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Pelvic arteriovenous malformation is a rare vascular abnormality, espescially in male patients, and is difficult to treat because of its nature supplied by multiple arterial feeders. We report a 70-year-old male patient admitted due to symptoms of benign prostatic hyperplasia. Ultrasound was performed initially, and no other abnormalities were found other than an enlarged prostate. CT scan later demonstrated a pelvic arteriovenous malformation adjacent to the prostate, with multiple arterial feeders from the right internal iliac artery. Angiography confirmed the diagnosis, and transaterial embolization was successfully done. The symptoms disappeared several days later, and the patient remained asymptompmatic during follow-up.

Stereotactic radiotherapy is a very hypofractionated radiotherapy (>7.5Gy per fraction), and therefore is more likely to induce late toxicities than conventional normofractionated irradiations. The present study examines four frequent and potentially serious late toxicities: brain radionecrosis, radiation pneumonitis, radiation myelitis, and radiation-induced pelvic toxicities. The critical review focuses on the toxicity scales, the definition of the dose constrained volume, the dosimetric parameters, and the non-dosimetric risk factors. The most commonly used toxicity scales remain: RTOG/EORTC or common terminology criteria for adverse events (CTCAE). The definition of organ-at-risk volume requiring protection is often controversial, which limits the comparability of studies and the possibility of accurate dose constraints. Nevertheless, for the brain, whatever the indication (arteriovenous malformation, benign tumor, metastasis of solid tumors...), the association between the volume of brain receiving 12Gy (V12Gy) and the risk of cerebral radionecrosis is well established for both single and multi-fraction stereotactic irradiation. For the lung, the average dose received by both lungs and the V20 seem to correlate well with the risk of radiation-induced pneumonitis. For the spinal cord, the maximum dose is the most consensual parameter. Clinical trial protocols are useful for nonconsensual dose constraints. Non-dosimetric risk factors should be considered when validating the treatment plan., (Copyright © 2023 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Despite recent advances, the prognosis of pancreatic adenocarcinomas remains poor, even for patients with resectable tumors. For these latter, new approaches based on neoadjuvant treatment have been developed. Two components are used: chemotherapy and radiation therapy (RT). Indeed, pre-operative RT has many advantages in terms of efficacy and tolerance. It increases notably the chances of subsequent complete tumor resection. Several prospective trials are currently ongoing to clarify its place in the therapeutic arsenal. Another crucial question is to know which is the best RT technique: conventional normofractionated chemoradiotherapy or hypofrationated stereotactic body RT?, (Copyright © 2022 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Major advances have been made in precision medicine of breast cancer patients with a series of molecular targeted therapies now in clinical use or in late clinical development. These new therapeutic measures need to be integrated with local treatments, particularly with radiation therapy in both curative and advanced settings. Although a synergistic effect could be obtained between targeted therapies and irradiation, potential safety concerns should be carefully considered. At present, scarce evidence exists due to a lack of quality assurance on radiation therapy in pivotal trials of new drugs and missing reports on safety in case of concurrent radiation therapy, commonly administered with heterogenous doses and fractionations, especially in advanced disease. A major contribution for effectively combining radiation and targeted therapies in breast cancer could derive from clinically relevant preclinical studies. This review integrates preclinical and clinical evidence on how targeted agents and radiation therapy could be combined to help physicians in their daily clinical practice and to improve the clinical management of patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Locally advanced Head and neck squamous cell carcinoma (SCCHN) represents a common oncologic pathology in older adults (OA). While radiotherapy represents a cornerstone in this context, it is unclear what is the optimal radiation regimen for SCCHN in the palliative setting, especially for OA. This article addresses issues related to palliative radiotherapy (PRT) in this setting with a focus on treatment modalities and toxicity. We also explore the use of quality of life and geriatric assessment in this setting. Medline, Scopus and Embase databases were queried for articles in this setting. We included studies published from January 1, 2000 through June 1, 2020, that were independently evaluated by two authors. Analyzed endpoints were progression free survival (PFS), overall survival (OS) and PRT toxicities. The meta-analysis was performed using Stata v.14. A total of 33 studies were included in this meta-analysis. The pooled median OS is 7.7 months, 2-years OS was worse for higher radiation dose (p = 0.02). The pooled median PFS was 5.4 months, PFS was influenced by EQD2 (p = 0.01), with patients receiving an EQD2 < 40 Gy that presented a poorer outcome. Regarding acute toxicities, most common pooled G3 toxicities were mucositis (7%) and dysphagia (15%). Among late toxicity, most common G3 toxicity was dysphagia in 7% of patients. Radiotherapy should be the most effective palliative treatment in symptomatic SCCHN OA. A tailored approach, guided by geriatric tools, would be indicated to choose the right therapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The tumor microenvironment is a complex mix of cancerous and noncancerous cells (especially immune cells and fibroblasts) with distinct metabolisms. These cells interact with each other and are influenced by the metabolic disorders of the host. In this review, we discuss how metabolic pathways that sustain biosynthesis