Stereotactic MR-guided adaptive radiotherapy (SMART) for primary rectal cancer: evaluation of early toxicity and pathological response.

Background: The purpose of this study is to measure the effects of stereotactic MR-guided adaptive radiotherapy (SMART) for rectal cancer patients in terms of early toxicity and pathological response. Materials and methods: For this prospective pilot study, patients diagnosed with locally advanced rectal cancer (LARC) with positive lymph node clinical staging underwent SMART on rectal lesion and mesorectum using hybrid MR-Linac (MRIdian ViewRay). Dose prescription at 80% isodose for the rectal lesion and mesorectum was 40 Gy (8 Gy/fr) and 25 Gy (5 Gy/fr), respectively, delivered on 5 days (3 fr/week). Response assessment by MRI was performed 3 weeks after SMART, then patients fit for surgery underwent total mesorectal excision. Primary endpoint was evaluation of adverse effect of radiotherapy. Secondary endpoint was pathological complete response rate. Early toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Results: From October 2020 to January 2022, twenty patients underwent rectal SMART. No grade 3-5 toxicity was recorded. Twelve patients were eligible for total mesorectal excision (TME). Mean interval between the completion of SMART and surgery was 4 weeks. Pathological downstaging occurred in all patients; rate of pathological complete response (pCR) was 17%. pCR occurred with a prolonged time to surgery (> 7 weeks). Conclusion: To our knowledge, this is the first study to use stereotactic radiotherapy for primary rectal cancer. SMART for rectal cancer is well tolerated and effective in terms of tumor regression, especially if followed by delayed surgery.

Effectiveness of clinical scores in predicting coronary artery disease in familial hypercholesterolemia: a coronary computed tomography angiography study.

PURPOSE: One of the major challenges in the management of familial hypercholesterolemia (FH) is the stratification of cardiovascular risk in asymptomatic subjects. Our purpose is to investigate the performance of clinical scoring systems, Montreal-FH-score (MFHS), SAFEHEART risk (SAFEHEART-RE) and FH risk score (FHRS) equations and Dutch Lipid Clinic Network (DLCN) diagnostic score, in predicting extent and severity of CAD at coronary computed tomography angiography (CCTA) in asymptomatic FH. MATERIAL AND METHODS: One-hundred and thirty-nine asymptomatic FH subjects were prospectively enrolled to perform CCTA. MFHS, FHRS, SAFEHEART-RE and DLCN were assessed for each patient. Atherosclerotic burden scores at CCTA (Agatston score [AS], segment stenosis score [SSS]) and CAD-RADS score were calculated and compared to clinical indices. RESULTS: Non-obstructive CAD was found in 109 patients, while 30 patients had a CAD-RADS ≥ 3. Classifying the two groups according to AS, values varied significantly for MFHS (p < 0.001), FHRS (p < 0.001) and SAFEHEART-RE (p = 0.047), while according to SSS only MFHS and FHRS showed significant differences (p < 0.001). MFHS, FHRS and SAFEHEART-RE, but not DLCN, showed significant differences between the two CAD-RADS groups (p < .001). MFHS proved to have the best discriminatory power (AUC = 0.819; 0.703-0.937, p < 0.001) at ROC analysis, followed by FHRS (AUC = 0.795; 0.715-0.875, p < .0001) and SAFEHEART-RE (AUC = .725; .61-.843, p < .001). CONCLUSIONS: Greater values of MFHS, FHRS and SAFEHEART-RE are associated to higher risk of obstructive CAD and might help to select asymptomatic patients that should be referred to CCTA for secondary prevention.

Determinants of LV mass in athletes: the impact of sport, constitutional traits and cardiovascular risk factors.

