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Carbohydrate intolerance, commonly linked to the consumption of lactose, fructose, or sorbitol, affects up to 30% of the population in high-income countries. Although sorbitol intolerance is attributed to malabsorption, the underlying mechanism remains unresolved. Here, we show that a history of antibiotic exposure combined with high fat intake triggered long-lasting sorbitol intolerance in mice by reducing Clostridia abundance, which impaired microbial sorbitol catabolism. The restoration of sorbitol catabolism by inoculation with probiotic Escherichia coli protected mice against sorbitol intolerance but did not restore Clostridia abundance. Inoculation with the butyrate producer Anaerostipes caccae restored a normal Clostridia abundance, which protected mice against sorbitol-induced diarrhea even when the probiotic was cleared. Butyrate restored Clostridia abundance by stimulating epithelial peroxisome proliferator-activated receptor-gamma (PPAR-γ) signaling to restore epithelial hypoxia in the colon. Collectively, these mechanistic insights identify microbial sorbitol catabolism as a potential target for approaches for the diagnosis, treatment, and prevention of sorbitol intolerance.
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Erros Inatos do Metabolismo dos Carboidratos , Microbioma Gastrointestinal , Sorbitol , Animais , Camundongos , Antibacterianos/farmacologia , Butiratos , Clostridium , Escherichia coli , Sorbitol/metabolismoRESUMO
Electrodeposition is a versatile method for synthesizing nanostructured films, but controlling the morphology of films containing two or more elements requires a detailed understanding of the deposition process. We used liquid cell transmission electron microscopy to follow the electrodeposition of PtNi nanoparticle films on a carbon electrode during cyclic voltammetry. These in situ observations show that the film thickness increases with each cycle, and by the fourth cycle, branched and porous structures could be deposited. Synchrotron studies using in situ transmission X-ray microscopy further revealed that Ni was deposited in the oxide phase. Ex situ studies of bulk electrodeposited PtNi nanoparticle films indicated the number of cycles and the scanning rate were the most influential parameters, resulting in a different thickness, a different homogeneity, a different nanoparticle size, and a different surface structure, while the precursor concentration did not have a significant influence. By varying the potential range, we were able to obtain films with different elemental compositions.
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Probiotic-containing fermented dairy foods have the potential to benefit human health, but the importance of the dairy matrix for efficacy remains unclear. We investigated the capacity of Lacticaseibacillus paracasei BL23 in phosphate-buffered saline (BL23-PBS), BL23-fermented milk (BL23-milk), and milk to modify intestinal and behavioral responses in a dextran sodium sulfate (DSS, 3% wt/vol) mouse model of colitis. Significant sex-dependent differences were found such that female mice exhibited more severe colitis, greater weight loss, and higher mortality rates. Sex differences were also found for ion transport ex vivo, colonic cytokine and tight junction gene expression, and fecal microbiota composition. Measurements of milk and BL23 effects showed BL23-PBS consumption improved weight recovery in females, whereas milk resulted in better body weight recovery in males. Occludin and Claudin-2 gene transcript levels indicated barrier function was impaired in males, but BL23-milk was still found to improve colonic ion transport in those mice. Proinflammatory and anti-inflammatory gene expression levels were increased in both male and female mice fed BL23, and to a more variable extent, milk, compared with controls. The female mouse fecal microbiota contained high proportions of Akkermansia (average of 18.1%) at baseline, and females exhibited more changes in gut microbiota composition following BL23 and milk intake. Male fecal microbiota harbored significantly more Parasutterella and less Blautia and Roseburia after DSS treatment, independent of BL23 or milk consumption. These findings show the complex interplay between dietary components and sex-dependent responses in mitigating inflammation in the digestive tract.NEW & NOTEWORTHY Sex-dependent responses to probiotic Lacticaseibacillus paracasei and milk and the potential of the dairy matrix to enhance probiotic protection against colitis in this context have not been previously explored. Female mice were more sensitive than males to colonic injury, and neither treatment effectively alleviated inflammation in both sexes. These sex-dependent responses may result from differences in the higher baseline proportions of Akkermansia in the gut microbiome of female mice.
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Colite , Sulfato de Dextrana , Modelos Animais de Doenças , Leite , Probióticos , Animais , Feminino , Probióticos/farmacologia , Masculino , Colite/microbiologia , Colite/induzido quimicamente , Colite/metabolismo , Camundongos , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Colo/metabolismo , Colo/microbiologia , Fatores Sexuais , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologiaRESUMO
Herein, we present a misleading case of advanced papillary thyroid carcinoma with lung, node, and pleural metastases, initially diagnosed as metastatic lung adenocarcinoma with papillary features, based on the histological and immunohistochemical analysis of a pleural biopsy. Between August 2019 and August 2020, the patient received 2 ineffective lines of systemic therapy, including a first line of chemotherapy with cisplatin and pemetrexed, and a second line of immunotherapy with atezolizumab. Comprehensive genomic profiling by next-generation sequencing on the archival pleural biopsy revealed an NTRK1-TMP3 fusion and comutation of the TERT promoter, commonly found in papillary thyroid carcinoma. After palliative partial thyroidectomy that confirmed the diagnosis of papillary thyroid carcinoma, in February 2021, the patient was enrolled in the STARTRK-2 GO40782 basket trial and received entrectinib, an oral pan-TRK inhibitor specifically targeting NTRK-rearranged tumors. After initially experiencing drug-related grade 2 anorexia, dysgeusia, and neurotoxicity and grade 3 asthenia, the dose was reduced, and an excellent and durable objective response was observed.
