Proton radiotherapy: a therapeutic opportunity for pediatric brain tumor patients

Proton radiation therapy is a form of external radiation that uses charged particles which have distinct physical advantages to deliver the majority of its dose in the target while minimizing the dose of radiation to normal tissues. In children who are particularly susceptible even at low and medium doses of radiation, the significant reduction of integral dose can potentially mitigate the incidence of side effects and improve quality of life. The aim of the first part of the thesis is to describe the physical and radiobiological properties of protons, the Proton Therapy Center of Trento (TCPT) active for clinical purpose since 2014, which use the most recent technique called active pencil beam scanning. The second part of the thesis describes the preliminary clinical results of 23 pediatric patients with central nervous system tumors as well as of two aggressive pediatric meningiomas treated with pencil beam scanning. All the patients were particularly well-suited candidates for proton therapy (PT) for possible benefits in terms of survival and incidence of acute and late side effects. We reported also a multicentric experience of 27 medulloblastoma patients (median age 6 years, M/F ratio 13/14) treated between 2015 and 2020 at TPTC coming from three Pediatric oncology centers: Bologna, Florence, and Ljubljana, with a focus on clinical results and toxicities related to radiotherapy (RT). Proton therapy was associated with mostly mild acute and late adverse effects and no cases of CNS necrosis or high grade of neuroradiological abnormailities. Comparable rates of survival and local control were obtained to those achievable with conventional RT. Finally, we performed a systematic review to specifically address the safety of PT for pediatric CNS patients, late side effects and clinical effectiveness after PT in this patient group.

Hypofractionated stereotactic radiotherapy after hyperbaric oxygenation for recurrent high-grade glioma: a pilot study

Purpose The presence of hypoxic cells in high-grade glioma (HGG) is one of the main reasons of local failure after radiotherapy (RT). The use of hyperbaric oxygen therapy (HBO) could help to overcome the problem of hypoxia in poorly oxygenated regions of the tumor. We performed a pilot study to evaluate the efficacy of hypofractionated image-guided helical TomoTherapy (HT) after HBO in the treatment of recurrent HGG (rHGG). Methods We enrolled 15 patients (aged >18 years) with diagnosis of rHGG. A total dose of 15-25 Gy was administered in daily 5-Gy fractions for 3-5 consecutive days after daily HBO. Each fraction was delivered up to maximum of 60 minutes after HBO. Results Median follow-up from HBO-RT was 28.6 (range: 5.3-56.8). No patient was lost to follow-up. Median progression-free survival (mPFS) for all patients was 3.2 months (95% CI: 1.34- 6.4 ), while 3-month, 6-month and 12 month PFS was 60% (95%CI: 31.8.4-79.7), 40% (95%CI: 16.5- 62.8) and10.0 (0.8-33.5) , respectively. Median overall survival (mOS) of HBO-RT was 11.7 months (95% CI: 7.3-29.3), while 3-month, 6-month and 12 month OS was 100% , 93.3% (61.3-99.0) and 46.7 % (21.2-68.8). No acute or late neurologic toxicity >grade 2 (CTCAE version 4.3) was observed in 86.66% of patients. Two patients developed G3 Radionecrosis. Conclusion HSRT combined to HBO seems effective and safe in the treatment of rHGG. One of advantages of HBO-RT is the reduced overall treatment time (3-5 consecutive days).

Ultra-hypofractionated stereotactic radiotherapy for prostate cancer in 5 fractions: current evidences and our clinical experience

AIMS: The present is a retrospective evaluation of acute genito-urinary (GU) and gastro-intestinal (GI) toxicity, in addition to biochemical recurrence rate in 57 prostate cancer patients treated at our Institution with ultra-hypofractionated RT (UHRT) schedule. METHODS: From January 2021 to December 2022 we have treated 57 patients with prostate cancer, using an UHRT scheme of 5-fractions every other day for a total dose delivered of 36.25 Gy, according to the PACE-B trial treatment schedule. Good urinary function, assessed by International Prostate Symptom Score (IPSS), were required. The simulation CT scans were acquired in supine position and fused with MRI for CTVs definition for every patient. Each treatment was performed by Accuray's TomoTherapy with daily IGRT. The evaluation of the set-up was very restrictive before daily treatment delivery. RESULTS: According to RTOG toxicity scale, the acute GU toxicity at 3 months from RT, GU toxicity was G0 for 30 patients (52.6%), G1 for 26 (45.6%) and G2 for one only (1.75%); rectal toxicity was G0 for 56 patients (98.25%) and G1 for one only (1.75%). The median follow-up (FU) was 9 months (2-24 months). In the following FU months, we observed progressively lower urinary and rectal toxicity, except for one patient who showed G2 GU toxicity at 12 months. All but one patient had a progressive PSA value decrease. CONCLUSIONS: In our experience, UHRT appears to be safe and well tolerated even without the use of rectal spacer devices. A longer FU is necessary to evaluate late toxicity and disease control rate.

