The potential preventive role of a dietary supplement containing hydroxytyrosol in COVID-19: a multi-center study.

OBJECTIVE: COVID-19 is a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged as a global pandemic in 2019. Its main symptoms include fever, cough, fatigue, and, in severe cases, pneumonia, acute respiratory distress syndrome, and organ failure, which can be life-threatening. Various therapies have been proposed for treating COVID-19, among which antiviral drugs and monoclonal antibodies, but natural molecules have gained attention for their potential antiviral properties against various viral infections, including COVID-19. The use of hydroxytyrosol (HT), a polyphenol from the olive tree possessing antioxidant, anti-inflammatory, and anti-viral properties, has been proposed to reduce COVID-19 infection. SUBJECTS AND METHODS: A total of 443 subjects were recruited from four centers, located in Albania, Germany, and Italy (Milan and Trento provinces). The participants were randomly assigned to receive either the dietary supplement containing HT or a placebo for a duration of one month. RESULTS: Analysis of the study data revealed that, among the subjects who tested positive for COVID-19 during the study, 36% belonged to the group that received the dietary supplement containing HT, while 64% belonged to the placebo group. The difference was statistically significant. These findings suggest that the use of a dietary supplement containing HT may have a possible preventive effect against COVID-19 infection. CONCLUSIONS: The study's results indicate that the dietary supplement containing HT shows promise as a possible preventive measure against COVID-19 infection. Large-scale, randomized clinical trials and animal studies could be useful to provide more definitive conclusions on HT's possible potential preventive effects against COVID-19, which could potentially supplement existing therapies and contribute to fighting COVID-19 infection.

The impact of modern radiotherapy on long-term cardiac sequelae in breast cancer survivor: a focus on deep inspiration breath-hold (DIBH) technique.

INTRODUCTION: One of the most feared side effects of radiotherapy (RT) in the setting of breast cancer (BC) patients is cardiac toxicity. This side effect can jeopardize the quality of life (QoL) of long-term survivors. The impact of modern techniques of RT such as deep inspiration breath hold (DIBH) have dramatically changed this setting. We report and discuss the results of the literature overview of this paper. MATERIALS AND METHODS: Literature references were obtained with a PubMed query, hand searching, and clinicaltrials.gov. RESULTS: We reported and discussed the toxicity of RT and the improvements due to the modern techniques in the setting of BC patients. CONCLUSIONS: BC patients often have a long life expectancy, thus the RT should aim at limiting toxicities and at the same time maintaining the same high cure rates. Further studies are needed to evaluate the risk-benefit ratio to identify patients at higher risk and to tailor the treatment choices.

Disinfection of roof harvested rainwater inoculated with E. coli and Enterococcus and post-treatment bacterial regrowth: Conventional vs solar driven advanced oxidation processes.

Solar driven advanced oxidation processes (AOPs) (an alternative solar photo Fenton like process (SPF), sunlight/H2O2 (SHP) and sunlight/chlorine (SCL)) and respective dark conditions, were compared for the first time to conventional (chlorination and UV-C radiation) disinfection processes, in the inactivation of E. coli and Entero strains inoculated in real roof-harvested rainwater (RHRW), to evaluate their possible safe use for crop irrigation. In this regard, bacterial regrowth was also evaluated 6, 12, 24 and 48 h after disinfection treatment. The SPF, using iminodisuccinic acid (IDS)-Cu complex as catalyst, was optimized (H2O2/IDS-Cu 55/1 best molar ratio) under mild conditions (spontaneous pH) and sunlight. The faster inactivation kinetics were observed for the SCL process (k = 1.473 min-1, t1/2 = 0.47 min for E. coli and k = 1.193 min-1, t1/2 = 0.57 min for Entero), while the most effective processes in controlling bacterial regrowth were SPF and SCL. Although UV-C radiation (0-1.3 × 104 µW s cm-2 dose range) was the second faster disinfection process (k = 1.242 min-1, t1/2 = 0.55 min for E. coli and k = 1.150 min-1, t1/2 = 0.60 min for Entero), it was the less effective process in controlling bacterial regrowth (>10 CFU 100 mL-1 already after 6 h post-treatment incubation). According to the bacterial inactivation and regrowth tests carried out in this work, SPF and SCL are interesting options for RHRW disinfection, in case of effluent use for crop irrigation.

