Adjuvant modern radiotherapy in resected pN2 NSCLC patients: results from a multicentre retrospective analysis on acute and late toxicity on behalf of AIRO thoracic oncology study group: the RAC-TAC study.

BACKGROUND: Recently, the PORT-C and LUNG-ART trials, which evaluated the role of postoperative radiation therapy (PORT), have significantly altered the treatment landscape for NSCLC pN2 patients who previously underwent surgery. In response, the Italian Association of Radiotherapy and Oncology Thoracic Oncology study group has initiated an observational multicenter trial to assess both acute and late toxicities of PORT in pN2 NSCLC patients treated with modern techniques. METHODS: Data on NSCLC patients submitted to PORT after radical surgery treated between 2015 and 2020 in six Italian Centers were collected. Heart, lung, and esophageal acute and late toxicities have been retrospectively analyzed and related to radiation therapy dosimetric parameters. Furthermore, loco-regional control, distant metastasis and overall survival have been analyzed. RESULTS: A total of 212 patients with a median age of 68 years from six different centers were included in this analysis (142 males and 70 females). Prior to undergoing PORT, 96 patients (45.8%) had a history of heart disease, 110 patients (51.9%) had hypertension, and 51 patients (24%) had COPD. Acute toxicity was observed in 147 patients (69.3%), with lung toxicity occurring in 93 patients (G1 in 70 patients, G2 in 17 patients, and G3 in 4 patients), esophageal toxicity in 114 patients (G1 in 89 patients, G2 in 23 patients, and G3 in 1 patient), and cardiac toxicity in 4 patients (G1 in 2 patients and G3 in 2 patients). Late side effects were found in 60 patients (28.3%), predominantly involving the lungs (51 patients: 32 G1, 11 G2, and 1 G3) and the esophagus (11 patients: 8 G1 and 3 G2), with no reported late cardiac side effects. Various clinical and dosimetric parameters were found to correlate with both acute and chronic toxicities. Over a median follow-up period of 54 months, 48 patients (22.6%) showed locoregional disease relapse, 106 patients (50%) developed distant metastases, and 66 patients (31.1%) died. CONCLUSIONS: RAC-TAC retrospective multicentric study showed the low toxicity of PORT when advanced technology is used. At the same time, it's noteworthy to underline that 50% of the patients develop distant recurrences in the follow up.

Oncological outcomes of cervical esophageal cancer treated primarily with surgery: a systematic review and meta-analysis.

PURPOSE: To determine the oncological outcomes of cervical esophageal cancer (CEC) treated primarily with surgery. METHODS: A systematic review and meta-analysis was performed according to the PRISMA guidelines. RESULTS: A total of 868 patients were included from 18 studies. Estimated pooled Overall Survival (OS) rates (95% Confidence Interval, CI) at 1 and 5 years were 74.4% (66.5-83.3), and 26.6% (20.3-34.7), respectively. Larynx non-preserving surgery (n = 229) showed an estimated pooled OS rates (95% CI) at 1 and 5 years of 59.3% (51.5-68.2) and 14.6% (8.8-24.3), respectively. On the other hand, larynx preserving surgery (n = 213) showed an estimated pooled OS rates (95% CI) at 1 and 5 years of 83.6% (78.2-89.4) and 35.1% (24.9-49.6), respectively. CONCLUSIONS: Primary larynx-preserving surgery remains a valuable option for the management of CEC, with similar survival outcomes compared to primary chemoradiotherapy (CRT). On the other hand, larynx non-preserving surgery showed a significantly reduced survival, that may reflect the more advanced T classification of these tumors. Further studies are mandatory to directly compare primary surgery and primary CRT, distinguishing larynx preserving and non-preserving surgery.

Preservation of Axillary Lymph Nodes Compared with Complete Dissection in T1-2 Breast Cancer Patients Presenting One or Two Metastatic Sentinel Lymph Nodes: The SINODAR-ONE Multicenter Randomized Clinical Trial.

