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Abstract Background Circulating cytokines can represent non-invasive biomarkers to improve prediction of clinical outcomes of cancer patients. Here, plasma levels of IL-8, CCL4, osteopontin, LIF and BDNF were determined at baseline (T0), after 2 months of therapy (T2) and, when feasible, at progression (TP), in 70 melanoma patients treated with BRAF and MEK inhibitors. The association of baseline cytokine levels with clinical response, progression-free survival (PFS) and overall survival (OS) was evaluated. Methods Cytokine concentrations were measured using the xMAP technology. Their ability to discriminate between responding (Rs) and non-responding (NRs) patients was assessed by Receiver Operating Characteristics analysis. PFS and OS were estimated with the Kaplan–Meier method. The Cox proportional hazard model was used in the univariate and multivariate analyses to estimate crude and adjusted hazard ratios with 95% confidence intervals. Results CCL4 and LIF were undetectable in the majority of samples. The median osteopontin concentration at T0 and T2 was significantly higher in NRs than in Rs. The median T0 and T2 values of IL-8 were also higher in NRs than in Rs, although the statistical significance was not reached. No differences were detected for BDNF. In 39 Rs with matched T0, T2, and TP samples, osteopontin and IL-8 significantly decreased from T0 to T2 and rose again at TP, while BDNF levels remained unchanged. In NRs, none of the cytokines showed a significant decrease at T2. Only osteopontin demonstrated a good ability to discriminate between Rs and NRs. A high IL-8 T0 level was associated with significantly shorter PFS and OS and higher risk of progression and mortality, and remained an independent negative prognostic factor for OS in multivariate analysis. An elevated osteopontin T0 concentration was also significantly associated with worse OS and increased risk of death. Patients with high IL-8 and high osteopontin showed the lowest PFS and OS, and in multivariate analysis this cytokine combination remained independently associated with a three- to six-fold increased risk of mortality. Conclusion Circulating IL-8 and osteopontin appear useful biomarkers to refine prognosis evaluation of patients undergoing targeted therapy, and deserve attention as potential targets to improve its clinical efficacy.

Abstract The 5-2-1 criteria was developed to facilitate the identification and referral of patients with Parkinson’s Disease (PD) inadequately controlled by oral medications. The criterion was not developed to screen patients with PD for device-aided therapy eligibility. The robust design and validation of the 5-2-1 criteria minimizes over or inappropriate referrals, and supports physicians in the timely identification of patients with PD who may warrant further evaluation for treatment optimization. This response letter clarifies concerns raised by Moes et al.

Erectile dysfunction (ED) poses a significant challenge in clinical practice, necessitating accurate diagnostic strategies to distinguish between organic and psychogenic causes. Current guidelines advocate a comprehensive approach involving medical history, physical examination and blood tests, with second-level analyses like the intracavernous injection of vasoactive drugs (ICI test) and penile duplex ultrasound (PDU) reserved for specific cases. A survey involving 24 urologists experienced in ED was conducted to assess their opinions on the appropriateness of the ICI test and PDU in six clinical scenarios. Results were analyzed using pie charts, revealing varied preferences among experts. The responses indicated diverse viewpoints, with preferences for the ICI test or PDU depending on the patient’s age, comorbidities, response to phosphodiesterase type 5 inhibitors (PDE5i) and concomitant Peyronie’s disease. In some cases, a significant proportion of experts opted for neither test. The study highlights the lack of consensus among experts regarding the routine use of PDU in ED management. Despite its diagnostic capabilities, the clinical utility of PDU remains unclear, and its role may be more justified in certain populations with anatomical abnormalities or specific conditions. The need for rigorous research to determine the impact of PDU on ED management decision-making is emphasized.