Linac-based STereotactic Arrhythmia Radioablation (STAR) for ventricular tachycardia: a treatment planning study.

OBJECT: To analyze geometrical approaches, prescription modalities, and delivery efficiency for linear accelerator (Linac)-based STereotactic Arrhythmia Radioablation (STAR) for ventricular tachycardia. METHODS: The anatomy and planning target volume (PTV) of the first Italian STAR patient were used. To assess geometrical approaches, 3 plans prescribed to 75% isodose-line, differing for number, length of arcs, and couch rotations, were generated and compared (Plans#1-3). Volumetric-arc with 6-MV flattening-filter-free (FFF) was employed. To evaluate prescription modality and delivery, the best geometrical plan was compared with other plans prescribed on 70%, 65%, and 60% isodose-line and with another one using 10MV-FFF beams (Plans#4-7). RESULTS: For Plans#1-3, PTV coverage, mean cardiac dose, monitor units (MUs), and beam-delivery-time (BDT) were 96-98.5%, 4.9-5.2 Gy, 7047-7790, and 5-6 min, respectively. Plans#4-7 were similar in terms of mean cardiac dose, MUs and BDT to Plans#1-3, except in maximum dose and lower time for 10MV-FFF plan. CONCLUSION: Linac-based STAR is safe and efficient in terms of BDT and MUs. To ensure high dose to PTV, different dose prescription modalities should be evaluated. The 10FFF approach was the faster but not suitable in patient with cardiac implantable electronic devices.

Older age and comorbidity in breast cancer: is RT alone the new therapeutic frontier?

AIM: To assess the impact of age, comorbidities and endocrine therapy (ET) in older breast cancer (BC) patients treated with hypofractionated radiotherapy (Hypo-RT). METHODS: From June 2009 to December 2017, we enrolled in this study 735 ER-positive BC patients (stage pT1-T2, pNx-1, M0 and age ≥ 65 years) receiving hypo-RT and followed them until September 2019. Baseline comorbidities included in the hypertension-augmented Charlson Comorbidity Index were retrospectively retrieved. Logistic regression model estimated adjusted-odds ratios (ORs) of ET prescription in relation to baseline patient and tumor characteristics. Competing risk analysis estimated 5-year cumulative incidence function (CIF) of ET discontinuation due to side effects (with BC progression or death as competing events), and its effect on locoregional recurrence (LRR) and distant metastasis (DM) (with death as competing event). RESULTS: ET has been prescribed in 89% patients. In multivariable analysis, the odds of ET prescription was significantly reduced in older patients (≥ 80 years, OR 0.08, 95% CI 0.03-0.20) and significantly increased in patients with moderate comorbidity. Patients ≥ 80 years discontinued the prescribed therapy earlier and more frequently than younger (65-69 years) patients (p = 0.060). Five-year CIF of LLR, DM and death from causes other that BC were 1.7%, 2.2% and 7.5%, respectively. Patients who discontinued ET had higher chance of LRR (p = 0.004). ET use did not impact on OS in any of the analyzed groups. CONCLUSIONS: In older patients, ET did not show a benefit in terms of overall survival. Further studies focusing on tailored treatment approaches are warranted to offer the best care in terms of adjuvant treatment to these patients.

Moderate hypofractionated helical tomotherapy for prostate cancer in a cohort of older patients: a mono-institutional report of toxicity and clinical outcomes.