Electrochemical Oxidation Of Landfill Leachate In A Flow Reactor: Optimization Using Response Surface Methodology.

Response surface methodology based on Box-Behnken (BBD) design was successfully applied to the optimization in the operating conditions of the electrochemical oxidation of sanitary landfill leachate aimed for making this method feasible for scale up. Landfill leachate was treated in continuous batch-recirculation system, where a dimensional stable anode (DSA(©)) coated with Ti/TiO2 and RuO2 film oxide were used. The effects of three variables, current density (milliampere per square centimeter), time of treatment (minutes), and supporting electrolyte dosage (moles per liter) upon the total organic carbon removal were evaluated. Optimized conditions were obtained for the highest desirability at 244.11 mA/cm(2), 41.78 min, and 0.07 mol/L of NaCl and 242.84 mA/cm(2), 37.07 min, and 0.07 mol/L of Na2SO4. Under the optimal conditions, 54.99 % of chemical oxygen demand (COD) and 71.07 ammonia nitrogen (NH3-N) removal was achieved with NaCl and 45.50 of COD and 62.13 NH3-N with Na2SO4. A new kinetic model predicted obtained from the relation between BBD and the kinetic model was suggested.

Fluoride Concentrations In The Water Of Maringá, Brazil, Considering The Benefit/risk Balance Of Caries And Fluorosis.

Current Brazilian law regarding water fluoridation classification is dichotomous with respect to the risks of and benefits for oral diseases, and fluoride (F) concentrations less than 0.6 or above 0.8 mg F/L are considered outside the normal limits. Thus, the law does not consider that both caries and fluorosis are dependent on the dosage and duration of fluoride exposure because they are both chronic diseases. Therefore, this study evaluated the quality of water fluoridation in Maringá, PR, Brazil, considering a new classification for the concentration of F in water the supply, based on the anticaries benefit and risk of fluorosis (CECOL/USP, 2011). Water samples (n = 325) were collected monthly over one year from 28 distribution water networks: 20 from treatment plants and 8 from artesian wells. F concentrations were determined using a specific ion electrode. The average F concentration was 0.77 mg F/L (ppm F), ranging from 0.44 to 1.22 mg F/L. Considering all of the water samples analyzed, 83.7% of them presented from 0.55 to 0.84 mg F/L, and according to the new classification used, they would provide maximum anticaries benefit with a low risk of fluorosis. This percentage was lower (75.4%) in the water samples supplied from artesian wells than from those distributed by the treatment plant (86%). In conclusion, based on the new classification of water F concentrations, the quality of water fluoridation in Maringá is adequate and is within the range of the best balance between risk and benefit.

Whey And Soy Protein Supplements Changes Body Composition In Patients With Crohn's Disease Undergoing Azathioprine And Anti-tnf-alpha Therapy.

Crohn´s disease (CD) is a chronic transmural inflammation of the gastrointestinal tract of unknown cause. Malnutrition associated with active CD has been reduced although obesity has increased. Dietary strategies such as those with high-protein have been proposed to reduce body fat. This study compares the effects of two supplements on the nutritional status of CD patients. 68 CD patients were randomized in two groups: whey protein group (WP) and soy protein group (SP). Using bioimpedance analysis, anthropometry and albumin and pre-albumin dosages the nutritional status was measured before starting the intervention and after 8 and 16 weeks. The disease activity was determined by Crohn's Disease Activity Index and serum C-reactive protein dosage and dietary intake by 24h dietary recalls. Forty-one patients concluded the study and both supplements changed body composition similarly. Triceps skin fold thickness (p< 0.001) and body fat percentage (p=0.001) decreased, whereas mid-arm muscle circumference (p=0.004), corrected arm muscle area (p=0.005) and body lean percentage (p=0.001) increased. For Crohn's disease patients undergoing anti TNF-alpha and azatioprine therapies, supplementation with whey and soy proteins changes body composition through reduction of body fat and thus contributes to control inflammation.

