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Adipose tissue (AT) secretes pro- and anti-inflammatory cytokines involved in AT homeostasis, including tumor necrosis factor-α (TNFα) and irisin. The functionality of AT is based on a regulated equilibrium between adipogenesis and extracellular matrix (ECM) remodeling. We investigated the contributions of adipose progenitors (ASCs) and adipocytes (AMCs) to TNFα-induced ECM remodeling and a possible implication of irisin in AT impairment in obesity. ASCs and AMCs were exposed to TNFα treatment and nuclear factor-kappa (NF-kB) pathway was investigated: Tissue Inhibitor of Metalloproteinase (TIMP-1), Twist Family Transcription Factor 1 (TWIST-1), and peroxisome proliferator-activated receptor-γ (PPARγ) expression levels were analyzed. The proteolytic activity of matrix metalloproteinases (MMPs) -2 and -9 was analyzed by zymography, and the irisin protein content was measured by ELISA. In inflamed AMCs, a TIMP-1/TWIST-1 imbalance leads to a drop in PPARγ. Adipogenesis and lipid storage ability impairment come with local tissue remodeling due to MMP-9 overactivation. In vitro and ex vivo measurements confirm positive correlations among inflammation, adipose secreting irisin levels, and circulating irisin levels in patients with visceral obesity. Our findings identify the NF-kB downstream effectors as molecular initiators of AT dysfunction and suggest irisin as a possible AT damage and obesity predictive factor.
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Fibronectinas , Inhibidor Tisular de Metaloproteinasa-1 , Humanos , Tejido Adiposo/metabolismo , Fibronectinas/metabolismo , FN-kappa B/metabolismo , Obesidad/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Debate is around the optimal immunization regimen for cancer vaccines since too intense vaccination schedules may exhaust reactive lymphocytes. GX301 is a telomerase-based cancer vaccine whose safety and immunological effects were tested in a phase I trial applying an eight administrations schedule. Main objective of this study was to comparatively analyse safety and immunological response to three GX301 regimens in metastatic castration-resistant prostate cancer patients with response/disease stability after docetaxel chemotherapy. This was a multicentre, randomized, parallel-group, open-label trial registered with EudraCT (2014-000095-26) and ClinicalTrials.gov (NCT02293707, 2014). Ninety-eight patients were randomized to receive either eight (regimen 1), four (regimen 2) or two (regimen 3) vaccine administrations. Sixty-three patients were assessable for the primary immunological end-point. Vaccine-specific immune responses were evaluated by intracellular staining for IFN, elispot and cytotoxic assay at 90 and 180 days from baseline. No major side effects were recorded. A 54% overall immune responder rate was observed with 95% of patients showing at least one vaccine-specific immune response. Rate of immunological responders and number of immunizations were proportionally related, suggesting superiority of regimens 1 and 2 over regimen 3. Overall survival did not differ among regimens in both immunological responders and non-responders and was inversely associated (P = 0.002) with increase in the number of circulating CD8 + T regulatory cells at 180 days. These data indicate that GX301 cancer vaccine is safe and immunogenic in metastatic castration-resistant prostate cancer patients. Schedules with high number of administrations should be preferred in future studies due to their better immunological outcome.
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Vacunas contra el Cáncer/inmunología , Neoplasias de la Próstata Resistentes a la Castración/inmunología , Neoplasias de la Próstata Resistentes a la Castración/terapia , Telomerasa/inmunología , Anciano , Antineoplásicos/inmunología , Linfocitos T CD8-positivos/inmunología , Supervivencia sin Enfermedad , Docetaxel/inmunología , Humanos , Inmunidad/inmunología , Inmunización/métodos , Masculino , Antígeno Prostático Específico/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
Penile cancer is a very rare malignancy and it is usually identified as a nodule or an ulceration. We report a case of locally advanced penile cancer presented as a urethral stricture and recurrent scrotal abscess. The patient had been treating for obstructive voiding symptoms and septic condition for 5 months. Because of persistent symptoms, a drainage of the abscess was performed and the histopathological examination showed infiltrating moderately differentiated squamous cell carcinoma of penis. He underwent a surgical Emasculation followed by the administration of a combination of chemotherapy (paclitaxel, ifosfamide, and cisplatin). We highlight the importance of including penile cancer in the differential diagnosis of scrotal abscess and urethral stricture. A multimodal approach is an effective strategy to manage the disease.
