Comparative physiological and transcriptomic analysis of sono-biochemical control over post-acidification of Lactobacillus delbrueckii subsp. bulgaricus.

Thermosonication (UT) prestress treatments combining with varied fermentation patterns has been revealed as an effective method to regulate post-acidification as exerted by Lactobacillus delbrueckii subsp. bulgaricus (L. delbrueckii), but sono-biochemical controlling mechanisms remain elusive. This study employed physiological and transcriptomic analysis to explore the response mechanism of L. delbrueckii to UT-induced microstress (600 W, 33 kHz, 10 min). UT stress-induced inhibition of acidification of L. delbrueckii during (post)-fermentation was first confirmed, relying on the UT process parameters such as stress exposure duration and UT power. The significantly enhanced membrane permeability in cells treated by 600 W for 10 min than the microbes stressed by 420 W for 20 min suggested the higher dependence of UT-derived stresses on the treatment durations, relative to the ultrasonic powers. In addition, ultrasonication treatment-induced changes in cell membrane integrity enhanced and/or disrupted permeability of L. delbrueckii, resulting in an imbalance in intracellular conditions associated with corresponding alterations in metabolic behaviors and fermentation efficiencies. UT-prestressed inoculum exhibited a 21.46% decrease in the membrane potential during the lag phase compared to untreated samples, with an intracellular pH of 5.68 ± 0.12, attributed to the lower activities of H+-ATPase and lactate dehydrogenase due to UT stress pretreatments. Comparative transcriptomic analysis revealed that UT prestress influenced the genes related to glycolysis, pyruvate metabolism, fatty acid synthesis, and ABC transport. The genes encoding 3-oxoacyl-[acyl-carrier-protein] reductases I, II, and III, CoA carboxylase, lactate dehydrogenase, pyruvate oxidase, glucose-6-phosphate isomerase, and glycerol-3-phosphate dehydrogenase were downregulated, thus identifying the relevance of the UT microstresses-downregulated absorption and utilization of carbohydrates with the attenuated fatty acid production and energy metabolisms. These findings could contribute to provide a better understanding of the inactivated effects on the post-acidification of L. delbrueckii by ultrasonic pretreatments, thus providing theoretical basis for the targeted optimization of acidification inhibition efficiencies for yogurt products during chilled preservation processes.

Functional imaging guided stereotactic ablative body radiotherapy (SABR) with focal dose escalation and bladder trigone sparing for intermediate and high-risk prostate cancer: study protocol for phase II safo trial.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is an emerging treatment alternative for patients with localized low and intermediate risk prostate cancer patients. As already explored by some authors in the context of conventional moderate hypofractionated radiotherapy, focal boost of the index lesion defined by magnetic resonance imaging (MRI) is associated with an improved biochemical outcome. The objective of this phase II trial is to determine the effectiveness (in terms of biochemical, morphological and functional control), the safety and impact on quality of life, of prostate SABR with MRI guided focal dose intensification in males with intermediate and high-risk localized prostate cancer. METHODS: Patients with intermediate and high-risk prostate cancer according to NCCN definition will be treated with SABR 36.25 Gy in 5 fractions to the whole prostate gland with MRI guided simultaneous integrated focal boost (SIB) to the index lesion (IL) up to 50 Gy in 5 fractions, using a protocol of bladder trigone and urethra sparing. Intra-fractional motion will be monitored with daily cone beam computed tomography (CBCT) and intra-fractional tracking with intraprostatic gold fiducials. Androgen deprivation therapy (ADT) will be allowed. The primary endpoint will be efficacy in terms of biochemical and local control assessed by Phoenix criteria and post-treatment MRI respectively. The secondary endpoints will encompass acute and late toxicity, quality of life (QoL) and progression-free survival. Finally, the subgroup of high-risk patients will be involved in a prospective study focused on immuno-phenotyping. DISCUSSION: To the best of our knowledge, this is the first trial to evaluate the impact of post-treatment MRI on local control among patients with intermediate and high-risk prostate cancer undergoing SABR and MRI guided focal intensification. The results of this trial will enhance our understanding of treatment focal intensification through the employment of the SABR technique within this specific patient subgroup, particularly among those with high-risk disease, and will help to clarify the significance of MRI in monitoring local responses. Hopefully will also help to design more personalized biomarker-based phase III trials in this specific context. Additionally, this trial is expected to be incorporated into a prospective radiomics study focused on localized prostate cancer treated with radiotherapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05919524; Registered 17 July 2023. TRIAL SPONSOR: IRAD/SEOR (Instituto de Investigación de Oncología Radioterápica / Sociedad Española de Oncología Radioterápica). STUDY SETTING: Clinicaltrials.gov identifier: NCT05919524; Registered 17 July 2023. TRIAL STATUS: Protocol version number and date: v. 5/ 17 May-2023. Date of recruitment start: August 8, 2023. Date of recruitment completion: July 1, 2024.

Biochemical Control in Cushing's syndrome: Outcomes of the treatment in a large single center cohort.

