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1.
Cir Esp (Engl Ed) ; 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38705257

RESUMO

INTRODUCTION: It is currently unknown which data sources from the clinical history, or combination thereof, should be evaluated to achieve the most complete calculation of postoperative complications (PC). The objectives of this study were: to analyze the morbidity and mortality of 200 consecutive patients undergoing major surgery, to determine which data sources or combination collect the maximum morbidity, and to determine the accuracy of the morbidity reflected in the discharge report. METHODS: Observational and prospective cohort study. The sum of all PC found in the combined review of medical notes, nursing notes, and a specific form was considered the gold standard. PC were classified according to the Clavien Dindo Classification and the Comprehensive Complication Index (CCI). RESULTS: The percentage of patients who presented PC according to the gold standard, medical notes, nursing notes and form were: 43.5%, 37.5%, 35% and 18.7% respectively. The combination of sources improved CCI agreement by 8%-40% in the overall series and 39.1-89.7 % in patients with PC. The correct recording of PC was inversely proportional to the complexity of the surgery, and the combination of sources increased the degree of agreement with the gold standard by 35 %-67.5% in operations of greater complexity. The CDC and CCI of the discharge report coincided with the gold-standard values in patients with PC by 46.8% and 18.2%, respectively. CONCLUSIONS: The combination of data sources, particularly medical and nursing notes, considerably increases the quantification of PC in general, most notably in complex interventions.

2.
Infect Dis Health ; 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38735778

RESUMO

BACKGROUND: Laminar airflow filters have been suggested as a potential preventive factor for surgical site infections, given their ability to reduce the airborne microbiological load. However, their role is still unclear, and evidence regarding vascular surgery patients is scarce. Our aim was to assess the impact of laminar-airflow filters on surgical site infections. METHODS: This single-centre retrospective cohort study was conducted with vascular surgery patients who underwent arterial vascular intervention through a groin incision between July 2018 and July 2019 (turbulent airflow cohort) and July 2020 and July 2021 (laminar airflow cohort). Data were prospectively collected from electronic medical files. We estimated the cumulative incidence of surgical site infections and its 95% confident interval (95%CI). A propensity score matching analysis was performed. RESULTS: We included 200 patients, 78 in the turbulent airflow cohort and 122 in the laminar airflow cohort. The cumulative incidence was 15.4% (12/78; 95%CI: 9.0-25.0%) in the turbulent-airflow cohort and 14.8% (18/122; 95%CI: 9.5 -22.1%) in the laminar-airflow cohort (p-value: 1.00). The propensity score matching yielded a cumulative incidence of surgical site infection of 13.9% (10/72) with turbulent airflow and 12.5% (9/72) with laminar airflow (p-value: 1.00). Risk factors associated with infection were chronic kidney disease (OR 2.70; 95%CI: 1.14-6.21) and a greater body mass index (OR 1.47; 95%CI: 1.01-2.14). CONCLUSION: Laminar airflow filters were associated with a non-significant reduction of surgical site infections. Further research is needed to determine its usefulness and cost-effectiveness. Surgical site infection incidence was associated with chronic kidney disease and a greater body mass index. Hence, efforts should be made to optimize the body mass index before surgery and prevent chronic kidney disease in patients with known arterial disease.