Abstract The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on anxiety in Parkinson’s disease (PD) are understudied. We identified clinical predictors of STN-DBS effects on anxiety in this study. In this prospective, open-label, multicentre study, we assessed patients with anxiety undergoing STN-DBS for PD preoperatively and at 6-month follow-up postoperatively. We assessed the Hospital Anxiety and Depression Scale (HADS-anxiety and depression subscales), Unified PD Rating Scale-motor examination, Scales for Outcomes in PD-motor (SCOPA-M)-activities of daily living (ADL) and -motor complications, Non-Motor Symptom Scale (NMSS), PDQuestionnaire-8 (PDQ-8), and levodopa-equivalent daily dose. We tested changes at follow-up with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We identified patients with a clinically relevant anxiety improvement of anxiety based on a designated threshold of ½ standard deviation of baseline HADS-anxiety. Moreover, we investigated predictors of HADS-anxiety changes with correlations and linear regressions. We included 50 patients with clinically relevant baseline anxiety (i.e., HADS-anxiety ≥ 8) aged 63.1 years ± 8.3 with 10.4 years ± 4.5 PD duration. HADS-anxiety improved significantly at 6-month follow-up as 80% of our cohort experienced clinically relevant anxiety improvement. In predictor analyses, worse baseline SCOPA-ADL and NMSS-urinary domain were associated with greater HADS-anxiety improvements. HADS-anxiety and PDQ-8 changes correlated moderately. Worse preoperative ADL and urinary symptoms predicted favourable postoperative anxiety outcome, which in turn was directly proportionate to greater QoL improvement. This study highlights the importance of detailed anxiety assessments alongside other non-motor and motor symptoms when advising and monitoring patients undergoing STN-DBS for PD.

Background: Mitotane is employed as adjuvant therapy in managing adrenocortical carcinoma in pediatric patients. While various adverse effects, such as estrogen-like manifestations, are well-documented in adults, there is limited knowledge regarding pediatric-specific toxicity. This report details an uncommon case of isosexual precocious pseudopuberty induced during childhood due to the estrogen-like effects of mitotane. Case report: A 2.8-year-old female diagnosed with adrenocortical carcinoma (pT4 pN0 M0) underwent adjuvant treatment with mitotane and cytotoxic chemotherapy following incomplete resection (tumor stage III). Approximately eight months into mitotane treatment, she exhibited signs of puberty (Tanner stage 2), including progressive breast development, uterine enlargement, vaginal discharge, and an advancement of bone age by nearly two years. Gonadotrophin-dependent puberty and endogenous estrogen production were ruled out. The precocious pseudopuberty was attributed to previously reported estrogen-like effects of mitotane therapy. Subsequent administration of the aromatase inhibitor anastrozole in combination with mitotane led to a reduction in clinical signs of puberty. Conclusion: Monitoring for estrogen-like effects of mitotane is crucial, particularly in pre-pubertal children, to avert potentially irreversible changes associated with precocious pseudopuberty. Aromatase inhibitors may serve as a prompt therapeutic option, enabling the continuation of mitotane treatment.

Background: Chronic obstructive pulmonary disease (COPD) represents a significant public health problem in Italy, with a high prevalence and a substantial economic burden on the National Health Service (NHS). Effective management of the disease is crucial for reducing exacerbations and improving patients’ quality of life. Methods: This study employs a dynamic predictive model to assess the economic impact of implementing three specific health policies aimed at improving COPD management over a five-year horizon. The analysis is conducted from the perspective of the NHS, focusing on the direct costs associated with disease management. Results: The implementation of the proposed policies demonstrated potential significant savings in direct healthcare costs. The first policy, focused on increasing therapeutic adherence, generated an estimated savings of 202 million €. The second, concerning the wider use of triple therapies, led to savings of about 142 million €. Finally, the third policy, aimed at reducing the delay in prescribing appropriate therapies, contributed to an additional saving of over 175 million € in the time horizon considered in the analysis. Overall, these results suggest a substantial improvement opportunity in COPD management, with significant economic benefits for the Italian NHS. Conclusion: The study confirms the importance of targeted policies in the management of COPD, highlighting how strategic interventions can lead to significant resource savings while simultaneously improving patient care. These results provide a solid foundation for further research and serve as a useful guide for decision-makers in planning effective intervention strategies, aimed at optimizing resources and enhancing disease management in the Italian healthcare context.

