Pattern OF recurrence AFTER stereotactic body radiotherapy OF nodal lesions: a single-institution analysis.

OBJECTIVES: Stereotactic body radiotherapy (SBRT) and/or single fraction stereotactic body radiosurgery (SRS) are effective treatment options for the treatment of oligometastatic disease of lymph nodes. Despite the encouraging local control rate, progression-free survival remains unfair due to relapses that might occur in the same district or at other sites. The recurrence pattern analysis after nodal local ablative RT (laRT) in oligometastatic patients is presented in this study. METHODS: The pattern of failure of patients with nodal metastases who were recruited and treated with SBRT in the Destroy-1 or SRS in the Destroy-2 trials was investigated in this single-institution, retrospective analysis. The different relapsed sites following laRT were recorded. RESULTS: Data on 190 patients who received SBRT or SRS on 269 nodal lesions were reviewed. A relapse rate of 57.2% (154 out of 269 nodal lesions) was registered. The pattern of failure was distant in 88 (57.4%) and loco-regional in 66 (42.6%) patients, respectively. The most frequent primary malignancies among patients experiencing loco-regional failure were genitourinary and gynaecological cancers. Furthermore, the predominant site of loco-regional relapse (62%) was the pelvic area. Only 26% of locoregional relapses occurred contra laterally, with 74% occurring ipsilaterally. CONCLUSIONS: The recurrence rates after laRT for nodal disease were more frequent at distance, with the exception of genitourinary and gynaecological cancers. Indeed, the most common scenarios for locoregional relapse appear to be genitourinary cancer and the pelvic site. In addition, recurrences often occur in the nearby nodal area of the irradiated site and failures were less common in patients who received laRT within 6 months from ENI. ADVANCES IN KNOWLEDGE: Local ablative Radiotherapy is an effective treatment in managing nodal oligometastasis. Despite the high local control rate, the progression free survival remains dismal with recurrences that can occur both loco-regionally or at distance. To understand the pattern of failure could aid the physicians to choose the best treatment strategy. This is the first study that reports the recurrence pattern of a significant number of nodal lesions treated with laRT.

Definitive chemoradiation in vulvar squamous cell carcinoma: outcome and toxicity from an observational multicenter Italian study on vulvar cancer (OLDLADY 1.1).

BACKGROUND: Vulvar carcinoma is a rather uncommon gynecological malignancy affecting elderly women and the treatment of loco-regional advanced carcinoma of the vulva (LAVC) is a challenge for both gynecologic and radiation oncologists. Definitive chemoradiation (CRT) is the treatment of choice, but with disappointing results. In this multicenter study (OLDLADY-1.1), several institutions have combined their retrospective data on LAVC patients to produce a real-world dataset aimed at collecting data on efficacy and safety of CRT. METHODS: The primary study end-point was 2-year-local control (LC), secondary end-points were 2-year-metastasis free-survival (MFS), 2-year-overall survival (OS) and the rate and severity of acute and late toxicities. Participating centers were required to fill data sets including age, stage, histology, grading as well as technical/dosimetric details of CRT. Data about response, local and regional recurrence, acute and late toxicities, follow-up and outcome measures were also collected. The toxicity was a posteriori documented through the Common Terminology Criteria for Adverse Events version 5 scale. RESULTS: Retrospective analysis was performed on 65 patients with primary or recurrent LAVC treated at five different radiation oncology institutions covering 11-year time interval (February 2010-November 2021). Median age at diagnosis was 72 years (range 32-89). With a median follow-up of 19 months (range 1-114 months), 2-year actuarial LC, MFS and OS rate were 43.2%, 84.9% and 59.7%, respectively. In 29 patients (44%), CRT was temporarily stopped (median 5 days, range 1-53 days) due to toxicity. The treatment interruption was statistically significant at univariate analysis of factors predicting LC (p: 0.05) and OS rate (p: 0.011), and it was confirmed at the multivariate analysis for LC rate (p: 0.032). In terms of toxicity profile, no G4 event was recorded. Most adverse events were reported as grade 1 or 2. Only 14 acute G3 toxicities, all cutaneous, and 7 late G3 events (3 genitourinary, 3 cutaneous, and 1 vaginal stenosis) were recorded. CONCLUSION: In the context of CRT for LAVC, the present study reports encouraging results even if there is clearly room for further improvements, in terms of both treatment outcomes, toxicity and treatment interruption management.