3.
ACS Appl Bio Mater ; 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38740514

RESUMO

Magnetic separation is a promising alternative to chromatography for enhancing the downstream processing (DSP) of monoclonal antibodies (mAbs). However, there is a lack of efficient magnetic particles for successful application. Aiming to fill this gap, we demonstrate the suitability of bare iron oxide nanoparticles (BION) with physical site-directed immobilization of an engineered Protein A affinity ligand (rSpA) as an innovative magnetic material. The rSpA ligand contains a short peptide tag that enables the direct and stable immobilization onto the uncoated BION surface without commonly required laborious particle activation. The resulting BION@rSpA have beneficial characteristics outperforming conventional Protein A-functionalized magnetic particles: a simple, fast, low-cost synthesis, a particle size in the nanometer range with a large effective specific surface area enabling large immunoglobulin G (IgG) binding capacity, and a high magnetophoretic velocity advantageous for fast processing. We further show rapid interactions of IgG with the easily accessible rSpA ligands. The binding of IgG to BION@rSpA is thereby highly selective and not impeded by impurity molecules in perfusion cell culture supernatant. Regarding the subsequent acidic IgG elution from BION@rSpA@IgG, we observed a hampering pH increase caused by the protonation of large iron oxide surfaces after concentrating the particles in 100 mM sodium acetate buffer. However, the pH can be stabilized by adding 50 mM glycine to the elution buffer, resulting in recoveries above 85% even at high particle concentrations. Our work shows that BION@rSpA enable efficient magnetic mAb separation and could help to overcome emerging bottlenecks in DSP.

6.
Sci Rep ; 14(1): 4866, 2024 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-38418932

RESUMO

There is no established treatment for progressive IgA nephropathy refractory to steroids and immunosuppressant drugs (r-IgAN). Interleukin 17 (IL-17) blockade has garnered interest in immune-mediated diseases involving the gut-kidney axis. However, single IL-17A inhibition induced paradoxical effects in patients with Crohn's disease and some cases of de novo glomerulonephritis, possibly due to the complete Th1 cell response, along with the concomitant downregulation of regulatory T cells (Tregs). Seven r-IgAN patients were treated with at least six months of oral paricalcitol, followed by the addition of subcutaneous anti-IL-17A (secukinumab). After a mean follow-up of 28 months, proteinuria decreased by 71% (95% CI: 56-87), P < 0.001. One patient started dialysis, while the annual eGFR decline in the remaining patients [mean (95% CI)] was reduced by 4.9 mL/min/1.73 m2 (95% CI: 0.1-9.7), P = 0.046. Circulating Th1, Th17, and Treg cells remained stable, but Th2 cells decreased, modifying the Th1/Th2 ratio. Intriguingly, accumulation of circulating Th17.1 cells was observed. This novel sequential therapy appears to optimize renal advantages in patients with r-IgAN and elicit alterations in potentially pathogenic T helper cells.


Assuntos
Ergocalciferóis , Glomerulonefrite por IGA , Humanos , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/patologia , Interleucina-17 , Diálise Renal , Células Th17/patologia
7.
Ann Surg Oncol ; 31(3): 1615-1622, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38063989

RESUMO

BACKGROUND: The effect of lumpectomy defect repair (a level 1 oncoplastic technique) on patient-reported breast satisfaction among patients undergoing lumpectomy has not yet been investigated. METHODS: Patients undergoing lumpectomy at our institution between 2018 and 2020 with or without repair of their lumpectomy defect during index operation, comprised our study population. The BREAST-Q quality-of-life questionnaire was administered preoperatively, and at 6 months, 1 year, and 2 years postoperatively. Satisfaction and quality-of-life domains were compared between those who did and did not have closure of their lumpectomy defect, and compared with surgeon-reported outcomes. RESULTS: A total of 487 patients met eligibility criteria, 206 (42%) had their partial mastectomy defect repaired by glandular displacement. Median breast volume, as calculated from the mammogram, was smaller in patients undergoing defect closure (826 cm3 vs. 895 cm3, p = 0.006). There were no statistically significant differences in satisfaction with breasts (SABTR), physical well-being of the chest (PWB-CHEST), or psychosocial well-being (PsychWB) scores between the two cohorts at any time point. While patients undergoing defect closure had significantly higher sexual well-being (SexWB) scores compared with no closure (66 vs. 59, p = 0.021), there were no predictors of improvement in SexWB scores over time on multivariable analysis. Patients' self-reported scores positively correlated with physician-reported outcomes. CONCLUSIONS: Despite a larger lumpectomy-to-breast volume ratio among patients undergoing defect repair, satisfaction was equivalent among those whose defects were or were not repaired at 2 years postsurgery. Defect repair was associated with clinically relevant improvement in patient-reported sexual well-being.