PURPOSE OR OBJECTIVE: To evaluate toxicity and outcomes of moderately hypofractionated helical tomotherapy for the curative treatment of a cohort of patients aged ≥ 75 years with localized prostate cancer (PC). MATERIALS AND METHODS: From January 2013 to February 2017, 95 patients with median age 77 years (range 75-88) were treated for PC. 39% were low risk, 33% intermediate risk (IR), 28% high risk (HR). Median iPSA was 9.42 ng/ml (1.6-107). Androgen deprivation was prescribed according to NCCN recommendations. All patients received 70 Gy in 28 fractions to the prostate; 61.6 Gy were delivered to the seminal vesicles for IR; whole pelvis irradiation with a total dose of 50.4 Gy was added in the HR group. Toxicity evaluation was based on CTCAE V4.0 criteria, biochemical failure was defined following Phoenix criteria. Quality of Life was assessed with the EPIC-26 index. Overall survival and biochemical failure-free survival were analysed with Kaplan-Meier method. RESULTS: With a median follow-up of 36 months (range 24-73), acute and late toxicity were acceptable. No correlation between toxicity patterns and clinical or dosimetric parameter was registered. EPIC-26 showed a negligible difference in urinary and bowel function post-treatment that did not reach statistical significance. The 2- and 3-years OS were 93% and 87% with cancer specific survival of 97.9% and 96.2%. CONCLUSION: Moderate hypofractionated RT reported excellent outcomes in our cohort of older patients. Shorter schedules may be proposed regardless of chronological age facilitating the treatment compliance in the older population.

Melilotus, Rutin and Bromelain in primary and secondary lymphedema.

As reported in the literature, benzopyrones (alpha and gamma) have important effects on the microcirculation through various mechanisms. Coumarins are an alpha-benzopyrone as derivatives of Melilotus Officinalis, while bioflavonoids are a gamma-benzopyrone and include Rutin. Alpha-benzopyrones have two fundamental pharmacological effects: they have pro-lymphokinetic action by activating contractility of lymphangions; and the activation of macrophages to provide a proteolytic effect. Gamma-benzopyrones, such as Rutin, have an important anti-exuding and membrane stabilizing effect. Bromelain is known for its anti-inflammatory effect. The present study enrolled 52 patients with primary and/or secondary lymphedema in clinical stages I or II (according to the ISL classification) with 31 cases involving the lower limbs and 21 cases involving the upper limbs. All subjects were given for six months a natural compound consisting of 100 mg of natural Melilotus, that contains 20 grams of Coumarin, 300 mg of Rutin and 100 mg of Bromelain. The following parameters were studied at zero time (T0), after three months (T1), and after six months of treatment (T2): pitting, Stemmer's sign, measurement of limb circumferences, measurement of superficial tissue thickness in the affected limbs using ultrasound, and blood tests to evaluate hepatic function (ALT, AST, GGT, total and fractional bilirubin). At the end of the treatment (T2), the following results were observed: disappearance of pitting in 72% of the cases; unchanged Stemmer's sign; average decrease in limb circumferences of 4.2 cm; and average reduction of the superficial thickness of 29%. There was no variation in the liver function parameters examined. The combination of natural compounds (Melilotus, Rutin, and Bromelain) has been shown to be a valuable aid in the clinical control of both primary and secondary lymphedema of clinical stages I and II as well as in control of inflammatory phenomena related to chronic stasis. There were no side effects and no alteration of liver function parameters found.

Adjuvant endocrine therapy in premenopausal patients with hormone receptor-positive early breast cancer: evidence evaluation and GRADE recommendations by the Italian Association of Medical Oncology (AIOM)

Premenopausal women with hormone receptor-positive early breast cancer are candidates for adjuvant endocrine therapy, as recommended by the major international guidelines. To date, adjuvant endocrine options for premenopausal women include tamoxifen with or without ovarian function suppression (OFS) or an aromatase inhibitor with OFS. Multiple strategies for endocrine treatment of premenopausal women with hormone-responsive breast cancer have been assessed, and the results of randomised clinical trials have been reported over the last years. Despite this evidence, the optimal algorithm for endocrine therapy for premenopausal women with hormone receptor-positive early stage invasive breast cancer shows open questions regarding the role of OFS in addition to tamoxifen and the optimal use of hormonal agents. The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer applied the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology on three critical questions on the choice of the adjuvant hormonal therapy in premenopausal breast cancer patients to summarise available evidence and to create recommendations to help physicians in their clinical practice.

Rare variant analysis in multiply affected families, association studies and functional analysis suggest a role for the ITGΒ4 gene in schizophrenia and bipolar disorder.

