BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are relatively rare but rank as the second most common pancreatic neoplasm. They can be functional, causing early metabolic disturbances due to hormone secretion, or non-functional and diagnosed later based on tumor size-related symptoms. Recent diagnoses of PNETs under 2 cm in size have sparked debates about their management; some practitioners advocate for surgical removal and others suggest observation due to the tumors' lower potential for malignancy. However, it is unclear whether managing these small tumors expectantly is truly safe. AIM: To evaluate poor prognostic factors in PNETs based on tumor size (> 2 cm or < 2 cm) in surgically treated patients. METHODS: This cohort study included 64 patients with PNETs who underwent surgical resection between 2006 and 2019 at a high-complexity reference hospital in Medellín, Colombia. To assess patient survival, quarterly follow-ups were conducted during the first year after surgery, followed by semi-annual consultations at the hospital's hepatobiliary surgery department. Qualitative variables were described using absolute and relative frequencies, and quantitative variables were expressed using measures of central tendency and their corresponding measures of dispersion. RESULTS: The presence of lymph node involvement, neural involvement, and lymphovascular invasion were all associated with an increased risk of mortality, with hazard ratios of 5.68 (95%CI: 1.26-25.61, P = 0.024), 6.44 (95%CI: 1.43-28.93, P = 0.015), and 24.87 (95%CI: 2.98-207.19, P = 0.003), respectively. Neural involvement and lymphovascular invasion were present in tumors smaller than 2 cm in diameter and those larger than 2 cm in diameter. The recurrence rates between the two tumor groups were furthermore similar: 18.2% for tumors smaller than 2 cm and 21.4% for tumors larger than 2 cm. Patient survival was additionally comparable between the two tumor groups. CONCLUSION: Tumor size does not dictate prognosis; lymph node and lymphovascular involvement affect mortality, which highlights that histopathological factors-rather than tumor size-may play a role in management.
OBJECTIVE: The aim of this study was to detect and compare the tissular expression of neutrophil extracellular traps (NETs) in peri-implant and periodontal samples of patients with peri-implantitis, periodontitis, and controls. MATERIALS AND METHODS: An observational study was performed on patients with peri-implantitis, periodontitis, and controls. Peri-implant and/or periodontal clinical examinations were performed on each participant. Tissue samples were collected during tooth/implant extraction for clinical reasons. Electron microscopy analysis, Picro-Sirius red staining, immunohistochemical (CD15), and immunofluorescence (citrullinated H3 and myeloperoxidase) techniques were performed to detect NET-related structures and the degree of connective tissue destruction, between the study groups. RESULTS: Sixty-four patients were included in the study: 28 peri-implantitis, 26 periodontitis, and 10 controls, with a total of 51 implants, 26 periodontal teeth, and 10 control teeth. Neutrophil release of nuclear content was observed in transmission electron microscopy. Immunohistochemical analysis showed a greater CD15 expression in both peri-implantitis and periodontitis compared to controls (p < 0.001), and peri-implantitis presented lower levels of connective tissue and collagen compared to both periodontitis (p = 0.044; p < 0.001) and controls (p < 0.001). Immunofluorescence showed greater citH3 expression in peri-implantitis than the one found in both periodontitis (p = 0.003) and controls (p = 0.048). CONCLUSIONS: A greater presence and involvement of neutrophils, as well as a greater connective tissue destruction were observed in cases of peri-implantitis. A higher expression of NET-related markers was found in mucosal samples of peri-implantitis compared to periodontitis and controls.
OBJECTIVES: The aim of this narrative review is to describe the emerging evidence concerning etiological factors and pathophysiological mechanisms involved in peri-implant inflammatory diseases. MATERIAL AND METHODS: An electronic search for articles published until November 2022 was conducted in MEDLINE by three independent reviewers to identify manuscripts reporting data on etiological factors and pathophysiological mechanisms associated with peri-implant diseases. RESULTS: Current evidence suggests that peri-implant mucositis and peri-implantitis are inflammatory conditions linked to a microbial challenge. However, in recent years, there has been increasing evidence indicating that certain peri-implant inflammatory conditions may not be primarily related to biofilm-mediated infectious processes but rather to other biological mechanisms, such as a foreign body response. CONCLUSION: The current evidence, not only in the dental literature, opens new avenues for a more complex interpretation of the etiopathogenetic factors involved in peri-implant diseases. A better understanding of various factors related to the host response, including dysbiosis mechanisms associated with changes in microbiota composition, is necessary for a more precise physiopathological characterization of these diseases.