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Receptor trkA , Neoplasias da Glândula Tireoide , Humanos , Receptor trkA/genética , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genéticaRESUMO
BACKGROUND: We aimed to evaluate the characteristics, clinical outcomes, and blood product transfusion (BPT) rates of patients undergoing cardiac transplant (CT) while receiving uninterrupted anticoagulation and antiplatelet therapy. METHODS: A retrospective, single-center, and observational study of adult patients who underwent CT was performed. Patients were classified into four groups: (1) patients without anticoagulation or antiplatelet therapy (control), (2) patients on antiplatelet therapy (AP), (3) patients on vitamin K antagonists (AVKs), and (4) patients on dabigatran (dabigatran). The primary endpoints were reoperation due to bleeding and perioperative BPT rates (packed red blood cells (PRBC), fresh frozen plasma, platelets). Secondary outcomes assessed included morbidity and mortality-related events. RESULTS: Of the 55 patients included, 6 (11%) received no therapy (control), 8 (15%) received antiplatelet therapy, 15 (27%) were on AVKs, and 26 (47%) were on dabigatran. There were no significant differences in the need for reoperation or other secondary morbidity-associated events. During surgery patients on dabigatran showed lower transfusion rates of PRBC (control 100%, AP 100%, AVKs 73%, dabigatran 50%, p = 0.011) and platelets (control 100%, AP 100%, AVKs 100%, dabigatran 69%, p = 0.019). The total intraoperative number of BPT was also the lowest in the dabigatran group (control 5.5 units, AP 5 units, AVKs 6 units, dabigatran 3 units; p = 0.038); receiving significantly less PRBC (control 2.5 units, AP 3 units, AVKs 2 units, dabigatran 0.5 units; p = 0.011). A Poisson multivariate analysis showed that only treatment on dabigatran reduces PRBC requirements during surgery, with an expected reduction of 64.5% (95% CI: 32.4%-81.4%). CONCLUSIONS: In patients listed for CT requiring anticoagulation due to nonvalvular atrial fibrillation, the use of dabigatran and its reversal with idarucizumab significantly reduces intraoperative BPT demand.
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Anticoagulantes , Transplante de Coração , Inibidores da Agregação Plaquetária , Humanos , Feminino , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Anticoagulantes/uso terapêutico , Seguimentos , Transplante de Coração/efeitos adversos , Prognóstico , Transfusão de Sangue , Fatores de Risco , Idoso , Adulto , Dabigatrana/uso terapêutico , Complicações Pós-Operatórias/prevenção & controleRESUMO
PURPOSE: Despite the evidence of higher effectiveness of psychological interventions for insomnia compared to pharmacological ones, drug prescriptions for insomnia remain frequent. This study has assessed patterns of prescriptions of BZDs for insomnia before and after the delivery of a training in psychological interventions to professionals working in the services of a Department of Mental Health in northern Italy. METHODS: The intervention consisted in two training sessions about psychological interventions for insomnia delivered to professionals of the participating services. The prevalence of users with a prescription of BZDs for insomnia in an index period after the delivery of the training was compared to the prevalence in an index period before the training. RESULTS: Among 727 people assessed for BZDs prescription at pre-intervention, 306 (42.1%, 95% CI 0.39-0.46) had a prescription, and 344 (49.2%, 95% CI 0.45-0.53) had a prescription among 699 people assessed at post-intervention, corresponding to a significant odds ratio of 1.33 to be prescribed with BZDs in the second index period compared to the first one. Psychological interventions were offered to a small group of patients. CONCLUSION: Prescribing attitudes of BZDs for insomnia were not modified after the training and delivery of a psychological intervention in a mental healthcare outpatient setting. Prescribing habits should be addressed more directly in training, and professionals should be more aware of risks of BZDs assumption. The failure in changing drug prescriptions in this study should prompt more real-world studies of the application of evidence-based strategies, particularly in outpatient mental health settings.