BACKGROUND: Whether cardiovascular (CV) risk factors might impact Left Ventricular (LV) mass in athletes is unknown. METHODS: The impact of CV risk factors (Total/LDL cholesterol, triglycerides, positive family history, smoking, body fat, blood pressure), constitutional characteristics (age, sex, body mass index) and type of sport was assessed in 1111 Olympic athletes. RESULTS: Multivariate logistic regression analysis demonstrated a significant impact: BMI ≥ 30 kg/m2 (odds ratio [OR] = 2.8. 95° Confidence Interval [CI] 0.9-13.7; < 0.001; in males); age ≥ 20-year (OR = 2.1, CI 1.4-3.3; p < 0.001) in males; (OR = 2.3; CI 1.4-3.7) in females; systolic blood pressure ≥ 130 mmHg (OR = 1.1, CI 1.01-1.16; p < 0.001) in males; (OR = 1.03; CI 1.01-1.06; p < 0.03) in females; diastolic ≥ 85 mmHg (OR = 1.1, CI 1.03-1.2; p = 0.003) in males; (OR = 1.05, CI 1.02-1.08, p < 0.001) in females. No association was found for family history, smoking, body fat, LDL, total cholesterol, triglycerides. Overall, constitutional traits explain > 60% of the LV mass. Sport explains on average 14%, but large differences existed among disciplines, i.e., endurance showed the highest impact (55%, mixed: 20%, power: 17%, skill: 8%; p < 0.001). CONCLUSION: LV mass in athletes is largely governed by constitutional traits and type of sport, and independent from CV risk factors, except for systolic and diastolic blood pressure. Overall, constitutional traits explain more than 60% of LV mass. The impact of sport is largely different in relation to the discipline, and highest in endurance, moderate mixed and power and mild in skill disciplines.

Ceftazidime-Avibactam for the Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections in Patients With Liver Cirrhosis.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections in patients with cirrhosis represent a significant therapeutic challenge as they are associated with poor outcomes due to high rates of treatment failure, and frequently induce liver decompensation. Aims: To evaluate treatment failure and in-hospital mortality in two cohorts of patients with cirrhosis and with CRKP infections treated with antibiotic regimens including or excluding Ceftazidime-avibactam. Methods: Data from hospitalized patients with liver cirrhosis and CRKP infections were extracted and retrospectively analyzed. Results: During the study period, 39 cirrhotic patients with confirmed invasive CRKP infections were enrolled. Overall, the median age was 60 years with a median MELD score of 16 points. Urinary tract infections were diagnosed in 46%, followed by pneumonia in 23%, and primary bacteremia in 18% of patients. Treatment failure was reported in 10 patients (26%), while in-hospital mortality in 15 patients (38%). A monotherapy was used in 8 patients (20.5%), while a combination therapy was required in 31 patients (79.5%). Ceftazidime-avibactam therapy was associated with lower rates of treatment failure (7% vs. 38%, P = 0.032) independent of severity of liver disease (Child Class) and mono or combination antibiotic therapy. Acute kidney injury, hepatorenal syndrome, and acute-on-chronic liver failure were the consequences more frequently observed in patients with treatment failure. In-hospital mortality was associated with treatment failure, and Ceftazidime-avibactam therapy improved in-hospital survival (log rank test: P = 0.035) adjusted for Child class and mono or combination therapy. Conclusion: Treatment including ceftazidime-avibactam was associated with a lower rate of treatment failure in cirrhotic patients with CRKP infections. Considering the favorable efficacy and outcomes of ceftazidime-avibactam, this drug should be considered for the treatment of these severe infections in patients with liver cirrhosis, though further investigation is required.

Clinical Characteristics and Outcome of Hospitalized COVID-19 Patients Treated with Standard Dose of Dexamethasone or High Dose of Methylprednisolone.

The hyperinflammatory phase represents the main cause for the clinical worsening of acute respiratory distress syndrome (ARDS) in Coronavirus disease 2019 (COVID-19), leading to the hypothesis that steroid therapy could be a mainstream treatment in COVID-19 patients. This is an observational study including all consecutive patients admitted to two Italian University Hospitals for COVID-19 from March 2020 to December 2021. The aim of this study was to describe clinical characteristics and outcome parameters of hospitalized COVID-19 patients treated with dexamethasone 6 mg once daily (standard-dose group) or methylprednisolone 40 mg twice daily (high-dose group). The primary outcome was the impact of these different steroid treatments on 30-day mortality. During the study period, 990 patients were evaluated: 695 (70.2%) receiving standard dosage of dexamethasone and 295 (29.8%) receiving a high dose of methylprednisolone. Cox regression analysis showed that chronic obstructive pulmonary disease (HR 1.98, CI95% 1.34−9.81, p = 0.002), chronic kidney disease (HR 5.21, CI95% 1.48−22.23, p = 0.001), oncologic disease (HR 2.81, CI95% 1.45−19.8, p = 0.005) and high-flow nasal cannula, continuous positive airway pressure or non-invasive ventilation oxygen therapy (HR 61.1, CI95% 5.12−511.1, p < 0.001) were independently associated with 30-day mortality; conversely, high-dose steroid therapy was associated with survival (HR 0.42, CI95% 0.38−0.86, p = 0.002) at 30 days. Kaplan−Meier curves for 30-day survival displayed a statistically significant better survival rate in patients treated with high-dose steroid therapy (p = 0.018). The results of this study highlighted that the use of high-dose methylprednisolone, compared to dexamethasone 6 mg once daily, in hospitalized patients with COVID-19 may be associated with a significant reduction in mortality.