in cancer cells could be targeted to increase the effectiveness of cancer therapies by limiting the nutrient uptake of the cell, inactivating metabolic enzymes (key regulatory ones or those linked to cell cycle progression), and inhibiting ATP production to induce cell death. Furthermore, we describe how the microenvironment could be targeted to activate the immune response by redirecting nutrients toward cytotoxic immune cells or inhibiting the release of waste products by cancer cells that stimulate immunosuppressive cells. We also examine metabolic disorders in the host that could be targeted to inhibit cancer development. To create future personalized therapies for targeting each cancer tumor, novel techniques must be developed, such as new tracers for positron emission tomography/computed tomography scan and immunohistochemical markers to characterize the metabolic phenotype of cancer cells and their microenvironment. Pending personalized strategies that specifically target all metabolic components of cancer development in a patient, simple metabolic interventions could be tested in clinical trials in combination with standard cancer therapies, such as short cycles of fasting or the administration of sodium citrate or weakly toxic compounds (such as curcumin, metformin, lipoic acid) that target autophagy and biosynthetic or signaling pathways., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background and Purpose: Between 30% and 47% of patients treated with definitive radiotherapy (RT) for prostate cancer are at risk of intraprostatic recurrence during follow-up. Re-irradiation with stereotactic body RT (SBRT) is emerging as a feasible and safe therapeutic option. However, no consensus or guidelines exist on this topic. The purpose of this ESTRO ACROP project is to investigate expert opinion on salvage SBRT for intraprostatic relapse after RT., Materials and Methods: A 40-item questionnaire on salvage SBRT was prepared by an internal committee and reviewed by a panel of leading radiation oncologists plus a urologist expert in prostate cancer. Following the procedure of a Delphi consensus, 3 rounds of questionnaires were sent to selected experts on prostate re-irradiation., Results: Among the 33 contacted experts, 18 (54.5%) agreed to participate. At the end of the final round, participants were able to find consensus on 14 out of 40 questions (35% overall) and major agreement on 13 questions (32.5% overall). Specifically, the consensus was reached regarding some selection criteria (no age limit, ECOG 0-1, satisfactory urinary flow), diagnostic procedures (exclusion of metastatic disease, SBRT target defined on the MRI) and therapeutic approach (no need for concomitant ADT, consideration of the first RT dose, validity of Phoenix criteria for salvage SBRT failure)., Conclusion: While awaiting the results of ongoing studies, our ESTRO ACROP Delphi consensus may serve as a practical guidance for salvage SBRT. Future research should address the existing disagreements on this promising approach., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The purpose of this study was to report preliminary data of a randomized phase III trial comparing hypofractionated whole breast irradiation (HWBI) and accelerated partial breast irradiation (APBI) using volumetric modulated arc therapy (VMAT)., Material and Methods: The HYPAB trial enrolled postmenopausal women with biopsy-proven infiltrating breast cancer, clinically negative axilla, single T1 to T2 tumors, who were treated with breast-conserving surgery. Patients were randomized 1:1 after surgery to HWBI (40.5 Gy whole breast, 48.0 Gy to surgical bed, 15 fractions over 3 weeks) or APBI (30 Gy delivered in 5 fractions of 6 Gy given on alternate days on the surgical bed). Cosmetic outcome was the primary end point of the study., Results: A total of 172 patients were enrolled. After a median follow-up of 36 months, 5 local failures and 3 locoregional failures were recorded, with no difference between the 2 treatment arms. Use of HWBI as compared with APBI was significantly correlated with increased incidence of overall (62% vs. 14%; P < .001) and grade 2 (18% vs. 1%; P < .001) acute skin toxicity. APBI was correlated with a lower incidence of overall late toxicity as compared with HWBI (18% vs. 41%; P = .001), but no significant difference was found in term of occurrence of grade 2 events (1% vs. 4%; P = NS). At comparative assessment between baseline and post-radiotherapy evaluation, impairment in cosmetic outcome was reported in 19 (11%) patients. Owing to premature closure of the study, no per-protocol comparison between the treatment arms was performed., Conclusion: APBI with the VMAT technique is safe and feasible, with lower acute toxicity when compared with HWBI., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: The purpose of this study was to evaluate the impact of breast size on long-term toxicity and cosmesis in patients with breast cancer treated with hypofractionated simultaneous integrated boost (SIB) using volumetric modulated arc therapy (VMAT)., Patients and Methods: Patients with early stage breast cancer were treated with 3-week hypofractionated SIB-VMAT to the whole breast (40.5 Gy) and tumor bed (48 Gy). Two cohorts were identified: small/medium- (< 1000 cm 3 ) and large- (> 1000 cm 3 ) breasted patients. Acute and late (at 2 and 5 years) skin toxicity and cosmetic data were analyzed. Univariate and multivariate analysis evaluated associations between toxicity and dosimetric/anatomical variables., Results: From August 2010 to March 2017, a total of 1160 patients were treated; 831 had at least 2 years of follow-up and were analyzed. Treated skin area (TSA) receiving at least 20 Gy > 400 cm 2 and V 105% of Boost > 5 cm 3 were significant predictors for acute skin toxicity. Multivariate analysis at 2 years was significant for boost volume > 70 cm 3 , TSA > 400 cm 2 , and breast size > 1500 cm 3 . At 5 year analysis (352 patients), none of the analyzed variables was significant. For cosmetic outcome, only the breast size (> 1000 cm 3 ) and the boost size > 70 cm 3 at 2 and 5 years, respectively, confirmed significance., Conclusions: The TSA > 400 