BACKGROUND: The SINODAR-ONE trial is a prospective noninferiority multicenter randomized study aimed at assessing the role of axillary lymph node dissection (ALND) in patients undergoing either breast-conserving surgery or mastectomy for T1-2 breast cancer (BC) and presenting one or two macrometastatic sentinel lymph nodes (SLNs). The endpoints were to evaluate whether SLN biopsy (SLNB) only was associated with worsening of the prognosis compared with ALND in terms of overall survival (OS) and relapse. METHODS: Patients were randomly assigned (1:1 ratio) to either removal of ≥ 10 axillary level I/II non-SLNs followed by adjuvant therapy (standard arm) or no further axillary treatment (experimental arm). RESULTS: The trial started in April 2015 and ceased in April 2020, involving 889 patients. Median follow-up was 34.0 months. There were eight deaths (ALND, 4; SNLB only, 4), with 5-year cumulative mortality of 5.8% and 2.1% in the standard and experimental arm, respectively (p = 0.984). There were 26 recurrences (ALND 11; SNLB only, 15), with 5-year cumulative incidence of recurrence of 6.9% and 3.3% in the standard and experimental arm, respectively (p = 0.444). Only one axillary lymph node recurrence was observed in each arm. The 5-year OS rates were 98.9% and 98.8%, in the ALND and SNLB-only arm, respectively (p = 0.936). CONCLUSIONS: The 3-year survival and relapse rates of T1-2 BC patients with one or two macrometastatic SLNs treated with SLNB only, and adjuvant therapy, were not inferior to those of patients treated with ALND. These results do not support the use of routine ALND.

Radiomics-based prognosis classification for high-risk prostate cancer treated with radiotherapy.

OBJECTIVE: The present study aimed to investigate if CT-based radiomics features could correlate to the risk of metastatic progression in high-risk prostate cancer patients treated with radical RT and long-term androgen deprivation therapy (ADT). MATERIALS AND METHODS: A total of 157 patients were investigated and radiomics features extracted from the contrast-free treatment planning CT series. Three volumes were segmented: the prostate gland only (CTV_p), the prostate gland with seminal vesicles (CTV_psv), and the seminal vesicles only (CTV_sv). The patients were split into two subgroups of 100 and 57 patients for training and validation. Five clinical and 62 radiomics features were included in the analysis. Considering metastases-free survival (MFS) as an endpoint, the predictive model was used to identify the subgroups with favorable or unfavorable prognoses (separated by a threshold selected according to the Youden method). Pure clinical, pure radiomic, and combined predictive models were investigated. RESULTS: With a median follow-up of 30.7 months, the MFS at 1 and 3 years was 97.2% ± 1.5 and 92.1% ± 2.0, respectively. Univariate analysis identified seven potential predictors for MFS in the CTV_p group, 11 in the CTV_psv group, and 9 in the CTV_sv group. After elastic net reduction, these were 4 predictors for MFS in the CTV_p group (positive lymph nodes, Gleason score, H_Skewness, and NGLDM_Contrast), 5 in the CTV_psv group (positive lymph nodes, Gleason score, H_Skewnesss, Shape_Surface, and NGLDM_Contrast), and 6 in the CTV_sv group (positive lymph nodes, Gleason score, H_Kurtosis, GLCM_Correlation, GLRLM_LRHGE, and GLZLM_SZLGE). The patients' group of the training and validation cohorts were stratified into favorable and unfavorable prognosis subgroups. For the combined model, for CTV_p, the mean MFS was 134 ± 14.5 vs. 96.9 ± 22.2 months for the favorable and unfavorable subgroups, respectively, and 136.5 ± 14.6 vs. 70.5 ± 4.3 months for CTV_psv and 150.0 ± 4.2 vs. 91.1 ± 8.6 months for CTV_sv, respectively. CONCLUSION: Radiomic features were able to predict the risk of metastatic progression in high-risk prostate cancer. Combining the radiomic features and clinical characteristics can classify high-risk patients into favorable and unfavorable prognostic groups.

Oligoscore: a clinical score to predict overall survival in patients with oligometastatic disease treated with stereotactic body radiotherapy.

BACKGROUND: to find clinical features that can predict prognosis in patients with oligometastatic disease treated with stereotactic body radiotherapy (SBRT). MATERIAL AND METHODS: Patients with less than 5 metastases in less than 3 different body sites were included in the analysis. Various clinical and treatment parameters were analyzed to create a Cox proportional hazard model for Overall Survival (OS). Subsequently, significant variables were used to create a score. RESULTS: 997 patients were analyzed. Median OS was 2.61 years, 1 and 3 years OS was respectively 85% and 43%. Location of the primary tumor, performance status, site of irradiated metastases, presence of extratarget non irradiated lesions and RT dose were significant prognostic factors for OS. These parameters were used to create a score and to distinguish three different classes, with median OS of 5.67 years in low risk, 2.47 years in intermediate risk and 1.82 years in high risk group. CONCLUSION: moving from easily accessible clinical parameters, a score was created to help the physician's decision about the better treatment or combination of treatments for the individual patient.

