From the mechanism of action to clinical management: A review of cardiovascular toxicity in adult treated with CAR-T therapy.

Chimeric antigen receptor T-cell therapy represents an innovative approach to immunotherapy and currently stands out, particularly for oncohematological patients refractory to traditional treatments. Ongoing trials are further expanding its clinical use for new oncological and non-oncological indications, potentially leading to newer treatment options soon. This new approach, however, also presents challenges, including cardiovascular toxicity. Little is reported in pivotal studies, and some recent retrospective observations suggest a non-negligible incidence of side effects with presentation ranging from mild adverse cardiovascular events to fatal complications in which, in most cases, there is a direct or indirect association with cytokine release syndrome. In this literature review, the hypotheses of an important interface between cytokine release syndrome and cardiotoxicity by chimeric antigen receptor T-cell therapy will be addressed, as will current knowledge about risk factors for cardiotoxicity and recommendations for pre-therapy evaluation, post-infusion monitoring and clinical management of these complications.

From HIV to Mpox: Socio-discursive Analysis of Communicable Diseases, Stigma, and Pathologization in Sexual Minorities in Brazil.

Discrimination and stigma are significant barriers to healthcare for the LGBTQIAPN+ community, necessitating a deeper analysis of their sociocultural causes. There is a notable gap in the literature regarding the understanding of socio-discursive representations and their impact on the stigmatization and pathologization of sexual minorities in the context of communicable diseases. This study aims to discuss the understanding of the sociodiscursive aspects of the health-disease process, particularly in stigmatized infectious diseases affecting the LGBTQIAPN+ community. The focus is on examining how news articles, or the set of analyzed texts (corpus), shape these perceptions. We conducted documentary research with a qualitative and discursive approach using news articles retrieved from Google NewsⓇ about diseases affecting the LGBTQIAPN+ population from 2011 to 2022. The analysis was based on critical discourse analysis, processed using MAXQDA and IRAMUTEQ software. The identified representations predominantly align with biomedical ideology, manifesting in a discourse that normalizes and medicalizes (normative-curative discourse), and notable for its pathologizing and stigmatizing nature. Six classes were found: Ethical professional dilemmas facing stigma, infection and contamination of the LGBT+ population, prejudice and discrimination in the form of information, stigma related to sexual behavior/orientation, Vulnerability and stigma related to infectious diseases, and strategies for minimizing health risk/stigma for the LGBT+ public. The most relevant analytical categories were related to infectious diseases and sexual identity. These themes were identified, indicating that media representations reinforce stigma and maintain unequal health practices (verticalization) for the LGBT+ community. Understanding these patterns within a broader historical context is crucial for promoting health education and strategies that challenge internalized prejudice. The need to reformulate cultural norms and develop health information and education policies is urgent. These policies should be led by professionals with a comprehensive and humanized vision, addressing the diverse needs of the LGBT+ population.

Exorbital Lacrimal Gland Ablation and Regrafting Induce Inflammation but Not Regeneration or Dry Eye.

The study evaluated the regenerative responses of the lacrimal functional unit (LFU) after lacrimal gland (LG) ablation. The LG of Wistar rats was submitted to G1) partial LG ablation, G2) partial ablation and transplantation of an allogeneic LG, or G3) total LG ablation, (n = 7-10/group). The eye wipe test, slit lamp image, tear flow, and histology were evaluated. RT-PCR analyzed inflammatory and proliferation mediators. The findings were compared to naïve controls after 1 and 2 months (M1 and M2). G3 presented increased corneal sensitivity, and the 3 groups showed corneal neovascularization. Histology revealed changes in the LG and corneal inflammation. In the LG, there was an increase in MMP-9 mRNA of G1 and G2 at M1 and M2, in RUNX-1 at M1 and M2 in G1, in RUNX-3 mRNA at M1 in G1, and at M2 in G2. TNF-α mRNA rose in the corneas of G1 and G2 at M2. There was an increase in the IL-1ß mRNA in the trigeminal ganglion of G1 at M1. Without changes in tear flow or evidence of LG regeneration, LG ablation and grafting are unreliable models for dry eye or LG repair in rats. The surgical manipulation extended inflammation to the LFU.

Relacorilant in recurrent ovarian cancer: clinical evidence and future perspectives.