cm 2 resulted as a significant predictor of both acute and late skin toxicity at 2 years; however, at 5 years, no breast size or dosimetric parameter suggested indications for increased toxicity. A worse cosmetic outcome was recorded at the 2-year follow up for large breasts, but was not confirmed at the 5-year follow-up. These long-term data suggest that hypofractionated SIB-VMAT is a viable modality also in large-breasted patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: In the context of metastatic breast cancer, dissemination to the liver is a frequent occurrence. We aimed to evaluate the outcome and toxicity of metastatic breast cancer with liver oligometastases treated with metastases-directed therapies (MDTs), including surgery, stereotactic body radiation therapy, or thermal ablation (radiofrequency or microwaves)., Patients and Methods: We included patients with diagnosis of 1 to 5 liver metastases. Selection criteria included also age > 18 years; Eastern Cooperative Oncology Group performance status 0 to 2; absence of extra-hepatic disease or other controlled metastatic sites. Endpoints were liver progression-free survival (LPFS), progression-free survival (PFS), and overall survival., Results: A total of 72 patients were included. Previous local treatments were performed in 13 (18.1%) patients, whereas systemic therapy was used in 81.9% of cases. Treatment of choice was stereotactic body radiation therapy in 54 (75%) patients followed by surgery (13 patients; 18%) and thermal ablation (5 patients; 7%). With a median follow-up of 26.2 months, LPFS at 1 and 2 years was 52.4% and 38.8%, respectively. The number of metastases predicted LPFS (hazard ratio [HR], 1.70; P = .004). Rates of PFS were 38.7% and 22% at 1 and 2 years, respectively. Systemic therapy before MDT (HR, 2.89; P = .016) was correlated with PFS. Overall survival at 1 and 2 years was 95.5% and 76.9%, respectively. Human epidermal growth factor receptor 2 status correlated with survival (HR, 1.82; P = .010)., Conclusion: Combination of systemic therapy with liver MDT in oligometastatic breast cancer results in durable disease control in a significant proportion of patients. Tumor biology, prior treatment, and extent of disease may be useful to guide the decision to add MDT to standard therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Caloric starvation, as well as various diets, has been proposed to increase the oxidative DNA damage induced by radiotherapy (RT). However, some diets could have dual effects, sometimes promoting cancer growth, whereas proposing caloric restriction may appear counterproductive during RT considering that the maintenance of weight is a major factor for the success of this therapy. A systematic review was performed via a PubMed search on RT and fasting, or caloric restriction, ketogenic diet (>75% of fat-derived energy intake), protein starvation, amino acid restriction, as well as the Warburg effect. Twenty-six eligible original articles (17 preclinical studies and 9 clinical noncontrolled studies on low-carbohydrate, high-fat diets popularized as ketogenic diets, representing a total of 77 patients) were included. Preclinical experiments suggest that a short period of fasting prior to radiation, and/or transient caloric restriction during treatment course, can increase tumor responsiveness. These regimens promote accumulation of oxidative lesions and insufficient repair, subsequently leading to cancer cell death. Due to their more flexible metabolism, healthy cells should be less sensitive, shifting their metabolism to support survival and repair. Interestingly, these regimens might stimulate an acute anticancer immune response, and may be of particular interest in tumors with high glucose uptake on positron emission tomography scan, a phenotype associated with poor survival and resistance to RT. Preclinical studies with ketogenic diets yielded more conflicting results, perhaps because cancer cells can sometimes metabolize fatty acids and/or ketone bodies. Randomized trials are awaited to specify the role of each strategy according to the clinical setting, although more stringent definitions of proposed diet, nutritional status, and consensual criteria for tumor response assessment are needed. In conclusion, dietary interventions during RT could be a simple and medically economical and inexpensive method that may deserve to be tested to improve efficiency of radiation., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Hemosuccus Pancreaticus (HP) is a very rare upper gastro-intestinal haemorrhagic event whose causes can be aneurismal lesions, acute and chronic pancreatic inflammatory conditions, and pancreatic masses. We present 2 cases of patients who underwent stereotactic radiotherapy for pancreatic lesions who manifested signs of HP after treatment. Two male patients were diagnosed with an inoperable locally advanced pancreatic cancer and underwent 8 cycles of chemotherapy followed by stereotactic radiotherapy to the pancreatic lesion delivering 40Gy in 8 fractions. The first patient complained of melena and had a necrotic tumoural mass with a new aneurysmal bulge 3 months after the SBRT. A stent was placed in the aneurysmal lesion, however, a few days later, the bleeding occurred again and the patient died. The other patient had local tumour progression 12 months after SBRT with a pancreatic mass eroding the near vessels. He developed a fast and massive bleeding. HP may occur after SBRT. Inflammation of the tumour mass can lead to erosion of the vessels with subsequent bleeding. The radiotherapy treatment may have contributed to the HP genesis. The treatment is complex and consists of the placement of a stent or surgery., (Copyright © 2020 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Adrenal gland metastases occur in up to 20% of patients with non-small-lung cancer. In selected cases with limited burden of disease, surgery may be offered to improve patient outcome; furthermore, tissue analysis would provide useful information on genotype of primary and secondary neoplasms., Materials and Methods: We report our experience in the management of adrenal metastasis by retrospectively reviewing