Among these, CP86 showed improved potency, efficacy and photostability when compared to retigabine. Patch-clamp experiments confirmed these preliminary data. CP86 is able to produce a marked leftward shift of the dose response curve and increased maximal currents in comparison to Kv7.2/7.3 prototypical agonists. Site-specific mutagenesis experiments validated the predicted binding mode, involving an interaction network with W236, V225, F240, S303, F304, F305 and L312, in the Kv7.2/7.3 subtype heterotetrameric assembly. CP86 was, then, subjected to an extensive in vitro and in vivo preclinical characterization resulting as a metabolically stable compound, with considerably improved half-life and CNS distribution if compared to retigabine. When challenged in vivo, by a pentylenetetrazol (PTZ) kindling model of epilepsy, CP86 showed a remarkable reduction of the incidence and severity of tonic PTZ seizures, at one-twelfth of the retigabine dose. Moreover, seizures modulation was combined with an outstanding protective effect. CP86 administration, indeed, largely prevented pentylenetetrazol-induced death, widely described2 and experimentally observed for retigabine-treated animal

Safety and immune response kinetics of GRAd-COV2 vaccine: phase 1 clinical trial results

Despite the successful deployment of efficacious vaccines and therapeutics, the development of novel vaccines for SARS-CoV-2 remains a major goal to increase vaccine doses availability and accessibility for lower income setting. We report here on the kinetics of Spike-specific humoral and T-cell response in young and old volunteers over 6 months follow-up after a single intramuscular administration of GRAd-COV2, a gorilla adenoviral vector-based vaccine candidate currently in phase-2 of clinical development. At all three tested vaccine dosages, Spike binding and neutralizing antibodies were induced and substantially maintained up to 3 months, to then contract at 6 months. Potent T-cell responses were readily induced and sustained throughout the study period, with only minor decline. No major differences in immune response to GRAd-COV2 vaccination were observed in the two age cohorts. In light of its favorable safety and immunogenicity, GRAd-COV2 is a valuable candidate for further clinical development and potential addition to the COVID-19 vaccine toolbox to help fighting SARS-CoV-2 pandemic

GRAd-COV2, a gorilla adenovirus-based candidate vaccine against COVID-19, is safe and immunogenic in younger and older adults

International audienceSafe and effective vaccines against coronavirus disease 2019 (COVID-19) are essential for ending the ongoing pandemic. Although impressive progress has been made with several COVID-19 vaccines already approved, it is clear that those developed so far cannot meet the global vaccine demand alone. We describe a COVID-19 vaccine based on a replication-defective gorilla adenovirus expressing the stabilized prefusion severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein named GRAd-COV2. We assessed the safety and immunogenicity of a single-dose regimen of this vaccine in healthy younger and older adults to select the appropriate dose for each age group. For this purpose, a phase 1, dose-escalation, open-labeled trial was conducted including 90 healthy participants (45 aged 18 to 55 years old and 45 aged 65 to 85 years old) who received a single intramuscular administration of GRAd-COV2 at three escalating doses. Local and systemic adverse reactions were mostly mild or moderate and of short duration, and no serious adverse events were reported. Four weeks after vaccination, seroconversion to spike protein and receptor binding domain was achieved in 43 of 44 young volunteers and in 45 of 45 older participants. Consistently, neutralizing antibodies were detected in 42 of 44 younger-age and 45 of 45 older-age volunteers. In addition, GRAd-COV2 induced a robust and T helper 1 cell (T H 1)-skewed T cell response against the spike protein in 89 of 90 participants from both age groups. Overall, the safety and immunogenicity data from the phase 1 trial support the further development of this vaccine