Modulation of Amyloid ß-Induced Microglia Activation and Neuronal Cell Death by Curcumin and Analogues.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is not restricted to the neuronal compartment but includes important interactions with immune cells, including microglia. Protein aggregates, common pathological hallmarks of AD, bind to pattern recognition receptors on microglia and trigger an inflammatory response, which contributes to disease progression and severity. In this context, curcumin is emerging as a potential drug candidate able to affect multiple key pathways implicated in AD, including neuroinflammation. Therefore, we studied the effect of curcumin and its structurally related analogues cur6 and cur16 on amyloid-ß (Aß)-induced microglia activation and neuronal cell death, as well as their effect on the modulation of Aß aggregation. Primary cortical microglia and neurons were exposed to two different populations of Aß42 oligomers (Aß42Os) where the oligomeric state had been assigned by capillary electrophoresis and ultrafiltration. When stimulated with high molecular weight Aß42Os, microglia released proinflammatory cytokines that led to early neuronal cell death. The studied compounds exerted an anti-inflammatory effect on high molecular weight Aß42O-stimulated microglia and possibly inhibited microglia-mediated neuronal cell toxicity. Furthermore, the tested compounds demonstrated antioligomeric activity during the process of in vitro Aß42 aggregation. These findings could be investigated further and used for the optimization of multipotent candidate molecules for AD treatment.

Moderate hypofractionated radiotherapy for post-operative treatment of prostate cancer: long-term outcome and pattern of toxicity.

OBJECTIVE: Postoperative radiotherapy (RT) is an established treatment for prostate cancer (PC). Though hypofractionation is commonly used for radical treatments, open issues still remain in the postoperative setting due to the lack of long-term data. Aim of this study was to evaluate long-term results of postoperative moderately hypofractionated RT (MHRT). METHODS: We conducted a retrospective analysis including PC patients treated with prostatectomy and postoperative MHRT delivered with volumetric modulated arc therapy (VMAT). Endpoints of the analysis included biochemical relapse-free survival (BRFS), distant metastases free-survival (DMFS), overall survival (OS), and pattern of acute and late toxicity. RESULTS: 181 patients were included. Pathological stage was classified as pT3a in 33.6% and pT3b in 30%. Median PSA value before RT was 0.23 ng/ml and median RT total dose was 70 Gy (65-74.2 Gy) in 25/28 fractions. With a median follow-up of 54.5 months, rates of BRFS at 3 and 5 years were 80.7 and 72.3%. ISUP grade group (HR 1.44, p = 0.015), pathological T stage (HR 2.03; p = 0.009), and pre-RT PSA >0.2 ng/ml (HR 2.64; p = 0.015) were correlated with BRFS. Three and 5­year DMFS were 87.4 and 80.8%. ISUP grade group (HR 1.50; p = 0.011) and pre-RT PSA (HR 5.34; p = 0.001) were correlated with DMFS. Five (2.7%) and 3 (1.6%) patients reported late grade 3 GU and GI toxicity, respectively. CONCLUSION: Our results confirm the long-term safety and efficacy of postoperative MHRT for PC. ADVANCES IN KNOWLEDGE: The present paper demonstrates the long-term safety and efficacy of MHRT for postoperative prostate cancer. Reduction of treatment time in long-course radiotherapy has advantages in terms of both patients' quality of life and departmental organization.

Dose coverage impacts local control in ultra-central lung oligometastases treated with stereotactic radiotherapy.

INTRODUCTION: The use of Stereotactic Body Radiotherapy (SBRT) is controversial in Ultra-Central lung tumors, a subset of central lung tumors characterized by proximity to critical mediastinal structures. This is of interest in oligometastatic (≤3 metastases) patients, who can yield survival benefit from local treatments. The aim of our study is to assess the determinants of efficacy and toxicity in this setting. MATERIALS AND METHODS: Clinical and dosimetric parameters were reviewed in a cohort of oligometastatic patients treated with SBRT for ultra-central tumors. Local control rate (LC) and toxicity were assessed. Statistical Analysis was carried out to assess the impact of those predictors on local recurrence and adverse events. RESULTS: One-hundred-nine consecutive patients were included. A median Biologic Effective Dose (BED) of 105 (75-132) Gy10 was prescribed. At a median follow-up of 17 (range 3-78) months, 2-year LC was 87%. Improved LC was correlated to Planning Treatment Volume (PTV) covered by 95% of the prescription dose (V95% PTV) > 85% (HR 0.15, 95%CI 0.05-0.49, p = 0.0017) and to Gross Tumor Volume (GTV) < 90 cm3 (HR 0.2, 95%CI 0.07-0.56, p = 0.0021). Overall and grade ≥ 3 toxicity incidence was 20% and 5%, respectively. Patients experiencing acute and late toxicities received significantly higher dose to 1 cm3 (D1cm3) of esophagus and lung volume receiving ≥5 Gy (V5Gy) (p = 0.016 and p = 0.013), and higher dose to 0.1 cm3 (D0.1cm3) of heart (p = 0.036), respectively. CONCLUSION: V95% PTV > 85% and GTV < 90 cm3 are independent predictors of LC. Dose to esophagus, lung and heart should be carefully assessed to minimize treatment-related toxicities.