data of 21 consecutive patients treated with curative intent to the primary tumor followed by adrenalectomy in a 15-year time span. Targeted next generation sequencing was performed to compare molecular profile of primary lung cancers and adrenal metastases. Patient overall survival was assessed by Kaplan-Meier method, using adrenalectomy as time zero. Survival rates were compared by log rank test., Results: No surgery-related mortality or morbidity was observed. Median survival was 50 months; 5-year overall survival was 34.5% (95% confidence interval, 12%-66%). No significant survival difference was observed with respect to timing of onset (synchronous vs. metachronous) or side (homolateral vs. contralateral) of adrenal metastasis, T or N status of primary lung cancer, mutational asset, and histologic type. Mutations in TP53 genes were found in 61% and 85% of primary and metastatic tumors, respectively. In 3 of 15 cases, we found differences between molecular mutation patterns in primary lung cancer and corresponding adrenal metastasis., Conclusions: Adrenalectomy is a safe and effective approach in selected cases. Discordance between primary and secondary tumor mutational profile was found in 20% of assessable patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Oligometastatic head and neck squamous cell carcinoma (HNSCC) is a rare entity with no evidence-based treatment recommendations available to support the use of local ablative therapies. The aim of our study was to report on the clinical benefit of stereotactic body radiotherapy (SBRT) for patients with lung-only oligometastases, defined by the presence of 1 to 5 pulmonary lesions., Material and Methods: SBRT was applied in case of single lesions deemed amenable to local treatment only ("de novo" pattern) or after first line chemotherapy at time of disease oligoprogression ("induced" pattern). To assess the potential deferral of systemic therapy in both time points, we analyzed time to progression (TTP) defined as the time from the last day of SBRT to disease progression or death from any cause. Cox regression analysis was performed to identify predictive factors of better outcome., Results: Twenty-seven patients were retrospectively evaluated. The majority (81.5%) had HPV negative disease and a "de novo" oligometastatic pattern (78.6%). The median maximum lesion diameter and target size were 1.5 cm and 22.7 cc, respectively. At a median follow-up of 22 months (range 6-73), the median TTP was 10 months (95% CI: 9.5-21.1), with 1- and 2-year rates of 56.2% and 35%, respectively. The objective response rate at 3 months after SBRT was 75%. At multivariate analysis baseline T3/T4 stage had a HR for worse outcome of 5.38 (p = 0.033). Acute toxicity was minimal (G1/G2 of 14.8%)., Conclusion: In properly selected oligometastatic patients, SBRT has potential for sustained deferral of systemic treatment., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Oligometastatic stage IV non-small lung cancer (NSCLC) patients have a 5-year overall survival of 30% versus 4% to 6% in historical cohorts of stage IV NSCLC patients. We reviewed data and patterns of care of patients affected by oligometastatic NSCLC in our center between 2001 and 2017., Methods: We retrospectively reviewed clinical and pathological files of all patients with lung cancer and synchronous isolated adrenal or brain metastases, or both, treated by locally ablative treatments (surgery or radiotherapy, or both) of both primary cancer and distant metastasis. Statistical analysis was performed to assess the effect on overall survival of patient- and tumor-related characteristics and therapeutic approaches. Overall survival was assessed by the Kaplan-Meier method. Survival rates were compared by log-rank test. Significance was accepted at a level of p of less than 0.05., Results: Our department treated 51 patients affected by NSCLC and synchronous brain metastasis (n = 41), adrenal metastasis (n = 9), or both (n = 1). Median survival was 42 months (95% confidence interval, 22.3 to 63.7). Overall survival was 62% at 2 years and 34.4% at 5 years. A univariate and multivariate analysis the positive prognostic factors for survival was cessation of smoking (p = 0.006) and lymphovascular and perineural spreading in the tissues (p = 0.024)., Conclusions: In selected oligometastatic synchronous NSCLC patients, a multimodality approach encompassing radical treatment of the primary tumor and ablative treatment of concurrent metastases is recommended, with encouraging results. Smoking cessation is a part of the treatment sequence., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Urothelial cancer is one of the most common malignancies; after relapse or disease progression available therapeutic options are limited. We analyze efficacy and toxicity of local treatment on metastases using stereotactic body radiation therapy (SBRT) in selected patients with oligometastatic disease from urothelial cancer. A significant percentage of treated lesions achieved local control, with a promising overall response rate., Objectives: to analyze efficacy and toxicity of local treatment on metastases using stereotactic body radiation therapy (SBRT) in selected patients with oligometastatic disease from urothelial cancer., Materials and Methods: Data from clinical records of 19 patients treated in our institution since May 2011 to October 2017 with SBRT for oligometastatic/oligoprogressive urothelial carcinoma were retrospectively collected. Clinical outcomes in terms of local control (LC), response rate, symptoms control, progression free and overall survival (PFS and OS), and adverse events were analyzed and reported., Results: Nineteen patients were treated on 25 metastatic lesions; 5 of them received treatment on multiple sites. After an average follow up of 11.5 months, LC was achieved in 17 lesions (68%) and there was no local recurrence in lesions with complete or partial response. OS was 13.8 months. Adverse events were reported only in 3 patients (5 overall events). No late toxicity was reported., Conclusions: An approach consisting in SBRT for local treatment of oligometastatic or persistent disease can be effective and