Introducción: El desarrollo e investigación de nuevas tecnologías para la identificación de microorganismos, ha permitido la identificación de microorganismos hasta ahora desconocidos. Auritidibacter ignavus es un bacilo grampositivo recientemente descrito, posiblemente asociado con la otitis, aunque su papel como patógeno ótico actualmente es controvertido.Métodos: Presentamos 2 casos de otitis recurrente en pacientes pediátricos en los que se aisló A. ignavus, y revisamos los casos previos descritos en la literatura. Resultados: Todos los aislamientos fueron identificados como A. ignavus por métodos proteómicos y genómicos. En ambos pacientes se resolvieron los síntomas clínicos. Conclusión: A. ignavus se recuperó de las secreciones del oído de los pacientes pediátricos con problemas crónicos del oído. Todos los casos descritos previamente en la literatura eran adultos. Es necesaria más evidencia para asociar A. ignavus con la enfermedad ótica, ya que los datos sobre esta especie aún son escasos.(AU)
Introduction: The development and research of new technologies for identifying microorganisms, has allowed the identification of hitherto unknown bacteria. Auritidibacter ignavus is a newly described Gram-positive rod possibly associated with otitis, although its role as an etiologic agent in otitis is currently controversial. Methods: We report two cases of recurrent otitis in paediatric patients in which A. ignavus was isolated and review the previous cases reported in the literature. Results: All the isolates were identified as A. ignavus by proteomic and genomic methods. Both patients recovered from their symptoms. Conclusion: A. ignavus was recovered from ear discharges of paedriatic patients with chronic ear problems. All the cases previously reported in the literature were adults. More evidence is needed for the association between A. ignavus and otitis, since data regarding this species are still scarce.(AU)
Humans , Male , Female , Child , Otitis , Mass Spectrometry , Micrococcaceae , Proteomics
Invasive species significantly impact biodiversity and ecosystem services, yet understanding these effects at large spatial scales remains a challenge. Our study addresses this gap by assessing the current and potential future risks posed by 94 invasive species to seven key ecosystem services in Europe. We demonstrate widespread potential impacts, particularly on outdoor recreation, habitat maintenance, crop provisioning, and soil and nitrogen retention. Exposure to invasive species was higher in areas with lower provision of ecosystem services, particularly for regulating and cultural services. Exposure was also high in areas where ecosystem contributions to crop provision and nitrogen retention were at their highest. Notably, regions vital for ecosystem services currently have low invasion suitability, but face an average 77% increase in potential invasion area. Here we show that, while high-value ecosystem service areas at the highest risk represent a small fraction of Europe (0-13%), they are disproportionally important for service conservation. Our study underscores the importance of monitoring and protecting these hotspots to align management strategies with international biodiversity targets, considering both invasion vulnerability and ecosystem service sustainability.