Dosimetric impact of volumetric modulated arc therapy for nasopharyngeal cancer treatment.

BACKGROUND: The purpose of the study was to evaluate the toxicity and outcome of nasopharyngeal carcinoma patients treated using 3-dimensional conformal radiotherapy (3DCRT) or volumetric modulated arc therapy (VMAT) technique. MATERIALS AND METHODS: 68 patients treated between 2006 and 2018 were retrospectively analysed. Since 2009 patients received 3DCRT with 50/70 Gy to the elective/boost volumes in 35 fractions; from then, VMAT with simultaneous integrated boost (SIB) with 54.45/69.96 Gy in 33, or 54/66 Gy in 30 fractions. Induction chemotherapy was administered in 74% of the patients, concomitant cisplatinum in 87%. Acute and late toxicity data, progression-free survival PSF and overall survival OS, and toxicity correlations with dose metrics were reported. RESULTS: With a median follow-up of 64 months, complete remission at the last evaluation was in 68% of the patients, while 28% and 9% had locoregional relapse and distant disease, respectively. The 5- and 10-year progression free survival (PFS) rates were 62.7 ± 6.5% and 53.2 ± 8.7%, respectively. The 5- and 10-year OS rates were 78.9 ± 5.5% and 61.4 ± 9.2%, respectively. At the multivariate Cox analysis TNM stage (p = 0.02) and concomitant chemotherapy (p = 0.01) resulted significant for PFS, concomitant chemotherapy (p = 0.04) for OS.Improvements in acute toxicity were presented for VMAT patients due to its ability to spare OARs. Odds ratio (OR) for acute salivary toxicity, between VMAT and 3DCRT, was 4.67 (p = 0.02). Dosimetrically, salivary toxicity correlated with mean parotid dose (p = 0.05), dysphagia with laryngeal (p = 0.04) and mean oral cavity (p = 0.06) doses, when dose-volume histograms (DVHs) are corrected for fractionation. CONCLUSION: This study is a proof of a significant benefit of the VMAT technique compared with 3DCRT in terms of side effects in nasopharynx patients, and adds dosimetric correlations.

A radiomic approach to predicting nodal relapse and disease-specific survival in patients treated with stereotactic body radiation therapy for early-stage non-small cell lung cancer.

PURPOSE: To describe the possibility of building a classifier for patients at risk of lymph node relapse and a predictive model for disease-specific survival in patients with early stage non-small cell lung cancer. METHODS: A cohort of 102 patients who received stereotactic body radiation treatment was retrospectively investigated. A set of 45 textural features was computed for the tumor volumes on the treatment planning CT images. Patients were split into two independent cohorts (70 patients, 68.9%, for training; and 32 patients, 31.4%, for validation). Three different models were built in the study. A stepwise backward linear discriminant analysis was applied to identify patients at risk of lymph node progression. The performance of the model was assessed by means of standard metrics derived from the confusion matrix. Furthermore, all textural features were correlated to survival data to build two separate predictive models for progression-free survival (PFS) and disease-specific survival (DS-OS). These models were built from the features/predictors found significant in univariate analysis and elastic net regularization by means of a multivarate Cox regression with backward selection. Low- and high-risk groups were identified by maximizing the separation by means of the Youden method. RESULTS: In the total cohort (77, 75.5%, males; and 25, 24.5%, females; median age 76.6 years), 15 patients presented nodal progression at the time of analysis; 19 patients (18.6%) died because of disease-specific causes, 25 (24.5%) died from other reasons, 28 (27.5%) were alive without disease, and 30 (29.4%) with either local or distant progression. The specificity, sensitivity, and accuracy of the classifier resulted 83.1 ± 24.5, 87.4 ± 1.2, and 85.4 ± 12.5 in the validation group (coherent with the findings in the training). The area under the curve for the classifier resulted in 0.84 ± 0.04 and 0.73 ± 0.05 for training and validation, respectively. The mean time for DS-OS and PFS for the low- and high-risk subgroups of patients (in the validation groups) were 88.2 month ± 9.0 month vs. 84.1 month ± 7.8 month (low risk) and 52.7 month ± 5.9 month vs. 44.6 month ± 9.2 month (high risk), respectively. CONCLUSION: Radiomics analysis based on planning CT images allowed a classifier and predictive models capable of identifying patients at risk of nodal relapse and high-risk of bad prognosis to be built. The radiomics signatures identified were mostly related to tumor heterogeneity.