Biochemical And Morphological Alterations In The Achilles Tendon Of Mdx Mice.

Dystrophin-deficient muscles have repeated cycles of necrosis and regeneration, being susceptible to injury induced by muscle contractions. Some studies have demonstrated that tendons are also affected in mdx mice, based especially on the changes in biomechanical properties arising from the respective linked muscles. However, most studies have focused only on alterations in the myotendinous junction. Thus, the purpose of this work was to study biochemical and morphological alterations in the Achilles tendons of 60-day-old mdx mice. Hydroxyproline quantification, showed higher collagen concentration in the mdx mice as compared with the control. No difference between the tendons of both groups was found in the noncollagenous proteins dosage, and in the amount of collagen type III detected in the western blotting analysis. The zymography for gelatinases detection showed higher amounts of metaloproteinase-2 (active isoform) and of metalloproteinase-9 (latent isoform) in the mdx mice. Measurements of birefringence, using polarization microscopy, showed higher molecular organization of the collagen fibers in the tendons of mdx mice in comparison to the control group, with presence of larger areas of crimp. Ponceau SS-stained tendon sections showed stronger staining of the extracellular matrix in the mdx groups. Toluidine blue-stained sections showed more intense basophilia in tendons of the control group. In morphometry, a higher number of inflammatory cells was detected in the epitendon of mdx group. In conclusion, the Achilles tendon of 60-day-old mdx mice presents higher collagen concentration and organization of the collagen fibers, enhanced metalloproteinase-2 activity, as well as prominent presence of inflammatory cells and lesser proteoglycans.

Investigation Of Genetic Factors Underlying Typical Orofacial Clefts: Mutational Screening And Copy Number Variation.

Typical orofacial clefts (OFCs) comprise cleft lip, cleft palate and cleft lip and palate. The complex etiology has been postulated to involve chromosome rearrangements, gene mutations and environmental factors. A group of genes including IRF6, FOXE1, GLI2, MSX2, SKI, SATB2, MSX1 and FGF has been implicated in the etiology of OFCs. Recently, the role of the copy number variations (CNVs) has been studied in genetic defects and diseases. CNVs act by modifying gene expression, disrupting gene sequence or altering gene dosage. The aims of this study were to screen the above-mentioned genes and to investigate CNVs in patients with OFCs. The sample was composed of 23 unrelated individuals who were grouped according to phenotype (associated with other anomalies or isolated) and familial recurrence. New sequence variants in GLI2, MSX1 and FGF8 were detected in patients, but not in their parents, as well as in 200 control chromosomes, indicating that these were rare variants. CNV screening identified new genes that can influence OFC pathogenesis, particularly highlighting TCEB3 and KIF7, that could be further analyzed. The findings of the present study suggest that the mechanism underlying CNV associated with sequence variants may play a role in the etiology of OFC.

Prognostic Impact Of Perineural Invasion And Lymphovascular Invasion In Advanced Stage Oral Squamous Cell Carcinoma.

Perineural invasion (PNI) and lymphovascular invasion (LVI) have been associated with the risk of local recurrences and lymph node metastasis. The aim of this study was to evaluate the prognostic impact of PNI and LVI in patients with advanced stage squamous cell carcinoma of the tongue and floor of the mouth. One hundred and forty-two patients without previous treatment were selected. These patients underwent radical surgery with neck dissection and adjuvant treatment. Clinicopathological data were retrieved from the medical charts, including histopathology and surgery reports. Univariate analysis was performed to assess the impact of studied variables on survival. Overall survival was negatively influenced by six tumour-related factors: increasing T stage (P = 0.003), more than two clinically positive nodes (P = 0.002), extracapsular spread of lymph node metastasis (P < 0.001), tumour thickness (P = 0.04), PNI (P < 0.001), and LVI (P = 0.012). Disease-free survival was influenced by PNI (P = 0.04), extracapsular spread of lymph node metastasis (P = 0.008), and N stage (P = 0.006). Multivariate analysis showed PNI to be an independent predictor for overall survival (P = 0.01) and disease-free survival (P = 0.03). Thus the presence of PNI in oral carcinoma surgical specimens has a significant impact on survival outcomes in patients with advanced stage tumours submitted to radical surgery and adjuvant radiotherapy/radiochemotherapy.