BACKGROUND: Normalization of hypercortisolism is essential to reduce morbidity and mortality in patients with Cushing's syndrome (CS). The aim of this analysis was to assess biochemical control rates in patients with Cushing's disease (CD), ectopic Cushing's syndrome (ECS) and adrenal Cushing's syndrome (ACS). METHODS: Patients with confirmed CS (n= 296) treated in a single tertiary care center were retrospectively analysed (185 CD, 27 ECS, 84 uni- and bilateral ACS). RESULTS: Firstline treatment led to biochemical control in 82% of the patients. Time to biochemical control (median, IQR) was longer in CD (11.0 weeks, 5.6-29.8; p< 0.05) than in ACS (7.7 weeks, 4.1-17.1) and ECS (5.6 weeks, 4.1-23.3). Disease persistence or recurrence after first-line therapy was observed more often in CD (24% and 18%; p< 0.05) than in ECS (15% and 15%) and ACS (6% and 4%). Total time in hypercortisolism since diagnosis was significantly shorter in patients with CD diagnosed since 2013, after specialized patient care was implemented, compared to patients diagnosed before 2013 (13.5 weeks, vs. 26.1 weeks; p< 0.0070). Control of hypercortisolism at last follow up (76 months, 38-163) was achieved in 94% of patients with ACS, 100% of patients with ECS and 92% of patients with CD. CONCLUSIONS: Biochemical control can be achieved in most patients with different subtypes of CS within a reasonable time frame. Control of hypercortisolism has improved over time.

Medical treatment of acromegaly-experience from the Croatian acromegaly registry.

PURPOSE: The aim of this study was to review therapeutic outcomes of the medical treatment of patients with acromegaly based on real-world data from the Croatian Acromegaly Registry. METHODS: In this retrospective study we investigated 163 patients (101 female, 62 male, age at diagnosis 47.2 ± 13.4 years) treated between 1990 and 2020, of which 53 were treated medically (32.5%). The duration of follow-up was 115.8 ± 304.4 months. The remission rate after the pituitary surgery was achieved in 66.5% (n = 105/158; 5 patients refused surgery). Patients who did not achieve disease remission or had a relapse during follow-up (n = 2), underwent reoperation (n = 18/60, 30%) and/or radiotherapy (n = 33/60, 55%) and/or medical treatment (n = 53/60, 88.3%). One patient refused further treatment after the failure of the first pituitary surgery. RESULTS: Out of 53 patients treated with medical therapy, monotherapy was used in 34 (64.2%) and combination therapy in 19 (35.8%) patients. Remission (IGF-I < 1.2 upper limit of normal, ULN) was achieved in 51 patients (96.2%). Out of 53 patients, 21 (39.6%) were treated with first-generation somatostatin receptor ligand (SRL-1) monotherapy, 10 (18.9%) with dopamine agonist (DA) monotherapy, one (1.9%) with pegvisomant monotherapy, 13 (24.4%) with a combination of SRL-1 and DA, three (5.7%) with a combination of SRL-1, DA and pegvisomant, two (3.8%) with a combination of second-generation somatostatin receptor ligand (SRL-2), DA and pegvisomant and in one (1.9%) temozolomide was added on top of SRL-1 and DA. Two patients currently have active disease, both on SRL-1 monotherapy, of whom one is non-adherent to the treatment. Radiotherapy was applied to 27 (50.9%) patients on medical therapy. CONCLUSION: Our results indicate that almost all patients with active acromegaly after pituitary surgery can achieve biochemical control with medical treatment.

Association between pain, arthropathy and health-related quality of life in patients suffering from acromegaly. A cross-sectional study.

INTRODUCTION: Despite successful therapy, acromegalic patients have reduced health-related quality of life (HRQoL) compared to healthy controls. Finding predictors of poor HRQoL can be crucial to improving these patients' global health state.  Aim: The primary objective of the study was to find out predictors of HRQoL. Secondary objectives were: (I) to determine correlations with AcroQoL subscales, and (II) to identify predictors for subscales. MATERIALS AND METHODS: In this cross-sectional study conducted in 2019 at the Messina Policlinic Hospital, 45 acromegalic patients were assessed at the Physical and Rehabilitative Medicine Ambulatory. During routine outpatient clinic attendances, the following questionnaires were administered: Acromegaly Quality of Life Questionnaire (AcroQoL), Patient-Assessed Acromegaly Symptom Questionnaire (PASQ), and Western Ontario and McMaster Universities Arthritis Index (WOMAC). We furthermore included the following variables obtained by medical record review: age, BMI, disease duration, previous surgery (Yes/No), previous radiotherapy (Yes/No), use of GH lowering medications (Yes/No), hypertension (Yes/No), diabetes mellitus (Yes/No), and biochemical control of the disease (Yes/No): immunoradiometric assays were employed to serum GH and IGF-1 measurements to identify biochemical control of the disease. Correlation between outcome measures and AcroQoL has been performed. Pearson's r was calculated for continuous data following normal distribution (AcroQoL, PASQ, AcroQoL-B, AcroQoL-R, WOMAC-P), while Spearman's rank order correlation was calculated for non-normally distributed data (WOMAC, WOMAC-F, WOMAC-S, AcroQoL-P) and point-biserial correlation for binary variables (biochemically controlled disease, use of GH lowering medications, radiotherapy, surgery).  The same correlation analysis was performed for the AcroQoL subscales. Multiple linear regression with backwards, stepwise analysis was used to assess the influence on AcroQoL of correlated variables. RESULTS: AcroQoL was strongly negatively correlated with PASQ (r=-0.700, p<0.001) and negatively correlated with WOMAC [rs (43)=-0.530, p<0.001] and among WOMAC subscales with WOMAC-Physical fitness [rs (43)=-0.518, p<0.001] WOMAC-Pain [r (43)=-0.428, p=0.003], WOMAC-Stiffness [rs (43)=-0.393, p=0.007], and radiotherapy [r (43) =-0.314, p=0.035]. After univariate stepwise regression, PASQ was the strongest independent predictor of AcroQoL, with R2 of 0.392 [F (1,43)=27.695, p<0.001]. CONCLUSIONS: This study shows that the severity of painful symptoms is the most important predictor of HRQoL in patients with acromegaly; at the same time, acromegalic arthropathy leads to pain and to a variable amount of functional impairment, exerting great impact on the patient's perception of his health status. Measure of the progression of arthropathy and symptomatic management could lead to a great HRQoL benefit.

