Selective sparing of bladder and rectum sub-regions in radiotherapy of prostate cancer combining knowledge-based automatic planning and multicriteria optimization

Background and Purpose: The association between dose to selected bladder and rectum symptom-related sub- regions (SRS) and late toxicity after prostate cancer radiotherapy has been evidenced by voxel-wise analyses. The aim of the current study was to explore the feasibility of combining knowledge-based (KB) and multi-criteria optimization (MCO) to spare SRSs without compromising planning target volume (PTV) dose delivery, including pelvic-node irradiation. Materials and Methods: Forty-five previously treated patients (74.2 Gy/28fr) were selected and SRSs (in the bladder, associated with late dysuria/hematuria/retention; in the rectum, associated with bleeding) were generated using deformable registration. A KB model was used to obtain clinically suitable plans (KB-plan). KB- plans were further optimized using MCO, aiming to reduce dose to the SRSs while safeguarding target dose coverage, homogeneity and avoiding worsening dose volume histograms of the whole bladder, rectum and other organs at risk. The resulting MCO-generated plans were examined to identify the best-compromise plan (KB + MCO-plan). Results: The mean SRS dose decreased in almost all patients for each SRS. D1% also decreased in the large majority, less frequently for dysuria/bleeding SRS. Mean differences were statistically significant (p < 0.05) and ranged between 1.3 and 2.2 Gy with maximum reduction of mean dose up to 3&#8211;5 Gy for the four SRSs. The better sparing of SRSs was obtained without compromising PTVs coverage. Conclusions: Selectively sparing SRSs without compromising PTV coverage is feasible and has the potential to reduce toxicities in prostate cancer radiotherapy. Further investigation to better quantify the expected risk reduction of late toxicities is warranted.This work has been supported by Fondazione Regionale per la Ricerca Biomedica, project nr. 110 - JTC PerPlanRT ERA PerMed, GA 779282.Publicad

Molecular Investigation on a Triple Negative Breast Cancer Xenograft Model Exposed to Proton Beams

Specific breast cancer (BC) subtypes are associated with bad prognoses due to the absence of successful treatment plans. The triple-negative breast cancer (TNBC) subtype, with estrogen (ER), progesterone (PR) and human epidermal growth factor-2 (HER2) negative receptor status, is a clinical challenge for oncologists, because of its aggressiveness and the absence of effective therapies. In addition, proton therapy (PT) represents an effective treatment against both inaccessible area located or conventional radiotherapy (RT)-resistant cancers, becoming a promising therapeutic choice for TNBC. Our study aimed to analyze the in vivo molecular response to PT and its efficacy in a MDA-MB-231 TNBC xenograft model. TNBC xenograft models were irradiated with 2, 6 and 9 Gy of PT. Gene expression profile (GEP) analyses and immunohistochemical assay (IHC) were performed to highlight specific pathways and key molecules involved in cell response to the radiation. GEP analysis revealed in depth the molecular response to PT, showing a considerable immune response, cell cycle and stem cell process regulation. Only the dose of 9 Gy shifted the balance toward pro-death signaling as a dose escalation which can be easily performed using proton beams, which permit targeting tumors while avoiding damage to the surrounding healthy tissue

Characterization of the energy dependent response of EBT3 radiochromic film to proton and carbon ion beams