Recent results imply that rare variants contribute to the risk of schizophrenia. Exome sequence data from the UK10K project was used to identify three rare, amino acid changing variants in the ITGB4 gene which segregated with schizophrenia in two families: rs750367954, rs147480547 and rs145976111. Association analysis was carried out in the exome-sequenced Swedish schizophrenia study and in UCL schizophrenia and bipolar cases and controls genotyped for these variants. A gene-wise weighted burden test was performed on a trio sample of schizophrenia cases and their parents. rs750367954 was seen in two Swedish cases and in no controls. The other two variants were commoner in cases than controls in both Swedish and UCL cohort samples and an overall burden test was significant at p=0.0000031. The variants were not observed in the trio sample but ITGB4 was most highly ranked out of 14,960 autosomal genes in a gene-wise weighted burden test. The effect of rs147480547 and rs145976111 was studied in human neuroblastoma SH-SY5Y cells. Cells transfected with both variants had increased proliferation at both 24 and 48h (p=0.013 and p=0.05 respectively) compared to those with wild-type ITGB4. Taken together, these results suggest that rare variants in ITGB4 which affect function may contribute to the aetiology of schizophrenia and bipolar disorder.

Fentanyl pectin nasal spray for painful mucositis in head and neck cancers during intensity-modulated radiation therapy with or without chemotherapy

Purpose. The aim of the current analysis was to evaluate the effectiveness and tolerability of rapid onset opioid in a cohort of head and neck cancer (HNC) patients affected by painful mucositis influencing swallowing function during RT ± ChT with definitive or adjuvant intent. Methods. A retrospective analysis was conduct on HNC patients during RT ± ChT that received fentanyl pectin na sal spray (FPNS) for incidental BTP due to painful mucositis 13 min before the main meals. The period of observation has been 90 days starting from the beginning of RT ± ChT. Results. Forty HNC patients with incidental BTP due to painful mucositis treated with FPNS were analyzed. The mean NRS of untreated episodes of BTP was 5.73 ± 1.54 decreasing to 2.25 ± 2.45 with FPNS (median dose 100 mcg). During the pain treatment, the number of meals increased from 2.08 ± 0.35 to 2.868 ± 0.4 (p = 0.000), and the BMI remained stable (from 25.086 ± 3.292 to 25.034 ± 3.090; p = 0.448). The 94.9% of patients was satisfied or very satisfied for the rapidity of the effect, and 97.4% for the easiness and convenience in the use. Conclusions. FPNS showed an acceptable safety activity profile in predictable BTP due to painful mucositis in HNC patients during RT ± ChT. FPNS was also effective in reducing the mucositis sequelae and allowing the completion of RT scheduled scheme. Moreover, patients declared satisfaction in terms of ease of use (AU)

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Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder.

Bipolar disorder affects about 1% of the world's population, and its estimated heritability is about 75%. Only few whole genome or whole-exome sequencing studies in bipolar disorder have been reported, and no rare coding variants have yet been robustly identified. The use of isolated populations might help finding variants with a recent origin, more likely to have drifted to higher frequency by chance. Following this approach, we investigated 28 bipolar cases and 214 controls from the Faroe Islands by whole exome sequencing, and the results were followed-up in a British sample of 2025 cases and 1358 controls. Seventeen variants in 16 genes in the single-variant analysis, and 3 genes in the gene-based statistics surpassed exome-wide significance in the discovery phase. The discovery findings were supported by enrichment analysis of common variants from genome-wide association studies (GWAS) data and interrogation of protein-protein interaction networks. The replication in the British sample confirmed the association with NOS1 (missense variant rs79487279) and NCL (gene-based test). A number of variants from the discovery set were not present in the replication sample, including a novel PITPNM2 missense variant, which is located in a highly significant schizophrenia GWAS locus. Likewise, PIK3C2A identified in the gene-based analysis is located in a combined bipolar and schizophrenia GWAS locus. Our results show support both for existing findings in the literature, as well as for new risk genes, and identify rare variants that might provide additional information on the underlying biology of bipolar disorder.