Risk evaluation of secondary malignancies after radiotherapy of breast cancer in light of the continuous development of planning techniques.

Secondary cancer risk is a significant concern for women treated with breast radiation therapy due to improved long-term survival rates. We evaluated the potential of new advanced automated planning algorithms together with hybrid techniques to minimize the excess absolute risk (EAR) for secondary cancer in various organs after radiation treatment for early staged breast cancer. Using CT data set of 25 patients, we generated 4 different radiation treatment plans of different complexity, including 3-dimensional conformal radiotherapy (3D-CRT), field-in-field (FinF), hybrid-IMRT (HMRT) and automated hybrid-VMAT (HVMAT) techniques. The organ-equivalent dose (OED) was calculated from differential dose-volume histograms on the basis of the "linear-exponential," "plateau," and "full mechanistic" dose-response models and was used to evaluate the EAR for secondary cancer in the contralateral breast (CB), contralateral lung (CL), and ipsilateral lung (IL). Statistical comparisons of data were performed by a Kruskal-Wallis analysis of variance. The planning objectives were fulfilled with all the planning techniques for both target coverage and organs-at-risk sparing. The differences in EAR for CB, CL and IL secondary tumor induction were not significant among the 4 techniques. For the CB and CL, the mean absolute difference did not reach 1 case of 10000 patient-years. For the IL, the mean absolute difference was up to 5 cases of 10,000 patient-years. In conclusion, the automated HVMAT technique allows an EAR reduction at the level of well-consolidated tangential 3D-CRT or FinF techniques, keeping all the HVMAT dosimetric improvements unchanged. On the basis of this analysis, the adoption of the HVMAT technique poses no increase in EAR and could be considered safe also for younger patients.

Reproducibility and stability of spirometer-guided deep inspiration breath-hold in left-breast treatments using an optical surface monitoring system.

The aim of this study was to evaluate the reproducibility and stability of left breast positioning during spirometer-guided deep-inspiration breath-hold (DIBH) radiotherapy using an optical surface imaging system (AlignRT). The AlignRT optical tracking system was used to monitor five left-sided breast cancer patients treated using the Active Breathing Coordinator spirometer with DIBH technique. Treatment plans were created using an automated hybrid-VMAT technique on DIBH CTs. A prescribed dose of 60 Gy to the tumor bed and 50 Gy to the breast in 25 fractions was planned. During each treatment session, the antero-posterior (VRT), superior-inferior (LNG), and lateral (LAT) motion of patients was continuously recorded by AlignRT. The intra-breath-hold stability and the intra- and inter-fraction reproducibility were analyzed for all breath-holds and treatment fractions. The dosimetric impact of the residual motion during DIBH was evaluated from the isocenter shifts amplitudes obtained from the 50%, 90%, and 100% cumulative distribution functions of intra-fractional reproducibility. The positional variations of 590 breath-holds as measured by AlignRT were evaluated. The mean intra-breath-hold stability during DIBH was 1.0 ± 0.4 mm, 2.1 ± 1.9 mm, and 0.7 ± 0.5 mm in the VRT, LNG, and LAT directions, with a maximal value of 8.8 mm in LNG direction. Similarly, the mean intra-breath-hold reproducibility was 1.4 ± 0.8 mm, 1.7 ± 1.0 mm, and 0.8 ± 0.5 mm in the VRT, LNG, and LAT directions, with a maximal value of 4.1 mm in LNG direction. Inter-fractional reproducibility showed better reliability, with difference in breathing levels in all fractions of 0.3 mm on average. Based on tolerance limits corresponding to the 90% cumulative distribution level, gating window widths of 1 mm, 2 mm, and 5 mm in the LAT, VRT, and LNG directions were considered an appropriate choice. In conclusion, despite the use of a dedicated spirometer at constant tidal volume, a non-negligible variability of the breast surface position has been reported during breath-holds. The real-time monitoring of breast surface using surface-guided optical technology is strongly recommended.