INTRODUCTION: Relacorilant (CORT125134, Corcept Therapeutics) is a selective glucocorticoid receptor modulator, which reverses the glucocorticoid-mediated anti-apoptotic effects and restores the taxane chemosensitivity in epithelial ovarian cancer cells. Given those preclinical findings, relacorilant is currently under investigation in clinical trials in combination with nab-paclitaxel for the platinum-resistant ovarian cancer setting. AREAS COVERED: Already published preclinical and clinical evidence of relacorilant antitumor activity was analyzed and discussed. Ongoing clinical trials registered on clincaltrials.gov were also reported. The review aimed to summarize the status of relacorilant, the mechanism of action, the published and ongoing trials, and its safety and efficacy. EXPERT OPINION: Relacorilant combined with nab-paclitaxel, may represent a promising strategy for the treatment of platinum-resistant ovarian cancer patients. After preliminary positive results in terms of clinical efficacy, a randomized phase III trial is ongoing to confirm the findings from the published phase II study.

Effects of niraparib dose reduction on short-term outcomes in ovarian cancer patients.

OBJECTIVES: Despite the individualized starting dose for maintenance therapy in ovarian cancer, the niraparib dose reduction rate remains high. The aim of this study was to evaluate the impact of niraparib dose reduction on progression-free survival in newly diagnosed primary advanced ovarian cancer and recurrent ovarian cancer patients. We also aimed to compare the reduction rates and the safety of niraparib on primary and relapse groups, and identify which factors may predict dose reduction. METHODS: Patients with primary or recurrent ovarian cancer in maintenance who received niraparib between 2019 and 2022 were retrospectively evaluated. Niraparib dosing was based on individualized starting dose of 300 or 200 mg/day. The impact of niraparib dose reductions was focused on patients treated with 200 or 100 mg in both groups. Reduction rates, adverse events and predictive factors of reduction were assessed in each study group. The primary endpoint was progression-free survival in primary and relapse groups; the secondary endpoints were the reduction rates, the safety and tolerability of niraparib in both groups. RESULTS: Of 215 patients identified, 124 (57.7%) primary and 91 (42.3%) recurrent ovarian cancer patients were included. The majority of patients started niraparib at 200 mg/day (92.7% primary and 80.2% relapse group); dose reductions from 300 or 200 mg/day to 200 or 100 mg/day occurred more frequently within cycles 1-3 (67% primary and 45% relapse group, p=0.001). Grade≥3 adverse events were lower in the relapse group (54.8% primary and 35.1% relapse, p=0.001). In both groups, dose modifications over the treatment did not significantly impair median progression-free survival. Univariate and multivariate analysis demonstrated that weight and platinum-doublets were possible risk factors for dose reduction. CONCLUSIONS: Niraparib dose reduction occurs in almost half of patients within cycles 1-3, although it is significantly more common in the first-line setting. Survival outcomes seem not to be impaired by dose reduction.

Focus on Trabectedin in Ovarian Cancer: What Do We Still Need to Know?

In the era of single and combination maintenance therapies as well as platinum and Poly (ADP-ribose) polymerase inhibitors (PARPi) resistance, the choice of subsequent treatments following first-line platinum-based chemotherapy in recurrent ovarian cancer (ROC) patients has become increasingly complex. Within the ovarian cancer treatment algorithm, particularly in the emerging context of PARPi resistance, the role of trabectedin, in combination with pegylated liposomal doxorubicin (PLD) still preserves its significance. This paper offers valuable insights into the multifaceted role and mechanism of action of trabectedin in ROC. The main results of clinical trials and studies involving trabectedin/PLD, along with hints of Breast Cancer genes (BRCA)-mutated and BRCAness phenotype cases, are critically discussed. Moreover, this review provides and contextualizes potential scenarios of administering trabectedin in combination with PLD in ROC, according to established guidelines and beyond.

Epithelial ovarian cancer and brain metastases: might the BRCA status, PARP inhibitor administration, and surgical treatment impact the survival?