Cambios enzimáticos durante el entrenamiento anaeróbico láctico y su influencia en la capacidad aeróbica / Enzymatic changes during lactic anaerobic training and their influence on aerobic capacity

Introducción: El entrenamiento deportivo es un proceso que requiere una planificación orientada a la adaptación del cuerpo a las cargas internas versus cargas externas; de allí, surge la necesidad de conocer el comportamiento de algunas enzimas musculoesqueléticas a través del control bioquímico y fisiológico del entrenamiento en el atletismo de medio fondo. Objetivo: Analizar los cambios enzimáticos de la creatinfosfoquinasa y la lactodeshidrogenasa durante el entrenamiento anaeróbico láctico y su influencia en la capacidad aeróbica en atletas de medio fondo. Método: Se utilizó el método descriptivo comparativo con una muestra de 20 sujetos aleatorizados en dos grupos: experimental y control; el análisis se realizó bajo el modelo estadístico Anova descriptiva, pruebas T y diseño de medidas repetidas con un intervalo del 95 por ciento de confianza (p<0,05). Resultados: En las variables creatinfosfoquinasa y lactodeshidrogenasa inicial y final no hubo variaciones significativas intergrupos; se observaron diferencias en la creatinfosfoquinasa en varianza (p=0,022) del orden del 97,8 por ciento; que en promedio (p=0,088) representó los niveles alcanzados del 91,2 por ciento. En las medidas repetidas no se presentaron cambios estadísticamente significativos intergrupos. Para la variable del VO2máx se aplicó la prueba T para comparar los estados inicial y final en cada grupo y hubo diferencias en ambos grupos (control p=0,002; experimental p=0,000). Conclusiones: No hubo cambios enzimáticos importantes durante los entrenamientos anaeróbico láctico y aeróbico, a su vez, el entrenamiento anaeróbico láctico si tuvo influencia en la capacidad aeróbica(AU)

Introduction: Sports training is a process that requires a planning oriented to the adaptation of the body to internal loads versus external loads; from there, arises the need to know the behavior of some musculoskeletal enzymes through the biochemical and physiological control of training in middle-distance athletics. Objective: To analyze the enzymatic changes of creatine phosphokinase and lactodehydrogenase during lactic anaerobic training and their influence on aerobic capacity in middle-distance athletes. Methods: The descriptive comparative method was used with a sample of 20 subjects randomized in two groups: experimental and control; the analysis was performed under the descriptive Anova statistical model, T-tests and repeated measures design with a 95 percent confidence interval (p<0.05). Results: In the initial and final creatine phosphokinase and lactodehydrogenase variables, there were no significant intergroup variations; differences were observed in creatine phosphokinase regarding variance or standard deviation (p=0.022) in the order of 97.8 percent; which in average (p=0.088) represented the levels reached of 91.2 percent. In the repeated measures, there were no statistically significant intergroup changes. For the VO2max variable, the T-test was applied to compare the initial and final states in each group and there were differences in both groups (control p=0.002; experimental p=0.000). Conclusions: There were no important enzymatic changes during lactic anaerobic and aerobic training, and lactic anaerobic training had an influence on aerobic capacity(AU)

Mortality of Orius insidiosus by contact with spinosad in the laboratory as well as in the field and a perspective of these as controllers of Frankliniella occidentalis.

Orius insidiosus, known as the pirate bug, is widely distributed throughout the Americas. It is employed for the biological control of Frankliniella occidentalis in organic berry crops in Mexico. In conventional crops, spinosad is the main control method for this pest. The LD50 of spinosad on O. insidiosus was determined. In addition, we monitored the population density of F. occidentalis in blackberry crops under two types of management (biochemical+mass trapping, and biological control). The LD50 was 225.65 ppm 3.8 times greater than the 60 ppm dose commonly used in blackberry crops. Both types of control are efficient; however, spinosad is less effective and should be combined with other environmentally friendly strategies. The possibility of combining chromatic traps+spinosad application and chromatic traps+strategic release of O. insidiosus to effectively control thrips without compromising fruit quality is discussed.

Advancements in the radiooncological treatment of high-risk prostate cancer: a quarter century of achievements.