Radiation dose intensification in pre-operative chemo-radiotherapy for locally advanced rectal cancer

Background. To assess the role of radiation dose intensification with simultaneous integrated boost guided by 18-FDG-PET/CT in pre-operative chemo-radiotherapy (ChT-RT) for locally advanced rectal cancer. Methods. A prospective study was approved by the Internal Review Board. Inclusion criteria were: age >18 years old, World Health Organization performance status of 0-1, locally advanced histologically proven adenocarcinoma of the rectum within 10 cm of the anal verge, signed specific informed consent. High-dose volumes were defined including the hyper-metabolic areas of 18-FDG-PET/CT of primary tumor and the corresponding mesorectum and/or pelvic nodes with at least a standardized uptake values (SUV) of 5. A dose of 60 Gy/30 fractions was delivered. A total dose of 54 Gy/30 fractions was delivered to prophylactic areas. Capecitabine was administered concomitantly with RT for a dose of 825 mg/mq twice daily for 5 days/every week. Results. Between September 2011 and July 2015 fortypatients were recruited. At the time of the analysis, median follow up was 20 months (range 5-51). The median interval from the end of ChT-RT to surgery was 9 weeks (range 8-12). Thirty-seven patients (92.5 %) were submitted to sphincter preservation. Tumor Regression Grade (Mandard scale) was recorded as follows: grade 1 in 7 (17.5 %), grade 2 in 17 (42.5 %), grade 3 in 15 (37.5 %) and grade 4 in 1 (2.5 %). Post-surgical circumferential resection margin was negative in all patients. A tumor downstaging was reported in 62.5 % (95 % CI: 0.78-0.47). A nodes downstaging was registered in 85 % (95 % CI: 0.55-0.25). 18-FDG-PET/CT was not able to predict pCR. No correlation was found between pre-treatment SUV-max values and pCR. A metabolic tumor volume >127 cc was related to ypT ≥2 (p 0.01). Patients with TRG >2 had higher tumor lesion glycolysis values (p 0.05). Conclusion. Preliminary results did not confirm some advantages in terms of primary tumor downstaging/downsizing compared to conventional schedules reported in historical series. The role of 18-FDG-PET/CT in neoadjuvant rectal cancer management needs to be confirmed in further investigations. Long terms results are necessary (AU)

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Radiation dose intensification in pre-operative chemo-radiotherapy for locally advanced rectal cancer.

BACKGROUND: To assess the role of radiation dose intensification with simultaneous integrated boost guided by 18-FDG-PET/CT in pre-operative chemo-radiotherapy (ChT-RT) for locally advanced rectal cancer. METHODS: A prospective study was approved by the Internal Review Board. Inclusion criteria were: age >18 years old, World Health Organization performance status of 0-1, locally advanced histologically proven adenocarcinoma of the rectum within 10 cm of the anal verge, signed specific informed consent. High-dose volumes were defined including the hyper-metabolic areas of 18-FDG-PET/CT of primary tumor and the corresponding mesorectum and/or pelvic nodes with at least a standardized uptake values (SUV) of 5. A dose of 60 Gy/30 fractions was delivered. A total dose of 54 Gy/30 fractions was delivered to prophylactic areas. Capecitabine was administered concomitantly with RT for a dose of 825 mg/mq twice daily for 5 days/every week. RESULTS: Between September 2011 and July 2015 fortypatients were recruited. At the time of the analysis, median follow up was 20 months (range 5-51). The median interval from the end of ChT-RT to surgery was 9 weeks (range 8-12). Thirty-seven patients (92.5 %) were submitted to sphincter preservation. Tumor Regression Grade (Mandard scale) was recorded as follows: grade 1 in 7 (17.5 %), grade 2 in 17 (42.5 %), grade 3 in 15 (37.5 %) and grade 4 in 1 (2.5 %). Post-surgical circumferential resection margin was negative in all patients. A tumor downstaging was reported in 62.5 % (95 % CI: 0.78-0.47). A nodes downstaging was registered in 85 % (95 % CI: 0.55-0.25). 18-FDG-PET/CT was not able to predict pCR. No correlation was found between pre-treatment SUV-max values and pCR. A metabolic tumor volume >127 cc was related to ypT ≥2 (p 0.01). Patients with TRG >2 had higher tumor lesion glycolysis values (p 0.05). CONCLUSION: Preliminary results did not confirm some advantages in terms of primary tumor downstaging/downsizing compared to conventional schedules reported in historical series. The role of 18-FDG-PET/CT in neoadjuvant rectal cancer management needs to be confirmed in further investigations. Long terms results are necessary.