Assuntos
Neoplasias da Mama , Mamoplastia , Humanos , Feminino , Mastectomia Segmentar/métodos , Mastectomia/métodos , Mama , Mamoplastia/métodos , Satisfação do Paciente , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida
8.
Ann Surg Oncol ; 31(2): 966-973, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37973646

RESUMO

BACKGROUND: Little is known regarding racial differences in satisfaction and quality of life (QOL) after contralateral prophylactic mastectomy (CPM). In this study, we aim to characterize associations between race, and postoperative satisfaction and well-being, utilizing the validated BREAST-Q patient-reported outcome measure. PATIENTS AND METHODS: Patients were eligible if they were diagnosed with stage 0-III unilateral breast cancer and underwent mastectomy with immediate reconstruction at our institution between 2016 and 2022. BREAST-Q surveys were administered in routine clinical care preoperatively and postoperatively to assess QOL. We assessed whether the relationship between race, and domains of satisfaction with breasts and psychosocial well-being differed by receipt of CPM compared with unilateral mastectomy at 6 months, 1 year, 2 years, and 3 years following reconstruction. RESULTS: Of 3334 women, 2040 (61%) underwent unilateral mastectomy and 1294 (39%) underwent CPM. Compared with White and Asian women who received CPM, Black women who underwent CPM were more likely to have higher BMI (p < 0.001), undergo autologous reconstruction (p = 0.006), and receive postmastectomy radiation (PMRT) (p < 0.001). There was no association between race and domains of satisfaction of breasts or psychosocial well-being for women who underwent unilateral mastectomy (p = 0.6 and p > 0.9, respectively) or CPM (p = 0.8 and p = 0.9, respectively). PMRT was negatively associated with both satisfaction with breasts (p < 0.001) and psychosocial well-being (p = 0.007). CONCLUSIONS: Differences in satisfaction with breasts and psychosocial well-being at 3-year follow-up were not associated with race but rather treatment variables, particularly the receipt of PMRT. Further investigations with a larger and more diverse population are needed to validate these findings.


Assuntos
Carcinoma de Mama in situ , Neoplasias da Mama , Mamoplastia , Mastectomia Profilática , Humanos , Feminino , Mastectomia , Mastectomia Profilática/psicologia , Qualidade de Vida , Neoplasias da Mama/cirurgia , Mamoplastia/efeitos adversos , Medidas de Resultados Relatados pelo Paciente
10.
Rev. Ciênc. Saúde ; 13(4): 46-51, Dezembro 2023.
Artigo em Inglês, Português | LILACS | ID: biblio-1526801

RESUMO

Este estudo relata um caso de flacidez abdominal após 3 gestações no qual foi utilizada a técnica de fios de polidioxanona (PDO) lisos e espiculados, técnica ainda não descrita na literatura paratratarestaqueixa.Apacientefoiacompanhadapor90dias,ehouvemelhoradaabertura da prega umbilical, do tônus da pele, de densidade dérmica e da flacidez tissular após 60 dias. Neste período, a paciente declarou estar totalmente satisfeita e foiestabelecidaaaltadotratamento.Comestepresenterelatodecasopodemosconcluirquea terapia combinada de fios de PDO parafusos e fios de PDO espiculados (Sculpt®) apresentam resultados muito expressivos em relação a qualidade da pele promovendo melhora visível na flacidez tissular