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Neoplasias del Pene , Estrechez Uretral , Absceso/complicaciones , Humanos , Masculino , Neoplasias del Pene/complicaciones , Pene , EscrotoRESUMEN
Ex vivo limbal stem cell transplantation is the main therapeutic approach to address a complete and functional re-epithelialization in corneal blindness, the second most common eye disorder. Although important key points were defined, the molecular mechanisms involved in the epithelial phenotype determination are unclear. Our previous studies have demonstrated the pluripotency and immune-modulatory of fibroblast limbal stem cells (f-LSCs), isolated from the corneal limbus. We defined a proteomic profile especially enriched in wound healing and cytoskeleton-remodelling proteins, including Profilin-1 (PFN1). In this study we postulate that pfn-1 knock down promotes epithelial lineage by inhibiting the integrin-ß1(CD29)/mTOR pathway and subsequent NANOG down-expression. We showed that it is possible modulate pfn1 expression levels by treating f-LSCs with Resveratrol (RSV), a natural compound: pfn1 decline is accompanied with up-regulation of the specific differentiation epithelial genes pax6 (paired-box 6), sox17 (sex determining region Y-box 17) and ΔNp63-α (p63 splice variant), consistent with drop-down of the principle stem gene levels. These results contribute to understand the molecular biology of corneal epithelium development and suggest that pfn1 is a potential molecular target for the treatment of corneal blindness based on epithelial cell dysfunction.
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Diferenciación Celular , Fibroblastos/citología , Integrina beta1/metabolismo , Limbo de la Córnea/citología , Profilinas/metabolismo , Células Madre/citología , Serina-Treonina Quinasas TOR/metabolismo , Apoptosis , Biomarcadores/metabolismo , Proliferación Celular , Células Cultivadas , Epitelio Corneal/citología , Epitelio Corneal/metabolismo , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Humanos , Integrina beta1/genética , Limbo de la Córnea/metabolismo , Profilinas/genética , Células Madre/metabolismo , Serina-Treonina Quinasas TOR/genética , Cicatrización de HeridasRESUMEN
The core components of regenerative medicine are stem cells with high self-renewal and tissue regeneration potentials. Adult stem cells can be obtained from many organs and tissues. NANOG, SOX2 and OCT4 represent the core regulatory network that suppresses differentiation-associated genes, maintaining the pluripotency of mesenchymal stem cells. The roles of NANOG in maintaining self-renewal and undifferentiated status of adult stem cells are still not perfectly established. In this study we define the effects of downregulation of NANOG in maintaining self-renewal and undifferentiated state in mesenchymal stem cells (MSCs) derived from subcutaneous adipose tissue (hASCs). hASCs were expanded and transfected in vitro with short hairpin Lentivirus targeting NANOG. Gene suppressions were achieved at both transcript and proteome levels. The effect of NANOG knockdown on proliferation after 10 passages and on the cell cycle was evaluated by proliferation assay, colony forming unit (CFU), qRT-PCR and cell cycle analysis by flow-cytometry. Moreover, NANOG involvement in differentiation ability was evaluated. We report that downregulation of NANOG revealed a decrease in the proliferation and differentiation rate, inducing cell cycle arrest by increasing p27/CDKN1B (Cyclin-dependent kinase inhibitor 1B) and p21/CDKN1A (Cyclin-dependent kinase inhibitor 1A) through p53 and regulate DLK1/PREF1. Furthermore, NANOG induced downregulation of DNMT1, a major DNA methyltransferase responsible for maintaining methylation status during DNA replication probably involved in cell cycle regulation. Our study confirms that NANOG regulates the complex transcription network of plasticity of the cells, inducing cell cycle arrest and reducing differentiation potential.