High prevalence of Merkel cell polyomavirus is associated with dysregulation in transcript levels of TLR9 and type I IFNs in a large cohort of CF patients from the Italian (Lazio) reference center for cystic fibrosis.

Merkel cell polyomavirus (MCPyV) has been detected in respiratory specimens including those from Cystic Fibrosis (CF) patients, raising questions about its immunological and clinical relevance in the respiratory tract. MCPyV might promote an inappropriate antiviral response contributing to a chronic inflammatory response and resulting in detrimental effects in CF. Respiratory samples (n = 1138) were randomly collected from respiratory tract of CF patients (n = 539) during July 2018-October 2019. MCPyV-DNA detection was performed by real time PCR and positive samples were characterized by sequencing of the NCCR genomic region. The transcript levels of Toll-like receptor 9 (TLR9) and type I interferon (IFN-I) genes (IFNα, IFNß and IFNε) were examined by real-time RT-PCR assays. MCPyV-DNA was detected in 268 out of 1138 respiratory specimens (23.5%) without any difference in the prevalence of MCPyV-DNA according to age, gender or bacteriological status of CF individuals. Thirteen out of 137 CF patients remained positive for MCPyV-DNA over the time (a median follow-up period of 8.8 months). Detection of MCPyV-DNA in respiratory specimens was not associated with the occurrence of exacerbation events. Both MCPyV positive adolescents (11-24 years) and adults (≥25 years) had lower mRNA levels of TLR9, IFNß, IFNε and IFNα than the negative patients of the same age group, while MCPyV positive children produced increased levels of TLR9 and IFN-I genes (p < 0.05 for TLR9, IFNß, IFNε) with respect to the negative ones. There were significant differences in TLR9 levels (p < 0.01), but not in those of IFNs, between MCPyV-DNA positive and negative patients with S. aureus, P. aeruginosa or both. Overall, these results indicate that MCPyV-DNA is frequently detected in the respiratory samples of CF patients and might influence the expression levels of IFN-related genes in an age dependent manner. The concomitant detection of MCPyV together with S. aureus and/or P. aeruginosa correlated with alterations in TLR9 levels suggesting that virus-bacteria coinfections might contribute to affect antiviral immunity in CF patients.

Clinical Effects of Oral Bacteriotherapy on Anal HPV Infection and Related Dysplasia in HIV-Positive MSM: Results from the "HPVinHIV" Trial.

BACKGROUND: Anal HPV infection, anal dysplasia and, ultimately, anal cancer are particularly common in HIV-infected men who have sex with men. Treatment of anal dysplasia, aiming to prevent evolution to squamous cell carcinoma of the anus, is currently limited to direct ablation and/or application of topical therapy. The aim of the present study is to investigate the effect of oral bacteriotherapy (Vivomixx® in EU, Visbiome® in USA) on anal HPV infection and HPV-related dysplasia of the anal canal in HIV-infected men who have sex with men. METHODS: In this randomized, placebo-controlled, quadruple-blinded trial (NCT04099433), HIV-positive men who have sex with men with anal HPV infection and HPV-related dysplasia were randomized to receive oral bacteriotherapy or placebo for 6 months. Anal HPV test, anal cytology and high resolution anoscopy with biopsies of anal lesions were performed at baseline and at the end of the study. Safety and tolerability of oral bacteriotherapy were also evaluated. Interim analysis results were presented. RESULTS: 20 participants concluded the study procedures to date. No serious adverse events were reported. In respect to participants randomized to placebo, individuals in the experimental arm showed higher rate of anal dysplasia regression (p = 0.002), lower rate of onset of new anal dysplasia (p = 0.023) and lower rates of worsening of persistent lesions (p = 0.004). Clearance of anal HPV infection was more frequently observed in the bacteriotherapy group (p = 0.067). CONCLUSION: Being an interim analysis, we limit ourselves to report the preliminary results of the current study. We refer the conclusions relating to the possible effectiveness of the intervention to the analysis of the definitive data.