Dyskinesia induced by phenytoin

Phenytoin is an effective antiepileptic drug, although, it can be associated with many side effects, including dyskinesia. OBJECTIVE: To describe the clinical characteristics of phenytoin induced dyskinesia. METHODS: We investigated the occurrence of involuntary movements in patients followed at our adult and pediatric epilepsy clinics during the period of one year. RESULTS: Three patients presented with phenytoin-induced dyskinesia: one adult with axial and orofacial dyskinesia, and two children with choreoathetosis. They did not have other signs of phenytoin intoxication and had complete recovery after phenytoin withdrawal. CONCLUSION: Phenytoin induced dyskinesia may occur during either chronic or initial treatment and with normal serum phenytoin levels. However, it occurs most often in patients on polytherapy, usually after increasing dosage and with toxic serum levels. Other signs of phenytoin intoxication may be present in these patients, but often the dyskinesia is the only side effect, which may delay the diagnosis and treatment. The clinical characteristics of the involuntary movements vary and may be focal or generalized, most often characterized by choreoathetosis and dyskinesias. These may last for hours, days or even years, but frequently disappear completely after phenytoin withdrawal.

Relação dose-dependente do uso crônico de fenitoína e atrofia cerebelar em pacientes com epilepsia

The chronic treatment with phenytoin or the acute intoxication by this drug may cause permanent cerebellar injury with atrophy of cerebellum vermis and hemispheres, which can be detected by neuroimaging studies. The aim of the present study was to investigate the correlation between the dosage and duration of treatment with phenytoin and the occurrence of cerebellar atrophy. Sixty-six patients were studied and had their tomographies analyzed for cerebellar atrophy. Of the 66 patients studied, 18 had moderate/severe atrophy, 15 had mild atrophy and 33 were considered to be normal. The patients with moderate/severe atrophy were those with higher exposure to phenytoin (longer duration of treatment and higher total dosage) showing statistically significant difference when compared to patients with mild atrophy or without atrophy (p=0.02). Further, the patients with moderate/severe atrophy had serum levels of phenytoin statistically higher than those of patients with mild atrophy or without atrophy (p = 0.008). There was no association between other antiepileptic drugs dosage or duration of treatment and degree of cerebellar atrophy. We also found that older patients had cerebellar atrophy more frequently, indicating that age or duration of the seizure disorder may also be important in the determination of cerebellar degeneration in these patients. We conclude that although there is a possibility that repeated seizures contribute to cerebellar damage, long term exposure to phenytoin, particularly in high doses and toxic serum levels, cause cerebellar atrophy.

Desempenho físico-mecânico de minipainéis de terra crua tratada com aditivos químicos

The aim of this research was to study the effect of chemical additives (lime and Portland cement) associated with sodium silicate on soil in order to obtain compressed soil bricks. Mini panels were constructed with such bricks being their physical and mechanical characteristics determined in laboratory conditions and their behavior evaluated through the association of destructive and non-destructive methods. For this purpose a sandy soil and a finely divided one were added to Portland cement and lime in the dosage of 6% and 10% taken in dry weight basis in relation to the dry soil. The sodium silicate dosage of 4% was also taken in dry weight basis in relation to the dry soil-cement or to the dry soil-lime. The compressed soil bricks were cured in a humidity chamber for 7; 28; 56 and 91 days. The bricks were laid on the fourteenth day to form prismatic mini panels each one with four layers of bricks. After 28; 56 and 91 days the mini panels were submitted to both; ultrasonic and compressive tests to determine its elastic properties (dynamic modulus) and the compressive resistance. The best results in terms of compressive strength, water absorption capacity or dynamic elastic modulus, were reached by the sandy soil added to 10% of Portland cement or lime associated with sodium silicate.