Objectives The objective of this study was to assess the impact of the COVID-19 pandemic, after 2 years, on mammographic screening in Brazil evaluating BIRADS® results, breast cancer diagnosis rates, and breast cancer stage. Study Design This was an ecological observational study based on retrospective data from Brazil’s mammographic screening program from 2015 to 2023. Methods Data were obtained from the national screening database DATASUS – SISCAN (Cancer System Information) and retrieved in March 2024. Inclusion criteria comprised completeness of mammogram data (incomplete records were excluded), female participants aged 50 to 69 years, and mammograms exclusively performed for screening purposes. The study analyzed the number of mammograms conducted during the specified period, focusing on BIRADS® test results. Results Out of 23,851,371 mammograms performed between 2015 and 2023, 15,000,628 were included for analysis. A significant reduction of 39.6% in mammograms was observed in 2020 compared to 2019, followed by a 12.6% decrease in 2021. Notably, a substantial rise in BIRADS categories 4 and 5 examinations was seen post-pandemic. Breast cancer staging analysis revealed a shift towards more advanced stages (III and IV) diagnosed post-pandemic, suggesting potential delays in detection and diagnosis. Conclusions In conclusion, the study highlighted significant discrepancies in mammographic screenings and breast cancer diagnosis rates over 9 years. The pandemic reflected significant influence on the timing and stage at diagnosis, suggesting potential delays in detection and diagnosis that resulted in later identification of more advanced disease stages.

Programa de Desenvolvimento da Enfermagem (PRODEN) criado pela Escola de Enfermagem da UFMG propõe apoiar as instituições de ensino de enfermagem em Minas Gerais para que se transformem em pólos de desenvolvimento, visando implementação de programas de preparação de pessoal de enfermagem através de modalidade de ensino a distância. O Banco de Dados foi criado pela comissão de avaliação do programa com a participação de discentes bolsistas do PIBIC/CNPq, com o objetivo de coletar, organizar, recuperar e distribuir as informações produzidas pelo programa. Foi construído um software contemplando as necessidades de informação evidenciadas pelo programa. A informação é recuperada e distribuída através da emissão de relatórios totais e parciais, possibilitando identificar a aderência dos atores ao programa e as atividades desenvolvidas.

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare genetic disorder characterized by an abnormal clotting process leading to serious health complications such as thrombocytopenia and hemolytic anemia. Despite its clinical significance, the estimated broader economic and social impacts in Italy on patients and society remain underexplored. Methods: A detailed questionnaire, developed and validated by a panel of cTTP experts, was distributed to healthcare professionals and patient associations to gather comprehensive data on the economic and social burden of cTTP in Italy. The study was focused on direct and indirect costs associated with the disease management of 15 patients with cTTP, as well as out-of-pocket expenses incurred by patients. Results: The analysis revealed that of the 15 patients diagnosed with cTTP in Italy, 60% were adults aged 40-55 years. Productivity loss and diminished quality of life dominated the economic burden of cTTP, accounting for 81.05% of total costs. Direct medical costs, while substantial, represented a smaller portion of the overall financial impact. Additionally, out-of-pocket expenses, though constituting the smallest fraction, underscored the financial contributions made by patients towards their own care management. Conclusion: The findings underscore the need for a multidisciplinary and holistic approach to cTTP management that extends beyond the clinical treatment. Addressing the economic and social implications of the disease is crucial for improving patient well-being and ensuring the sustainability of healthcare systems. The study advocates for increased awareness, research, and access to care for cTTP patients, highlighting the importance of comprehensive support networks to mitigate the disease’s broader societal impacts, estimated to be around 2 million euro for 15 patients in 10 years.