Recurrence pattern of stereotactic body radiotherapy in oligometastatic prostate cancer: a multi-institutional analysis.

PURPOSE: For patients with oligometastatic/oligorecurrent/oligoprogressive lymph node metastases from PCa, metastases-directed therapy is an emerging strategy. The aim of this retrospective study was to evaluate the oncological outcome and pattern of recurrence in patients treated with stereotactic body radiation therapy (SBRT) to lymph node metastases. METHODS: In this multi-institutional analysis, patients with a maximum of five lymph node metastases from PCa treated with SBRT were included. Primary endpoints of the analysis were local control (LC), out-of-field nodal progression-free survival (NPFS), overall progression-free survival (PFS), and overall survival (OS). RESULTS: 109 patients and 155 lymph node metastases were evaluated. Patients' median age was 70.8 years (range 51-84) and median PSA before SBRT was 1.88 ng/ml (range 0.3-45.5 ng/ml). The dose delivered to the target ranged from 25 to 48 Gy in 4-7 fractions; median BED1.5 Gy was 198 Gy (range 108.3-432 Gy). With a median follow-up of 16 months, LC rates at 1 and 3 years were 93% and 86%, respectively. In-field progression of disease was observed in 11 (7%) lesions. One- and 3­year NPFS was 59% and 29%, and median NPFS was 15 months. Rates of OS at 1 and 3 years were 100% and 95%. The median time to administration of a systemic treatment after SBRT was 7.8 months (1.7-54.8). CONCLUSION: SBRT is an effective and well-tolerated treatment option in the management of lymph node metastases from PCa. Prospective trials are necessary to better select patients who benefit most from this ablative focal treatment and better define the recurrence patterns.

Linac-based stereotactic body radiation therapy for low and intermediate-risk prostate cancer : Long-term results and factors predictive for outcome and toxicity.

INTRODUCTION: Stereotactic body radiation therapy (SBRT) is considered an effective and safe treatment in patients with low- and intermediate-risk prostate cancer (PC). However, due to a lack of long-term follow-up and late toxicity data, this treatment is not universally accepted. The present study aimed to evaluate outcome and early and late toxicity in a cohort of patients with low- and intermediate-risk PC treated prospectively with linear accelerator (linac)-based SBRT. PATIENTS AND METHODS: Patients with low- or intermediate-risk (NCCN criteria) PC were included. All patients received linac-based SBRT to 35 Gy in 5 fractions delivered on alternate days. Endpoints were toxicity, biochemical relapse-free survival (BRFS), metastatic progression-free survival (mPFS), and overall survival (OS). RESULTS: From 2012 to 2018, 178 patients were treated. Median baseline prostate-specific antigen (iPSA) was 6.37 ng/ml (range 1.78-20). Previous transurethral resection of the prostate (TURP) was present in 23 (12.9%) patients. Median follow-up was 58.9 months (range 9.7-89.9). BRFS rates at 1, 3, and 5 years were 98.3 (95% confidence interval, CI, 94.7-99.4%), 94.4 (95%CI 89.4-97), and 91.6% (95%CI 85.4-95.2), respectively. In univariate analysis, performance status (PS), iPSA, and nadir PSA (nPSA) were correlated with BRFS. In multivariable analysis iPSA and nPSA remained significant. BRFS rates at 5 years were 94.9% (95%CI 86.8-98) for International Society of Urological Pathology (ISUP) grade group 1, 93.2% (95%CI 80.5-97.7) for ISUP group 2, and 74.8% (95%CI 47.1-89.5) for ISUP group 3. At 1, 3, and 5 years, mPFS rates were 98.8 (95%CI 95.5-99.7), 96.2 (95%CI 91.9-98.3), and 92.9% (95%CI 87.2-96.2), respectively; OS rates were 100, 97.2 (95%CI 92.9-98.9), and 95.1% (95%CI 90-97.6), respectively. One (0.56%) case of grade 3 acute genitourinary (GU), one case of acute gastrointestinal (GI), and one case of grade 3 late GU toxicity were observed. GI toxicity positively correlated with prostate volume. CONCLUSION: At long-term follow-up, linac-based SBRT continues to be a valid option for the management localized PC. Biochemical control remains high at 5 years, albeit with some concerns regarding the optimal schedule for unfavorable intermediate-risk PC. Considering the excellent prognosis, patient selection is crucial for prevention of severe late toxicity.

Is multidisciplinary management possible in the treatment of lung cancer? A report from three Italian meetings.