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Benzodiazepinas , Serviços de Saúde Mental , Distúrbios do Início e da Manutenção do Sono , Humanos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Itália , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Benzodiazepinas/uso terapêutico , Padrões de Prática Médica/estatística & dados numéricos , Prescrições de Medicamentos/estatística & dados numéricos , IdosoRESUMO
BACKGROUND: The sars-Cov-2 pandemic has determined psychological stress, particularly in the young population of medical students. We studied the impact of the pandemic on menstrual cycle alteration in relation to psychological stress, presence of depression, sleep disturbances and post-traumatic stress, on a population of medical students. METHODS: 293 female students at the Faculty of Medicine and Psychology of the Sapienza University of Rome (23.08 years old ± 3.8) were enrolled. In March 2021, one year after quarantine, a personal data sheet on menstrual cycle, examining the quality of the menstrual cycle during the pandemic, compared to the previous period. Concomitantly, the Beck Depression Inventory and the Impact of Event Scale have been administered. A Pearson chi-square test was assessed to evaluate the difference between the characteristics of the menstrual cycle and the scores obtained with the questionnaires. RESULTS: A statistically significant association between menstrual alterations and stress during pandemic had been found. The onset of depressive symptoms and sleep disturbances was observed in 57.1% and in 58.1% of young women with cycle's alterations, respectively. Amenorrhea was three times more common in female students with depressive symptoms, premenstrual syndrome had a significant correlation with both depression and sleep disturbances. The pandemic has been related to menstrual alterations, with depressive symptoms and sleep disorders. Amenorrhea is connected to depression, as observed on the functional hypothalamic amenorrhea. CONCLUSIONS: The pandemic affected the menstrual cycle as well as the depressive symptoms and sleep. Practical implications of the study lead to the development of strategies for psychological intervention during the pandemic experience, in order to help medical trainees, with specific attention to women's needs. Future studies should analyze the impact of other types of social stress events, on sleep, depression and the menstrual cycle beside the pandemic.
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COVID-19 , Transtornos do Sono-Vigília , Estudantes de Medicina , Feminino , Humanos , Adulto Jovem , Adulto , COVID-19/epidemiologia , Amenorreia , Depressão/epidemiologia , SARS-CoV-2 , Menstruação , Transtornos do Sono-Vigília/epidemiologia , SonoRESUMO
INTRODUCTION: Many studies have investigated patients' understandings of how to optimise mental health services. However, only a few studies in the Italian context have involved experts by experience (EbEs), who can be ex-users, family members of ex-users or current service collaborators. Their role is crucial in implementing collaborative service quality assessment projects. METHOD: The study investigated the experience of 35 EbEs,⯠users, and family members who carried out a 9-month fortnightly project aimed at imagining an 'ideal service'. The facilitators of the discussion groups (two EbEs) were interviewed; written reports of each meeting were produced with relevant comments, notes and specific suggestions; and content analysis was applied. RESULTS: The most important result concerns the effectiveness of the project management method and group leadership carried out by the two EbEs. This approach allowed for complete autonomy of the work, without professional gaze or power imbalance. Also, the ideas and specific contents focused on by the two groups offer strategies to facilitate users' entry and reception in health care centres, to reduce the stigma of mental illness, to improve the centres' physical environment, to improve organisational aspects, to keep family members actively involved and to network mental health services with other territorial services. CONCLUSIONS: EbEs have proven to be key figures in ensuring equity of role in the service co-design process. This also concerns a context, the Italian one, where their role has not yet been recognised and legalised. Their contribution and ideas to improve services could be fundamental not only in mental health centres, but also in other health facilities, and could concern the entire service delivery process rather than being limited to quality assurance, according to a virtuous circle based on active participation and transformation of the role of users. PATIENT OR PUBLIC CONTRIBUTION: This work resulted from close collaboration between the two EbEs who conducted the groups, users and family members, the university, and the psychiatrist in charge of the service. All of them contributed to the research. The EbEs, researchers and psychiatrist participated in the interpretation of the data and are the co-authors of this paper.
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Família , Serviços de Saúde Mental , Humanos , Saúde Mental , Meio Ambiente , Instalações de SaúdeRESUMO
Surgery and endovascular therapy are the primary treatment options for spinal dural arteriovenous fistula (SDAVF). Due to the absence of a consensus regarding which therapy yields a superior outcome, we conducted a comparative analysis of the surgical and endovascular treatment of SDAVF through a multicenter case series and a systematic literature review. Patients with SDAVF, surgically or endovascularly treated at four neurosurgical centers from January 2001 to December 2021, were included in this study. Level of SDAVF, primary treatment modality, baseline and post-procedural neurological status were collected. The primary outcomes were failure, complication rates, and a newly introduced parameter named as therapeutic delay. A systematic review of the literature was performed according to PRISMA-P guidelines. The systematic review identified 511 papers, of which 18 were eligible for analysis, for a total of 814 patients, predominantly male (72%) with a median age of 61 and mainly thoracic SDAVFs (65%). The failure rate was significantly higher for endovascular therapy (20%) compared to surgery (4%) (p < 0.01). Neurological complications were generally rare, with similar rates among the two groups (endovascular 2.9%; surgery 2.6%). Endovascular treatment showed a statistically significantly higher rate of persistent neurological complications than surgical treatment (2.9% versus 0.2%; p < 0.01). Both treatments showed similar rates of clinical improvement based on Aminoff Logue scale score. The multicenter, retrospective study involved 131 patients. The thoracic region was the most frequent location (58%), followed by lumbar (37%). Paraparesis (45%) and back pain (41%) were the most common presenting symptoms, followed by bladder dysfunction (34%) and sensory disturbances (21%). The mean clinical follow-up was 21 months, with all patients followed for at least 12 months. No statistically significant differences were found in demographic and clinical data, lesion characteristics, or outcomes between the two treatment groups. Median pre-treatment Aminoff-Logue score was 2.6, decreasing to 1.4 post-treatment with both treatments. The mean therapeutic delay for surgery and endovascular treatment showed no statistically significant difference. Surgical treatment demonstrated significantly lower failure rates (5% vs. 46%, p < 0.01). In the surgical group, 2 transient neurological (1 epidural hematoma, 1 CSF leak) and 3 non-neurological (3 wound infections) complications were recorded; while 2 permanent neurological (spinal infarcts), and 5 non-neurological (inguinal hematomas) were reported in the endovascular group. According to the literature review and this multicenter clinical series, surgical treatment has a significantly lower failure rate than endovascular treatment. Although the two treatments have similar complication rates, endovascular treatment seems to have a higher rate of persistent neurological complications.