Ecosystem , Introduced Species , Biodiversity , Conservation of Natural Resources , Europe , Nitrogen , Animals
PURPOSE: To compare giredestrant and physician's choice of endocrine monotherapy (PCET) for estrogen receptor-positive, HER2-negative, advanced breast cancer (BC) in the phase II acelERA BC study (ClinicalTrials.gov identifier: NCT04576455). METHODS: Post-/pre-/perimenopausal women, or men, age 18 years or older with measurable disease/evaluable bone lesions, whose disease progressed after 1-2 lines of systemic therapy (≤1 targeted, ≤1 chemotherapy regimen, prior fulvestrant allowed) were randomly assigned 1:1 to giredestrant (30 mg oral once daily) or fulvestrant/aromatase inhibitor per local guidelines (+luteinizing hormone-releasing hormone agonist in pre-/perimenopausal women, and men) until disease progression/unacceptable toxicity. Stratification was by visceral versus nonvisceral disease, prior cyclin-dependent kinase 4/6 inhibitor, and prior fulvestrant. The primary end point was investigator-assessed progression-free survival (INV-PFS). RESULTS: At clinical cutoff (February 18, 2022; median follow-up: 7.9 months; N = 303), the INV-PFS hazard ratio (HR) was 0.81 (95% CI, 0.60 to 1.10; P = .1757). In the prespecified secondary end point analysis of INV-PFS by ESR1 mutation (m) status in circulating tumor DNA-evaluable patients (n = 232), the HR in patients with a detectable ESR1m (n = 90) was 0.60 (95% CI, 0.35 to 1.03) versus 0.88 (95% CI, 0.54 to 1.42) in patients with no ESR1m detected (n = 142). Related grade 3-4 adverse events (AEs), serious AEs, and discontinuations due to AEs were balanced across arms. CONCLUSION: Although the acelERA BC study did not reach statistical significance for its primary INV-PFS end point, there was a consistent treatment effect with giredestrant across most key subgroups and a trend toward favorable benefit among patients with ESR1-mutated tumors. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks. Overall, these data support the continued investigation of giredestrant in other studies.
As CDK4/6 inhibitor (CDK4/6i) approval changed treatment strategies for patients with hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer (BC), understanding how exposure to CDK4/6i affects the tumor genomic landscape is critical for precision oncology. Using real-world data (RWD) with tumor genomic profiling from 5910 patients with metastatic HR+/HER2- BC, we investigated the evolution of alteration prevalence in commonly mutated genes across patient journeys. We found that ESR1 is more often altered in tumors exposed to at least 1 year of adjuvant endocrine therapy, contrasting with TP53 alterations. We observed a similar trend after first-line treatments in the advanced setting, but strikingly exposure to aromatase inhibitors (AI) combined with CDK4/6i led to significantly higher ESR1 alteration prevalence compared to AI alone, independent of treatment duration. Further, CDK4/6i exposure was associated with higher occurrence of concomitant alterations in multiple oncogenic pathways. Differences based on CDK4/6i exposure were confirmed in samples collected after 2L and validated in samples from the acelERA BC clinical trial. In conclusion, our work uncovers opportunities for further treatment personalization and stresses the need for effective combination treatments to address the altered tumor genomic landscape following AI+CDK4/6i exposure. Further, we demonstrated the potential of RWD for refining patient treatment strategy and guiding clinical trial design.
PURPOSE: Giredestrant is a potent, orally bioavailable, small-molecule selective estrogen receptor antagonist and degrader (SERD) that is being developed for the treatment of patients with estrogen receptor (ER)-positive breast cancer. In vitro, giredestrant was primarily metabolized by UGT1A4. The goal of this study was to investigate if UGT1A4 polymorphism had a clinically relevant impact on giredestrant exposure. METHODS: Genotyping and pharmacokinetic data were obtained from 118 and 61 patients in two clinical studies, GO39932 [NCT03332797] and acelERA Breast Cancer [NCT04576455], respectively. RESULTS: The overall allelic frequencies of UGT1A4*2 and UGT1A4*3 were 3.3% and 11%, respectively. Giredestrant exposure was consistent between patients with wild-type UGT1A4 and UGT1A4*2 and *3 polymorphisms, with no clinically relevant difference observed. In addition, haplotype analysis indicated that no other UGT1A4 variants were significantly associated with giredestrant exposure. CONCLUSION: Therefore, this study indicates that UGT1A4 polymorphism status is unlikely a clinically relevant factor to impact giredestrant exposure and giredestrant can be administered at the same dose level regardless of patients' UGT1A4 polymorphism status.
PURPOSE: To analyze the influence of abutment height (AH) on marginal bone loss (MBL). MATERIALS AND METHODS: A literature search was performed for human studies (RCTs, prospective and retrospective cohorts) reporting on AH and MBL. The data obtained-including clinical outcomes, treatment covariates, and patient characteristics-were analyzed. Meta-regression was performed on the effect size of the differences between the shorter and larger AHs on the MBL of each study. The estimation was done using the restricted maximum likelihood method. RESULTS: The initial screening and full-text analysis resulted in 7,936 and 46 articles, respectively. Finally, 14 articles were included in the systematic review, reporting a total of 1,606 implants. An overall high-to-moderate risk of bias was determined among the included investigations. Meta-regression analysis revealed that AH had a significant effect on MBL (b = -1.630, P < .003), demonstrating that longer abutments were correlated with less MBL. No effects were observed for the study type (P = .607), the number of stages (P = .510), or the elapsed time (P = .491). CONCLUSIONS: The height of the abutment has a significant impact on MBL. As such, increased AH is related to less MBL. Nevertheless, the role of confounding variables remains to be studied and determined.