OBJECTIVE: To evaluate disease characteristics and survival according to BRCA status, administration of poly-(ADP-ribose) polymerase inhibitors (PARPi), and surgery in patients with ovarian cancer and brain metastases. METHODS: This is a monocentric retrospective cohort of patients with ovarian cancer and brain metastases treated between 2000 and 2021. Data were collected by a retrospective review of medical records and analyzed according to: (1) BRCA mutation; (2) PARPi before and after brain metastases; (3) surgery for brain metastases. RESULTS: Eighty-five patients with ovarian cancer and brain metastasis and known BRCA status (31 BRCA mutated (BRCAm), 54 BRCA wild-type (BRCAwt)) were analyzed. Twenty-two patients had received PARPi before brain metastases diagnosis (11 BRCAm, 11 BRCAwt) and 12 after (8 BRCAm, 4 BRCAwt). Brain metastases occurred >1 year later in patients who had received previous PARPi. Survival was longer in the BRCAm group (median post-brain metastasis survival: BRCAm 23 months vs BRCAwt 8 months, p=0.0015). No differences were found based on BRCA status analyzing the population who did not receive PARPi after brain metastasis (median post-brain metastasis survival: BRCAm 8 months vs BRCAwt 8 months, p=0.31). In the BRCAm group, survival was worse in patients who had received previous PARPi (median post-brain metastasis survival: PARPi before, 7 months vs no-PARPi before, 24 months, p=0.003). If PARPi was administered after brain metastases, survival of the overall population improved (median post-brain metastasis survival: PARPi after, 46 months vs no-PARPi after, 8 months, p=0.00038).In cases of surgery for brain metastases, the prognosis seemed better (median post-brain metastasis survival: surgery 13 months vs no-surgery 8 months, p=0.036). Three variables were significantly associated with prolonged survival at multivariate analysis: BRCA mutation, multimodal treatment, and ≤1 previous chemotherapy line. CONCLUSIONS: BRCA mutations might impact brain metastasis occurrence and lead to better outcomes. In a multimodal treatment, surgery seems to affect survival even in cases of extracranial disease. PARPi use should be considered as it seems to prolong survival if administered after brain metastasis.

Purulent Pericarditis as the First Manifestation of Esophageal Carcinoma.

INTRODUCTION: Purulent pericarditis secondary to esophago-pericardial fistula is a serious complication that has been previously reported in patients with esophageal cancer treated with radio/chemotherapy and esophageal stenting. However, the presence of esophago-pericardial fistula as the first manifestation of advanced carcinoma of the esophagus is exceedingly infrequent. We report the case of a 61-year-old male who presented with sepsis, cardiac tamponade and septic shock who was found to have an esophago-pericardial fistula secondary to squamous carcinoma of the esophagus. Emergency pericardiocentesis was performed with subsequent hemodynamic improvement. The drained pericardial fluid was purulent in nature and cultures were positive for Streptococcus anginosus. A CT scan followed by upper gastrointestinal endoscopy with tissue biopsy confirmed the diagnosis of squamous cell carcinoma of the esophagus. A self-expanding covered stent was endoscopically placed to exclude the fistula and restore the esophageal lumen. In this report, we discuss some aspects related to the diagnosis and management of this serious clinical entity.

Health-related quality of life in patients with conditions affecting the hand: meta-analysis.

BACKGROUND: Health state utility values provide the quality component of quality-adjusted life years and are essential for health economic analyses, such as the National Institute for Health and Care Excellence Technology Appraisal. The aims of this systematic review were to: catalogue utility values for health states experienced by patients with hand conditions; provide pooled utility estimates for common hand conditions; and determine how utilities have been estimated. METHODS: A PRISMA-compliant systematic review and meta-analysis was conducted (registered in PROSPERO, the international prospective register of systematic reviews (CRD42021226098)). Five databases were searched from inception until April 2023 (Embase, MEDLINE, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Cochrane Central Register of Controlled Trials (CENTRAL)). All studies that reported primary utility values for hand health states in adult patients were eligible for inclusion. Pooled utility estimates were determined across conditions and intervention status using random-effects meta-analysis. RESULTS: A total of 10 254 articles were identified; 57 studies met the full inclusion criteria and reported 363 distinct health state utility values. Health state utility values were estimated using a range of methods; the most common measure was the EQ-5D. Pooled utility estimates for carpal tunnel syndrome and hand osteoarthritis before surgical intervention were 0.69 (95% c.i. 0.66 to 0.73) and 0.63 (95% c.i. 0.60 to 0.67) respectively. CONCLUSION: Pooled utility estimates for patients with untreated carpal tunnel syndrome and hand osteoarthritis are 11% and 18% lower than age-matched population norms respectively. Hand conditions have a significant detrimental impact on health-related quality of life and this study provides catalogued utility values for use in future economic analyses to support the delivery of value-based hand surgery.