Observational multicenter Italian study on vulvar cancer adjuvant radiotherapy (OLDLADY 1.2): a cooperation among AIRO Gyn, MITO and MaNGO groups.

BACKGROUND: Adjuvant radiotherapy (aRT) has been shown to reduce the risk of local relapse in vulvar cancer (VC). In this multicentre study (OLDLADY-1.2), several Institutions have combined their retrospective data on VC patients to produce a real-world dataset aimed at collecting data on efficacy and safety of aRT. METHODS: The primary study end-point was the 2-year-local control, secondary end-points were the 2-year-metastasis free-survival, the 2-year-overall survival and the rate and severity of acute and late toxicities. Participating centres were required to fill data sets including age, stage, tumor diameter, type of surgery, margin status, depth of invasion, histology, grading as well technical/dosimetric details of radiotherapy. Data about response, local and regional recurrence, acute and late toxicities, follow-up and outcome measures were also collected. RESULTS: One hundred eighty-one patients with invasive VC from 9 Institutions were retrospectively identified. The majority of patients were stage III (63%), grade 2 (62.4%) squamous carcinoma (97.2%). Positive nodes were observed in 117 patients (64.6%), moreover tumor diameter > 4 cm, positive/close margins and depth of invasion deeper than 5 mm were found in 59.1%, 38.6%, 58% of patients, respectively. Sixty-one patients (33.7%) received adjuvant chemoradiation, and 120 (66.3%) received radiotherapy alone. aRT was started 3 months after surgery in 50.8% of patients. Prescribed volumes and doses heterogeneity was recorded according to margin status and nodal disease. Overall, 42.5% locoregional recurrences were recorded. With a median follow-up of 27 months (range 1-179), the 2-year actuarial local control rate, metastasis free and overall survival were 68.7%, 84.5%, and 67.5%, respectively. In term of safety, aRT leads to a prevalence of acute skin toxicity with a low incidence of severe toxicities. CONCLUSIONS: In the context of aRT for VC the present study reports a broad spectrum of approaches which would deserve greater standardization in terms of doses, volumes and drugs used.

A SHort course Accelerated RadiatiON therapy (SHARON) dose-escalation trial in older adults head and neck non-melanoma skin cancer.

OBJECTIVES: To assess feasibility and safety of a SHort-course Accelerated RadiatiON therapy (SHARON) regimen, in the treatment of non-melanoma skin cancers (NMSC) in older patients. METHODS: Old patients (age ≥ 80 years) with histological confirmed non-melanoma skin cancers were enrolled. The primary endpoint was to determine the maximum tolerated dose (MTD). Radiotherapy regimen was based on the delivery of four radiotherapy fractions (5 Gy per fraction) with a twice daily fractionation in two consecutive days. Three different level of dose were administered: 20 Gy (one cycle), 40 Gy (two cycles) and 60 Gy (three cycles). RESULTS: Thirty patients (median age: 91 years; range: 80-96) were included in this analysis. Among fourteen patients who completed the one cycle, only one (7%) experimented acute G4 skin toxicity. Twelve patients reported an improvement or resolution of baseline symptoms (overall palliative response rate: 85.8%). Nine and seven patients underwent to two and three RT cycles, respectively: of these, no G3 toxicities were recorded. The overall response rate was 100% when three cycles were delivered. The overall six-month symptom-free survival was 78.7% and 77.8% in patients treated with one course and more courses, respectively. CONCLUSIONS: Short-course accelerated radiotherapy in older patients with non-melanoma skin cancers is well tolerated. High doses seem to be more effective in terms of response rate. ADVANCES IN KNOWLEDGE: This approach could represent an option for older adults with NMSC, being both palliative (one course) or potentially curative (more courses) in the aim, accordingly to the patient's condition.