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Proliferación Celular , Puntos de Control de la Fase G1 del Ciclo Celular , Células Madre Mesenquimatosas/citología , Proteína Homeótica Nanog/genética , Adulto , Diferenciación Celular , Autorrenovación de las Células , Células Cultivadas , Regulación hacia Abajo , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Células Madre Mesenquimatosas/metabolismo , Persona de Mediana EdadRESUMEN
The stromal vascular cell fraction (SVF) of visceral and subcutaneous adipose tissue (VAT and SAT) has increasingly come into focus in stem cell research, since these compartments represent a rich source of multipotent adipose-derived stem cells (ASCs). ASCs exhibit a self-renewal potential and differentiation capacity. Our aim was to study the different expression of the embryonic stem cell markers NANOG (homeobox protein NANOG), SOX2 (SRY (sex determining region Y)-box 2) and OCT4 (octamer-binding transcription factor 4) and to evaluate if there exists a hierarchal role in this network in ASCs derived from both SAT and VAT. ASCs were isolated from SAT and VAT biopsies of 72 consenting patients (23 men, 47 women; age 45 ± 10; BMI between 25 ± 5 and 30 ± 5 range) undergoing elective open-abdominal surgery. Sphere-forming capability was evaluated by plating cells in low adhesion plastic. Stem cell markers CD90, CD105, CD29, CD31, CD45 and CD146 were analyzed by flow cytometry, and the stem cell transcription factors NANOG, SOX2 and OCT4 were detected by immunoblotting and real-time PCR. NANOG, SOX2 and OCT4 interplay was explored by gene silencing. ASCs from VAT and SAT confirmed their mesenchymal stem cell (MSC) phenotype expressing the specific MSC markers CD90, CD105, NANOG, SOX2 and OCT4. NANOG silencing induced a significant OCT4 (70 ± 0.05%) and SOX2 (75 ± 0.03%) downregulation, whereas SOX2 silencing did not affect NANOG gene expression. Adipose tissue is an important source of MSC, and siRNA experiments endorse a hierarchical role of NANOG in the complex transcription network that regulates pluripotency.
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Tejido Adiposo/citología , Proteína Homeótica Nanog/metabolismo , Adulto , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteína Homeótica Nanog/genética , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismoRESUMEN
Inhibitors of Apoptosis proteins (IAPs) were discovered through experiments aimed at rescuing apoptosis in insects. Classically associated with the inhibition of apoptosis, the IAP member Survivin also regulates cell cycle progression and is an essential component of the Chromosomal Passenger Complex (CPC), responsible for chromosomal segregation. Although undetectable in most adult tissues, Survivin is expressed in Adult Stem Cells (ASCs) and plays a crucial role in their maintenance. Survivin is overexpressed in most cancers, contributing to their clonal expansion. As a result, it has been proposed as a possible anticancer target for nearly two decades. In this discussion, we will explore the rationale behind Survivin as a therapeutic target, focusing on common cancer types such as carcinomas, sarcomas, and leukemias. We will delve into the modulation of Survivin by cancer pro-survival cell signaling, the association between SNPs and tumorigenesis, and its regulation by miRNAs. Finally, we will compare cell growth, clonogenic capacity, and apoptosis, along with different strategies for Survivin inhibition, including gene expression and protein activity modulation.