Fentanyl pectin nasal spray for painful mucositis in head and neck cancers during intensity-modulated radiation therapy with or without chemotherapy.

PURPOSE: The aim of the current analysis was to evaluate the effectiveness and tolerability of rapid onset opioid in a cohort of head and neck cancer (HNC) patients affected by painful mucositis influencing swallowing function during RT ± ChT with definitive or adjuvant intent. METHODS: A retrospective analysis was conduct on HNC patients during RT ± ChT that received fentanyl pectin na sal spray (FPNS) for incidental BTP due to painful mucositis 13 min before the main meals. The period of observation has been 90 days starting from the beginning of RT ± ChT. RESULTS: Forty HNC patients with incidental BTP due to painful mucositis treated with FPNS were analyzed. The mean NRS of untreated episodes of BTP was 5.73 ± 1.54 decreasing to 2.25 ± 2.45 with FPNS (median dose 100 mcg). During the pain treatment, the number of meals increased from 2.08 ± 0.35 to 2.868 ± 0.4 (p = 0.000), and the BMI remained stable (from 25.086 ± 3.292 to 25.034 ± 3.090; p = 0.448). The 94.9% of patients was satisfied or very satisfied for the rapidity of the effect, and 97.4% for the easiness and convenience in the use. CONCLUSIONS: FPNS showed an acceptable safety activity profile in predictable BTP due to painful mucositis in HNC patients during RT ± ChT. FPNS was also effective in reducing the mucositis sequelae and allowing the completion of RT scheduled scheme. Moreover, patients declared satisfaction in terms of ease of use.

Cachexia induces head and neck changes in locally advanced oropharyngeal carcinoma during definitive cisplatin and image-guided volumetric-modulated arc radiation therapy.

BACKGROUND/OBJECTIVES: Cancer cachexia is a syndrome characterized by weight loss (WL) and sarcopenia. Aim of the study was to assess the impact of cachexia on head and neck changes during definitive cisplatin and image-guided volumetric-modulated arc radiation therapy in a series of locally advanced oropharyngeal cancer. SUBJECTS/METHODS: Volume variations of sternocleidomastoid muscle (SCM) were considered as surrogate of muscle changes related to sarcopenia. Two head and neck diameters, encompassing the cranial limits of II and III nodal levels (defined as 'head diameter' and 'neck diameter', respectively), were measured. All parameters were defined retrospectively by means of on-board cone beam computed tomography images at 1-8th to 15-22th and at last fraction (fx) of radiotherapy (RT). Cachexia was defined as WL >5% during treatment. Analysis was conducted correlating the parameter changes with three WL ranges: <5, 5-9 and>10%. RESULTS: Thirty patients were evaluated. One hundred and fifty contoured SCMs and three hundred diameters were collected. Median WL was 6.5% (range, 0-16%). The most significant SCM shrinkage was recorded at 15th fx (mean 1.6 cc) related to WL 5-9% and WL >10% (P 0.001). For 'head diameter', the peak reduction was recorded at the 15th fx (mean 8 mm), statistically correlated to WL >10% (P 0.001). The peak reduction in 'neck diameter' was registered at the 22th fx (mean 6 mm), with a gradual reduction until the end of treatment for WL >5%. CONCLUSIONS: In a homogeneous cohort of patients, present study quantified the impact of cachexia on head and neck changes. Present data could provide adaptive RT implications for further investigations.

The impact of prostate gland dimension in genitourinary toxicity after definitive prostate cancer treatment with moderate hypofractionation and volumetric modulated arc radiation therapy