Automated hybrid volumetric modulated arc therapy (HVMAT) for whole-breast irradiation with simultaneous integrated boost to lumpectomy area : A treatment planning study.

PURPOSE: To develop an automated treatment planning approach for whole breast irradiation with simultaneous integrated boost using an automated hybrid VMAT class solution (HVMAT). MATERIALS AND METHODS: Twenty-five consecutive patients with left breast cancer received 50 Gy (2 Gy/fraction) to the whole breast and an additional simultaneous 10 Gy (2.4 Gy/fraction) to the tumor cavity. Ipsilateral lung, heart, and contralateral breast were contoured as main organs-at-risk. HVMAT plans were inversely optimized by combining two open fields with a VMAT semi-arc beam. Open fields were setup to include the whole breast with a 2 cm flash region and to carry 80% of beams weight. HVMAT plans were compared with three tangential techniques: conventional wedged-field tangential plans (SWF), field-in-field forward planned tangential plans (FiF), and hybrid-IMRT plans (HMRT). Dosimetric differences among the plans were evaluated using Kruskal-Wallis one-way analysis of variance. Dose accuracy was validated using the PTW Octavius-4D phantom together with the 1500 2D-array. RESULTS: No significant differences were found among the four techniques for both targets coverage. HVMAT plans showed consistently better PTVs dose contrast, conformity, and homogeneity (p < 0.001 for all metrics) and statistically significant reduction of high-dose breast irradiation. V55 and V60 decreased by 30.4, 26.1, and 20.8% (p < 0.05) and 12.3, 9.9, and 6.0% (p < 0.05) for SWF, FIF, and HMRT, respectively. Pretreatment dose verification reported a gamma pass-rate greater than the acceptance threshold of 95% for all HVMAT plans. In addition, HVMAT reduced the time for full planning optimization to about 20 min. CONCLUSIONS: HVMAT plans resulted in superior target dose conformity and homogeneity compared to other tangential techniques. Due to fast planning time HVMAT can be applied for all patients, minimizing the impact on human or departmental resources.

Machine-learning prediction model for acute skin toxicity after breast radiation therapy using spectrophotometry.

Purpose: Radiation-induced skin toxicity is a common and distressing side effect of breast radiation therapy (RT). We investigated the use of quantitative spectrophotometric markers as input parameters in supervised machine learning models to develop a predictive model for acute radiation toxicity. Methods and materials: One hundred twenty-nine patients treated for adjuvant whole-breast radiotherapy were evaluated. Two spectrophotometer variables, i.e. the melanin (IM) and erythema (IE) indices, were used to quantitatively assess the skin physical changes. Measurements were performed at 4-time intervals: before RT, at the end of RT and 1 and 6 months after the end of RT. Together with clinical covariates, melanin and erythema indices were correlated with skin toxicity, evaluated using the Radiation Therapy Oncology Group (RTOG) guidelines. Binary group classes were labeled according to a RTOG cut-off score of ≥ 2. The patient's dataset was randomly split into a training and testing set used for model development/validation and testing (75%/25% split). A 5-times repeated holdout cross-validation was performed. Three supervised machine learning models, including support vector machine (SVM), classification and regression tree analysis (CART) and logistic regression (LR), were employed for modeling and skin toxicity prediction purposes. Results: Thirty-four (26.4%) patients presented with adverse skin effects (RTOG ≥2) at the end of treatment. The two spectrophotometric variables at the beginning of RT (IM,T0 and IE,T0), together with the volumes of breast (PTV2) and boost surgical cavity (PTV1), the body mass index (BMI) and the dose fractionation scheme (FRAC) were found significantly associated with the RTOG score groups (p<0.05) in univariate analysis. The diagnostic performances measured by the area-under-curve (AUC) were 0.816, 0.734, 0.714, 0.691 and 0.664 for IM, IE, PTV2, PTV1 and BMI, respectively. Classification performances reported precision, recall and F1-values greater than 0.8 for all models. The SVM classifier using the RBF kernel had the best performance, with accuracy, precision, recall and F-score equal to 89.8%, 88.7%, 98.6% and 93.3%, respectively. CART analysis classified patients with IM,T0 ≥ 99 to be associated with RTOG ≥ 2 toxicity; subsequently, PTV1 and PTV2 played a significant role in increasing the classification rate. The CART model provided a very high diagnostic performance of AUC=0.959. Conclusions: Spectrophotometry is an objective and reliable tool able to assess radiation induced skin tissue injury. Using a machine learning approach, we were able to predict grade RTOG ≥2 skin toxicity in patients undergoing breast RT. This approach may prove useful for treatment management aiming to improve patient quality of life.