Alveolar Bone Loss , Dental Implants , Humans , Dental Implants/adverse effects , Dental Implantation, Endosseous/methods , Retrospective Studies , Prospective Studies , Alveolar Bone Loss/etiology
The activation of inflammasomes is thought to induce the inflammatory process around dental implants. No information is available on the correlation between microbiota and inflammasomes in clinical samples from patients suffering peri-implantitis. For this cross-sectional study, 30 biofilm samples were obtained from 19 patients undergoing surgical treatment for peri-implantitis because of the presence of bleeding on probing, probing depth higher than 6 mm, and radiographic bone loss higher than 3 mm. Then, soft tissue samples from around the implant were also collected. The relative abundance of bacteria and alpha-diversity indexes were calculated after analyzing the 16S rRNA gene using next-generation sequencing. The soft-tissue samples were processed for evaluation of the inflammasomes NLRP3 and AIM2 as well as caspase-1 and IL-1ß. The relative abundance (mean (SD)) of specific species indicated that the most abundant species were Porphyromonas gingivalis (10.95 (14.17)%), Fusobacterium vincentii (10.93 (13.18)%), Porphyromonas endodontalis (5.89 (7.23)%), Prevotella oris (3.88 (4.94)%), Treponema denticola (2.91 (3.19)%), and Tannerella forsythia (2.84 (4.15)%). Several correlations were found between the species and the immunohistochemical detection of the inflammasomes NLRP3 and AIM2 as well as caspase-1 and IL-1ß, both in the epithelium and the lamina propria. A network analysis found an important cluster of variables formed by NLRP3 in the lamina propria and AIM2, caspase-1, and IL-1ß in the lamina propria and the epithelium with Prevotella dentalis, Prevotella tannerae, Tannerella forsythia, or Selenomonas timonae. Thus, it could be concluded that inflammasomes NLRP3 and AIM2 and their downstream effectors caspase-1 and interleukin-1ß can be significantly associated with specific bacteria.
Microbiota , Peri-Implantitis , Humans , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Cross-Sectional Studies , RNA, Ribosomal, 16S , Caspase 1
Seawater desalination by reverse osmosis is growing exponentially due to water scarcity. Byproducts of this process (e.g. brines), are generally discharged directly into the coastal ecosystem, causing detrimental effects, on benthic organisms. Understanding the cellular stress response of these organisms (biomarkers), could be crucial for establishing appropriate salinity thresholds for discharged brines. Early stress biomarkers can serve as valuable tools for monitoring the health status of brine-impacted organisms, enabling the prediction of long-term irreversible damage caused by the desalination industry. In this study, we conducted laboratory-controlled experiments to assess cellular and molecular biomarkers against brine exposure in two salinity-sensitive Mediterranean seagrasses: Posidonia oceanica and Cymodocea nodosa. Treatments involved exposure to 39, 41, and 43 psu, for 6 h and 7 days. Results indicated that photosynthetic performance remained unaffected across all treatments. However, under 43 psu, P. oceanica and C. nodosa exhibited lipid oxidative damage, which occurred earlier in P. oceanica. Additionally, P. oceanica displayed an antioxidant response at higher salinities by accumulating phenolic compounds within 6 h and ascorbate within 7 d; whereas for C. nodosa the predominant antioxidant mechanisms were phenolic compounds accumulation and total radical scavenging activity, which was evident after 7 d of brines exposure. Finally, transcriptomic analyses in P. oceanica exposed to 43 psu for 7 days revealed a poor up-regulation of genes associated with brassinosteroid response and abiotic stress response, while a high down-regulation of genes related to primary metabolism was detected. In C. nodosa, up-regulated genes were involved in DNA repair, cell cycle regulation, and reproduction, while down-regulated genes were mainly associated with photosynthesis and ribosome assembly. Overall, these findings suggest that 43 psu is a critical salinity-damage threshold for both seagrasses; and despite the moderate overexpression of several transcripts that could confer salt tolerance, genes involved in essential biological processes were severely downregulated.