BACKGROUND: The aim of the study was to evaluate the development of treatment of primary high-risk prostate cancer in regards to biochemical no evidence of disease (bNED), acute and late gastrointestinal (GI) and genitourinary (GU) side effects. PATIENTS AND METHODS: Primary high-risk prostate cancer patients treated between 1994 and 2016 were included. Applied doses ranged from 60 to 80 Gy, with a dose of 1.8 or 2 Gy per fraction. Techniques were either 3D conformal or intensity modulated radiotherapy and volumetric intensity modulated arc therapy. RESULTS: 142 patients were treated with doses up to 70 Gy (median dose 66 Gy; 66 Gy group), 282 with doses between 70 and 76 Gy (median dose 74 Gy; 74 Gy group), and 141 with doses >76 Gy (median dose 78 Gy; 78 Gy group). The median follow-up was 48 months. The bNED rates were 50% after 5 years and 44% after 9 years in the 66 Gy group; 65% and 54%, respectively, in the 74 Gy group; and 83% and 66%, respectively, in the 78 Gy group (p = 0.03 vs. 74 Gy and p < 0.0001 vs. 66 Gy). We found a higher rate of acute GI side effects in the 78 Gy group compared to the other groups, but not in maximum acute GU side effects and late maximum GI and GU effects. CONCLUSIONS: High-risk prostate cancer patients treated with doses of 78 Gy had significantly better bNED rates. Compared to the historical 66 Gy group, 50% more patients achieved bNED after a follow-up of 9 years.

Comparative effectiveness of moderate hypofractionation with volumetric modulated arc therapy versus conventional 3D-radiotherapy after radical prostatectomy.

PURPOSE: Hypofractionated radiotherapy for prostate cancer is well established for definitive treatment, but not well defined in the postoperative setting. The purpose of this analysis was to assess oncologic outcomes and toxicity in a large cohort of patients treated with conventionally fractionated three-dimensional (3D) conformal radiotherapy (CF) and hypofractionated volumetric modulated arc therapy (HF) after radical prostatectomy. METHODS: Between 1994 and 2019, a total of 855 patients with prostate carcinoma were treated by postoperative radiotherapy using CF (total dose 65-72 Gy, single fraction 1.8-2 Gy) in 572 patients and HF (total dose 62.5-63.75 Gy, single fraction 2.5-2.55 Gy) in 283 patients. The association of treatment modality with biochemical control, overall survival (OS), and gastrointestinal (GI) and genitourinary (GU) toxicity was assessed using logistic and Cox regression analysis. RESULTS: There was no difference between the two modalities regarding biochemical control rates (77% versus 81%, respectively, for HF and CF at 24 months and 58% and 64% at 60 months; p = 0.20). OS estimates after 5 years: 95% versus 93% (p = 0.72). Patients undergoing HF had less frequent grade 2 or higher acute GI or GU side effects (p = 0.03 and p = 0.005, respectively). There were no differences in late GI side effects between modalities (hazard ratio 0.99). Median follow-up was 23 months for HF and 72 months for CF (p < 0.001). CONCLUSION: For radiation therapy of resected prostate cancer, our analysis of this largest single-centre cohort (n = 283) treated with hypofractionation with advanced treatment techniques compared with conventional fractionation did not yield different outcomes in terms of biochemical control and toxicities. Prospective investigating of HF is merited.

Evaluation of acromegaly treatment direct costs with respect to biochemical control and follow-up length.

PURPOSE: Acromegaly is a severe chronic endocrine disease. Achieving biochemical control often needs a multimodal treatment approach, including prolonged medical treatment. Aim of the study is to evaluate the burden of treatment direct costs with respect to the different therapeutic strategies, disease control, and follow-up length. METHODS: Single center retrospective study on 73 acromegaly patients. Costs of acromegaly treatments were computed based on a detailed revision of patients' clinical charts. RESULTS: Median total treatment cost/patient was €47,343 during the entire follow-up (8 years), while median treatment cost/patient/year was €6811. The majority of patients received medical therapy (71/73, 97.3%). Median cost for first-line medical treatment (first-generation somatostatin receptor ligands) was lower compared to second-line treatments (pegvisomant monotherapy or combination therapies), considering both total (€22,824 vs €76,140; p < 0.001), and yearly cost/patient (€4927 vs €9161; p < 0.001). Sixty patients (82.2%) reached biochemical control at last follow-up (IGF-1 ≤ 1 xULN). The percentage of patients treated with first- or second-line medical therapies was comparable between controlled and uncontrolled patients (p = 1.000), and the yearly cost/patient did not significantly differ between the two groups (€6936 vs €6680; p = 0.829). Follow-up duration was significantly longer in controlled patients compared to the uncontrolled ones (8.7 vs 3.5 years; p = 0.019). CONCLUSIONS: Direct costs for the management of acromegaly have a significant burden on the healthcare systems. However, more than 80% of our patients reached biochemical control using multimodal approaches. Treatment modalities and yearly costs did not significantly differ between controlled and uncontrolled patients, while follow-up length represented a major determinant of biochemical outcome.

Comparison of EBRT and I-125 seed brachytherapy concerning outcome in intermediate-risk prostate cancer.