Metabolic evaluation of young women with congenital adrenal hyperplasia

OBJECTIVE: To evaluate insulin resistance and lipid profile in women with congenital adrenal hyperplasia (CAH) caused by classical 21-hydroxylase deficiency (21OHD), and their association with body mass index (BMI) and corticosteroid dosage. SUBJECTS AND METHODS: We assessed BMI, waist circumference, current glucocorticoid dosage, glucose, insulin and lipid profile in eighteen young women (mean ± SD, 19.3 ± 3.0 years) with 21OHD CAH. RESULTS: BMI was normal in 12 patients, 5 of them were overweight, and 1 was obese. Waist circumference was high in 7 patients. Fasting insulin and HOMA-IR were elevated in seven and eight patients, respectively. Total cholesterol and triglycerides were high in only two patients, and HDL-cholesterol was low in four. Insulin resistance was not associated with BMI, waist circumference or glucocorticoid dose. CONCLUSIONS: Young women with 21OHD CAH had infrequent dyslipidemia, but had a higher prevalence of insulin resistance and central obesity, that were independent of BMI or corticosteroid dosage.

Association of insulin resistance and GLP-2 secretion in obesity: a pilot study

OBJECTIVE: The objective of this pilot study was to determine whether glugagon-like peptide 2 (GLP-2) secretion relates to insulin sensitivity (IS) in obese subjects. SUBJECTS AND METHODS: Twenty four obese subjects [body mass index (BMI) 40.0 ± 3.0 kg/m² (mean ± standard deviation)] were included, nine of which were male, age 43 ± 8 years. Twelve subjects had type 2 diabetes, all treated with oral anti-diabetic agents only. The subjects were submitted to standard meal tolerance test (MTT) for dosage of the curves: glucose, insulin, and GLP-2. Insulin sensitivity was measured by HOMA-IR, and OGIS was derived from the MTT. Spearman linear correlations and partial correlations were obtained. RESULTS: There was an inverse relationship between the GLP-2 secretion and IS: HOMA-IR correlated with GLP-2 AUC (R = 0.504; p = 0.012), and OGIS correlated with GLP-2 incremental AUC (R = -0.54; p = 0.054). The correlation persisted after controlling for BMI. CONCLUSION: We found an association of GLP-2 secretion and insulin resistance (IR). The understanding of the underlying mechanisms may provide future directions in the pharmacological manipulation of incretins, and in the treatment of obesity and related metabolic disorders.

Reprodutibilidade das mensurações da espessura das tábuas ósseas na tomografia computadorizada Cone-Beam utilizando diferentes protocolos de aquisição de imagem

INTRODUÇÃO: quanto menor a dimensão do voxel, maior a nitidez da imagem de tomografia computadorizada Cone-Beam (TCCB), porém, maior a dose de radiação emitida. OBJETIVOS: avaliar e comparar a reprodutibilidade da mensuração da espessura das tábuas ósseas vestibular e lingual em imagens de TCCB, utilizando diferentes protocolos de aquisição de imagem com variação da dimensão do voxel. MÉTODOS: exames de TCCB foram tomados de 12 mandíbulas humanas secas, com dimensão do voxel de 0,2; 0,3 e 0,4mm, no aparelho i-CAT Cone-Beam 3-D Dental Imaging System. No software i-CAT Viewer, foi mensurada a espessura das tábuas ósseas vestibular e lingual, em um corte axial passando 12mm acima do forame mentoniano do lado direito. A reprodutibilidade intraexaminador foi avaliada por meio da aplicação do teste t pareado. Para a comparação interexaminadores, foi utilizado o teste t independente. Os resultados foram considerados com o nível de significância de 5%. RESULTADOS: observou-se uma excelente reprodutibilidade interexaminadores para os três protocolos avaliados. A reprodutibilidade intraexaminadores foi muito boa, com exceção de algumas regiões dos dentes anteriores, que mostraram diferenças estatisticamente significativas, independentemente da dimensão do voxel. CONCLUSÃO: a mensuração da espessura das tábuas ósseas vestibular e lingual em imagens de TCCB mostrou boa precisão para exames obtidos com voxel de 0,2; 0,3 ou 0,4mm. A reprodutibilidade das mensurações na região anterior da mandíbula foi mais crítica do que na região posterior.