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Neoplasias , Survivin , Humanos , Survivin/metabolismo , Survivin/genética , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Animales , Proteínas Inhibidoras de la Apoptosis/metabolismo , Proteínas Inhibidoras de la Apoptosis/genética , Apoptosis , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
OBJECTIVE: Adrenal insufficiency (AI) is characterized by increased mortality compared to general population, mainly due to cardiovascular disease. Conventional glucocorticoid (GC) replacement therapy has a role in determining the increased mortality risk. Primary outcome of the current study was to evaluate the impact of 10 years of conventional GCs and DR-HC on body weight changes in treatment-naïve patients with AI. Secondary outcomes were changes from baseline to 5 and 10 years in anthropometric and metabolic profile, insulin sensitivity, cardiovascular and bone parameters. DESIGN AND METHODS: We prospectively randomised 42 patients to conventional GCs (cortisone acetate or hydrocortisone) and 44 to DR-HC (1:1). Anthropometric, metabolic, cardiovascular and bone parameters were evaluated at baseline and after 5 and 10 years of follow-up. This trial is registered at ClinicalTrials.gov NCT06260462. RESULTS: At 10 years of follow-up, patients with conventional GCs had significantly higher values ââof BMI (p=0.031), waist circumference (p=0.047), systolic blood pressure (p=0.039), total and LDL cholesterol (p=0.041 and p=0.042), HbA1c (p=0.040), HOMA-IR (p=0.006), AUC2h of glucose (p<0.001), thickness of the interventricular septum in diastole and of the posterior wall (both p<0.001) and significantly lower values ââof oral disposition index (p=0.001) and ISI-Matsuda (p<0.001), lumbar spine T score (p=0.036) and femoral neck Z score (p=0.026), compared to patients treated with DR-HC. CONCLUSIONS: In patients with treatment-naïve AI, 10 years of conventional GC treatment is associated with a worsening of metabolic, insulin-sensitivity, cardiac and bone outcomes, while DR-HC had no impact on them achieving a lower risk of developing comorbidities.
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Molecular imaging of muscle-invasive bladder cancer (MBC) is restricted to its locoregional and distant metastases, since most radiopharmaceuticals have a urinary excretion that limits the visualization of the primary tumor. 64CuCl2 , a positron-emitting radiotracer with nearly exclusive biliary elimination, could be well suited to exploring urinary tract neoplasms. In this study, we evaluated the feasibility of 64CuCl2-based staging of patients with MBC; furthermore, we compared the diagnostic capability of this method with those of the current gold standards, that is, contrast-enhanced CT (ceCT) and 18F-FDG PET/CT. Methods: We prospectively enrolled patients referred to our institution for pathology-confirmed MBC staging/restaging between September 2021 and January 2023. All patients underwent ceCT, 18F-FDG, and 64CuCl2 PET/CT within 2 wk. Patient-based analysis and lesion-based analysis were performed for all of the potentially affected districts (overall, bladder wall, lymph nodes, skeleton, liver, lung, and pelvic soft tissue). Results: Forty-two patients (9 women) were enrolled. Thirty-six (86%) had evidence of disease, with a total of 353 disease sites. On patient-based analysis, ceCT and 64CuCl2 PET/CT showed higher sensitivity than 18F-FDG PET/CT in detecting the primary tumor (P < 0.001); moreover, 64CuCl2 PET/CT was slightly more sensitive than 18F-FDG PET/CT in disclosing soft-tissue lesions (P < 0.05). Both PET methods were more specific and accurate than ceCT in classifying nodal lesions (P < 0.05). On lesion-based analysis, 64CuCl2 PET/CT outperformed 18F-FDG PET/CT and ceCT in detecting disease localizations overall (P < 0.001), in the lymph nodes (P < 0.01), in the skeleton (P < 0.001), and in the soft tissue (P < 0.05). Conclusion: 64CuCl2 PET/CT appears to be a sensitive modality for staging/restaging of MBC and might represent a "one-stop shop" diagnostic method in these scenarios.