Alismatales , Ecosystem , Salts , Antioxidants/metabolism , Alismatales/physiology , Gene Expression Profiling , Mediterranean Sea
INTRODUCTION: The development and research of new technologies for identifying microorganisms, has allowed the identification of hitherto unknown bacteria. Auritidibacter ignavus is a newly described Gram-positive rod possibly associated with otitis, although its role as an etiologic agent in otitis is currently controversial. METHODS: We report two cases of recurrent otitis in paediatric patients in which A. ignavus was isolated and review the previous cases reported in the literature. RESULTS: All the isolates were identified as A. ignavus by proteomic and genomic methods. Both patients recovered from their symptoms. CONCLUSION: A. ignavus was recovered from ear discharges of paedriatic patients with chronic ear problems. All the cases previously reported in the literature were adults. More evidence is needed for the association between A. ignavus and otitis, since data regarding this species are still scarce.
Micrococcaceae , Otitis , Adult , Humans , Child , Patient Discharge , Proteomics
INTRODUCTION: Insulin-like growth factor-II messenger RNA-binding protein-3 (IMP3) over-expression is a predictor of tumor recurrence and metastases in some types of human melanoma. Our objective was to evaluate the immunohistochemical expression of IMP3 and other molecules related to tumor prognosis in melanoma-xeno-tumors undergoing treatment. We test the effect of radiotherapy (RT) and mesenchymal stromal cells (MSCs) treatment, analyzing the tumorigenic and metastatsizing capacity in a mice melanoma xenograft model. MATERIALS AND METHODS: We inoculated A375 and G361 human melanoma cell lines into NOD/SCID gamma mice (n = 64). We established a control group, a group treated with MSCs, a group treated with MSCs plus RT, and a group treated with RT. We assessed the immunohistochemical expression of IMP3, E-cadherin, N-cadherin, PARP1, HIF-1α, and the proliferation marker Ki-67. Additionally, we performed a retrospective study including 114 histological samples of patients diagnosed with malignant cutaneous superficial spreading melanoma (n = 104) and nodular melanoma (n = 10) with at least 5 years of follow-up. RESULTS: Most morphological and immunohistochemical features show statistically significant differences between the 2 cell lines. The A375 cell line induced the formation of metastases, while the G361 cell line provoked tumor formation but not metastases. All three treatments reduced the cell proliferation evaluated by the Ki-67 nuclear antigen (p = 0.000, one-way ANOVA test) and reduced the number of metastases (p = 0.004, one-way ANOVA test). In addition, the tumor volumes reduced in comparison with the control groups, 31.74% for RT + MSCs in the A357 tumor cell line, and 89.84% RT + MSCs in the G361 tumor cell line. We also found that IMP3 expression is associated with greater tumor aggressiveness and was significantly correlated with cell proliferation (measured by the expression of Ki-67), the number of metastases, and reduced expression of adhesion molecules. CONCLUSIONS: The combined treatment of RT and MSCs on xenografted melanomas reduces tumor size, metastases frequency, and the epithelial to mesenchymal transition/PARP1 metastatic phenotype. This treatment also reduces the expression of molecules related to cellular proliferation (Ki-67), molecules that facilitate the metastatic process (E-cadherin), and molecules related with prognosis (IMP3).