PURPOSE: To report criticisms and barriers to the "real-life" application of international guidelines and recent developments in the management of locally advanced non-small cell lung cancer (NSCLC) in Italy. METHODS: Three 2-day courses were organized. During the first day, experts in different fields of thoracic oncology gave their lecture on diagnosis and therapy for locally advanced NSCLC. During the second day, all participants were divided into four groups to discuss on a clinical case as a multidisciplinary team (MDT). The aim was to stimulate the discussion on practical issues in the management of NSCLC patients in the real-life practice. RESULTS: A total of 196 physicians were involved in the courses as learners. Invasive diagnosis of nodal disease for staging purposes, a priori definition of "surgical resectability" and a regular MDT with all crucial participants available were the three main key points identified for a good management of these patients. The main barriers to the clinical application of a good diagnostic and therapeutic approach to the patient were the absence of a regular and complete MDT in the South and Centre of Italy, while in the North of Italy, time for discussion of clinical cases in the MDT and waiting lists for staging and therapeutic interventions were deemed as the major concerns. CONCLUSION: The meetings showed that diagnosis and treatment of locally advanced NSCLC are still extremely variable between different Italian regions. Logistic issues, waiting lists, paucity of well-trained staff and expertise seem to be the main barriers to international guidelines application.

A co-ultramicronized palmitoylethanolamide/luteolin composite mitigates clinical score and disease-relevant molecular markers in a mouse model of experimental autoimmune encephalomyelitis.

BACKGROUND: Persistent and/or recurrent inflammatory processes are the main factor leading to multiple sclerosis (MS) lesions. The composite ultramicronized palmitoylethanolamide, an endogenous N-acylethanolamine, combined with the flavonoid luteolin, PEALut, have been found to exert neuroprotective activities in experimental models of spinal and brain injury and Alzheimer disease, as well as a clinical improvement in human stroke patients. Furthermore, PEALut enhances the expression of different myelin proteins in oligodendrocyte progenitor cells suggesting that this composite might have protective effects in MS experimental models. METHODS: The mouse model of experimental autoimmune encephalomyelitis (EAE) based on active immunization with a fragment of myelin oligodendrocyte glycoprotein (MOG35-55) was used. The daily assessment of clinical score and the expression of serum amyloid A (SAA1), proinflammatory cytokines TNF-α, IL-1ß, IFN-γ, and NLRP3 inflammasome, as well as TLR2, Fpr2, CD137, CD3-γ, and TCR-ζ chain, heterodimers that form T cell surface glycoprotein (TCR), and cannabinoid receptors CB1, CB2, and MBP, were evaluated in the brainstem and cerebellum at different postimmunization days (PIDs). RESULTS: Vehicle-MOG35-55-immunized (MOG35-55) mice developed ascending paralysis which peaked several days later and persisted until the end of the experiment. PEALut, given intraperitoneally daily starting on day 11 post-immunization, dose-dependently improved clinical score over the range 0.1-5 mg/kg. The mRNA expression of SAA1, TNF-α, IL-1ß, IFN-γ, and NLRP3 were significantly increased in MOG35-55 mice at 14 PID. In MOG35-55 mice treated with 5 mg /kg PEALut, the increase of SAA1, TNF- α, IL-1ß, and IFN-γ transcripts at 14 PID was statistically downregulated as compared to vehicle-MOG35-55 mice (p < 0.05). The expression of TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB2 receptors showed a significant upregulation in vehicle-MOG35-55 mice at 14 PID. Instead, CB1 and MBP transcripts have not changed in expression at any time. In MOG/PEALut-treated mice, TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB2 mRNAs were significantly downregulated as compared to vehicle MOG35-55 mice. CONCLUSIONS: The present results demonstrate that the intraperitoneal administration of the composite PEALut significantly reduces the development of clinical signs in the MOG35-55 model of EAE. The dose-dependent improvement of clinical score induced by PEALut was associated with a reduction in transcript expression of the acute-phase protein SAA1, TNF-α, IL-1ß, IFN-γ, and NLRP3 proinflammatory proteins and TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB2 receptors.

Ciprofloxacin and levofloxacin attenuate microglia inflammatory response via TLR4/NF-kB pathway.