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BACKGROUND: Anti-tumor vaccination is a new frontier in cancer treatment applicable to immunogenic neoplasms such as prostate and renal cancers. GX301 is a vaccine constituted by four telomerase peptides and two adjuvants, Montanide ISA-51 and Imiquimod. OBJECTIVE: The aim of this study was to analyze safety and tolerability of GX301 in an open-label, phase I/II trial. Immunological and clinical responses were also evaluated as secondary endpoints. EXPERIMENTAL DESIGN: GX301 was administered by intradermally injecting 500 µg of each peptide (dissolved in Montanide ISA-51) in the skin of the abdomen. Imiquimod was applied as a cream at the injection sites. The protocol included 8 administrations at days 1, 3, 5, 7, 14, 21, 35, 63. Eligible patients were affected with stage IV prostate or renal cancer resistant to conventional treatments. Patients were clinically and immunologically monitored up to 6 months from the first immunization. RESULTS: No grade 3-4 adverse events were observed. Evidence of vaccine-specific immunological responses was detected in 100 % of patients. Disease stabilization occurred in 4 patients. Prolonged progression-free survival and overall survival were observed in patients showing a full pattern of vaccine-specific immunological responses. CONCLUSION: GX301 demonstrated to be safe and highly immunogenic. Further studies are needed to determine its clinical efficacy.
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Vacunas contra el Cáncer/administración & dosificación , Neoplasias Renales/inmunología , Neoplasias Renales/terapia , Péptidos/administración & dosificación , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/terapia , Adyuvantes Inmunológicos , Anciano , Anciano de 80 o más Años , Aminoquinolinas/inmunología , Antígenos de Neoplasias/química , Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Proliferación Celular , Terapia Combinada , Citotoxicidad Inmunológica , Humanos , Imiquimod , Interferón gamma/metabolismo , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Manitol/análogos & derivados , Manitol/inmunología , Persona de Mediana Edad , Estadificación de Neoplasias , Ácidos Oléicos/inmunología , Péptidos/efectos adversos , Péptidos/inmunología , Fenotipo , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Telomerasa/química , Telomerasa/inmunología , Resultado del TratamientoRESUMEN
Prostate cancer still represents one of the most frequent cancers and causes of death worldwide, despite the huge therapeutic advances in the last decades. The introduction into clinical practice of prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) has significantly improved diagnostic capacity, allowing for the identification of lesions previously undetectable. The case we are presenting is about a 90-year-old man affected by metastatic prostate cancer and treated with hormonal therapies. At the second progression, the restaging with PSMA PET/CT pointed out a millimetric cardiac intra-atrial metastasis, on which little/scarce literature data are still available. On one hand, this finding confirms the high sensitivity of this technique, which should be preferred over traditional imaging. On the other hand, it suggests that introducing next-generation imaging into clinical practice may provide novel insights about prostate cancer metastatic spread.
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Introduction: The onset of precision medicine has led to the integration of traditional morphologic tissues evaluation with biochemical and molecular data for a more appropriate pathological diagnosis. The preanalytic phase and, particularly, timing of cold ischemia are crucial to guarantee high-quality biorepositories of formalin-fixed paraffin-embedded (FFPE) tissues for patients' needs and scientific research. However, delayed fixation using the gold-standard and carcinogenic fixative neutral-buffered formalin (NBF) can be a significant limitation to diagnosis and biopathological characterization. HistoCold (patented; Bio-Optica Milano S.p.A., Milano, Italy) is a nontoxic, stable, and refrigerated preservative solution for tissue handling. This study examined HistoCold's potential role in improving the preanalytic phase of the pathological diagnostic process. Materials and Methods: Breast, lung, or colorectal cancers (20, 25, and 10 cases, respectively) that were to be surgically resected were recruited between 2019 and 2021. Once specimens were surgically removed, three residual samples for each patient were first promptly immersed into HistoCold for 24, 48, and 72 hours and then FFPE. These were compared with routine specimens regarding morphologic features (hematoxylin and eosin) and tissue antigenicity (immunohistochemical stains). Results: Good concordance regarding both the morphologic characteristics of the neoplasms and their proteins expression between the routine and HistoCold handled tissues were found. The tissue handling with the solution never affected the histopathological diagnosis. Conclusions: The use of HistoCold for samples transporting is easy, allows for improving the management of cold ischemia time, and monitoring the fixation times in NBF, resulting in good quality tissue blocks for biobanking. Moreover, it could be a candidate to eliminate formalin from operating theaters. HistoCold looks very promising for the preanalytic phase of human tissues handling in the era of precision medicine, to provide the best service to patients, and to scientific research.