Melanoma , Skin Neoplasms , Animals , Mice , Humans , Ki-67 Antigen , Retrospective Studies , Heterografts , Epithelial-Mesenchymal Transition , Mice, Inbred NOD , Mice, SCID , Cell Line, Tumor , Cadherins , Biomarkers, Tumor/metabolism
OBJECTIVE: The aim of this study was to analyze the effects of periodontal treatment on markers of atherosclerotic coronary artery disease and circulating levels of periostin. BACKGROUND: Periostin is necessary for periodontal stability, but it is highly present in atherosclerotic plaques. Treatment of periodontal disease, with low levels of local periostin, is thought to reduce systemic levels of periostin. Thus, this may contribute to cardiovascular health. METHODS: A pilot randomized controlled clinical trial was designed to include patients with severe periodontal disease and history of atherosclerotic coronary artery disease. Samples of gingival crevicular fluid (GCF) and serum were collected before and after periodontal treatment by periodontal surgery or non-surgical therapy. The levels of several markers of inflammation and cardiovascular damage were evaluated including CRP, IFN-γ, IL-1ß, IL-10, MIP-1α, periostin, and TNF-α in GCF and CRP, Fibrinogen, IFN-γ, IL-1ß, IL-6, IL-10, L-Selectin, MIP-1α, Periostin, TNF-α, and vWF in serum. RESULTS: A total of 22 patients with an average of 56 years old were recruited for participating in this study. Twenty of them were male. Most of them (82%) had suffered an acute myocardial event and underwent surgery for placing 1, 2, or 3 stents in the coronary arteries more than 6 months ago but less than 1 year. The treatment of periodontal disease resulted in an overall improvement of all periodontal parameters. Regarding the evaluation of GCF and serum, a significant increase of periostin in the GCF was observed after periodontal surgery. In contrast, although other markers in GCF and serum improved, no significant correlations were found. CONCLUSION: Treatment of periodontal disease through periodontal surgery induces a local and transient increase in the levels of periostin in the gingival crevicular fluid. The effects on systemic markers of inflammation and cardiovascular function have not been confirmed.
Biomarkers , Cell Adhesion Molecules , Coronary Artery Disease , Gingival Crevicular Fluid , Periodontal Diseases , Humans , Male , Pilot Projects , Middle Aged , Female , Cell Adhesion Molecules/analysis , Cell Adhesion Molecules/blood , Cell Adhesion Molecules/metabolism , Coronary Artery Disease/surgery , Coronary Artery Disease/complications , Gingival Crevicular Fluid/chemistry , Gingival Crevicular Fluid/metabolism , Biomarkers/analysis , Biomarkers/blood , Periodontal Diseases/metabolism , Periodontal Diseases/complications , Interleukin-10/analysis , Interleukin-10/blood , C-Reactive Protein/analysis , Interferon-gamma/analysis , Interferon-gamma/blood , Aged , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/metabolism , Interleukin-1beta/analysis , Interleukin-1beta/blood , Interleukin-1beta/metabolism , Periostin
In December 2022 the US Food and Drug Administration (FDA) removed the requirement that drugs in development must undergo animal testing before clinical evaluation, a declaration that now demands the establishment and verification of ex vivo preclinical models that closely represent tumor complexity and that can predict therapeutic response. Fortunately, the emergence of patient-derived organoid (PDOs) culture has enabled the ex vivo mimicking of the pathophysiology of human tumors with the reassembly of tissue-specific features. These features include histopathological variability, molecular expression profiles, genetic and cellular heterogeneity of parental tissue, and furthermore growing evidence suggests the ability to predict patient therapeutic response. Concentrating on the highly lethal and heterogeneous gastrointestinal (GI) tumors, herein we present the state-of-the-art and the current methodology of PDOs. We highlight the potential additions, improvements and testing required to allow the ex vivo of study the tumor microenvironment, as well as offering commentary on the predictive value of clinical response to treatments such as chemotherapy and immunotherapy.
Gastrointestinal Neoplasms , United States , Animals , Humans , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/metabolism , Organoids/metabolism , Organoids/pathology , Tumor Microenvironment
This paper investigates the hemp limecrete mechanical and microstructural performance of a new sustainable and environmental friendly building material. Several studies have investigated the hemp limecrete focusing on the non-structural applications. The newly developed hemp limecrete consists of high mechanical and microstructural properties. The specimens were prepared with varying lengths and proportions of hemp fibers with lime and tested for compressive strength, flexural strength, thermal conductivity and microstructural analysis like SEM and EDS. The study found that the optimal fiber content for making mortars was between 2 and 4%. This conclusion was reached after analyzing the influence of fiber length and ratio on the properties of the mortars. The dry unit weight decreased when the fiber content was higher than 4%. In terms of strength, the study found that the flexural strength of the hemp limecrete improved with an increase in fiber ratio, but the compressive strength decreased. However, with 2% hemp fiber, compressive strengths of 3.48 MPa and above were obtained. The study also highlighted the good thermal insulation properties and dimensional stability of hemp limecrete. These findings have important implications for the use of hemp limecrete as a sustainable building material. The results suggest that hemp limecrete has the potential to be a viable alternative to conventional concrete in specific applications, particularly in areas where environmental sustainability is a priority.