safe in selected patients. Prospective studies are needed, to find correct selection criteria and optimal dose and fractionation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Stereotactic ablative body radiation therapy (SBRT) has evolved as the standard treatment for patients with inoperable stage I non-small-cell lung cancer (NSCLC). We report the results of a retrospective analysis conducted on a large, well-controlled cohort of patients with stage I to II NSCLC who underwent lobectomy (LOB) or SBRT., Materials and Methods: One hundred eighty-seven patients with clinical-stage T1a-T2bNoMO NSCLC were treated in 2 academic hospitals between August 2008 and May 2015. Patients underwent LOB or SBRT; those undergoing SBRT were sub-classified as surgical candidates and nonsurgical candidates, according to the presence of surgical contraindications or comorbidities., Results: In univariate analysis, no significant difference was found in local control between patients who underwent SBRT and LOB, with a trend in favor of surgery (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.07-1.01; P < .053). Univariate analysis showed that overall survival (OS) was significantly better in patients who underwent LOB (HR, 0.44; 95% CI, 0.23-0.85) with a 3-year OS of 73.4% versus 65.2% for surgery and radiation therapy patients, respectively (P < .01). However, no difference in OS was observed between operable patients undergoing SBRT and patients who underwent LOB (HR, 1.68; 95% CI, 0.72-3.90). Progression-free survival was comparable between patients who underwent LOB and SBRT (HR, 0.61; P = .09)., Conclusion: SBRT is a valid therapeutic approach in early-stage NSCLC. Furthermore, SBRT seems to be very well-tolerated and might lead to the same optimal locoregional control provided by surgery for patients with either operable or inoperable early-stage NSCLC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Invasive triple negative apocrine carcinoma (TNAC) of the breast is a rare type of triple negative breast cancer. Several studies reported significantly distinct prognosis for TNAC when compared with most of the non-apocrine triple negative (NATN) tumors. This is a case-control study reporting onoutcomes from our long-term single-center experience., Patients and Methods: We analyzed the clinicopathologic features of a series of 46 TNAC tumors treated in a 15-year period. Tumor characteristics and outcomes have been compared with a homogeneous control series of 43 NATN tumors treated during the same follow-up period. Local relapse-free survival (LRFS), distant metastases-free survival (DMFS), and overall survival (OS) have been evaluated., Results: LRFS in the TNAC group was 85% and 78% at 5 and 10 years, respectively. LRFS in the NATN group was 90% and 79% at 5 and 10 years, respectively (hazard ratio [HR], 1.14; 95% confidence interval [CI], 0.41-3.19; P = .80). DMFS in the TNAC group was 85% and 85% at 5 and 10 years, respectively. DMFS in the NATN group was 85% and 75% at 5 and 10 years, respectively (HR, 0.39; 95% CI, 0.14-1.08; P = .071). OS in the TNAC group was 86% and 83% at 5 and 10 years, respectively. OS in the NATN group was 86% and 63% at 5 and 10 years, respectively. OS was significantly better in the TNAC group (HR, 0.45; 95% CI, 0.20-0.99; P = .049)., Conclusions: TNAC seems to represent a distinct group of triple negative breast cancer, characterized by a favorable long-term outcome when compared with NATN tumors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The macroautophagy machinery supports membrane remodeling and fusion events that lead to the engulfment of cytoplasmic constituents in autophagosomes and their degradation in lysosomes. The capacity of this machinery to regulate membrane adaptors and influence vesicle fusion with lysosomes seems to be used not only for autophagosomes, but also for endosomes. We summarize recent evidence that two aspects of endocytosis are regulated by parts of the macroautophagy machinery. These are recruitment of adaptors for the internalization of surface receptors and the fusion of phagosomes with lysosomes. Antigen processing for MHC presentation is affected by these alternative functions of the macroautophagy machinery. Primarily extracellular antigen presentation by MHC class II molecules after phagocytosis benefits from this regulation of phagosome maturation. Furthermore, MHC class I molecules are more efficiently internalized in the presence of the core macroautophagy machinery. The identification of these alternative functions of macroautophagy proteins not only complicates the interpretation of their deficiencies in biological processes, but could also be harnessed for the regulation of antigen presentation to T cells., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Metastatic involvement of the pancreas occurs in 5% of patients affected by advanced malignancies. Surgical resection has been reported by number of authors as a valuable option to improve disease control, in particular in patients with limited disease burden and favourable histotypes; however, the benefit of this procedure has been questioned due to patient selection, technical challenges and relevant risk of perioperative mortality and severe complications. In the present study, a cohort of surgically unfit patients affected by a solitary metastasis in the pancreas from various primary tumours received stereotactic radiotherapy with an ablative dose schedule, obtaining promising local and distant disease progression-free delay with minor toxicity. This is the first report to our knowledge on the use of ablative stereotactic radiotherapy of metastasis in the pancreatic gland., (Copyright © 2017 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Objectives: The aim of our work was to report on the clinical outcome of a moderately hyprofractionated radiotherapy regimen in elderly patients affected by head and neck squamous cell carcinoma (HNSCC)., Material and Methods: HNSCC aged ≥65 deemed unsuitable for curatively-intended concurrent chemo-radiotherapy or high-dose radiotherapy by clinical judgement were further evaluated with the Geriatric 8 (G8) questionnaire and Charlson comorbidity