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Malformações Vasculares do Sistema Nervoso Central , Procedimentos Endovasculares , Humanos , Malformações Vasculares do Sistema Nervoso Central/cirurgia , Procedimentos Endovasculares/métodos , Procedimentos Neurocirúrgicos/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Resultado do Tratamento , Idoso , Complicações Pós-Operatórias/epidemiologia , Embolização Terapêutica/métodosRESUMO
BACKGROUND: Multiple radiomics models have been proposed for grading glioma using different algorithms, features, and sequences of magnetic resonance imaging. The research seeks to assess the present overall performance of radiomics for grading glioma. METHODS: A systematic literature review of the databases Ovid MEDLINE PubMed, and Ovid EMBASE for publications published on radiomics for glioma grading between 2012 and 2023 was performed. The systematic review was carried out following the criteria of Preferred Reporting Items for Systematic Reviews and Meta-Analysis. RESULTS: In the meta-analysis, a total of 7654 patients from 40 articles, were assessed. R-package mada was used for modeling the joint estimates of specificity (SPE) and sensitivity (SEN). Pooled event rates across studies were performed with a random-effects meta-analysis. The heterogeneity of SPE and SEN were based on the χ2 test. Overall values for SPE and SEN in the differentiation between high-grade gliomas (HGGs) and low-grade gliomas (LGGs) were 84% and 91%, respectively. With regards to the discrimination between World Health Organization (WHO) grade 4 and WHO grade 3, the overall SPE was 81% and the SEN was 89%. The modern non-linear classifiers showed a better trend, whereas textural features tend to be the best-performing (29%) and the most used. CONCLUSIONS: Our findings confirm that present radiomics' diagnostic performance for glioma grading is superior in terms of SEN and SPE for the HGGs vs. LGGs discrimination task when compared to the WHO grade 4 vs. 3 task.
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Neoplasias Encefálicas , Glioma , Imageamento por Ressonância Magnética , Gradação de Tumores , Glioma/diagnóstico por imagem , Glioma/patologia , Humanos , Imageamento por Ressonância Magnética/normas , Imageamento por Ressonância Magnética/métodos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neuroimagem/normas , Neuroimagem/métodos , RadiômicaRESUMO
Telemedicine and remote monitoring devices, including implantable loop recorders (ILR), are increasingly adopted in the cardiologic setting. These are valuable tools in the arrhythmic stratification of patients at risk of sudden cardiac death, providing a tailored therapeutic management to prevent lethal arrhythmias. We report a case of an asymptomatic 18-year-old boy with a family history of syncope and cardiac arrest, who had a diagnosis of Brugada syndrome with an inducible type 1 pattern and carrier of a missense mutation of the SCN5A gene. In light of the risk factors, although not recommended by current guidelines, we decided to proceed with the implantation of an ILR with remote monitoring service. A few months later, an episode of asymptomatic sustained polymorphic ventricular tachycardia was promptly observed by the remote monitoring, leading to a timely implantation of a subcutaneous cardiac implantable defibrillator.