Physical Activity and HIV: Effects on Fitness Status, Metabolism, Inflammation and Immune-Activation.

Several studies evidenced that a sedentary lifestyle is related with higher levels of systemic inflammation and highlighted that physical activity can trigger anti-inflammatory effects. To evaluate the impact of self-prescribed physical activity on fitness status, metabolism, inflammation and immune-activation in people living with HIV, an interim analysis of the results of the clinical trial PRIMO (NCT03392805) was performed. Patients enrolled were divided in 2 groups on the basis of self-prescribed physical activity: a physically active group (self-prescribed physical activity) and a sedentary group. Physical fitness was evaluated by sport medicine specialists and related to nutritional status, anthropometric variables, adipokines levels (adiponectin, leptin, resistin), peripheral immune-activation (CD38, HLA-DR on CD4 and CD8), and plasma inflammatory markers (IL-6 and TNF-α). The physically active group had a better profile in anthropometric measures and aerobic fitness but did not show lower levels of immune-activation compared to sedentary group. Also serum IL-6, TNF-α, and adipokines levels showed no statistical differences. On the basis of these data, a regular self-organized physical activity seems useful to improve cardio-respiratory fitness, but unable to control HIV-related immune-activation.

Carotid Artery Aneurysm in HIV: A Review of Case Reports in Literature.

BACKGROUND: HIV infection may affect the cardiovascular system through different physiopathological patterns. Rarely reported in HIV negative patients, aneurysms involving the carotid artery have been described for the first time in seropositive patients in 1989. AIMS: In our study, we have focused on aneurysm pathology affecting carotid arteries in HIV patients, analyzing clinical and surgical presentation, management, and outcome, through a review of cases published in the literature. METHODS: The MEDLINE (www.ncbi.nlm.nih.gov/pubmed) database was reviewed for "carotid artery aneurysm AND HIV OR AIDS OR immunodeficiency." RESULTS: Nineteen articles including a total of 46 cases were included in our report. The mean age of patients was 30.6 ± 14.2 years; 30 patients (65.2%) were male. Aneurysms were localized in the intracranial carotid (41.3%) or extracranial artery (58%). Presenting features included symptoms due to compression of neck structures; positivity for neurological symptoms occurred in 36.9%. Patients were managed surgically in 58.7% of cases; surgical morbidity and mortality were of 22.2% and 7.4% respectively, higher for endovascular procedures. The overall mortality in treated and untreated cases was 26.1%. CONCLUSIONS: Aneurysms may occur in both the extracranial and intracranial carotid artery in patients with HIV at younger age than in non-HIV patients and are linked to a high morbidity and mortality. Seropositivity must be ruled out whenever this rare vascular condition may occur in the absence of a more likely aetiology and must also be suspected in HIV patients presenting with compressive symptoms of the neck, neurological impairment or stroke.

Many Different Patterns under a Common Flag: Aortic Pathology in HIV-A Review of Case Reports in Literature.