ABSTRACT Objective: To evaluate the knowledge and practices of gynecologists, obstetricians, and family and community physicians in Brazil regarding breast cancer screening, mammographic findings defined by the BIRADS™ system, and their approach to suspected clinical lesions. Methods: This was an observational, cross-sectional, descriptive study conducted using an online research questionnaire distributed via email to 9,000 gynecologists and obstetricians and 5,600 family and community and preventive medicine doctors actively practicing in Brazil. Results: Among gynecologists and obstetricians, 42.8% follow the 40-74 years screening, 33.5% follow the 50-69 years screening, and 23.6% do not follow any specific protocol. Among the family and community physicians, 76.6% follow the 50-69 years screening protocol, and 23.4% do not follow any specific protocol. When we evaluated the responses regarding the behaviors of each BIRADS™ classification, 46.3% of responses were wrong among gynecologists and obstetricians, and 77.9% were wrong among community and preventive medicine doctors, exhibiting a significant difference. The role of breast ultrasound in screening was evaluated; 39.1% of gynecologists and obstetricians and 20.3% of community and preventive medicine doctors consider it as a screening method. Among gynecologists and obstetricians who do not follow any screening protocol, 94.7% consider ultrasound as a screening method. Among community and preventive medicine doctors, only 26.5% of physicians who follow the 50-69 years screening method consider it as a screening method. Conclusion: Inadequate training results in gynecologists and obstetricians, and family and community physicians performing inadequate screening and not following the recommended practices outlined in the BIRADS™ system.

Background: Gastrointestinal dysfunction has emerged as a prominent early feature of Parkinson's Disease, shedding new light on the pivotal role of the enteric nervous system in its pathophysiology. However, the role of immune-cell clusters and inflammatory and glial markers in the gut pathogenetic process needs further elucidation. Objectives: We aimed to study duodenum tissue samples to characterize PD's enteric nervous system pathology further. Twenty patients with advanced PD, six with early PD, and 18 matched controls were included in the PADUA-CESNE cohort. Methods: Duodenal biopsies from 26 patients with early to advanced stage PD and 18 age-matched HCs were evaluated for the presence of surface markers (CD3+, CD4+, CD8+, CD20+, CD68+, HLA-DR), presence of misfolded alpha-synuclein and enteric glial alteration (GFAP). Correlation of immulogic pattern and clinical characteristic were analyzed. Results: The findings validate that in patients with Parkinson's Disease, the activation and reactive gliosis are linked to the neurodegeneration triggered by the presence of misfolded alpha-synuclein in the enteric nervous system. This process intensifies from the initial to the advanced stages of the disease. The clusters of T- and B-lymphocytes in the enteric system, along with the overall expression of HLA-DR in antigen-presenting cells, exceeded those in the control group. Conversely, no differences in terms of macrophage populations were found. Conclusions: These findings broaden our understanding of the mechanisms underlying the enteric nervous system's involvement in PD and point to the gastrointestinal system as a potential therapeutic target, especially in the early stages of the disease. Moreover, our results propose a role of T- and B-lymphocytes in maintaining inflammation and ultimately influencing alpha-synuclein misfolding and aggregation.

Male breast cancer (MBC) is a rare condition, accounting for approximately 1 % of all breast cancer cases. Nevertheless, the paucity of MBC-specific research has impeded a thorough understanding of MBC. In this study, we aimed to delineate the epidemiological implications of MBC in Brazil and benchmarked it against female breast cancer (FBC). This retrospective study analyzed data from the DATASUS database (2017–2021), which assessed the incidence of breast cancer in both sexes. All statistical analyses were performed using descriptive statistics and inferential methods, with significance set at a 95 % confidence interval. We identified 4,326 (1.7 %) and 233,793 (94.2 %) patients with MBC and FBC, respectively, in Brazil. Despite the general population concentration in the Southeast, MBC cases were more prevalent in the Northeast (p