BACKGROUND: Neuroinflammation is the response of the central nervous system to events that interfere with tissue homeostasis and represents a common denominator in virtually all neurological diseases. Activation of microglia, the principal immune effector cells of the brain, contributes to neuronal injury by release of neurotoxic products. Toll-like receptor 4 (TLR4), expressed on the surface of microglia, plays an important role in mediating lipopolysaccharide (LPS)-induced microglia activation and inflammatory responses. We have previously shown that curcumin and some of its analogues harboring an α,ß-unsaturated 1,3-diketone moiety, able to coordinate the magnesium ion, can interfere with LPS-mediated TLR4-myeloid differentiation protein-2 (MD-2) signaling. Fluoroquinolone (FQ) antibiotics are compounds that contain a keto-carbonyl group that binds divalent ions, including magnesium. In addition to their antimicrobial activity, FQs are endowed with immunomodulatory properties, but the mechanism underlying their anti-inflammatory activity remains to be defined. The aim of the current study was to elucidate the molecular mechanism of these compounds in the TLR4/NF-κB inflammatory signaling pathway. METHODS: The putative binding mode of five FQs [ciprofloxacin (CPFX), levofloxacin (LVFX), moxifloxacin, ofloxacin, and delafloxacin] to TLR4-MD-2 was determined using molecular docking simulations. The effect of CPFX and LVFX on LPS-induced release of IL-1ß and TNF-α and NF-κB activation was investigated in primary microglia by ELISA and fluorescence staining. The interaction of CPFX and LVFX with TLR4-MD-2 complex was assessed by immunoprecipitation followed by Western blotting using Ba/F3 cells. RESULTS: CPFX and LVFX bound to the hydrophobic region of the MD-2 pocket and inhibited LPS-induced secretion of pro-inflammatory cytokines and activation of NF-κB in primary microglia. Furthermore, these FQs diminished the binding of LPS to TLR4-MD-2 complex and decreased the resulting TLR4-MD-2 dimerization in Ba/F3 cells. CONCLUSIONS: These results provide new insight into the mechanism of the anti-inflammatory activity of CPFX and LVFX, which involves, at least in part, the activation of TLR4/NF-κB signaling pathway. Our findings might facilitate the development of new molecules directed at the TLR4-MD-2 complex, a potential key target for controlling neuroinflammation.

Role of Stereotactic Body Radiation Therapy for the Management of Oligometastatic Renal Cell Carcinoma.

PURPOSE: Kidney cancer has been increasing 1.7% annually. Renal cell carcinoma is the most common kidney cancer and it can metastasize. Our aim was to analyze patients treated with stereotactic body radiation therapy of renal cell carcinoma metastases. MATERIALS AND METHODS: A total of 58 patients (73 lesions) were treated from 2004 to 2016. Patients were candidates for analysis if a maximum of 3 metastases were diagnosed and the primary tumor was resected. Toxicity was classified according to Common Terminology Criteria for Adverse Events version 3. RESULTS: All patients had renal cell carcinoma, in particular the clear cell type in 82.7%. A total of 39 metastases (53.4%) were located in the lungs and 19 (26%) were in the lymph nodes. Less common were metastases to bone (9.5% of cases), the liver (4.1%) and the adrenal gland (6.8%). Median followup was 16.1 months (range 3.5 to 157.1). The local control rate at 12 and 18 months was 90.2% and 90.2%, respectively. The progression-free survival rate at 12 and 18 months was 46.2% (95% CI 32.2-59) and 35% (95% CI 21.4-48.9), respectively. On univariate and multivariable analyses metachronous and single metastases predicted better progression-free survival. Systemic therapy before stereotactic body radiation therapy predicted improved local control in clear cell cases. CONCLUSIONS: Stereotactic body radiation therapy can be considered a safe approach and it provides effective local control of oligometastatic renal cell carcinoma. However, future prospective studies are necessary to evaluate the impact on survival and quality of life.

Role of Stereotactic Body Radiation Therapy for the Management of Oligometastatic Renal Cell Carcinoma.

PURPOSE: Kidney cancer has been increasing 1.7% annually. Renal cell carcinoma is the most common kidney cancer and it can metastasize. Our aim was to analyze patients treated with stereotactic body radiation therapy of renal cell carcinoma metastases. MATERIALS AND METHODS: A total of 58 patients (73 lesions) were treated from 2004 to 2016. Patients were candidates for analysis if a maximum of 3 metastases were diagnosed and the primary tumor was resected. Toxicity was classified according to Common Terminology Criteria for Adverse Events version 3. RESULTS: All patients had renal cell carcinoma, in particular the clear cell type in 82.7%. A total of 39 metastases (53.4%) were located in the lungs and 19 (26%) were in the lymph nodes. Less common were metastases to bone (9.5% of cases), the liver (4.1%) and the adrenal gland (6.8%). Median followup was 16.1 months (range 3.5 to 157.1). The local control rate at 12 and 18 months was 90.2% and 90.2%, respectively. The progression-free survival rate at 12 and 18 months was 46.2% (95% CI 32.2-59) and 35% (95% CI 21.4-48.9), respectively. On univariate and multivariable analyses metachronous and single metastases predicted better progression-free survival. Systemic therapy before stereotactic body radiation therapy predicted improved local control in clear cell cases. CONCLUSIONS: Stereotactic body radiation therapy can be considered a safe approach and it provides effective local control of oligometastatic renal cell carcinoma. However, future prospective studies are necessary to evaluate the impact on survival and quality of life.