Bipolar Patients and Bullous Pemphigoid after Risperidone Long-Acting Injectable: A Case Report and a Review of the Literature.

Neuropsychiatric disorders are found to be associated with bullous pemphigoid (BP), an autoimmune subepidermal blistering disease. Antipsychotics have emerged as possible inducing factors of BP. However, large sample studies concerning BP associated with antipsychotics, as well as with specific mental disorders, are still lacking. Our review retrieved a few clinical studies and case reports on the topic, producing controversial results. We report for the first time a bipolar patient case presenting BP following five-month therapy with risperidone long-acting injectable (LAI). We hypothesize that the dermatological event is associated with the medication administered. The issue emerged during psychiatric consultation and was confirmed by histological examination, direct and indirect immunofluorescence studies, plus positive plasma and cutaneous BP180 and BP230 IgG. Neurodegeneration or neuroinflammation might represent a primary process leading to a cross-reactive immune response between neural and cutaneous antigens and contributing to self-tolerance failure. Furthermore, the time sequence of the shared biological mechanisms leading to clinical manifestations of the neuropsychiatric disorder and BP remains undefined. BP comorbid with bipolar disorder might occasionally represent a serious health risk and affect patients' physical and psychosocial quality of life. Thus, clinicians treating psychiatric patients should consider BP as a possible adverse effect of psychotropic medications.

Challenges in lung and heart avoidance for postmastectomy breast cancer radiotherapy: Is automated planning the answer?

Postmastectomy radiotherapy (PMRT) has been shown to improve the overall survival for invasive breast cancer patients. However, it represents a challenging treatment geometry and individualized planning strategies with complex field arrangements are usually adopted to decrease radiotoxicity to heart and lungs. Automated treatment planning has the potential to improve plan quality consistency and planning efficiency. Herein, we describe the application of the Pinnacle3 Autoplanning engine as a valuable technological resource able to allow the treatment of challenging patients theoretically unfit for radiotherapy for major cardiac and pulmonary comorbidities. Treatment was planned for three left-sided chest wall and regional lymph-nodes postmastectomy breast cancer patients. A deep inspiration breath-hold (DIBH) technique was used aiming to reduce the OARs irradiation. Three manually generated plans (hybrid-IMRT (HMRT), hybrid-VMAT (HVMAT) and full VMAT (MP-VMAT) and a fully automated plan created by the Autoplanning engine (AP-VMAT) were optimized in order to ensure a safe radiation therapy to the patients. The plans were evaluated based on planning target volumes (PTVs) coverage, dose homogeneity index (HI), conformity index (CN), dose to organs at risk (OARs) and normal tissue complication probabilities (NTCPs) of pericarditis, long term mortality and pneumonitis. Despite the use of deep moderated breath-hold, all human-driven plans failed to reach the stringent dose objectives for OARs. All plans provided an optimal coverage for chest wall and lymph-nodal area. AP-VMAT delivered the lowest mean dose to the heart (3.4 to 4.9 Gy) and ipsilateral lung (7.5 to 12.5 Gy) reporting the lowest NTCP for pneumonitis (<1%), confirming the only chance to comply the dose objectives. Moreover, AP-VMAT reported a decrease of the integral dose, which was lower by about 4-8% with respect to manual plans. AP-VMAT plan resulted in up to 58% increase of MUs with respect to manual plans, suggesting a more pronounced fluence modulation and plan complexity. A major difference was found for the planning time which was reduced to less than 30 minutes by using the Auto-Planning module. With improved planning quality and efficiency, Auto-planning is an effective tool to enable high-quality plans in challenging postmastectomy breast cancer radiotherapy.