Purpose: To analyze clinical-dosimetric predictors of genitourinary (GU) toxicity in a cohort of prostate cancer (PC) patients treated with moderate hypofractionation and simultaneous integrated boost (SIB) using volumetric modulated arc therapy (VMAT) technique. Materials and methods: 60 patients were selected. Patients were stratified into low (43 %), intermediate (30 %) and high-risk (27 %) groups. Low-risk patients received 73.5 Gy to PTV1; intermediate-risk received 73.5 Gy to PTV1 and 60 Gy to PTV2; high-risk received 73.5 Gy to PTV1, 60 Gy to PTV2, and 54 Gy to PTV3. All patients were treated in 30 fractions. Androgen deprivation therapy (ADT) was prescribed upfront in intermediate and high-risk categories. Toxicity was scored according to Common Terminology Criteria for Adverse Events v4.0 scoring system. Results: Median follow-up was 30 months (range 16-36 months). GU acute toxicity was recorded as followS: G0 = 16/60 (27 %), G1 = 18/60 (30 %); G2 = 26/ 60 (43 %). GU late toxicity was recorded as follows: G0 = 20/60 (34 %); G1 = 29/60 (48 %); G2 = 11/56 (18 %). The risk of acute G2 GU toxicity was three times higher for prostate volume C80 cc. In 60 % of the patients with a prostate volume C80 cc, the first 3 weeks are at particular risk for toxicity onset. In the late setting, no statistical significance was found between GU toxicity and prostate gland dimension. Conclusion: Prostate volume C80 cc resulted a predictive factor of acute G2 GU toxicity, in moderate hypofractionation and volumetric modulated arc radiation therapy for definitive PC (AU)

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Genetic Screening in a Large Cohort of Italian Patients Affected by Primary Lymphedema Using a Next Generation Sequencing (NGS) Approach.

Primary lymphedema is a rare inherited condition characterized by swelling of body tissues caused by accumulation of fluid, especially in the lower limbs. In many patients, primary lymphedema has been associated with variations in a number of genes involved in the development and maintenance of the lymphatic system. In this study, we performed a genetic screening in patients affected by primary lymphedema using a next generation sequencing (NGS) approach. With this technology, based on a custom-made oligonucleotide probe library, we were able to analyze simultaneously in each patient all the coding exons of 10 genes (FLT4, FOXC2, CCBE1, GJC2, MET, HGF, GATA2, SOX18, VEGFC, KIF11) associated with primary lymphedema. In the study population, composed of 45 familial and 71 sporadic cases, we identified the presence of rare variants with a potential pathogenic effect in 33% of subjects. Overall, we found a total of 36 different rare nucleotidic alterations, 30 of which had not been previously described. Among these, we identified 23 mutations that we considered most likely to be disease causing. Patients with an FLT4 or FOXC2 alteration accounted for the largest percentage of the sample, followed by MET, HGF, KIK11, GJC2 and GATA2. No alterations were identified in SOX18, VEGFC, and CCBE1 genes. In conclusion, we showed that NGS technology can be successfully applied to perform molecular screening of lymphedema-associated genes in large cohort of patients with a reasonable effort in terms of cost, work, and time.

The impact of prostate gland dimension in genitourinary toxicity after definitive prostate cancer treatment with moderate hypofractionation and volumetric modulated arc radiation therapy.

PURPOSE: To analyze clinical-dosimetric predictors of genitourinary (GU) toxicity in a cohort of prostate cancer (PC) patients treated with moderate hypofractionation and simultaneous integrated boost (SIB) using volumetric modulated arc therapy (VMAT) technique. MATERIALS AND METHODS: 60 patients were selected. Patients were stratified into low (43 %), intermediate (30 %) and high-risk (27 %) groups. Low-risk patients received 73.5 Gy to PTV1; intermediate-risk received 73.5 Gy to PTV1 and 60 Gy to PTV2; high-risk received 73.5 Gy to PTV1, 60 Gy to PTV2, and 54 Gy to PTV3. All patients were treated in 30 fractions. Androgen deprivation therapy (ADT) was prescribed upfront in intermediate and high-risk categories. Toxicity was scored according to Common Terminology Criteria for Adverse Events v4.0 scoring system. RESULTS: Median follow-up was 30 months (range 16-36 months). GU acute toxicity was recorded as followS: G0 = 16/60 (27 %), G1 = 18/60 (30 %); G2 = 26/60 (43 %). GU late toxicity was recorded as follows: G0 = 20/60 (34 %); G1 = 29/60 (48 %); G2 = 11/56 (18 %). The risk of acute G2 GU toxicity was three times higher for prostate volume ≥80 cc. In 60 % of the patients with a prostate volume ≥80 cc, the first 3 weeks are at particular risk for toxicity onset. In the late setting, no statistical significance was found between GU toxicity and prostate gland dimension. CONCLUSION: Prostate volume ≥80 cc resulted a predictive factor of acute G2 GU toxicity, in moderate hypofractionation and volumetric modulated arc radiation therapy for definitive PC.