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Síndrome de Brugada , Desfibriladores Implantáveis , Telemedicina , Humanos , Masculino , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/genética , Síndrome de Brugada/terapia , Adolescente , Telemedicina/métodos , Medição de Risco/métodos , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/terapia , Eletrocardiografia , Eletrocardiografia Ambulatorial/instrumentação , Eletrocardiografia Ambulatorial/métodos , Mutação de Sentido Incorreto , Morte Súbita Cardíaca/prevenção & controle , Morte Súbita Cardíaca/etiologiaRESUMO
Gliomas' aggressive nature and resistance to therapy make them a major problem in oncology. Gliomas continue to have dismal prognoses despite significant advancements in medical science, and traditional treatments like surgery, radiation (RT), and chemotherapy (CT) frequently prove to be ineffective. After glioma stem cells (GSCs) were discovered, the traditional view of gliomas as homogeneous masses changed. GSCs are essential for tumor growth, treatment resistance, and recurrence. These cells' distinct capacities for differentiation and self-renewal are changing our knowledge of the biology of gliomas. This systematic literature review aims to uncover the molecular mechanisms driving glioma progression associated with GSCs. The systematic review adhered to PRISMA guidelines, with a thorough literature search conducted on PubMed, Ovid MED-LINE, and Ovid EMBASE. The first literature search was performed on 1 March 2024, and the search was updated on 15 May 2024. Employing MeSH terms and Boolean operators, the search focused on molecular mechanisms associated with GCSs-mediated glioma progression. Inclusion criteria encompassed English language studies, preclinical studies, and clinical trials. A number of 957 papers were initially identified, of which 65 studies spanning from 2005 to 2024 were finally included in the review. The main GSC model distribution is arranged in decreasing order of frequency: U87: 20 studies (32.0%); U251: 13 studies (20.0%); A172: 4 studies (6.2%); and T98G: 2 studies (3.17%). From most to least frequent, the distribution of the primary GSC pathway is as follows: Notch: 8 studies (12.3%); STAT3: 6 studies (9.2%); Wnt/ß-catenin: 6 studies (9.2%); HIF: 5 studies (7.7%); and PI3K/AKT: 4 studies (6.2%). The distribution of molecular effects, from most to least common, is as follows: inhibition of differentiation: 22 studies (33.8%); increased proliferation: 18 studies (27.7%); enhanced invasive ability: 15 studies (23.1%); increased self-renewal: 5 studies (7.7%); and inhibition of apoptosis: 3 studies (4.6%). This work highlights GSC heterogeneity and the dynamic interplay within the glioblastoma microenvironment, underscoring the need for a tailored approach. A few key pathways influencing GSC behavior are JAK/STAT3, PI3K/AKT, Wnt/ß-catenin, and Notch. Therapy may target these pathways. This research urges more study to fill in knowledge gaps in the biology of GSCs and translate findings into useful treatment approaches that could improve GBM patient outcomes.
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Progressão da Doença , Glioma , Células-Tronco Neoplásicas , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Glioma/genética , Glioma/patologia , Glioma/terapia , Glioma/metabolismo , Terapia de Alvo Molecular , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/metabolismo , Animais , Transdução de SinaisRESUMO
Craniopharyngiomas present unique challenges in surgical management due to their proximity to critical neurovascular structures. This systematic review investigates genetic and immunological markers as potential targets for therapy in craniopharyngiomas, assessing their involvement in tumorigenesis, and their influence on prognosis and treatment strategies. The systematic review adhered to PRISMA guidelines, with a thorough literature search conducted on PubMed, Ovid MED-LINE, and Ovid EMBASE. Employing MeSH terms and Boolean operators, the search focused on craniopharyngiomas, targeted or molecular therapy, and clinical outcomes or adverse events. Inclusion criteria encompassed English language studies, clinical trials (randomized or non-randomized), and investigations into adamantinomatous or papillary craniopharyngiomas. Targeted therapies, either standalone or combined with chemotherapy and/or radiotherapy, were examined if they included clinical outcomes or adverse event analysis. Primary outcomes assessed disease response through follow-up MRI scans, categorizing responses as follows: complete response (CR), near-complete response (NCR), partial response, and stable or progressive disease based on lesion regression percentages. Secondary outcomes included treatment type and duration, as well as adverse events. A total of 891 papers were initially identified, of which 26 studies spanning from 2000 to 2023 were finally included in the review. Two tables highlighted adamantinomatous and papillary craniopharyngiomas, encompassing 7 and 19 studies, respectively. For adamantinomatous craniopharyngiomas, Interferon-2α was the predominant targeted therapy (29%), whereas dabrafenib took precedence (70%) for papillary craniopharyngiomas. Treatment durations varied, ranging from 1.7 to 28 months. Positive responses, including CR or NCR, were observed in both types of craniopharyngiomas (29% CR for adamantinomatous; 32% CR for papillary). Adverse events, such as constitutional symptoms and skin changes, were reported, emphasizing the need for vigilant monitoring and personalized management to enhance treatment tolerability. Overall, the data highlighted a diverse landscape of targeted therapies with encouraging responses and manageable adverse events, underscoring the importance of ongoing research and individualized patient care in the exploration of treatment options for craniopharyngiomas. In the realm of targeted therapies for craniopharyngiomas, tocilizumab and dabrafenib emerged as prominent choices for adamantinomatous and papillary cases, respectively. While adverse events were common, their manageable nature underscored the importance of vigilant monitoring and personalized management. Acknowledging limitations, future research should prioritize larger, well-designed clinical trials and standardized treatment protocols to enhance our understanding of the impact of targeted therapies on craniopharyngioma patients.