Introduction: The authors characterized the response of EBT3 radiochromic films to proton and carbon ion beams. EBT3 films are adopted routinely for dosimetry and for QA at linear accelerators used for conventional radiotherapy, and for QA in hadrontherapy. In contrast to sparsely ionizing radiations, irradiation by ions leads to a strongly inhomogeneous dose deposition. A quenching effect occurs in the film response consisting of an under-response of the EBT3 to ion beams with respect to MV-photon beams, likely due to the ion track structure. The authors investigated the response of EBT3 films to proton and carbon ion beams, and compared it with photon and electron beams' response, for assessment of a dose–response correction procedure. Method and materials: The EBT3 films were calibrated in the dose range of 0.4–20 Gy with proton (63, 150 and 230 MeV) and carbon ion (115 MeV/u and 400 MeV/u) beams as well as to radiotherapy photon (6, 18 MV and 60 Co) and electron (6 and 12 MeV) beams. The measurements were performed at ‘National Center for Oncological Hadrontherapy’ (CNAO Pavia, Italy) for proton and carbon ion beams and at ‘San Raffaele Hospital’ (HSR Milan, Italy) for photon and electron beams. Results: The dose–response curves were fitted to a quadratic-like function with a relative error of less than 3%. The EBT3 response to protons was found to be very similar to the response of photon and electron beams and no saturation occurred. The relative response of carbon ions was less than unity for all dose values and lower for low-energy ions. The carbon ion curves show an under-response, up to 25% for the lower investigated energy, in comparison with photon and electron curves. Conclusions: For proton beams, at all energies, the dose–response curves are statistically not different from photon and electron curves. For carbon ions an under-response was observed which is higher for lower energy (higher LET) beam

CD14 and NFAT mediate lipopolysaccharide-induced skin edema formation in mice

Inflammation is a multistep process triggered when innate immune cells — for example, DCs — sense a pathogen or injured cell or tissue. Edema formation is one of the first steps in the inflammatory response; it is fundamental for the local accumulation of inflammatory mediators. Injection of LPS into the skin provides a model for studying the mechanisms of inflammation and edema formation. While it is known that innate immune recognition of LPS leads to activation of numerous transcriptional activators, including nuclear factor of activated T cells (NFAT) isoforms, the molecular pathways that lead to edema formation have not been determined. As PGE2 regulates many proinflammatory processes, including swelling and pain, and it is induced by LPS, we hypothesized that PGE2 mediates the local generation of edema following LPS exposure. Here, we show that tissue-resident DCs are the main source of PGE2 and the main controllers of tissue edema formation in a mouse model of LPS-induced inflammation. LPS exposure induced expression of microsomal PGE synthase-1 (mPGES-1), a key enzyme in PGE2 biosynthesis. mPGES-1 activation, PGE2 production, and edema formation required CD14 (a component of the LPS receptor) and NFAT. Therefore, tissue edema formation induced by LPS is DC and CD14/NFAT dependent. Moreover, DCs can regulate free antigen arrival at the draining lymph nodes by controlling edema formation and interstitial fluid pressure in the presence of LPS. We therefore suggest that the CD14/NFAT/mPGES-1 pathway represents a possible target for antiinflammatory therapies

Ten Year Results of Extensive Nodal Radiotherapy and Moderately Hypofractionated Simultaneous Integrated Boost in Unfavorable Intermediate-, High-, and Very High-Risk Prostate Cancer

Aims: To report 10-year outcomes of WPRT and HD moderately hypofractionated SIB to the prostate in UIR, HR, and VHR PCa. Methods: From 11/2005 to 12/2015, 224 UIR, HR, and VHR PCa patients underwent WPRT at 51.8 Gy/28 fractions and SIB at 74.2 Gy (EQD2 88 Gy) to the prostate. Androgen deprivation therapy (ADT) was prescribed in up to 86.2% of patients. Results: Median follow-up was 96.3 months (IQR: 71–124.7). Median age was 75 years (IQR: 71.3–78.1). At last follow up, G3 GI–GU toxicity was 3.1% and 8%, respectively. Ten-year biochemical relapse-free survival (bRFS) was 79.8% (95% CI: 72.3–88.1%), disease-free survival (DFS) 87.8% (95% CI: 81.7–94.3%), overall survival (OS) 65.7% (95% CI: 58.2–74.1%), and prostate cancer-specific survival (PCSS) 94.9% (95% CI: 91.0–99.0%). Only two patients presented local relapse. At univariate analysis, VHR vs. UIR was found to be a significant risk factor for biochemical relapse (HR: 2.8, 95% CI: 1.17–6.67, p = 0.021). After model selection, only Gleason Score ≥ 8 emerged as a significant factor for biochemical relapse (HR = 2.3, 95% CI: 1.12–4.9, p = 0.023). Previous TURP (HR = 3.5, 95% CI: 1.62–7.54, p = 0.001) and acute toxicity ≥ G2 (HR = 3.1, 95% CI = 1.45–6.52, p = 0.003) were significant risk factors for GU toxicity ≥ G3. Hypertension was a significant factor for GI toxicity ≥ G3 (HR = 3.63, 95% CI: 1.06–12.46, p = 0.041). ADT (HR = 0.31, 95% CI: 0.12–0.8, p = 0.015) and iPsa (HR = 0.37, 95% CI: 0.16–0.83, p = 0.0164) played a protective role. Conclusions: WPRT and HD SIB to the prostate combined with long-term ADT, in HR PCa, determine good outcomes with acceptable toxicity