Background: Muscle-specific tyrosine kinase (MuSK) autoantibody-positive (Ab+) generalised myasthenia gravis (gMG) is a rare and frequently severe subtype of gMG. Objectives: To assess the efficacy and safety of rozanolixizumab in the subgroup of patients with MuSK Ab+ gMG in the MycarinG study. Design: A randomised, double-blind, placebo-controlled phase III study. Methods: Patients with acetylcholine receptor (AChR) Ab+ or MuSK Ab+ gMG (aged ⩾18 years, Myasthenia Gravis Foundation of America Disease Class II–IVa, Myasthenia Gravis Activities of Daily Living [MG-‍ADL] score ⩾3.0 [non-ocular symptoms], Quantitative Myasthenia Gravis score ⩾11.0) were randomly assigned (1:1:1) to receive once-weekly subcutaneous infusions of rozanolixizumab 7 mg/kg, rozanolixizumab 10 mg/kg or placebo for 6 weeks, followed by an 8-week observation period. Randomisation was stratified by AChR and MuSK autoantibody status. The primary study endpoint was change from baseline to Day 43 in MG-ADL score. Treatment-emergent adverse events (TEAEs) were also assessed. Results: Overall, 200 patients were randomised, of whom 21 had MuSK Ab+ gMG and received rozanolixizumab 7 mg/kg ( n = 5), 10 mg/kg ( n = 8) or placebo ( n = 8). In patients with MuSK Ab+ gMG, reductions from baseline to Day 43 in MG-ADL scores were observed: rozanolixizumab 7 mg/kg least squares mean (LSM) change (standard error), –7.28 (1.94); 10 mg/kg, –4.16 (1.78); and placebo, 2.28 (1.95). Rozanolixizumab 7 mg/kg LSM difference from placebo was −9.56 (97.5% confidence interval: −15.25, −3.87); 10 mg/kg, −6.45 (−11.03, –1.86). TEAEs were experienced by four (80.0%), five (62.5%) and three (37.5%) patients with MuSK Ab+ gMG receiving rozanolixizumab 7 mg/kg, 10 mg/kg and placebo, respectively. No patients experienced serious TEAEs. No deaths occurred. Conclusion: This subgroup analysis of adult patients with MuSK Ab+ gMG enrolled in the MycarinG study supports the use of rozanolixizumab as an effective treatment option for patients with gMG who have MuSK autoantibodies. Trial registration: ClinicalTrials.gov: NCT03971422 ( https://clinicaltrials.gov/study/NCT03971422 ); EU Clinical Trials Register: EudraCT 2019-000968-18 ( https://www.clinicaltrials‌register.eu/ctr-search/trial/2019-000968-18/GB ).

BackgroundEosinophilic esophagitis (EoE) is a chronic and progressive type 2 inflammatory disease affecting the esophagus. Its prevalence has increased in recent years due to increased awareness, evolving clinical guidelines, and heightened sensitivity among healthcare professionals managing the condition. The exact causes behind EoE’s development remain unknown, and its clinical presentation varies, often leading to significant diagnostic delays depending on the age at which symptoms manifest. Consequently, achieving long-term disease control through heightened awareness becomes imperative. EoE generates a significant clinical burden, resulting in substantial economic consequences for patients, healthcare systems, and society. This study aimed to assess the economic and social impacts on EoE patients within the Italian context.MethodsA cost-of-illness analysis was conducted from two perspectives: the National Health System (NHS) and the societal perspective. This analysis encompassed direct healthcare, indirect healthcare, and non-healthcare costs. Data were collected and assessed through a survey administered to a panel of expert clinicians and EoE-affected patients.ResultsManaging EoE incurs a significant burden on healthcare systems, amounting to €6,852.28 per patient per year. The primary cost component appears to be direct costs, comprising 60.73% of the total cost per patient for this condition, while indirect costs contribute to 29.68% of the overall management expenses.ConclusionThis analysis underscores a substantial financial burden on both the healthcare system and patients affected by eosinophilic esophagitis. It emphasizes the imperative need for a continuous and combined effort from clinicians, patients, and families to promptly recognize symptoms and adaptive behavior to mitigate diagnostic delays.