Thisstudyreportsacaseofabdominalflaccidityafterthreepregnancies,inwhichthetechnique ofsmoothandspiculatedpolydioxanonethreadswasused,atechniquenotyetdescribedinthe literature to treat this complaint. The patient was followed up for 90 days, but there was an improvement in the opening of the umbilical fold, skin tone, increase in dermal density and especially a reduction in tissue flaccidity in 60 days. During this period, the patient declared thatshewascompletelysatisfied,anddischargefromtreatmentwasestablished.Withthiscase report, we can conclude that the combined therapy of PDO threads screws and PDO threads spiculated (Sculpt®) presentvery expressive results about the quality of the skin, promoting a visible improvement in tissue flaccidity


Assuntos
Humanos , Relatos de Casos , Abdome , Hipotonia Muscular
11.
Invest Ophthalmol Vis Sci ; 64(15): 25, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38117244

RESUMO

Purpose: To evaluate the effects of mechanical disruption of the inner limiting membrane (ILM) on the ability to target interventions to the inner neurosensory retina in a rodent model. Our study used an animal model to gain insight into the normal physiology of the ILM and advances our understanding of the effects of mechanical ILM removal on the viral transduction of retinal ganglion cells and retinal ganglion cell transplantation. Methods: The ILM in the in vivo rat eye was disrupted using mechanical forces applied to the vitreoretinal interface. Immunohistology and electron microscopy were used to verify the removal of the ILM in retina flatmounts and sections. To assess the degree to which ILM disruption enhanced transvitreal access to the retina, in vivo studies involving intravitreal injections of adeno-associated virus (AAV) to transduce retinal ganglion cells (RGCs) and ex vivo studies involving co-culture of human stem cell-derived RGCs (hRGCs) on retinal explants were performed. RGC transduction efficiency and transplanted hRGC integration with retinal explants were evaluated by immunohistology of the retinas. Results: Mechanical disruption of the ILM in the rodent eye was sufficient to remove the ILM from targeted retinal areas while preserving the underlying retinal nerve fiber layer and RGCs. Removal of the ILM enhanced the transduction efficiency of intravitreally delivered AAV threefold (1380.0 ± 290.1 vs. 442.0 ± 249.3 cells/mm2; N = 6; P = 0.034). Removal of the ILM was also sufficient to promote integration of transplanted RGCs within the inner retina. Conclusions: The ILM is a barrier to transvitreally delivered agents including viral vectors and cells. Mechanical removal of the ILM is sufficient to enhance access to the inner retina, improve viral transduction efficiencies of RGCs, and enhance cellular integration of transplanted RGCs with the retina.


Assuntos
Retina , Células Ganglionares da Retina , Animais , Humanos , Ratos , Técnicas de Cocultura , Dependovirus , Injeções Intravítreas
13.
Cell Metab ; 35(8): 1373-1389.e8, 2023 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-37527658

RESUMO

There has been an intense focus to uncover the molecular mechanisms by which fasting triggers the adaptive cellular responses in the major organs of the body. Here, we show that in mice, hepatic S-adenosylmethionine (SAMe)-the principal methyl donor-acts as a metabolic sensor of nutrition to fine-tune the catabolic-fasting response by modulating phosphatidylethanolamine N-methyltransferase (PEMT) activity, endoplasmic reticulum-mitochondria contacts, ß-oxidation, and ATP production in the liver, together with FGF21-mediated lipolysis and thermogenesis in adipose tissues. Notably, we show that glucagon induces the expression of the hepatic SAMe-synthesizing enzyme methionine adenosyltransferase α1 (MAT1A), which translocates to mitochondria-associated membranes. This leads to the production of this metabolite at these sites, which acts as a brake to prevent excessive ß-oxidation and mitochondrial ATP synthesis and thereby endoplasmic reticulum stress and liver injury. This work provides important insights into the previously undescribed function of SAMe as a new arm of the metabolic adaptation to fasting.