BACKGROUND: Availability of highly active antiretroviral therapy (HAART) for HIV has prolonged life expectancy of patients but has also increased the incidence of non-AIDS comorbid conditions. Among these, there are cardiovascular diseases, and aortic involvement has been described in patients with HIV in the form of aortitis, aneurysms, or dissections. Our study aims to describe aortic pathology occurring in patients with HIV, focusing on clinical and surgical presentation, management, and outcome, through a review of cases published in literature. METHODS: MEDLINE (www.ncbi.nlm.nih.gov/pubmed) database was reviewed for "aortitis" OR "aortic aneurysm" OR "aortic dissection" AND HIV. Research was restricted to English language. Only case reports were included. Data on patients' age, sex, traditional risk factors, timing from HIV diagnosis, pharmacological details, coinfection (syphilis, hepatitis C virus [HCV], and hepatitis B virus [HBV]), anatomical localization of lesion, presence of inflammatory involvement, rapid growing or rupture, and surgical treatment and outcomes were collected and summarized in tables. RESULTS: Forty articles (51 cases) were included in the study. The mean age of patients was 48.8 ± 8.3 years. Male sex was preponderant (43 cases, 84.3%). Among traditional risk factors, hypertension and smoking were the most frequently reported ones (14 and 13 cases, respectively), followed by vasculopathy involving other arterial districts, dyslipidemia, diabetes, and drug addiction. In 3 cases, HIV was diagnosed in the same time as aortic pathology, whereas in most cases, aortic event occurred after five years from HIV diagnosis. In 30.5% of cases for which data on pharmacologic management were available, no treatment or poor adherence was reported. Coinfection occurred in some cases (syphilis in 6, HCV in 5, and HBV in 3). As for anatomical involvement, isolated thoracic lesions were more frequent (24, 47.1%), followed by abdominal and thoracoabdominal lesions. The etiology ranged from bacterial mycotic aneurysms to tertiary syphilis, postsurgical complications, or atherosclerosis. In 3 cases, HIV vasculitis was directly suggested, and in another 2, no other potential etiology had been diagnosed through cultural tests. Open surgical treatment was carried out in 30 cases (58.8%), and in addition, 10 endovascular (19.6%) and 2 hybrid procedures were described. Inflammatory features occurred in 7 cases, and a rapid evolution of lesions in 6. In 9 cases (17.6%), rupture occurred. Mortality was reported in 8 cases (15.7%). CONCLUSIONS: Aortic pathology may occur in patients with HIV. The entanglement of different patterns of pathological involvement of the aortic wall, secondary to immune dysregulation, infectious process, or atherosclerotic damage that may co-occur in one single case, results in a very challenging management of the condition. Because of the increased life expectancy of patients and immigration from regions with both high HIV and coinfection prevalence, the incidence of aortic pathology could increase in the upcoming years, suggesting the urgent need for further studies to optimize management in these very complex cases.

Fast and high temperature hyperthermia coupled with radiotherapy as a possible new treatment for glioblastoma.

BACKGROUND: A new transcranial focused ultrasound device has been developed that can induce hyperthermia in a large tissue volume. The purpose of this work is to investigate theoretically how glioblastoma multiforme (GBM) can be effectively treated by combining the fast hyperthermia generated by this focused ultrasound device with external beam radiotherapy. METHODS/DESIGN: To investigate the effect of tumor growth, we have developed a mathematical description of GBM proliferation and diffusion in the context of reaction-diffusion theory. In addition, we have formulated equations describing the impact of radiotherapy and heat on GBM in the reaction-diffusion equation, including tumor regrowth by stem cells. This formulation has been used to predict the effectiveness of the combination treatment for a realistic focused ultrasound heating scenario. Our results show that patient survival could be significantly improved by this combined treatment modality. DISCUSSION: High priority should be given to experiments to validate the therapeutic benefit predicted by our model.

A computational tool for evaluating HIFU safety.

BACKGROUND: High Intensity Focused Ultrasound (HIFU) is a noninvasive treatment for therapeutic applications, in particular the treatment of either benign or malignant tumor lesions. HIFU treatment is based on the power of a focused ultrasound beam to locally heat biological tissues over a necrotic level with minimal impact on the surrounding tissues. Therapies based on HIFU are becoming widely spread in the panorama of options offered by the Health Care System. Consequently, there is an ever increasing need to standardise quality assurance protocols and to develop computational tools to evaluate the output of clinical HIFU devices and ensuring safe delivery of HIFU treatment. AIMS: Goal of this study is the development of a computational tool for HIFU ablation therapy to assure safety of the patient and effectiveness of the treatment. RESULTS: The simulated results provide information about the behaviour of the focalized ultrasound in their interaction with different biological tissues. CONCLUSIONS: Numerical simulation represents a useful approach to predict the heath deposition and, consequently, to assess the safety and effectiveness of HIFU devices.