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Ameloblastoma , Craniofaringioma , Neoplasias Hipofisárias , Humanos , Craniofaringioma/tratamento farmacológico , Craniofaringioma/genética , Imidazóis , Oximas , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/genéticaRESUMO
The most common primary brain tumor is glioblastoma (GBM), yet the current therapeutic options for this disease are not promising. Although immunotherapeutic techniques have shown poor success in GBM thus far despite efforts, new developments provide optimism. One of these developments is chimeric antigen receptor (CAR)-T cell treatment, which includes removing and genetically modifying autologous T cells to produce a receptor that targets a GBM antigen before reintroducing the cells into the patient's body. A number of preclinical studies have produced encouraging results, which have led to the start of clinical trials assessing these CAR-T cell treatments for GBM and other brain tumors. Although results in tumors such as diffuse intrinsic pontine gliomas and lymphomas have been promising, preliminary findings in GBM have not produced any clinical benefits. The paucity of particular antigens in GBM, their inconsistent expression patterns, and the possible immunoediting-induced loss of these antigens after antigen-targeted therapy are some possible causes for this discrepancy. The goal of this systematic literature review is to assess potential approaches for creating CAR-T cells that are more effective for this indication, as well as the clinical experiences that are already being had with CAR-T cell therapy in GBM. Up until 9 May 2024, a thorough search was carried out across the three main medical databases: PubMed, Web of Science, and Scopus. Relevant Medical Subject Heading (MeSH) terms and keywords associated with "glioblastoma", "CAR-T", "T cell therapy", "overall survival", and "progression free survival" were employed in the search approach. Preclinical and clinical research on the application of CAR-T cells as a therapeutic approach for GBM are included in the review. A total of 838 papers were identified. Of these, 379 articles were assessed for eligibility, resulting in 8 articles meeting the inclusion criteria. The included studies were conducted between 2015 and 2023, with a total of 151 patients enrolled. The studies varied in CAR-T cell types. EGFRvIII CAR-T cells were the most frequently investigated, used in three studies (37.5%). Intravenous delivery was the most common method of delivery (62.5%). Median OS ranged from 5.5 to 11.1 months across the studies. PFS was reported in only two studies, with values of 7.5 months and 1.3 months. This systematic review highlights the evolving research on CAR-T cell therapy for GBM, emphasizing its potential despite challenges. Targeting antigens like EGFRvIII and IL13Rα2 shows promise in treating recurrent GBM. However, issues such as antigen escape, tumor heterogeneity, and immunosuppression require further optimization. Innovative delivery methods, combination therapies, and personalized approaches are crucial for enhancing CAR-T cell efficacy. Ongoing research is essential to refine these therapies and improve outcomes for GBM patients.
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Neoplasias Encefálicas , Glioblastoma , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Humanos , Glioblastoma/terapia , Glioblastoma/imunologia , Imunoterapia Adotiva/métodos , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/imunologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , AnimaisRESUMO
High-grade glial tumors (HGGs) exhibit aggressive growth patterns and high recurrence rates. The prevailing treatment approach comprises radiation therapy (RT), chemotherapy (CMT), and surgical resection. Despite the progress made in traditional treatments, the outlook for patients with HGGs remains bleak. Tumor metabolism is emerging as a potential target for glioma therapies, a promising approach that harnesses the metabolism to target tumor cells. However, the efficacy of therapies targeting the metabolism of HGGs remains unclear, compelling a comprehensive review. This study aimed to assess the outcome of present trials on HGG therapies targeting metabolism. A comprehensive search of PubMed, Ovid MEDLINE, and Ovid EMBASE was conducted until November 2023. The search method used pertinent Medical Subject Heading (MeSH) terminologies and keywords referring to "high-grade gliomas", "metabolism", "target therapies", "monoclonal antibodies", "overall survival", and "progression-free survival". The review analyzed studies that focused on therapies targeting the metabolism of HGGs in human subjects. These studies included both randomized controlled trials (RCTs) and non-randomized controlled trials (NRCTs). Out of 284 articles identified, 23 trials met the inclusion criteria and were thoroughly analyzed. Phase II trials were the most numerous (62%). Targeted metabolic therapies were predominantly used for recurrent HGGs (67%). The most common targeted pathways were the vascular endothelial growth factor (VEGF, 43%), the human epidermal growth factor receptor (HER, 22%), the platelet-derived growth factor (PDGF, 17%), and the mammalian target of rapamycin (mTOR, 17%). In 39% of studies, the subject treatment was combined with CMT (22%), RT (4%), or both (13%). The median OS widely ranged from 4 to 26.3 months, while the median PFS ranged from 1.5 to 13 months. This systematic literature review offers a thorough exploration of the present state of metabolic therapies for HGGs. The multitude of targeted pathways underscores the intricate nature of addressing the metabolic aspects of these tumors. Despite existing challenges, these findings provide valuable insights, guiding future research endeavors. The results serve as a foundation for refining treatment strategies and enhancing patient outcomes within the complex landscape of HGGs.