PURPOSE: We describe the clinical pharmacology characterization of giredestrant in a first-in-human study. EXPERIMENTAL DESIGN: This phase Ia/Ib dose-escalation/-expansion study (NCT03332797) evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of giredestrant in estrogen receptor-positive HER2-negative locally advanced/metastatic breast cancer. The single-agent dose-escalation stage evaluated giredestrant 10, 30, 90, or 250 mg once daily. The dose-expansion stage evaluated single-agent giredestrant at 30, 100, and 250 mg once daily. Dose-escalation and -expansion phases also evaluated giredestrant 100 mg combined with palbociclib 125 mg. RESULTS: Following single-dose oral administration, giredestrant was rapidly absorbed and generally showed a dose-proportional increase in exposure at doses ranging from 10 to 250 mg. At the 30 mg clinical dose, maximum plasma concentration was 266 ng/mL (50.1%) and area under the concentration-time curve from 0 to 24 hours at steady state was 4,320 ng·hour/mL (59.4%). Minimal giredestrant concentrations were detected in urine, indicating that renal excretion is unlikely to be a major elimination route for giredestrant. Mean concentration of 4beta-hydroxycholesterol showed no apparent increase over time at both the clinical dose (30 mg) and a supratherapeutic dose (90 mg), suggesting that giredestrant may have low CYP3A induction potential in humans. No clinically relevant drug-drug interaction was observed between giredestrant and palbociclib. Giredestrant exposure was not affected by food and was generally consistent between White and Asian patients. CONCLUSIONS: This study illustrates how the integration of clinical pharmacology considerations into early-phase clinical trials can inform the design of pivotal studies and accelerate oncology drug development. SIGNIFICANCE: This work illustrates how comprehensive clinical pharmacology characterization can be integrated into first-in-human studies in oncology. It also demonstrates the value of understanding clinical pharmacology attributes to inform eligibility, concomitant medications, and combination dosing and to directly influence late-stage trial design and accelerate development.
Breast Neoplasms , Pharmacology, Clinical , Humans , Female , Breast Neoplasms/drug therapy , Drug Interactions
Introducción En los estudios multicéntricos la protocolización de los datos es una fase crítica que puede generar sesgos, sobre todo en estudios clínicos con presupuesto limitado. El objetivo es analizar la concordancia y la confiabilidad de los datos obtenidos en un estudio multicéntrico clínico entre la protocolización del centro de origen y la protocolización centralizada mediante un data-manager. Método Estudio clínico multicéntrico de prevalencia nacional sobre un carcinoma familiar infrecuente, realizándose una doble protocolización de los datos: a)en el centro de origen, y b)centralizada con un data-manager. La concordancia se analiza para el global de los datos y para los dos subgrupos del proyecto: a)grupo a estudio (carcinoma familiar; protocolizan 30 investigadores) y b)grupo control (carcinoma esporádico; protocolizan 4). Las diferencias interobservador se evalúan mediante el índice de Kappa de Cohen. Resultados Se incluyen 689 pacientes: 252 del grupo a estudio y 437 del grupo control. Respecto al análisis de concordancia del estadio tumoral, se han objetivado un 2,5% de discordancias, siendo alta la concordancia entre protocolizadores (Kappa=0,931). Respecto a la valoración del riesgo de recidiva, las discordancias fueron del 7% de los casos, siendo alta la concordancia (Kappa=0,819). Respecto a la clasificación ecográfica TIRADS, las discordancias son del 6,9% y la concordancia es alta (Kappa=0,922). Se han detectado un 4,6% de errores de transcripción. Conclusiones En los estudios multicéntricos clínicos la protocolización centralizada de los datos por un data-manager parece presentar resultados similares a la protocolización directa en la base de datos en el centro de origen. (AU)