PURPOSE: This study's objective was the comparison of external beam radiotherapy (EBRT) and I­125 seed brachytherapy regarding clinical outcome and development of side effects. PATIENTS AND METHODS: In all, 462 localized intermediate-risk prostate cancer patients treated between 2000 and 2019 at our department using either I­125 seed brachytherapy or EBRT with a dose of 74 or 78 Gy were included: 297 patients were treated with EBRT and 165 with seeds. Biochemical no evidence of disease (bNED) rates according to Phoenix definition as well as late gastrointestinal and urogenital side effects (EORTC/RTOG) were assessed. RESULTS: Patients were followed up yearly with a median follow-up of 54 (3-192) months. Observed bNED rates for 74 Gy, 78 Gy and seeds were 87, 92, and 88% after 5 years and 71, 85, and 76% after 9 years, respectively. No significant differences were found comparing seeds with 74 Gy (p = 0.81) and 78 Gy (p = 0.19), as well as between 74 and 78 Gy (p = 0.32). Concerning gastrointestinal side effects, EBRT showed significantly higher rates of RTOG grade ≥ 2 toxicity compared to seeds, but at no point of the follow-up more than 10% of all patients. However, genitourinary side effects were significantly more prevalent in patients treated with seeds, with 33% RTOG grade ≥ 2 toxicity 12 months after treatment. Nevertheless, both types of side effects decreased over time. CONCLUSION: Favorable intermediate-risk prostate cancer patients can be treated either by external beam radiotherapy (74/78 Gy) or permanent interstitial seed brachytherapy.

Particularities of the changes in young swimmers' body adaptation to the stimuli of physical and mental stress in sports training process.

BACKGROUND: A factor favoring the swimming performance increase is the adaptation and readaptation of body energetic and functional systems to the physical and mental stress stimuli in training and competitions. The efficiency of monitoring the young swimmers' training is based on a precise determination of the changes in the specific adaptations. The evaluation and control of the biochemical, mental and motor changes ensure the knowledge of the particularities of body adaptation in different training stages. METHODS: Six young swimmers aged 12-16 years specialized in 100 m event participated in this study, conducted in four stages (E1-general, E2-specific, E3-pre-competitive and E4-competitive). The distress occurrence during adaptation to training and competition stimuli was studied in 3 levels: mental (Cohen & Williamson Test (CWT), Cohen Perceived Stress Test (CPST), Competition Anxiety Test (SCAT), Craciun Test (CT)), motor (workouts monitoring, planning of means on training areas, anaerobic threshold assessment and average training speed calculation) and biochemical (blood lactate (La) and blood glucose (Glu) before and after effort-5 and 15 minutes; level of metabolic biochemical parameters, lymphocytes and blood glucose, and also hormonal parameters-norepinephrine, prolactin and cortisol-before and after competition effort). RESULTS: Quantity results of the mental, motor and biochemical tests were analyzed in groups; the quality results for each subject in dynamics were analyzed by comparison and correlation. Psychological tests showed increases in athletes' mental behavior by 34% at CWT (p < 0.05), by 37.5% at CPST (p < 0.05), average stress level at SCAT and 70% stress in self-confidence at CT (p < 0.01). Biochemical tests revealed an ascending dynamics of La accumulated after specific effort, with peaks in E2 period (p < 0.05) and decreases in E3 compared to E2 (p < 0.05), revealing the adaptation to specific effort and the increase in anaerobic capacity. The Glu values decrease in pre-effort and increase in minute 5 and 15 post-effort (p < 0.05) in E2 and decrease in pre- and post- effort in E3 (p < 0.05), showing the effort impact on body and ability to recover after effort. Athletes' individual metabolic results were 50% above maximum values, mainly post-effort (42%); hormonal results were 17% over maximum values, mainly post-effort (14%). Spearman's correlative analysis of the induced-stress stimuli in workouts revealed 6.06% significant correlations at p < 0.05 and 9.1% strong connections in competitions: 4.67% significant correlations at p < 0.05 and 6.4% strong connections. CONCLUSION: The research demonstrated that the mental and biochemical tests results correlation with the specific motor tests facilitated the correct individualization of effort orientation in training and recovery and contributed to the knowledge of the particularities of young swimmers' body adaptation to training and competition effort.

Stereotactic Body Radiotherapy for High-Risk Prostate Cancer: A Systematic Review.