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Bancos de Muestras Biológicas , Formaldehído , Humanos , Fijación del Tejido/métodos , Fijadores , Hematoxilina , Adhesión en ParafinaRESUMEN
The superior diagnostic accuracy of [68Ga]Ga-prostate-specific membrane antigen-11 (PSMA) ([68Ga]Ga-PSMA-11) compared to [18F]F-Fluorocholine Positron Emission Tomography/Computed Tomography (PET/CT) in Prostate Cancer (PCa) is established. However, it is currently unclear if the added diagnostic accuracy actually translates into improved clinical outcomes in oligometastatic PCa patients treated with [68Ga]Ga-PSMA-11 PET-guided metastasis-directed therapy (MDT). The present study aimed to assess the impact of these two imaging techniques on Progression-Free Survival (PFS) in a real-world sample of oligometastatic PCa patients submitted to PET-guided MDT. Thirty-seven oligometastatic PCa patients treated with PET-guided MDT were retrospectively enrolled. MDT was guided by [18F]F-Fluorocholine PET/CT in eleven patients and by [68Ga]Ga-PSMA-11 PET/CT in twenty-six. Progression was defined as biochemical recurrence (BR), radiological progression at subsequent PET/CT imaging, clinical progression, androgen deprivation therapy initiation, or death. Clinical and imaging parameters were assessed as predictors of PFS. [18F]F-Fluorocholine PET-guided MDT was associated with significantly lower PFS compared to the [68Ga]Ga-PSMA-11 group (median PFS, mPFS 15.47 months, 95% CI: 4.13−38.00 vs. 40.93 months, 95% CI: 40.93−40.93, respectively; p < 0.05). Coherently, the radiotracer used for PET-guided MDT resulted in predictive PFS at the univariate analysis, as well as the castration-resistant status at the time of MDT and the PSA nadir after MDT. However, in the multivariate analysis, castration resistance and PSA nadir after MDT remained the sole independent predictors of PFS. In conclusion, in the present proof-of-concept study, [68Ga]Ga-PSMA-11 provided higher PFS rates than [18F]F-Fluorocholine imaging in oligometastatic PCa patients receiving PET-guided MDT. Although preliminary, this finding suggests that enlarging the "tip of the iceberg", by detecting a major proportion of the submerged disease thanks to next-generation imaging may favourably impact the oncological outcome of oligometastatic PCa treated with MDT.
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To assess the differences between patients with normal glucose tolerance (NGT) and prediabetes/diabetes mellitus (DM) in secondary adrenal insufficiency (SAI). We cross-sectionally evaluated 102, out of a total of 140, patients with SAI, who were on hydrocortisone (HC) (n = 50) and cortisone acetate (n = 52) replacement therapy. Clinical, anthropometric, and metabolic parameters were compared in patients with NGT (n = 60) and DM (n = 42). Patients with prediabetes/DM have a more marked family history of DM (p = 0.002), BMI (p < 0.001), higher waist circumference (p < 0.001), total cholesterol (p = 0.012), LDL-cholesterol (p = 0.004), triglycerides (p = 0.031), fasting glucose (p = 0.002), fasting insulin (p = 0.035), glutamate pyruvate transaminase (p = 0.018), HOMA-IR (p = 0.039), area under curves of glucose (p = 0.001) and insulin (p = 0.002), HbA1c (p < 0.001), Visceral adiposity index (VAI) (p = 0.038) and lower ISI-Matsuda (p = 0.008) and oral disposition index (p < 0.001) than patients with NGT. Multivariate analysis showed that family history of DM and VAI are independent predictive factors for DM in patients with SAI. Family history of DM and VAI can be predictors of the development of DM in patients with SAI and need to be investigated during steroid replacement therapy. Interestingly, the type and the dose of replacement steroid do not impact on diabetes mellitus.