index (CCI). In case of a G8 score ≤14, a de-intensified radiation schedule of 40 Gy delivered in 16 fractions was prescribed., Results: Thirty-six patients were treated between 2011 and 2016. The median age of the cohort was 77.5 (range: 65-91 years) with a combined ECOG PS of 2-3 in 77.8% and CCI of ≥8 in 25% patients, respectively. At a median follow-up of 13 months (range 2-62 months), the 6-month and 1-year rates of loco-regional control and progression-free survival were 42%, 28% and 36% and 20%, respectively. At univariate analysis, log-rank test showed that age >75 years (p=0.036), worse PS (ECOG≥2; p=0.027), lower G8 score (<9; p=0.027) and PTV volume greater than 200 cc (p=0.038) had a significant correlation with PFS. The negative impact of the PTV volume on PFS was the only parameter confirmed in the multivariate analysis (HR 2.68; 95% CI: 1.24-5.81, p=0.013). No grade 4-5 toxicity was observed, while 13/36 patients (36%) had G3 acute side effects., Conclusion: The hypofractionated radiation schedule evaluated provides clinical benefit with low toxicity in frail, elderly patients affected by locally advanced HNSCC., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Due to its anti-inflammatory, antifibrotic and antineoplastic properties, the PPAR gamma agonist rosiglitazone is of interest in prevention and therapy of radiation-induced toxicities. We aimed to evaluate the radioprotective effect of rosiglitazone in a mouse model of radiation-induced oral mucositis., Material and Methods: Oral mucositis was obtained by irradiation of the oral region of C57BL/6J mice, pretreated or not with rosiglitazone. Mucositis was assessed by macroscopic scoring, histology and molecular analysis. Tumor xenograft was obtained by s.c. injection of Hep-2 cells in CD1 mice. Tumor volume was measured twice a week to evaluate effect of rosiglitazone alone and combined with radiotherapy., Results: Irradiated mice showed typical features of oral mucositis, such as oedema and reddening, reaching the peak of damage after 12-15days. Rosiglitazone markedly reduced visible signs of mucositis and significantly reduced the peak. Histological analysis showed the presence of an inflammatory cell infiltrate after irradiation; the association with rosiglitazone noticeably reduced infiltration. Rosiglitazone significantly inhibited radiation-induced tnfα, Il-6 and Il-1β gene expression. Rosiglitazone controlled the increase of TGF-β and NF-kB p65 subunit proteins induced by irradiation, and enhanced the expression of catalase. Irradiation and rosiglitazone significantly reduced tumor volume as compared to control. Rosiglitazone did not protect tumor from the therapeutic effect of radiation., Conclusion: Rosiglitazone exerted a protective action on normal tissues in radiation-induced mucositis. Moreover, it showed antineoplastic properties on head-neck carcinoma xenograft model and selective protection of normal tissues. Thus, PPAR gamma agonists should be further investigated as radioprotective agents in head and neck cancer., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate the efficacy and safety of Gamma Knife Radiosurgery (GKRS) in the treatment of single and multiple brain metastases., Patients and Methods: From October 2012 to June 2014 106 patients were treated with Radiosurgery (RS) for brain metastases at University of Florence. 77 out of 106 patients had a radiological follow up and their data were analyzed. The target was defined as the enhancing lesion. The prescription dose was defined depending on tumor volume and tumor location. Each patient performed an MRI one month after GKRS for the first three months and every 3 months thereafter. Overall survival was calculated from the day of RS until death. Local recurrence (LR) was defined as radiologic growth of the irradiated lesion, while distant brain recurrence (DBR) was the evidence of brain lesion outside the previous irradiated field. Both the LR and DBR were calculated from the RS till the day of radiological evidence of relapse. The correlations within patient and disease characteristics and the outcomes of survival and disease control were analyzed., Results: Mean follow up was 7.2 ± 4.8 months (range: 2.4-22.8 months). At the time of analysis 21 patients (27.3%) were dead. The overall survival (OS) at 1 year was 74%. On univariate Cox Regression analysis female gender (p=0.043, HR: 0.391, 95% CI: 0.157-0.972) and age >65 years (p=0.003 HR: 4.623, 95% CI: 1.687-12.663) were predictive for survival. On multivariate analysis, age older than 65 years (p=0.005HR: 4.254, 95% CI: 1.544-11.721) was confirmed as associated with worsened overall survival. 19 patients (24.7%) had recurrence in the radiosurgery field. The median time to local failure was 4.8 ± 2.0 months (range: 1.8-9.4 months) from GKRS. On Cox Regression univariate analysis, the only factor associated with higher risk of local failure was a number of treated lesions more than 4 (p=0.015, HR: 3.813, 95% CI: 1.298-11.202), no significant parameters were found at the multivariate analysis. The median time to develop distant brain failure was 6 ± 4.32 months (range: 1.08-21.6 months). Median distant brain control was 74% at 1 year. None of the factors analyzed was statistically significant for the distant brain relapse. The radiosurgery treatment was well tolerated. One patient treated for seven metastases developed seizures 8h after GKRS, he was treated with steroids and anticonvulsants. One patient had radiologic evidence of radionecrosis without any neurological symptoms., Conclusions: In well-performing patients with stable systemic disease radiosurgery can be performed as an exclusive treatment for brain metastases. Younger patients could have a greater benefit from the RS, on the other hand our finding confirm no correlation between the survival outcome and the number of lesions treated., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Hormone therapy is the most prescribed systemic therapy for patients with breast cancer (BC). Some patients fail to respond to tamoxifen; one pathway seems to involve human epidermal growth factor receptor 2 (HER2) overexpression. To better understand this matter, we