BACKGROUND: Radiotherapy (RT) is an established, potentially curative treatment option for all risk constellations of localized prostate cancer (PCA). Androgen deprivation therapy (ADT) and dose-escalated RT can further improve outcome in high-risk (HR) PCA. In recent years, shorter RT schedules based on hypofractionated RT have shown equal outcome. Stereotactic body radiotherapy (SBRT) is a highly conformal RT technique enabling ultra-hypofractionation which has been shown to be safe and efficient in patients with low- and intermediate-risk PCA. There is a paucity of data on the role of SBRT in HR PCA. In particular, the need for pelvic elective nodal irradiation (ENI) needs to be addressed. Therefore, we conducted a systematic review to analyze the available data on observed toxicities, ADT prescription practice, and oncological outcome to shed more light on the value of SBRT in HR PCA. METHODS: We searched the PubMed and Embase electronic databases for the terms "prostate cancer" AND "stereotactic" AND "radiotherapy" in June 2020. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. RESULTS: After a rigorous selection process, we identified 18 individual studies meeting all selection criteria for further analyses. Five additional studies were included because their content was judged as relevant. Three trials have reported on prostate SBRT including pelvic nodes; 2 with ENI and 1 with positive pelvic nodes only. The remaining studies investigated SBRT of the prostate only. Grade 2+ acute genitourinary (GU) toxicity was between 12% and 46.7% in the studies investigating pelvic nodes irradiation and ranged from 0% to 89% in the prostate only studies. Grade 2+ chronic GU toxicity was between 7% and 60% vs. 2% and 56.7%. Acute gastrointestinal (GI) grade 2+ toxicity was between 0% to 4% and 0% to 18% for studies with and without pelvic nodes irradiation, respectively. Chronic GI grade 2+ toxicity rates were between 4% and 50.1% vs. 0% and 40%. SBRT of prostate and positive pelvic nodes only showed similar toxicity rates as SBRT for the prostate only. Among the trials that reported on ADT use, the majority of HR PCA patients underwent ADT for at least 2 months; mostly neoadjuvant and concurrent. Biochemical control rates ranged from 82% to 100% after 2 years and 56% to 100% after 3 years. Only a few studies reported longer follow-up data. CONCLUSION: At this point, SBRT with or without pelvic ENI cannot be considered the standard of care in HR PCA, due to missing level 1 evidence. Treatment may be offered to selected patients at specialized centers with access to high-precision RT. While concomitant ADT is the current standard of care, the necessary duration of ADT in combination with SBRT remains unclear. Ideally, all eligible patients should be enrolled in clinical trials.

Biochemical control after adjuvant radiation therapy for prostate cancer: a unicentric, retrospective analysis.

PURPOSE: To retrospectively evaluate the biochemical no evidence of disease (bNED) and late side effects after adjuvant radiotherapy in prostate cancer patients. METHODS: Patients (n = 85) treated with external beam radiotherapy between 1997 and 2013 following radical prostatectomy (RPE) with pathological tumour stage pT2c with positive surgical margins or pT3 and pT4 tumours with or without positive margins who presented with a postoperative and a preradiation prostate-specific antigen (PSA) level below 0.1 ng/ml. The mean dose applied was 66 Gy with conventional fractionation (4 field box-technique). No androgen deprivation therapy was administered, and patients with incomplete data (missing Gleason score, pT stage, or PSA values postoperatively and/or prior to radiation at the presentation at our department) have been excluded from the analysis. Biochemical recurrence was defined as reaching a PSA level > 0.2 ng/ml during follow-up and bNED rates were assessed. In addition, patients were divided into two groups according to the Roach formula for predicting the risk of pelvic node involvement at a cut-off value of 15%. Late urogenital and gastrointestinal side effects (EORTC/RTOG) were assessed. RESULTS: After a median follow-up of 60 months the bNED rate was 88% at 5 years and 72% at 10 years for all patients. Patients with low risk of lymph node involvement (group < 15%) had a 5 year and 10 year bNED of 97% and 85%, while patients with high risk of positive lymph node involvement (group > 15%) showed corresponding bNED rates of 77% and 52%, respectively. A significant difference according to the Roach stratification was detected (p ≤ 0.002). Late urogenital (UG) and gastrointestinal (GI) grade ≥ 2 side effects were detected in 10% and 15%, respectively. CONCLUSION: Postoperative radiotherapy with an average dose of 66 Gy to the prostatic fossa following RPE provides excellent tumour control rates with acceptable side effects. Patients with a higher risk of positive lymph nodes (> 15%) according to the Roach formula show significant worse tumour control rates.

HDR brachytherapy as monotherapy for prostate cancer: A systematic review with meta-analysis.

PURPOSE: The effectiveness and safety of high dose brachytherapy as monotherapy (HDR-BRT-M) in prostate cancer is limited to retrospective studies. We performed a meta-analysis to summarize existing data and identify trends in biochemical recurrence-free survival (bRFS) and toxicity after HDR-BRT-M in patients with prostate cancer. METHODS AND MATERIALS: Retrospective, prospective, or randomized clinical trials were identified on electronical databases through June 2020. We followed the PRISMA and MOOSE guidelines. A meta-regression analysis was performed to assess if there is a relationship between moderator variables and bRFS. A p-value < 0.05 was considered significant. RESULTS: Fourteen studies with a total of 3534 patients treated were included. The cumulative size of the bRFS at 5 years was 0.92 (95% confidence interval (CI) 0.48-0.61). The five-year bRFS for low, intermediate, and high risk was 97.5% (95% CI 96-98%), 93.5% (95% CI 91-96%), and 91% (95% CI 88-93%), respectively. The total biological effective dose (BED) (p = 0.02), the BED per fraction (p = 0.001), androgen deprivation therapy usage (p = 0.04), and the number of fractions of HDR-BRT-M (p = 0.024) were significantly associated with bRFS rate. The rate of late Grade 2/3 or > genitourinary and gastrointestinal toxicity was 22.4% (95% CI 9-35,2%)/1.4% (95% CI 0.8-2.1%) and 2.7% (95% CI 0-6.8%) and 0.2% (95% CI 0.1%-0.4%), respectively. CONCLUSIONS: HDR-BRT-M is safe with excellent rates of bRFS for all risk groups. The total BED, the BED per fraction, and number of fractions were the key factors associated with the biochemical control. These data can be useful to choose the size and number of BRT fractionation.