Skin toxicity following radiotherapy in patients with breast carcinoma: is anthocyanin supplementation beneficial?

BACKGROUND: The EU-supported ATHENA project stems from a previous study suggesting that moderate wine consumption reduced the side-effects of radiotherapy (RT) in breast cancer patients, an effect possibly due to non-alcoholic anthocyanin fractions of wine. OBJECTIVE: To evaluate the role of anthocyanins on RT skin side effects in breast cancer patients. METHODS: Randomized, controlled, double-blind clinical trial. Patients were assigned to an intensity modulated radiation therapy (IMRT) either for three or five weeks, then randomized to receive three times a day a water-soluble anthocyanin (125 mg)-rich extract of corn cob or a placebo. Supplementation started one week before till the end of RT. Skin characteristics were detected by a standardized, non-invasive Cutometer® dual-MPA580, providing quantitative indices of skin maximal distensibility (R0), elasticity (R2, R5, R7) and viscoelasticity (R6); a Mexameter® MX18 probe evaluated the skin erythema (Er) and melanin (M). Measures were performed before (T0), at the end of RT and of supplementation (T1), and 1, 6 and 12 months after RT (T2-T4). Acute and late skin toxicity were scored according to the RTOG/EORTG scale. Selected biomarkers were measured at T0 and T1. RESULTS: 193 patients previously assigned to 3- or 5-week RT schedules were randomized to either anthocyanin (97) or placebo (96) supplementation. RT induced changes in skin parameters: R0, R2, R5 and R7 decreased, while R6 increased; the changes in R0 and R6 continued in the same direction up to one year, while the others recovered towards basal values; Er and M peaked at T1 and T2, respectively, and returned to basal values at T4. Comparable skin changes were apparent in anthocyanin and placebo groups. A moderate RT-induced increase in total and HDL cholesterol and triglycerides was prevented by anthocyanins. CONCLUSIONS: Anthocyanin supplementation did not prevent RT-induced local skin toxicity. The supplementation was well tolerated and safe.

Advanced head and neck cancer in older adults: Results of a short course accelerated radiotherapy trial.

OBJECTIVES: To assess the feasibility and safety of a repeated SHort course Accelerated RadiatiON therapy (SHARON) regimen in the palliative setting of Head and Neck (H&N) cancer in older adults. MATERIAL AND METHODS: Patients with histological confirmed H&N cancers, age ≥ 80 years, expected survival >3 months, and Eastern Cooperative Oncology Group (ECOG) performance status of ≤3 were enrolled. Patients were treated in cohorts of six patients: a total dose of 20 Gy was delivered in 2 consecutive days with a twice-daily fractionation (5 Gy per fraction) and at least 8-h interval. If no Grade 3 toxicity was registered, a second enrollment started with another cohort of six patients to whom were administered two cycles (total dose of 40 Gy). The primary endpoint was to evaluate the feasibility of the two cycles of treatment. Secondary endpoints were evaluation of symptoms control rate, symptoms-free survival (SFS), and Quality of Life (QoL) scores. RESULTS: Seventeen consecutive patients (median age: 85 years) were treated. Nine patients were treated with one cycle and 8 patients with two cycles. No G3 toxicity was reported in either cohort. With a median follow-up time of 4 months, 3-month SFS in the first and second cohorts was 83.3%, and 87.5%, respectively. The overall palliative response rate was 88%. Among 13 patients reporting pain, 8 (61.5%) showed an improvement or resolution of their pain. CONCLUSION: Repeated short course accelerated radiotherapy in a palliative setting of H&N cancers is safe and well-tolerated in older adults.