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Insuficiencia SuprarrenalRESUMEN
Primary cardiac lymphoma (PCL) is among the rarest heart neoplasms. Its estimated incidence is about 1%-2% among primary cardiac tumor and 0.5% of extranodal lymphoma. It usually causes heart failure, pericardial effusion, tamponade, and arrhythmias. Prognosis is poor; treatment is combined medical and surgical. We described the case of a 62-year-old male with PLC that presented with syncope and cardiac tamponade, submitted to R-CHOP therapy because of failure of surgery. Clinical state is stable 3 months after diagnosis and first chemotherapy cycle.
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BACKGROUND: Despite the survival advantage, not all metastatic renal cell carcinoma (mRCC) patients achieve a long-term benefit from immunotherapy. Moreover, the identification of prognostic biomarkers is still an unmet clinical need. METHODS: This multicenter retrospective study investigated the prognostic role of peripheral-blood inflammatory indices and clinical factors to develop a novel prognostic score in mRCC patients receiving at least second-line nivolumab. The complete blood count before the first cycle of therapy was assessed by calculating neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and systemic inflammation response index (SIRI). Clinical factors included pre-treatment International Metastatic RCC Database Consortium (IMDC) score, line of therapy, and metastatic sites. RESULTS: From October 2015 to November 2019, 571 mRCC patients received nivolumab as second- and further-line treatment in 69% and 31% of cases. In univariable and multivariable analyses all inflammatory indices, IMDC score, and bone metastases significantly correlated with overall survival (OS). The multivariable model with NLR, IMDC score, and bone metastases had the highest c-index (0.697) and was chosen for the developing of the score (Schneeweiss scoring system). After internal validation (bootstrap re-sampling), the final index (Meet-URO score) composed by NLR, IMDC score, and bone metastases had a c-index of 0.691. It identified five categories with distinctive OSs: group 1 (median OS - mOS = not reached), group 2 (mOS = 43.9 months), group 3 (mOS = 22.4 months), group 4 (mOS = 10.3 months), and group 5 (mOS = 3.2 months). Moreover, the Meet-URO score allowed for a fine risk-stratification across all three IMDC groups. CONCLUSION: The Meet-URO score allowed for the accurate stratification of pretreated mRCC patients receiving nivolumab and is easily applicable for clinical practice at no additional cost. Future steps include its external validation, the assessment of its predictivity, and its application to first-line combinations.
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Parathyroid carcinoma is one of the least frequent malignant neoplasms, diagnosis and treatment are often complex; however, the prognosis is not bad and, although recurrences are frequent, the mortality rate is low. We describe the clinical case of a 42-years-old patient, the evolution of the natural history and treatment.