Assuntos
Neoplasias Hepáticas , S-Adenosilmetionina , Camundongos , Animais , S-Adenosilmetionina/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Jejum , Trifosfato de Adenosina/metabolismo , Metionina Adenosiltransferase/metabolismo , Fosfatidiletanolamina N-Metiltransferase/metabolismo
14.
J Immunol ; 211(7): 1073-1081, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37566492

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fibrotic age-related chronic lung disease characterized by the accumulation of senescent cells. Whether impaired immune response is responsible for the accumulation of senescent cells in the IPF lung remains unknown. In this study, we characterized the NK phenotype in IPF lungs via flow cytometry using 5-dodecanoylaminofluorescein di-ß-d-galactopyranoside, markers of tissue residence, and chemokine receptors. The effect of the lung microenvironment was evaluated using lung fibroblast (LF) conditioned media (CM), and the bleomycin-induced pulmonary fibrosis mouse model was used to assess the in vivo relationship between NK cells and the accumulation of senescent cells. We found that NK cells from the lower lobe of IPF patients exhibited immune-senescent and impaired CD57-NKG2A+ phenotype. We also observed that culture of NK cells from healthy donors in CM from IPF lower lobe lung fibroblasts induced a senescent-like phenotype and impaired cytotoxic capacity. There is an impaired NK recruitment by LF, and NKs presented decreased migration toward their CM. In addition, NK cell-depleted mice treated with bleomycin showed increased collagen deposition and accumulation of different populations of senescent cells compared with controls. The IPF lung microenvironment induces a dysfunctional NK phenotype limiting the clearance of lung senescent cells and the resolution of lung fibrosis. We propose that impaired NK activity could be one of the mechanisms responsible for perpetuating the accumulation of senescent cells in IPF lungs.


Assuntos
Antineoplásicos , Fibrose Pulmonar Idiopática , Camundongos , Animais , Pulmão/patologia , Fibrose Pulmonar Idiopática/induzido quimicamente , Bleomicina/efeitos adversos , Fibrose , Antineoplásicos/farmacologia , Fibroblastos
15.
Pharmaceutics ; 15(8)2023 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-37631264

RESUMO

To date, the treatment for cysticercosis and neurocysticercosis consists of a single oral intake of praziquantel (5-10 mg/kg), which since it is only available as tablets, hinders its administration to pediatric patients. Praziquantel is a poorly water-soluble drug which represents a challenge for its formulation in solution, particularly for the pediatric population. Thus, this study aimed to develop a palatable solution for praziquantel using pharmaceutical-accepted co-solvent systems. A design of experiments approach was applied to identify the optimal conditions for achieving a suitable amount of praziquantel in solution using co-solvent mixtures. Thus, praziquantel solubility increased from 0.38 up to 43.50 mg/mL in the optimized system. A taste masking assay in healthy human volunteers confirmed a successful reduction of drug bitterness after the addition of selected flavors and a sweetener. Stability studies were also conducted at different temperatures (4, 25, and 40 °C) for 12 months Even though the presence of the three known impurities of praziquantel was observed, their amounts never exceeded the acceptance criteria of the USP. Thus, this novel approach should be considered a valuable alternative for further preclinical studies considering the high prevalence of this infection worldwide.