Post-Operative Accelerated-Hypofractionated Chemoradiation With Volumetric Modulated Arc Therapy and Simultaneous Integrated Boost in Glioblastoma: A Phase I Study (ISIDE-BT-2).

BACKGROUND: Glioblastoma Multiforme (GBM) is the most common primary brain cancer and one of the most lethal tumors. Theoretically, modern radiotherapy (RT) techniques allow dose-escalation due to the reduced irradiation of healthy tissues. This study aimed to define the adjuvant maximum tolerated dose (MTD) using volumetric modulated arc RT with simultaneous integrated boost (VMAT-SIB) plus standard dose temozolomide (TMZ) in GBM. METHODS: A Phase I clinical trial was performed in operated GBM patients using VMAT-SIB technique with progressively increased total dose. RT was delivered in 25 fractions (5 weeks) to two planning target volumes (PTVs) defined by adding a 5-mm margin to the clinical target volumes (CTVs). The CTV1 was the tumor bed plus the MRI enhancing residual lesion with 10-mm margin. The CTV2 was the CTV1 plus 20-mm margin. Only PTV1 dose was escalated (planned dose levels: 72.5, 75, 77.5, 80, 82.5, 85 Gy), while PTV2 dose remained unchanged (45 Gy/1.8 Gy). Concurrent and sequential TMZ was prescribed according to the EORTC/NCIC protocol. Dose-limiting toxicities (DLTs) were defined as any G ≥ 3 non-hematological acute toxicity or any G ≥ 4 acute hematological toxicities (RTOG scale) or any G ≥ 2 late toxicities (RTOG-EORTC scale). RESULTS: Thirty-seven patients (M/F: 21/16; median age: 59 years; median follow-up: 12 months) were enrolled and treated as follows: 6 patients (72.5 Gy), 10 patients (75 Gy), 10 patients (77.5 Gy), 9 patients (80 Gy), 2 patients (82.5 Gy), and 0 patients (85 Gy). Eleven patients (29.7%) had G1-2 acute neurological toxicity, while 3 patients (8.1%) showed G ≥ 3 acute neurological toxicities at 77.5 Gy, 80 Gy, and 82.5 Gy levels, respectively. Since two DLTs (G3 neurological: 1 patient and G5 hematological toxicity: 1 patient) were observed at 82.5 Gy level, the trial was closed and the 80 Gy dose-level was defined as the MTD. Two asymptomatic histologically proven radionecrosis were recorded. CONCLUSIONS: According to the results of this Phase I trial, 80 Gy in 25 fractions accelerated hypofractionated RT is the MTD using VMAT-SIB plus standard dose TMZ in resected GBM.

Psychological Wellbeing and Healthy Aging: Focus on Telomeres.

Stress and depression are known to modulate the aging process, and might also affect telomere biology. In fact, exposure to some biochemical pathways involved in stress-related depression may contribute to an ''accelerated aging" phenotype, as well as the incidence of age-related diseases, including metabolic disorders and dementia. Basic studies support the notion that the telomere and telomerase system plays a pivotal role in the aging process and disease promotion. Interestingly, short and dysfunctional telomeres are associated with reduced lifespan, as shown in animal models. In this context, telomeres are very sensitive to stress, mindset, and lifestyle, and their rescue may be sufficient to restore cell and organism viability. This mini-review discusses conceptual models of healthy and active aging and their relationship with telomere biology and mental health.