Assuntos
Glioma , Humanos , Glioma/tratamento farmacológico , Neuroglia , Agressão , Anticorpos Monoclonais , Receptores ErbB , Fator de Crescimento Derivado de PlaquetasRESUMO
Hepatocellular carcinoma is the most common primary liver tumor. Orthotopic liver transplant is one of the best treatment options, but its waiting list has to be considered. Bridge therapies have been introduced in order to limit this issue. The aim of this study is to evaluate if bridge therapies in advanced hepatocellular carcinoma can improve overall survival and reduce de-listing. We selected 185 articles. The search was limited to English articles involving only adult patients. These were deduplicated and articles with incomplete text or irrelevant conclusions were excluded. Sorafenib is the standard of care for advanced hepatocellular carcinoma and increases overall survival without any significant drug toxicity. However, its survival benefit is limited. The combination of transarterial chemoembolization + sorafenib, instead, delays tumor progression, although its survival benefit is still uncertain. A few studies have shown that patients undergoing transarterial chemoembolization + radiation therapy have similar or even better outcomes than those undergoing transarterial chemoembolization or sorafenib alone for rates of histopathologic complete response (89% had no residual in the explant). Also, the combined therapy of transarterial chemoembolization + radiotherapy + sorafenib was compared to the association of transarterial chemoembolization + radiotherapy and was associated with a better survival rate (24 vs. 17 months). Moreover, immunotherapy revealed new encouraging perspectives. Combination therapies showed the most encouraging results and could become the gold standard as a bridge to transplant for patients with advanced hepatocellular carcinoma.
Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Transplante de Fígado , Sorafenibe , Carcinoma Hepatocelular/terapia , Humanos , Neoplasias Hepáticas/terapia , Transplante de Fígado/métodos , Sorafenibe/uso terapêutico , Quimioembolização Terapêutica/métodos , Terapia Combinada , Antineoplásicos/uso terapêutico , Terapia PonteRESUMO
Since the early1990s, laparoscopic right colon resections have been the most performed advanced laparoscopic procedures just after laparoscopic left colectomies and sigmoid resections. Indications for laparoscopic right colectomies are either benign or malignant diseases. Despite its many indications, a laparoscopic right or extended right colectomy is mostly performed for cancer of the caecum, the ascending colon, the hepatic flexure or the proximal transverse colon. Worldwide, colorectal cancer is the third most diagnosed cancer: an estimated 1,880,725 people were diagnosed with colorectal cancer in 2020, out of which 1,148,515 were colon cancer cases and 40% were located in the right colon. These figures make an oncologic sound surgery for right colon cancer of the utmost relevance. More recently, complete mesocolic excision has been advocated as the optimal choice in term of radicality, especially in node-positive patients with right colon cancer. Laparoscopic standard right colectomy and extended right colectomy with or without CME should be performed according to defined principles based on a close knowledge of key anatomical landmarks. This knowledge will allow to trace anatomical structures and drive instruments along the correct surgical planes and has its foundations in teachings from surgeons and scientists of past and present time.
Assuntos
Colectomia , Neoplasias do Colo , Laparoscopia , Humanos , Colectomia/métodos , Laparoscopia/métodos , Neoplasias do Colo/cirurgiaRESUMO
BACKGROUND: Trop-2 and Nectin-4 are transmembrane proteins overexpressed in many tumours and targets of antibody-drug conjugates (ADC). In metastatic colorectal cancer (mCRC), the role of Trop-2 and Nectin-4 has been poorly investigated. METHODS: Tumour samples of patients randomised in the phase III TRIBE2 were assessed for Trop-2 and Nectin-4 expression. RESULTS: Three hundred eighty-six tumours were assessed for Trop-2 expression. 90 (23%), 115 (30%) and 181 (47%) were Trop-2 high, medium and low, respectively. Patients with low Trop-2 tumours achieved longer PFS (12 versus 9.9 months, p = 0.047) and OS (27.3 versus 21.3 months, p = 0.015) than those with high/medium Trop-2 tumours. These findings were confirmed in multivariate analysis (p = 0.022 and p = 0.023, respectively). A greater OS benefit from treatment intensification with FOLFOXIRI/bevacizumab was observed in patients with high/medium Trop-2 tumours (p-for-interaction = 0.041). Two hundred fifty-one tumours were assessed for Nectin-4 expression. Fourteen (5%), 67 (27%) and 170 (68%) were high, medium and low, respectively. No prognostic impact was observed based on Nectin-4 expression and no interaction effect was reported between Nectin-4 expression groups and treatment arm. CONCLUSIONS: In mCRC, expression levels of Trop-2 and Nectin-4 are heterogeneous, suggesting a target-driven development of anti-Trop2 and anti-Nectin-4 ADCs. Medium/high Trop-2 expression is associated with worse prognosis and higher benefit from chemotherapy intensification.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Bevacizumab/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Prognóstico , Neoplasias Retais/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina , Fluoruracila , LeucovorinaRESUMO