Discordant GH and IGF-1 Results in Treated Acromegaly: Impact of GH Cutoffs and Mean Values Assessment.

CONTEXT: Discordant growth hormone (GH) and insulin-like growth factor-1 (IGF-1) values are frequent in acromegaly. OBJECTIVE: To evaluate the impact of different GH cutoffs on discordance rate. To investigate whether the mean of consecutive GH measurements impacts discordance rate when matched to the last available IGF-1 value. DESIGN: Retrospective study. SETTING: Referral center for pituitary diseases. PATIENTS: Ninety acromegaly patients with at least 3 consecutive evaluations for GH and IGF-1 using the same assay in the same laboratory (median follow-up 13 years). INTERVENTIONS: Multimodal treatment of acromegaly. MAIN OUTCOME MEASURES: Single fasting GH (GHf) and IGF-1 (IGF-1f). Mean of 3 GH measurements (GHm), collected during consecutive routine patients' evaluations. RESULTS: At last evaluation GHf values were 1.99 ± 2.79 µg/L and age-adjusted IGF-1f was 0.86 ± 0.44 × upper limit of normality (mean ± SD). The discordance rate using GHf was 52.2% (cutoff 1 µg/L) and 35.6% (cutoff 2.5 µg/L) (P = 0.025). "High GH" discordance was more common for GHf <1.0 µg/L, while "high IGF-1" was predominant for GHf <2.5 µg/L (P < 0.0001). Using GHm mitigated the impact of GH cutoffs on discordance (GHm <1.0 µg/L: 43.3%; GHm <2.5 µg/L: 38.9%; P = 0.265). At receiver-operator characteristic curve (ROC) analysis, both GHf and GHm were poor predictors of IGF-1f normalization (area under the curve [AUC] = 0.611 and AUC = 0.645, respectively). The prevalence of disease-related comorbidities did not significantly differ between controlled, discordant, and active disease patients. DISCUSSION: GH/IGF-1 discordance strongly depends on GH cutoffs. The use of GHm lessen the impact of GH cutoffs. Measurement of fasting GH levels (both GHf and GHm) is a poor predictor of IGF-1f normalization in our cohort.

Dose-response with stereotactic body radiotherapy for prostate cancer: A multi-institutional analysis of prostate-specific antigen kinetics and biochemical control.

BACKGROUND AND PURPOSE: The optimal dose for prostate stereotactic body radiotherapy (SBRT) is still unknown. This study evaluated the dose-response relationships for prostate-specific antigen (PSA) decay and biochemical recurrence (BCR) among 4 SBRT dose regimens. MATERIALS AND METHODS: In 1908 men with low-risk (50.0%), favorable intermediate-risk (30.9%), and unfavorable intermediate-risk (19.1%) prostate cancer treated with prostate SBRT across 8 institutions from 2003 to 2018, we examined 4 regimens (35 Gy/5 fractions [35/5, n = 265, 13.4%], 36.25 Gy/5 fractions [36.25/5, n = 711, 37.3%], 40 Gy/5 fractions [40/5, n = 684, 35.8%], and 38 Gy/4 fractions [38/4, n = 257, 13.5%]). Between dose groups, we compared PSA decay slope, nadir PSA (nPSA), achievement of nPSA ≤0.2 and ≤0.5 ng/mL, and BCR-free survival (BCRFS). RESULTS: Median follow-up was 72.3 months. Median nPSA was 0.01 ng/mL for 38/4, and 0.17-0.20 ng/mL for 5-fraction regimens (p < 0.0001). The 38/4 cohort demonstrated the steepest PSA decay slope and greater odds of nPSA ≤0.2 ng/mL (both p < 0.0001 vs. all other regimens). BCR occurred in 6.25%, 6.75%, 3.95%, and 8.95% of men treated with 35/5, 36.25/5, 40/5, and 38/4, respectively (p = 0.12), with the highest BCRFS after 40/5 (vs. 35/5 hazard ratio [HR] 0.49, p = 0.026; vs. 36.25/5 HR 0.42, p = 0.0005; vs. 38/4 HR 0.55, p = 0.037) including the entirety of follow-up, but not for 5-year BCRFS (≥93% for all regimens, p ≥ 0.21). CONCLUSION: Dose-escalation was associated with greater prostate ablation and PSA decay. Dose-escalation to 40/5, but not beyond, was associated with improved BCRFS. Biochemical control remains excellent, and prospective studies will provide clarity on the benefit of dose-escalation.

Quality of Life and its Determinants in Patients With Treated Acromegaly: A Cross-Sectional Nationwide Study in China.