reviewed our single-center experience of premenopausal patients who were chemotherapy naive and treated with 5 years of tamoxifen for early-stage BC by focusing on estrogen receptor (ER), progesterone receptor, HER2 status, and Ki-67 proliferative index., Patients and Methods: We reviewed 425 patients treated with tamoxifen for early-stage BC. Previous solid tumors, age less than 18 years, BC recurrences or contralateral tumor, tamoxifen discontinuation, adjuvant chemotherapy, and a follow-up shorter than 6 months were considered exclusions criteria of the study., Results: At a mean follow-up of 8.1 years, the mean (SD) time to local relapse was 6.7 ± 3.6 years; range, 2.0-10.7 years), whereas the mean (SD) time to distant metastases was 4.7 ± 2.3 years; range, 2.2-8.8 years). HER2 status did not influence local relapse-free survival (log-rank test, 0.40), distant metastases-free survival (log-rank test, 0.72), and overall survival rate (log-rank test, 0.87)., Conclusions: Resistance to tamoxifen is a complex trait, and its pathway is still unclear; in patients with BC, a multidisciplinary approach is highly recommended. In our experience, we did not find a statistically significant difference in tamoxifen treatment efficacy according to HER2 status., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Ferula communis (L.), a plant belonging to Apiaceae, is widely present in Sardinia, Italy. Currently, interest in F. communis focuses on the presence of two chemotypes in the wild. One chemotype is poisonous to animals, whereas the other chemotype is non-poisonous. Polyphenol oxidase (PPO) has been extracted and partially purified from the two chemotypes of F. communis. The biochemical characterization of the enzymes showed significant differences. In particular, while the two PPOs were not able to use 6- and 7-hydroxycoumarin as substrates, they showed distinct specificity for 6,7- and 7,8-dihydroxycoumarin. Significant differences in the enzyme behavior towards common PPO inhibitors were also observed. In addition, activation energy and activation energy for denaturation were determined, showing significant differences between FP-PPO and FNP-PPO, particularly for denaturation kinetics. The possible roles of the two PPOs in determining differences in composition and toxicity of the two F. communis chemotypes are also discussed., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The incidence of vascular and lymphatic emboli in a specimen of resected non-small cell lung cancer is variable according to different authors' experience as well as prognostic significance in patients treated by surgery. We aimed at evaluating these factors in an unselected population of patients with primary pulmonary adenocarcinoma treated by major surgical resection., Methods: Clinical and pathology records of all patients treated by lobectomy or pneumonectomy and nodal dissection for pulmonary adenocarcinoma between June 2001 and June 2006 were retrospectively reviewed. Impact on survival of age, sex, tobacco use, history of chronic obstructive pulmonary disease, extent of resection, pathologic stage, and presence of vascular and lymphatic emboli was studied by univariate analysis and multivariate analysis (for factors significantly associated with survival at univariate analysis)., Results: Five hundred three patients underwent lobectomy or pneumonectomy with nodal dissection for pathologically proven lung adenocarcinoma. There were 355 men and 148 women; mean age was 61.1 years, and 181 patients were 65 years old or older; 87% were current or former smokers; 90.3% had pulmonary lobectomy; and 9.7% had pneumonectomy. Pathologic stages were I, II, and III/IV in 45%, 17.9%, and 37.1%, respectively. Vascular emboli and lymphatic emboli were found in 183 of 503 patients (36.4%) and 149 of 503 (29.6%), respectively. Overall 5-year survival for the whole population was 50.7%. At univariate analysis, age more than 65 years (p=0.0019), chronic obstructive pulmonary disease (p=0.042), extent of resection (p=0.047), pathologic stage (p<0.0000001), T size (p=0.0020), T and N variables (p=0.0000016 and p<0.0000001, respectively), presence of vascular emboli (p=0.026), and presence of lymphatic emboli (p=0.000021) were associated with worse prognosis. At multivariate analysis, age more than 65 years (p=0.0047, relative risk 1.5), stage I versus II versus III versus IV (p=0.00000032), and presence of lymphatic emboli (p=0.05, relative risk 1.34) were identified as independent negative prognostic factors., Conclusions: In an unselected population of patients with pulmonary adenocarcinoma treated by lobectomy or pneumonectomy, the presence of lymphatic emboli is an independent negative prognostic factor., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Cerebral cavernous malformations (CCMs) are CNS vascular anomalies associated with seizures, headaches and hemorrhagic strokes and represent 10-20% of cerebral lesions. CCM is present in 0.1-0.5 of the population. This disorder most often occurs sporadically but may also be familial. Familial cases are inherited as a dominant trait with incomplete penetrance and are estimated to account for KRIT1 10-40% of the patients. The identification of the genes involved in such disorders allows to characterize carriers of the mutations without clear symptoms. The first gene involved in CCM1 is KRIT1. In addition to two other genes have been described: MGC4607 (CCM2) and PDCD10 (CCM3). We selected 13 patients belonging to seven Sardinian families on the basis of clinical symptoms and Magnetic Resonance results. In MGC4607 gene an undescribed exon five deletion likely producing a truncated protein was identified in one family. In two patients with clear phenotype and in three asymptomatic relatives a 4 bp deletion in exon 9 of KRIT1 gene, leading to a premature stop codon, was detected. A unique nonsense mutation (C329X) has been found in seven patients and two asymptomatic subjects belonging to four unrelated families. Haplotype analysis revealed a common origin of this mutation. These data suggest a "founder effect" in Sardinia for the C329X mutation, similar to other mutations described in different populations.