BACKGROUND: Diabetic foot is a significant cause of morbidity in diabetic patients, with a rate that is approximately twice that of patients without foot ulcers. "Metabolic memory" represents the epigenetic changes induced by chronic hyperglycaemia, despite the correction of the glucose levels themselves. These epigenetic modifications appear to perpetuate the damage caused by persistently elevated glucose levels even in their absence, acting at various levels, mostly affecting the molecular processes of diabetic ulcer healing. METHODS: The aim of our cross-sectional study was to analyse a cohort of patients with diabetes with and without lower limb ulcers. We examined the effects of epigenetic changes on miRNA 126, 305, and 217 expression and the frequency of the SNPs of genes encoding inflammatory molecules (e.g., IL-6 and TNF-alpha) and their correlations with serum levels of proangiogenic molecules (e.g., ENOS, VEGF and HIF-1alpha) and several adipokines as well as with endothelial dysfunction, assessed noninvasively by reactive hyperaemia peripheral artery tonometry. Between March 2021 and June 2022, 110 patients were enrolled into the study: 50 diabetic patients with diabetic foot injuries, 40 diabetic patients without ulcerative complications and 20 nondiabetic patients as the control group. RESULTS: Diabetic subjects with lower limb ulcerative lesions exhibited higher levels of inflammatory cytokines, such as VEGF (191.40 ± 200 pg/mL vs. 98.27 ± 56.92 pg/mL vs. 71.01 ± 52.96 pg/mL; p = 0.22), HIF-1alpha (40.18 ± 10.80 ng/mL vs. 33.50 ± 6.16 ng/mL vs. 33.85 ± 6.84 ng/mL; p = 0.10), and Gremlin-1 (1.72 ± 0.512 ng/mL vs. 1.31 ± 0.21 ng/mL vs. 1.11 ± 0.19 ng/mL; p < 0.0005), than those without lower limb ulcers and healthy controls. Furthermore, we observed that miR-217-5p and miR-503-5p were 2.19-fold (p < 0.05) and 6.21-fold (p = 0.001) more highly expressed in diabetic foot patients than in healthy controls, respectively. Additionally, diabetic patients without lower limb ulcerative complications showed 2.41-fold (p = 0) and 2.24-fold (p = 0.029) higher expression of miR-217-5p and miR-503-5p, respectively, than healthy controls. Finally, diabetic patients with and without ulcerative complications of the lower limbs showed higher expression of the VEGFC2578A CC polymorphism (p = 0.001) and lower expression of the VEGFC2578A AC polymorphism (p < 0.005) than the healthy control population. We observed a significant increase in Gremlin-1 levels in patients with diabetic foot, suggesting that this inflammatory adipokine may serve as a predictive marker for the diagnosis of diabetic foot. CONCLUSIONS: Our results highlighted that patients with diabetic foot showed predominant expression of the VEGF C2578A CC polymorphism and reduced expression of the AC allele. Additionally, we found an overexpression of miR-217-5p and miR-503-5p in diabetic patients with and without diabetic foot syndrome compared with healthy controls. These results align with those reported in the literature, in which the overexpression of miR-217-5p and miR-503-5p in the context of diabetic foot is reported. The identification of these epigenetic modifications could therefore be helpful in the early diagnosis of diabetic foot and the treatment of risk factors. However, further studies are necessary to confirm this hypothesis.
Assuntos
Diabetes Mellitus , Pé Diabético , MicroRNAs , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Pé Diabético/diagnóstico , Pé Diabético/genética , Polimorfismo de Nucleotídeo Único , Úlcera , Fator A de Crescimento do Endotélio Vascular/genética , Estudos Transversais , GlucoseRESUMO
BACKGROUND: Live dietary microbes have been hypothesized to contribute to human health but direct evidence is lacking. OBJECTIVES: This study aimed to determine whether the dietary consumption of live microbes is linked to improved health outcomes. METHODS: Data from the NHANES 2001-2018 were used to assess microbial intake and their adjusted associations with selected physiological parameters (e.g., blood pressure, anthropometric measures, and biomarkers) among adults aged 19 y and older. Regression models were constructed to assess the microbial intake with each physiological parameter and adjusted for demographics and other covariates. Microbial intake was assessed as both a continuous variable and a 3-level categorical variable. Fermented foods were assessed in a separate model. RESULTS: In continuous models, an additional 100-g intake of microbe-containing foods was associated with a lower systolic blood pressure (regression coefficient: -0.331; 95% CI: -0.447, -0.215 mm Hg), C-reactive protein (-0.013; 95% CI: -0.019, -0.008 mg/dL), plasma glucose -0.347; 95% CI: -0.570, -0.124 mg/dL), plasma insulin (-0.201; 95% CI: -0.304, -0.099 µU/mL), triglyceride (-1.389; 95% CI: -2.672, -0.106 mg/dL), waist circumference (-0.554; 95% CI: -0.679, -0.428 cm), and BMI -0.217; 95% CI: -0.273, -0.160 kg/m2) levels and a higher level of high density lipoprotein cholesterols (0.432; 95% CI: 0.289, 0.574 mg/dL). Patterns were broadly similar when microbial intake was assessed categorically and when fermented foods were assessed separately. CONCLUSIONS: To our knowledge, this study is the first to quantify, in a nationally representative data set of American adults and using stable sets of covariates in the regression models, the adjusted associations of dietary intakes of live microbes with a variety of outcomes, such as anthropometric measures, biomarkers, and blood pressure levels. Our findings suggest that foods with higher microbial concentrations are associated with modest health improvements across a range of outcomes.