Efficacy and safety of 3D-conformal half body irradiation in patients with multiple bone metastases.

Half-body irradiation (HBI) represented a standard treatment for multiple painful bone metastases (BMs). However, its use has progressively reduced due to the associated toxicity rates. The aim of this paper was to evaluate HBI delivered by conformal radiotherapy (RT) technique in a large patients population with widespread BMs. HBI was delivered in 3 Gy fractions, bid, ≥ 6 h apart, on 2 consecutive days (total dose: 12 Gy) using 3-dimensional conformal RT (3D-CRT) box technique. The target included pelvic bones, lumbar-sacral vertebrae and upper third of femurs. Acute and late toxicity was scored based on RTOG and EORTC-RTOG scales, respectively. Pain was evaluated using the Pain-Drug scores and the Visual Analog Scale (VAS). One hundred and eighty patients were eligible for inclusion in this retrospective analysis. Grade 3 and 4 acute toxicity rates were 1.1% and 0.0%, respectively. Mean VAS before and after HBI was 5.3 versus 2.7, respectively (p: 0.0001). Based on VAS, 37.5% of patients showed complete pain relief (VAS: 0) while 38.1% had partial response (≥ 2-point VAS reduction). Overall, Pain and Drug Score reduction was observed in 76.3% and 50.4% of patients, respectively. 1-, 2-, and 3-year pain progression free survival was 77.0%, 63.4%, and 52.7%, respectively. Thirty patients (16.7%) underwent RT retreatment on the same site with median 15.9 months interval (range 2-126 months). HBI delivered with 3D-CRT technique is safe and effective. It provides long lasting pain control in patients with multiple BMs with negligible rates of relevant toxicity.

[Drug safety warnings in psychiatry: adverse drug reactions' signaling from 2002 to 2014]. / Safety warning dei farmaci in psichiatria: segnalazioni di reazioni avverse ai farmaci dal 2002 al 2014.

OBJECTIVE: Monitoring drug-related side effects in psychiatric patients is highly recommended. In fact, frequent exposure to long-term polipharmacotherapy, poor compliance to pharmachological treatment and comorbidity with organic illnesses requiring the prescription of other drugs are causes of pharmacokinetic/pharmacodynamic interactions. These vulnerability factors result in a certain increase in adverse drug reactions (ADRs). METHODS: This study performes an analysis of Italian Medicine Agency data, in the section "signal analysis", to attempt an assessment of the safety warnings among the different psychotropic drug classes, belonging to the ATC class: N03 (antiepileptics), N05 (antipsychotics), N06 (psycho-analectic drugs). Then we analysed, in a descriptive way, the different association between the drug and the related ADR, evaluating the different safety profiles, in relation to experimental studies, supporting the importance of the signal. RESULTS: In the last years, among the new 25 ADRs, 10 were related to antidepressant drugs (8 SSRI, 1 mirtazapine, 1 agomelatine). In relation to antipsychotic drugs, 6 new correlations were found between drug and ADR onset, mainly among atypical antispychotics. Other correlations (6 above all) were found among antiepileptic drugs. Among benzodiazepines, a signal linked to rabdomylysis onset was found. It is also recommended an evaluation of safety profile in relation to zolpidem prescription. DISCUSSION: The results of our systematic review are a motivational input, considering the continuous increase of safety warnings, to attentively monitor drug's prescription. Spontaneous ADRs' signaling is a classical system to provide the required attention in relation to a potential risk. The clinician in charge must report this because he is the key figure in the drugs' safety process. CONCLUSIONS: In psychiatry, in which a long-term pharmachological therapy is frequent, clinicians are requested to find and signal ADRs to the competent authority.