Predicting survival and local control after radiochemotherapy in locally advanced head and neck cancer by means of computed tomography based radiomics.

PURPOSE: To appraise the ability of a radiomics signature to predict clinical outcome after definitive radiochemotherapy (RCT) of stage III-IV head and neck cancer. METHODS: A cohort of 110 patients was included in a retrospective analysis. Radiomics texture features were extracted from the gross tumor volumes contoured on planning computed tomography (CT) images. The cohort of patients was randomly divided into a training (70 patients) and a validation (40 patients) cohorts. Textural features were correlated to survival and control data to build predictive models. All the significant predictors of the univariate analysis were included in a multivariate model. The quality of the models was appraised by means of the concordance index (CI). RESULTS: A signature with 3 features was identified as predictive of overall survival (OS) with CI = 0.88 and 0.90 for the training and validation cohorts, respectively. A signature with 2 features was identified for progression-free survival (PFS; CI = 0.72 and 0.80); 2 features also characterized the signature for local control (LC; CI = 0.72 and 0.82). In all cases, the stratification in high- and low-risk groups for the training and validation cohorts led to significant differences in the actuarial curves. In the validation cohort the mean OS times (in months) were 78.9 ± 2.1 vs 67.4 ± 6.0 in the low- and high-risk groups, respectively, the PFS was 73.1 ± 3.7 and 50.7 ± 7.2, while the LC was 78.7 ± 2.1 and 63.9 ± 6.5. CONCLUSION: CT-based radiomic signatures that correlate with survival and control after RCT were identified and allow low- and high-risk groups of patients to be identified.

Survival outcome of tyrosine kinase inhibitors beyond progression in association to radiotherapy in oligoprogressive EGFR-mutant non-small-cell lung cancer.

Aim: The association of tyrosine kinase inhibitors (TKIs) and local radiotherapy in EGFR-mutated non-small-cell lung cancer patients experiencing disease progression under TKIs could be a valid an option. Patients & methods: We included 131 patients experiencing disease progression during first-line TKI. In group A, patients received TKI beyond progression and site(s) of progression were irradiated; in group B, patients remained on TKI alone beyond progression; and group C stopped TKI at first disease progression. Results: Median overall survival resulted longer in group A versus B and C (p < 0.0001). Group A had a trend toward a longer second progression-free survival (measured from the time of first progression until second progression) versus group B (p = 0.06). Conclusion: TKI beyond progression in association with local ablative treatment is a valid treatment option in oligoprogressive patients.

Hypofractionated radiation therapy in the management of locally advanced NSCLC: a narrative review of the literature on behalf of the Italian Association of Radiation Oncology (AIRO)-Lung Working Group.

A systematic literature was performed to assess the benefit in terms of effectiveness and feasibility of hypofractionated radiotherapy (HypoRT), with or without chemotherapy (CT), in the treatment of locally advanced non-small cell lung cancer (NSCLC). We have identified all studies, published from 2007 onwards, on patients with locally advanced NSCLC treated with HypoRT with radical intent, with a minimal dose per fraction of 2.4 Gy, with or without concurrent chemotherapy. Twenty-nine studies were identified, for a total of 2614 patients. Patients were divided in the concurrent chemo-radiation therapy group (CT-RT) and radiotherapy alone (RT). In RT group, the delivered dose ranged from 45 to 85.5 Gy, with a dose/fraction from 2.4 to 4 Gy. Actuarial 2-year PFS ranged from 13 to 57.8%, and 1, 2- and 3-year overall survival (OS) ranged from 51.3 to 95%, from 22 to 68.7%, and from 7 to 32%, respectively. Acute Grade ≥ 3 esophagitis occurred in 0-15%, while late esophageal toxicity was 0-16%. Acute pneumonitis occured in 0-44%, whereas late pneumonitis occured in 0-47%, most commonly grade ≤ G3. In CT-RT group, the delivered dose ranged from 52.5 to 75 Gy, with a dose/fraction ranging from 2.4 to 3.5 Gy. Actuarial 2-year PFS ranged from 19 to 57.8%, and OS at 1, 2 and 3 years ranged from 28 to 95%, 38.6 to 68.7%, and 31 to 44%, respectively. Acute Grade 2 and 3 esophagitis occurred in 3-41.7%, while late esophageal toxicity occurred in 0-8.3%. Acute pneumonitis ranged from 0 to 23%, whereas late pneumonitis occured 0-47%. HypoRT seems to be safe in patients with locally advanced NSCLC. The encouraging survival results of several studies analyzed suggest that hypofractionated radiation schemes should be further investigated in the future.