16.
Ann Surg Oncol ; 30(12): 7116-7123, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37581851

RESUMO

INTRODUCTION: Contralateral prophylactic mastectomy (CPM) is recommended for BRCA mutation carriers; its use in noncarriers relies on patient choice. We characterized differences in satisfaction and well-being after CPM between BRCA carriers and noncarriers. METHODS: BREAST-Q data were obtained before and after CPM with immediate reconstruction performed at a single institution from 2016 to 2022. Associations between BRCA status and satisfaction with breasts, psychosocial well-being, and sexual well-being were assessed, with adjustment for preoperative scores and relevant confounders. RESULTS: In total, 149 BRCA carriers and 842 noncarriers were included. Response rates varied over time (preoperative, 56%; 6 months, 78%; 1 year, 51%; 2 years, 52%; 3 years, 59%). BRCA carriers were younger (p < 0.001), with a higher rate of neoadjuvant chemotherapy (p < 0.001). More noncarriers had HR+/HER2- tumors (p < 0.001) and underwent endocrine therapy (p < 0.001). Baseline satisfaction with breasts was higher among BRCA carriers (median [interquartile range] score, 70 [53-82] vs. 58 [48-70]; p = 0.006); psychosocial (p = 0.20) and sexual (p = 0.14) well-being were not significantly different between groups. BRCA carriers had a greater decrease in satisfaction with breasts (p = 0.04) and psychological well-being (p = 0.05) from baseline to 6 months; decrease in sexual well-being (p = 0.38) was not significantly different between groups. On univariate and multivariable analyses, BRCA status was not associated with satisfaction with breasts, sexual well-being, or psychosocial well-being. CONCLUSIONS: Satisfaction and well-being were similar between BRCA carriers and noncarriers treated with CPM. Relative to noncarriers, BRCA carriers experienced a greater decline in satisfaction with breasts and psychological well-being at 6 months after CPM.


Assuntos
Neoplasias da Mama , Mastectomia Profilática , Humanos , Feminino , Mastectomia/psicologia , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Mutação , Satisfação Pessoal , Satisfação do Paciente
17.
Medicine (Baltimore) ; 102(32): e34641, 2023 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-37565893

RESUMO

BACKGROUND: Surgical site infection (SSI) is one of the most frightening complications after surgery. Adhesive drapes (AD) are widely used as an infection prevention tool. They can be non-impregnated or iodophor-impregnated, although non-impregnated are less used as they might be related to higher number of infections. One of the most common ways to study their efficacy is by analyzing the intraoperative contamination, which is a useful primary endpoint as it does not need follow-up and it has been strongly associated with infections. Therefore, we believe a systematic review (SR) and meta-analysis is needed to determine which is the literature available about this topic and to explore their results. METHODS: All randomized controlled trials (RCT) published since 1984 through to January 15, 2023 will be included. Non-human and experimental studies will be excluded. We will only include studies written in English. We will conduct searches in the following electronic databases: MEDLINE (via PubMed), SCOPUS and Web Of Science. The protocol of the SR was registered in PROSPERO under the number CRD42023391651 and was written according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol guidelines. DISCUSSION: The evidence regarding the benefits of using iodophor-impregnated adhesive drapes (IIAD) is scarce. Therefore, this SR and meta-analysis is required to determine if they are related with a lower intraoperative contamination incidence, compared to no AD.


Assuntos
Adesivos , Campos Cirúrgicos , Humanos , Iodóforos , Infecção da Ferida Cirúrgica/prevenção & controle , Infecção da Ferida Cirúrgica/epidemiologia , Incidência , Revisões Sistemáticas como Assunto , Metanálise como Assunto
18.
Foods ; 12(14)2023 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-37509890

RESUMO

The consumption of dietary fiber (DF) has been associated with a reduced incidence of non-communicable diseases. Despite various strategies implemented worldwide to increase DF intake, it remains low. Therefore, the development of new fiber-rich food products that are widely consumed could be a strategy to improve DF intake. In this study, an agro-industrial by-product, pomegranate peel powder (PPP), was used as an innovative source of DF and antioxidant. The objective was to develop a bread enriched with DF, antioxidants, and sensory characteristics by partially replacing wheat flour (WF) with PPP at levels of 0%, 2.5%, 5%, 7.5%, and 10%. Bread with 2.5% and 5% PPP was chosen for a clinical trial to evaluate glycemic response (GR) in healthy subjects and determine the bread's glycemic index (GI). As the percentage of PPP increased, both the DF and total polyphenol content increased significantly. The highest overall acceptability was achieved with bread containing up to 5% PPP. Consumption of bread with 2.5% and 5.0% PPP significantly reduced the GI compared to the control bread, while the decrease in GR was not significant. PPP could be a potential food and low-cost ingredient to improve the bread's nutritional quality through its contribution to DF and antioxidants.