Objective: The only known genetic cause of early-onset primary torsion dystonia is the GAG deletion in the DYT1 gene. Due to the reduced penetrance, many mutation carriers remain clinically asymptomatic, despite the presence of subclinical abnormalities, mainly in the motor control circuitry. Our aim was to investigate whether the DYT1 mutation impairs the inner simulation of movements, a fundamental function for motor planning and execution, which relies upon cortical and subcortical systems, dysfunctional in dystonia., Methods: DYT1 manifesting patients, DYT1 non-manifesting carriers and control subjects were asked to fixate body (hand, foot, face) or non-body (car) stimuli on a computer screen. Stimuli were presented at different degrees of orientations and subjects had to mentally rotate them, in order to give a laterality judgement. Reaction times and accuracy were collected., Results: DYT1 carriers, manifesting and non-manifesting dystonic symptoms, were slower in mentally rotating body parts (but not cars) than control subjects., Conclusions: The DYT1 gene mutation is associated with a slowness in mental simulation of movements, independently from the presence of motor symptoms., Significance: These findings suggest that the cognitive representation of body movements may be altered subclinically in dystonia, thus contributing to the endophenotypic trait of disease.

Anagyris foetida extracts were investigated in preliminary cytotoxic tests against two tumour cell lines. Chromatographic separations on active extracts led to the isolation of two alkaloids, anagyrine (1) and baptifoline (2), as well of isorhamnetin (3) and syringin 4-O-beta-D-glucopyranoside (4). In vitro cytotoxicity of compounds 1-3 was also evaluated.

Background: The combination of indomethacin, prochlorperazine and caffeine (IPC) is one of the most utilized formulations for the treatment of migraine attacks in Italy. Several patients suffering from chronic headache overuse this symptomatic medication in the attempt to control their headache., Objective: To verify whether overuse of IPC combination by chronic headache patients is associated with modified disposition of its components., Methods: We studied indomethacin, prochlorperazine, and caffeine disposition in 34 female subjects suffering from primary headaches, subdivided into four groups: eight migraine patients occasionally using IPC combination suppositories-group 1; nine patients with chronic headache and probable medication-overuse headache, daily taking one or more suppositories of the IPC combination-group 2; 11 migraine patients occasionally using "mild" suppositories of the IPC combination-group 3; six migraine patients occasionally taking tablets of the IPC combination-group 4. The IPC combination habitually used was administered to each patient. Blood samples were taken at baseline and at fixed intervals up to 6h after administration. Plasma levels of indomethacin and prochlorperazine were assayed by high-pressure liquid chromatographic (HPLC) method; caffeine levels were assayed by enzyme multiplied immunoassay test (EMIT). Pharmacokinetic parameters were calculated by means of a computer software (P K Solutions 2.0. Summit Research Services, Montrose, CO, USA)., Results: Half-life of indomethacin was longer, and clearance lower, in group 2 than in the other groups; AUC of indomethacin in group 2 was twice that in group 1 (P<0.05, Newman-Keuls' test). Peak concentrations and AUC(0-->infinity) of caffeine were significantly higher in group 2 than in the other groups (P<0.05, Newman-Keuls' test). We could not define prochlorperazine disposition because it was not detectable in the majority of blood samples., Conclusion: Overuse of IPC combination in chronic headache patients is associated with increased plasma levels of indomethacin and caffeine, and with delayed elimination of indomethacin; the high and sustained concentrations of these drugs may cause rebound headache, organ damages, and perpetuate medication-overuse headache.

We report on two patients with reflex periodic spasms (PS) triggered by eating. Both patients also had significant cognitive and motor deficits. In both patients, reflex eating PS started during meal and occurred repeatedly at intervals of about 5-30 s, and the whole episode lasted about 10-15 min with 15-20 consecutive PS. Clinically, each PS was characterized by the trunk and head flexion, eyeball elevation, abduction of the upper limbs, and loss of consciousness. Ictal EEG recordings of PS revealed high-voltage sharp slow waves followed by a brief 1-2s voltage attenuation. Simultaneous EMG recording of right and left deltoid muscles revealed an abrupt increase of tone lasting 0.5-1.5s. In two patients, the origins of reflex PS were perirolandic suprasylvian and temporolimbic, respectively, because the first patient had focal epilepsy associated with cortical malformation including bilateral opercular dysplasia and the second one had cryptogenic temporal lobe epilepsy.

The use of medicinal and aromatic plants was investigated in a group of 200 elderly people (60-104-year-old) from Villagrande Strisaili (Ogliastra, Sardinia, Italy), recording the use of 78 species for the treatment of various ailments, especially of the respiratory tract, the mouth, and the skin. Seventeen plants had never been described as medicinal species in peninsular Italy, while a few others turn out to have an original use for Sardinia., (Copyright 2004 Elsevier B.V.)

Sardinian wild Euphorbia pithyusa, E. semiperfoliata, E. dendroides and E. characias seed oils were analyzed for their fatty acids, unsaponifiable and tocopherol content. Total tocopherol content showed a wide variability, ranging from 939 mg/kg in E. semiperfoliata seeds to its absence in E. characias. The results on tocopherol content were statistically correlated with both 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging test and the beta-carotene bleaching antioxidant test. All seeds were rich in linolenic acid, while no uncommon fatty acids were detected.

Needles from a series of wild yews (Taxus baccata L.) from Sardinia were investigated for their contents of 10-deacetyl baccatin III (DAB-III, 1), paclitaxel (Taxol) (2) and taxine (3). Despite a common geographical origin, ample variation of the taxoid profile was discovered, and several samples were surprisingly devoid of all terpenoid markers above. This finding is unprecedented within the European yew, while the general lack of taxine might rationalize the observation that most plants investigated are actively and impunently browsed by goats.

The results of an ethnobotanical survey in the territory of Fluminimaggiore (south-western Sardinia) are presented. Sixty-five species with medicinal properties used for different pathologies, such as diseases of the skin and of the gastro-intestinal system have been recorded.