Introduction In multicenter studies, the protocolization of data is a critical phase that can generate biases. The objective is to analyze the concordance and reliability of the data obtained in a clinical multicenter study between the protocolization in the center of origin and the centralized protocolization of the data by a data-manager. Methods National multicenter clinical study about an infrequent carcinoma. A double protocolization of the data is carried out: (i)center of origin; and (ii)centralized by a data manager. The concordance between the data is analyzed for the global data and for the two groups of the project: (i)study group (familiar carcinoma, 30 researchers protocolize); (ii)control group (sporadic carcinoma, 4 people protocolize). Interobserver variability is evaluated using Cohen's kappa coefficient. Results The study includes a total of 689 patients with carcinoma: 252 in the study group and 437 in the control group. Regarding the concordance analysis of the tumor stage, 2.5% of disagreements were observed and the concordance between people who protocolize was near perfect (Kappa=0.931). Regarding the evaluation of the recurrence risk, disagreements occurred in 7% of the cases and the concordance was near perfect (Kappa=0.819). Regarding the sonography evaluation (TIRADS), the disagreements were 6.9% and the concordance was near perfect (Kappa=0.922). Also, 4.6% of transcription errors were detected. Conclusions In multicenter clinical studies, the centralized data protocolization by a data-manager seems to present similar results to the direct protocolization in the database in the center of origin. (AU)
Humans , Multicenter Studies as Topic , Carcinoma/complications , Clinical Protocols , Databases as Topic
INTRODUCTION: In multicenter studies, the protocolization of data is a critical phase that can generate biases.The objective is to analyze the concordance and reliability of the data obtained in a clinical multicenter study between the protocolization in the center of origin and the centralized protocolization of the data by a data -manager. METHODS: National multicenter clinical study about an infrequent carcinoma. A double protocolization of the data is carried out: (a) center of origin; and (b) centralized by a data manager: The concordance between the data is analyzed for the global data and for the two groups of the project: (a) study group (Familiar carcinoma, 30 researchers protocolize); (b) control group (Sporadic carcinoma, 4 people protocolize). Interobserver variability is evaluated using Cohen's kappa coefficient. RESULTS: The study includes a total of 689 patients with carcinoma, 252 in the study group and 437 in the control group. Regarding the concordance analysis of the tumor stage, 2.5% of disagreements were observed and the concordance between people who protocolize was near perfect (Kappa = 0.931). Regarding the evaluation of the recurrence risk, disagreements occurred in 7% of the cases and the concordance was near perfect (Kappa = 0.819). Regarding the sonography evaluation (TIRADS), the disagreements were 6.9% and the concordance was near perfect (Kappa = 0.922). Also, 4.6% of transcription errors were detected. CONCLUSIONS: In multicenter clinical studies, the centralized data protocolization o by a data-manager seems to present similar results to the direct protocolization in the database in the center of origin.
Carcinoma , Humans , Reproducibility of Results
MicroRNAs (miRNAs) constitute a subclass of non-coding RNAs that exert substantial influence on gene-expression regulation. Their tightly controlled expression plays a pivotal role in various cellular processes, while their dysregulation has been implicated in numerous pathological conditions, including cancer. Among cancers affecting women, breast cancer (BC) is the most prevalent malignant tumor. Extensive investigations have demonstrated distinct expression patterns of miRNAs in normal and malignant breast cells. Consequently, these findings have prompted research efforts towards leveraging miRNAs as diagnostic tools and the development of therapeutic strategies. The aim of this review is to describe the role of miRNAs in BC. We discuss the identification of oncogenic, tumor suppressor and metastatic miRNAs among BC cells, and their impact on tumor progression. We describe the potential of miRNAs as diagnostic and prognostic biomarkers for BC, as well as their role as promising therapeutic targets. Finally, we evaluate the current use of artificial intelligence tools for miRNA analysis and the challenges faced by these new biomedical approaches in its clinical application. The insights presented in this review underscore the promising prospects of utilizing miRNAs as innovative diagnostic, prognostic, and therapeutic tools for the management of BC.