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Neoplasias de las Paratiroides , Adulto , Humanos , Neoplasias de las Paratiroides/diagnóstico , Neoplasias de las Paratiroides/cirugía , PronósticoRESUMEN
BACKGROUND: In periodontal patients with jawbone resorption, the autologous bone graft is considered a "gold standard" procedure for the placing of dental prosthesis; however, this procedure is a costly intervention and poses the risk of clinical complications. Thanks to the use of adult mesenchymal stem cells, smart biomaterials, and active biomolecules, regenerative medicine and bone tissue engineering represent a valid alternative to the traditional procedures. AIMS: In the past, mesenchymal stem cells isolated from periodontally compromised gingiva were considered a biological waste and discarded during surgical procedures. This study aims to test the osteoconductive activity of FISIOGRAFT Bone Granular® and Matriderm® collagen scaffolds on mesenchymal stem cells isolated from periodontally compromised gingiva as a low-cost and painless strategy of autologous bone tissue regeneration. MATERIALS AND METHODS: We isolated human mesenchymal stem cells from 22 healthy and 26 periodontally compromised gingival biopsy tissues and confirmed the stem cell phenotype by doubling time assay, colony-forming unit assay, and expression of surface and nuclear mesenchymal stem cell markers, respectively by cytofluorimetry and real-time quantitative PCR. Healthy and periodontally compromised gingival mesenchymal stem cells were seeded on FISIOGRAFT Bone Granular® and Matriderm® scaffolds, and in vitro cell viability and bone differentiation were then evaluated. RESULTS: Even though preliminary, the results demonstrate that FISIOGRAFT Bone Granular® is not suitable for in vitro growth and osteogenic differentiation of healthy and periodontally compromised mesenchymal stem cells, which, instead, are able to grow, homogeneously distribute, and bone differentiate in the Matriderm® collagen scaffold. CONCLUSION: Matriderm® represents a biocompatible scaffold able to support the in vitro cell growth and osteodifferentiation ability of gingival mesenchymal stem cells isolated from waste gingiva, and could be employed to develop low-cost and painless strategy of autologous bone tissue regeneration.
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Developmental coordination disorder (DCD) and attention-deficit hyperactivity disorder (ADHD) are neuro-developmental disorders, starting in childhood, which can affect the planning of movements and the coordination. We investigated how and in which measure a system based on wearable inertial measurement units (IMUs) can provide an objective support to the diagnosis of motor impairments in school-aged children. The IMUs measured linear and rotational movements of 37 schoolchildren, 7-10yo, 17 patients and 20 control subjects, during the execution of motor exercises, performed under medical and psychiatric supervision, to assess different aspects of the motor coordination. The measured motor parameters showed a high degree of significance in discriminating the ADHD/DCD patients from the healthy subjects, pointing out which motor tasks are worth focusing on. So, medical doctors have a novel key lecture to state a diagnosis, gaining in objectivity with respect to the standard procedures which mainly involve subjective human judgment. Differently to other works, we propose a novel approach in terms of number of used IMUs and of performed motor tasks. Moreover, we demonstrate the meaningful parameters to be considered as more discriminant in supporting the medical diagnosis.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastornos de la Destreza Motora/diagnóstico , Instituciones Académicas , Dispositivos Electrónicos Vestibles , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Niño , Femenino , Humanos , Masculino , Destreza Motora , Trastornos de la Destreza Motora/fisiopatología , Trastornos de la Destreza Motora/psicología , MovimientoRESUMEN
The production and characterization of a double-layer scaffold, to be used as a system for the "on-demand" release of corneal limbal stem cells, are reported here. The devices used in the clinics and proposed so far in the scientific literature, for the release of corneal stem cells in the treatment of limbal stem cell deficiency, cannot control the in vivo space-time release of cells as the biomaterial of which they are composed is devoid of the stimuli-responsive feature. Our approach was to produce a scaffold composed of two different polymeric layers that give the device the appropriate mechanical properties to be placed on the ocular surface and the possibility of releasing the stem cells following a noninvasive and cell-friendly treatment. This device consists of an electrospun microfibrillar scaffold of poly-l-lactic acid coated by a polymeric film based on an amphiphilic derivative of hyaluronic acid sensitive to the ionic strength of the external medium and to the presence of a complexing agent. The latter represents the "sacrificial" cell containing layer of the scaffold that can be dissolved "on demand" by the treatment with a solution of cyclodextrins. The rapid removal of the external polymeric film from the device is exploited to control the space-time release of the cells. In vitro and ex vivo experiments showed that fibroblast-like limbal stem cells cultured on the scaffold without the use of the feeder layer maintained their characteristics of stem cells and can be released "on demand" on the culture well coated with Matrigel or on the decellularized bovine cornea, respectively.