The Role of Uniform Textures in Making Texture Elements Visible in the Visual Periphery.

There are important differences between central and peripheral vision. With respect to shape, contours retain phenomenal sharpness, although some contours disappear if they are near other contours. This leads to some uniform textures to appear non-uniform (Honeycomb illusion, Bertamini et al., 2016). Unlike other phenomena of shape perception in the periphery, this illusion is showing how continuity of the texture does not contribute to phenomenal continuity. We systematically varied the relationship between central and peripheral regions, and we collected subjective reports (how far can one see lines) as well as judgments of line orientation. We used extended textures created with a square grid and some additional lines that are invisible when they are located at the corners of the grid, or visible when they are separated from the grid (control condition). With respects to subjective reports, we compared the region of visibility for cases in which the texture was uniform (Exp 1a), or when in a central region the lines were different (Exp 1b). There were no differences, showing no role of objective uniformity on visibility. Next, in addition to the region of visibility we measured sensitivity using a forced-choice task (line tilted left or right) (Exp 2). The drop in sensitivity with eccentricity matched the size of the region in which lines were perceived in the illusion condition, but not in the control condition. When participants were offered a choice to report of the lines were present or absent (Exp 3) they confirmed that they did not see them in the illusion condition, but saw them in the control condition. We conclude that mechanisms that control perception of contours operate differently in the periphery, and override prior expectations, including that of uniformity. Conversely, when elements are detected in the periphery, we assign to them properties based on information from central vision, but these shapes cannot be identified correctly when the task requires such discrimination.

Taxonomy of Candida parapsilosis complex isolated from neonates and the role of Hsp90 inhibitors to enhanced the antifungal activity of micafungin.

Species from Candida parapsilosis complex are frequently found in neonatal candidemia. The antifungal agents to treat this infection are limited and the occurrence of low in vitro susceptibility to echinocandins such as micafungin has been observed. In this context, the chaperone Hsp90 could be a target to reduce resistance. Thus, the objective of this research was to identify isolates from the C. parapsilosis complex and verify the action of Hsp90 inhibitors associated with micafungin. The fungal identification was based on genetic sequencing and mass spectrometry. Minimal inhibitory concentrations were determined by broth microdilution method according to Clinical Laboratory and Standards Institute. The evaluation of the interaction between micafungin with Hsp90 inhibitors was realized using the checkerboard methodology. According to the polyphasic taxonomy, C. parapsilosis sensu stricto was the most frequently identified, followed by C. orthopsilosis and C. metapsilosis, and one isolate of Lodderomyces elongisporus was identified by genetic sequencing. The Hsp90 inhibitor geladanamycin associated with micafungin showed a synergic effect in 31.25% of the isolates, a better result was observed with radicicol, which shows synergic effect in 56.25% tested yeasts. The results obtained demonstrate that blocking Hsp90 could be effective to reduce antifungal resistance to echinocandins.

On the relationship between foveal mask interference and mental imagery in peripheral object recognition.

A delayed foveal mask affects perception of peripheral stimuli. The effect is determined by the timing of the mask and by the similarity with the peripheral stimulus. A congruent mask enhances performance, while an incongruent one impairs it. It is hypothesized that foveal masks disrupt a feedback mechanism reaching the foveal cortex. This mechanism could be part of a broader circuit associated with mental imagery, but this hypothesis has not as yet been tested. We investigated the link between mental imagery and foveal feedback. We tested the relationship between performance fluctuations caused by the foveal mask-measured in terms of discriminability (d') and criterion (C)-and the scores from two questionnaires designed to assess mental imagery vividness (VVIQ) and another exploring object imagery, spatial imagery and verbal cognitive styles (OSIVQ). Contrary to our hypotheses, no significant correlations were found between VVIQ and the mask's impact on d' and C. Neither the object nor spatial subscales of OSIVQ correlated with the mask's impact. In conclusion, our findings do not substantiate the existence of a link between foveal feedback and mental imagery. Further investigation is needed to determine whether mask interference might occur with more implicit measures of imagery.