CONTEXT: Quality of life (QoL) continues to be impaired in acromegaly after treatment. OBJECTIVE: We conducted the first nationwide survey assessing QoL status among Chinese patients with treated acromegaly and explored correlations with clinical parameters, treatment modalities, and outcomes. DESIGN: Cross-sectional study. SETTING: Survey via Chinese Association of Patients with Acromegaly (CAPA) online platform. PATIENTS: Treated patients from CAPA. MAIN OUTCOME MEASURES: QoL was assessed using acromegaly QoL questionnaire (AcroQoL), 5-level EuroQoL five-dimensional questionnaire (EQ-5D-5L), and 12-item short-form health survey questionnaire (SF-12). RESULTS: Complete, valid questionnaires from 327 patients (mean age: 39.2 years, 61.5% females) at a mean of 10 years after treatment were included. Biochemical control was satisfied in 52.9% of these patients. The controlled patients had significantly better QoL than the uncontrolled patients in all AcroQoL dimensions, most SF-12 dimensions, and pain/discomfort and anxiety/depression dimensions of the EQ-5D-5L. Patients with either controlled or uncontrolled acromegaly had significantly worse QoL than the age- and sex-adjusted population reference in most SF-12 dimensions except for physical functioning. More acromegaly-associated symptoms and comorbidities at follow-up were independent risk factors for decreased QoL across all questionnaires. Medical treatment, especially with somatostatin analogs (SSAs), and radiotherapy were predictors of worse QoL. Female patients had lower scores of physical-related QoL than male patients. CONCLUSIONS: Our study suggests that biochemical control improved but did not normalize QoL in acromegaly. Numbers of symptoms and comorbidities at follow-up, sex, radiotherapy, and medical treatment with SSAs were factors determining QoL of patients with treated acromegaly.

Creatinine is a biochemical marker for assessing how untrained people adapt to fitness training loads.

BACKGROUND: To study the peculiarities of changes in creatinine concentration in blood serum of untrained men during the prolonged usage of training loads different in volume and intensity, and to determine the value of this biochemical marker for the assessment of adaptive body changes during fitness training. METHODS: We examined 50 untrained men aged 18-20 years who had no contraindications for practicing fitness. Taking into account the aim of the research, we divided these people into two groups: group A and group B. The research participants used training load regimes different in volume and intensity: representatives of group Aused low intensity training load regime (Ra = 0.53) and representatives of group B used high intensity training load regime (Ra = 0.72). To assess the adaptive body changes in the examined contingent, we used the anthropometry method (circumference body size) and bioimpedansometry (body composition indicators). We also determined the features of adaptation-compensatory body reactions to different training loads by means of biochemical control of creatinine concentration in blood serum. RESULTS: The obtained results showed a significant increase in basal level of creatinine concentration in blood serum (by 17.6%) of group B representatives fixed after 3 months of practicing fitness in high intensity training load regime (R a  = 0.72). This group representative also revealed the most pronounced manifestation of adaptive body changes confirmed by the results of the maximal muscle strength growth (1RM) and circumference body size, which was almost 2.5 times higher than the results of group A representatives for the same period of time. The parameters indicating the load volume in a set (Wn) were almost 62.0 % higher in group A representatives in comparison with group B during all stages of control. Nonetheless, the highest creatinine concentration in blood serum (by 11.1 % (p < 0.05) was fixed in group A representatives in response to training load after 3 months of practicing. This fact testifies to the important role of the creatine phosphokinase mechanism of energy supply of muscular activity in the conditions of high volume and low intensity training load regime (R a  = 0.53). CONCLUSION: The analysis of the results obtained during a series of experimental studies indicates the need and feasibility of using the indicator of basal level of creatinine concentration in blood during fitness training, especially in the conditions of high intensity and low volume training load regime (R a  = 0.72), as an informative marker for assessing the process of long-term adaptation.

Stereotactic radiosurgery for acromegaly: an international systematic review and meta-analysis of clinical outcomes.

INTRODUCTION: We performed a systematic review and meta-analysis of clinical outcomes for patients with acromegaly treated with stereotactic radiosurgery (SRS). METHODS: Primary outcomes were 5- and 10-year endocrine remission (ER) and endocrine control (EC). Secondary outcomes were 10-year radiographic local control (LC), visual toxicity, and hypopituitarism rates. Weighted random effects meta-analyses using the DerSimonian and Laird methods were conducted to characterize and compare effect sizes. Mixed effects regression models were used to examine correlations between potential prognostic factors and primary and secondary outcomes. RESULTS: In total, 1533 patients across 20 published studies with acromegaly treated with SRS were included. At 5-years, estimated ER and EC rates were 43.2% (95% CI 31.7-54.6%) and 55.0% (95% CI 27.6-82.4%), respectively. At 10-years, estimated ER and EC rates were 56.9% (95% CI 47.5-66.4%) and 69.7% (95% CI 47.7-91.8%), respectively. The estimated 10-year LC rate was 92.8% (95% CI 83.0-100%). Visual toxicity and hypopituitarism following SRS were estimated to be 2.7% (95% CI 1.3-4.2%) and 26.8% (95% CI 16.9-36.7%), respectively. Every 1 Gy increase in margin prescription dose beyond 17 Gy was estimated to result in a 0.41% increased risk of visual toxicity (p = 0.03). No prognostic factors were associated with EC, ER, LC, or hypopituitarism. CONCLUSIONS: SRS was well-tolerated in the management of pituitary acromegaly resulting in gradually improving ER and EC rates over time that approached 60% and 70%. SRS-related visual loss is an uncommon treatment-related side effect, and patient-specific clinical decision making remains critical.