PARMA CITTÀ FUTURA VOLUME II Il libro bianco

Secondo volume di Parma Città Futura Il libro bianco raccoglie il lavoro di riflessione strategica organizzato in dieci tavoli di discussione che si sono spontaneamente attivati grazie all’impegno di docenti di vari Dipartimenti dell’Università di Parma che si sono dedicati a elaborare proposte collegate all’attuazione del Progetto Urbano Strategico documentato nel primo volume. Come le varie politiche urbane possono orientarsi e svilupparsi nella prospettiva di concretizzare una idea di città verde accessibile ed accogliente come quella prefigurata? Cultura con la proposta di realizzare un museo/laboratorio della città, Sport e tempo libero orientato all’uso consapevole e condiviso dello spazio pubblico, cittadi- nanza attiva, comunicazione scientifica come nuovo cromosoma nel DNA della città, musica come identità e risorsa, economia di territorio ed area integrata, mobilità sostenibile, tecnologie innovative per la casa e la città, salute e benessere, strategie di attuazione, sono i temi affrontati da oltre 130 persone provenienti da 66 enti, fondazioni, istituzioni e associazioni per elaborare progettualità di settore mirate e complementari. Oltre alle proposte dei vari tavoli offerte alla città ed alla sua amministrazione comunale, l’esperienza di un network flessibile di lavoro collettivo come quello coagulatosi nel 2016 viene presentato come strumento di riflessione operativa e di confronto permanente da mantenere in vita e rilanciare per stimolare un processo prezioso quanto raro di democrazia deliberativa

A prospective cohort analysis of the prevalence and predictive factors of delayed discharge after laparoscopic cholecystectomy in Italy: the DeDiLaCo Study

Background: The concept of early discharge ≤24 hours after Laparoscopic Cholecystectomy (LC) is still doubted in Italy. This prospective multicentre study aims to analyze the prevalence of patients undergoing elective LC who experienced a delayed discharge &gt;24 hours in an extensive Italian national database and identify potential limiting factors of early discharge after LC. Methods: This is a prospective observational multicentre study performed from January 1, 2021 to December 31, 2021 by 90 Italian surgical units. Results: A total of 4664 patients were included in the study. Clinical reasons were found only for 850 patients (37.7%) discharged &gt;24 hours after LC. After excluding patients with nonclinical reasons for delayed discharge &gt;24 hours, 2 groups based on the length of hospitalization were created: the Early group (≤24 h; 2414 patients, 73.9%) and the Delayed group (&gt;24 h; 850 patients, 26.1%). At the multivariate analysis, ASA III class ( P &lt;0.0001), Charlson's Comorbidity Index (P=0.001), history of choledocholithiasis (P=0.03), presence of peritoneal adhesions (P&lt;0.0001), operative time &gt;60 min (P&lt;0.0001), drain placement (P&lt;0.0001), pain ( P =0.001), postoperative vomiting (P=0.001) and complications (P&lt;0.0001) were independent predictors of delayed discharge &gt;24 hours. Conclusions: The majority of delayed discharges &gt;24 hours after LC in our study were unrelated to the surgery itself. ASA class &gt;II, advanced comorbidity, the presence of peritoneal adhesions, prolonged operative time, and placement of abdominal drainage were intraoperative variables independently associated with failure of early discharge