Danish translation and validation of the Parotidectomy Outcome Inventory 8.

INTRODUCTION: Complications and recurrence within benign salivary gland surgery are not systematically registered in Denmark. Patient-reported outcome measures are increasingly included in clinical and health policy decision-making, and therefore it is crucial that this type of data is valid. A patient-reported questionnaire regarding outcome after benign parotid gland surgery has been developed and implemented in a national German database. We aimed to translate the Parotidectomy Outcome Inventory 8 (POI-8) into Danish and validate it. METHODS: The questionnaire was translated. The study population was recruited from a single centre from 6 December 2019 to 1 June 2022. Patients > 18 years of age who had undergone their first parotid salivary gland surgery for a benign tumour were included. The questionnaire underwent pilot-testing and test-retesting; it was sent to respondents twice at a 14-day interval. For the categorical variables, the reliability of the items was tested using the weighted kappa-coefficient. RESULTS: A weighted kappa coefficient of 0.74 and Cronbach's alpha of 0.78 were found. No significant difference was found between testing at day 0 and 14. CONCLUSIONS: We have translated and validated the Danish version of the POI-8, finding acceptable levels of the weighted kappa coefficient and Cronbach's alpha. We suggest the systematic use of PROMs in Danish healthcare and specifically in parotidectomy for benign neoplasms. FUNDING: No funding. TRIAL REGISTRATION: Not relevant.

Foveal feedback in perceptual processing: Contamination of neural representations and task difficulty effects.

Visual object recognition was traditionally believed to rely on a hierarchical feedforward process. However, recent evidence challenges this notion by demonstrating the crucial role of foveal retinotopic cortex and feedback signals from higher-level visual areas in processing peripheral visual information. The nature of the information conveyed through foveal feedback remains a topic of debate. To address this, we conducted a study employing a foveal mask paradigm with varying stimulus-mask onset asynchronies in a peripheral same/different task, where peripheral objects exhibited different degrees of similarity. Our hypothesis posited that simultaneous arrival of feedback and mask information in the foveal cortex would lead to neural contamination, biasing perception. Notably, when the two peripheral objects were identical, we observed a significant increase in the number of "different" responses, peaking at approximately 100 ms. Similar effect was found when the objects were dissimilar, but with an overall later timing (around 150 ms). No significant difference was found when comparing easy (dissimilar objects) and difficult trials (similar objects). The findings challenge the hypothesis that foveation planning alone accounts for the observed effects. Instead, these and previous observations support the notion that the foveal cortex serves as a visual sketchpad for maintaining and manipulating task-relevant information.

European Respiratory Society short guidelines for the use of as-needed ICS/formoterol in mild asthma

Recent clinical trials of as-needed fixed-dose combination of inhaled corticosteroid (ICS)/formoterol have provided new evidence that may warrant a reconsideration of current practice. A Task Force was set up by the European Respiratory Society to provide evidence-based recommendations on the use of as-needed ICS/formoterol as treatment for mild asthma. The Task Force defined two questions that were assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. The Task Force utilised the outcomes to develop recommendations for a pragmatic guideline for everyday clinical practice. The Task Force suggests that adults with mild asthma use as-needed ICS/formoterol instead of regular ICS maintenance treatment plus as-needed short-acting ß2-antagonist (SABA) and that adolescents with mild asthma use either as-needed ICS/formoterol or ICS maintenance treatment plus as-needed SABA (conditional recommendation; low certainty of evidence). The recommendation for adults places a relatively higher value on the reduction of systemic corticosteroid use and the outcomes related to exacerbations, and a relatively lower value on the small differences in asthma control. Either treatment option is suggested for adolescent patients as the balance is very close and data more limited. The Task Force recommends that adult and adolescent patients with mild asthma use as-needed ICS/formoterol instead of as-needed SABA (strong recommendation; low certainty of evidence). This recommendation is based on the benefit of as-needed ICS/formoterol in mild asthma on several outcomes and the risks related to as-needed SABA in the absence of anti-inflammatory treatment. The implementation of this recommendation is hampered in countries (including European Union countries) where as-needed ICS/formoterol is not approved for mild asthma.