Intensity modulated radiation therapy with simultaneous integrated boost in early breast cancer irradiation. Report of feasibility and preliminary toxicity.

PURPOSE: To investigate the feasibility and tolerance in the use of adjuvant intensity modulated radiation therapy (IMRT) and simultaneous integrated boost in patients with a diagnosis of breast cancer after breast-conserving surgery. PATIENTS AND METHODS: Between September 2011 to February 2013, 112 women with a diagnosis of early breast cancer (T1-2, N0-1, M0) were treated with IMRT and simultaneous integrated boost after breast-conserving surgery in our institution. A dose of 50Gy in 25 fractions was prescribed to the whole breast and an additional dose of radiation was prescribed on the tumour bed. A dose prescription of 60Gy in 25 fractions to the tumour bed was used in patients with negative margins after surgery, whereas if the margins were close (<1mm) or positive (without a new surgical resection) a dose of 64Gy was prescribed. All patients were followed with periodic clinical evaluation. Acute and late toxicity were scored using the EORTC/RTOG radiation morbidity score system. Both patient and physician recorded cosmetic outcome evaluation with a subjective judgment scale at the time of scheduled follow-up. RESULTS: The median follow-up was 28 months (range 24-40 months). The acute skin grade toxicity during the treatment was grade 0 in 8 patients (7%), grade 1 in 80 (72%), grade 2 in 24 cases (21%). No grade 3 or higher acute skin toxicity was observed. At 12 months, skin toxicity was grade 0 in 78 patients (70%), grade 1 in 34 patients (30%). No toxicity grade 2 or higher was registered. At 24 months, skin toxicity was grade 0 in 79 patients (71%), grade 1 in 33 patients (29%). No case of grade 2 toxicity or higher was registered. The pretreatment variables correlated with skin grade 2 acute toxicity were adjuvant chemotherapy (P=0.01) and breast volume ≥700cm(3) (P=0.001). Patients with an acute skin toxicity grade 2 had a higher probability to develop late skin toxicity (P<0.0001). In the 98% of cases, patients were judged to have a good or excellent cosmetic outcome. The 2-year-overall survival and 2-year-local control were 100%. CONCLUSION: These data support the feasibility and safety of IMRT with simultaneous integrated boost in patients with a diagnosis of early breast cancer following breast-conserving surgery with acceptable acute and late treatment-related toxicity. A longer follow-up is needed to define the efficacy on outcomes.

Clinical radiobiology of head and neck cancer: the hypothesis of stem cell activation

Purpose To estimate and reduce uncertainties of a selfconsistent set of radiobiological parameters based on the outcome of head and neck cancer (HNC) patients treated with radiotherapy (RT). Methods Published studies comparing at least two RT schedules for HNC patients were selected. The method used to estimate the radiobiological parameters consists of three sequential steps that allow a significant reduction of uncertainties: the first, in which the intrinsic (a) and the repair (b) radio-sensitivities were estimated together with the doubling time (Td) by an analytical/graphical method; the second, in which the kick-off time for accelerated proliferation (Tk) was estimated applying the hypothesis of activation for sub-populations of stem cells during the RT; the third, in which the number of clonogens (N) was obtained by the Tumor Control Probability (TCP) model. Independent clinical data were used to validate results. Results The best estimate and the 95 % confidence intervals (95 % CIs) were: a = 0.24 Gy-1 (0.23–0.26), b = 0.023 Gy-2 (0.021–0.025), a/b = 10.6 Gy (8.4–12.6), Td = 3.5 days (3.1–3.9), Tk = 19.2 days (15.1–23.3), N = 7 9 107 (4 9 107 –1 9 108 ). From these data, the dose required to offset repopulation occurring in 1 day (Dprolif) and starting after Tk was also estimated as 0.69 Gy/day (0.52–0.86). Conclusions The estimation of all the radiobiological parameters of HNC was obtained based on the hypothesis of activation for specifically tumorigenic sub-populations of stem cells. The similarity of results to those from other studies strengthens such a hypothesis that could be very useful for the predictivity of the TCP model and to design new treatment strategies for HNC (AU)

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