19.
Br J Cancer ; 129(5): 811-818, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37488446

RESUMO

BACKGROUND: The first-in-class brain-penetrating synthetic hydroxylated lipid idroxioleic acid (2-OHOA; sodium 2-hydroxyoleate), activates sphingomyelin synthase expression and regulates membrane-lipid composition and mitochondrial energy production, inducing cancer cell autophagy. We report the findings of a multicentric first-in-human Phase 1/2A trial (NCT01792310) of 2-OHOA, identifying the maximum tolerated dose (MTD) and assessing safety and preliminary efficacy. METHODS: We performed an open-label, non-randomised trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumour activity of daily oral treatment with 2-OHOA monotherapy (BID/TID) in 54 patients with glioma and other advanced solid tumours. A dose-escalation phase using a standard 3 + 3 design was performed to determine safety and tolerability. This was followed by two expansion cohorts at the MTD to determine the recommended Phase-2 dose (RP2D). RESULTS: In total, 32 recurrent patients were enrolled in the dose-escalation phase (500-16,000 mg/daily). 2-OHOA was rapidly absorbed with dose-proportional exposure. Treatment was well-tolerated overall, with reversible grade 1-2 nausea, vomiting, and diarrhoea as the most common treatment-related adverse events (AEs). Four patients had gastrointestinal dose-limiting toxicities (DLTs) of nausea, vomiting, diarrhoea (three patients at 16,000 mg and one patient at 12,000 mg), establishing an RP2D at 12,000 mg/daily. Potential activity was seen in patients with recurrent high-grade gliomas (HGG). Of the 21 patients with HGG treated across the dose escalation and expansion, 5 (24%) had the clinical benefit (RANO CR, PR and SD >6 cycles) with one exceptional response lasting >2.5 years. CONCLUSIONS: 2-OHOA demonstrated a good safety profile and encouraging activity in this difficult-to-treat malignant brain-tumour patient population, placing it as an ideal potential candidate for the treatment of glioma and other solid tumour malignancies. CLINICAL TRIAL REGISTRATION: EudraCT registration number: 2012-001527-13; Clinicaltrials.gov registration number: NCT01792310.


Assuntos
Glioma , Neoplasias , Humanos , Diarreia , Glioma/tratamento farmacológico , Dose Máxima Tolerável , Náusea , Recidiva Local de Neoplasia , Neoplasias/tratamento farmacológico , Esfingolipídeos/uso terapêutico , Vômito
20.
Ann Surg Oncol ; 30(10): 6061-6069, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37493892

RESUMO

BACKGROUND: The clinical significance of nonclassic, lobular carcinoma in situ (NC-LCIS) at the surgical margin of excisions for invasive cancer is unknown. We sought to determine whether NC-LCIS at or near the margin in the setting of a concurrent invasive carcinoma is associated with risk of ipsilateral breast tumor recurrence (IBTR) and locoregional recurrence (LRR). METHODS: Patients with stage 0-III breast cancer and NC-LCIS who underwent lumpectomy between January 2010 and January 2022 at a single institution were retrospectively identified. NC-LCIS margins were stratified as <2 mm, ≥2 mm, or within shave margin. Rates of IBTR and LRR were examined. RESULTS: A total of 511 female patients (median age 60 years [interquartile range (IQR) 52-69]) with NC-LCIS and an associated ipsilateral breast cancer with a median follow-up of 3.4 years (IQR 2.0-5.9) were identified. Final margins for NC-LCIS were ≥2 mm in 348 patients (68%), <2 mm in 37 (7.2%), and within shave margin in 126 (24.6%). Crude incidence of IBTR was 3.3% (n = 17) and that of LRR was 4.9% (n = 25). There was no difference in the crude rate of IBTR by NC-LCIS margin status (IBTR rate: 3.7% ≥2 mm, 0% <2 mm, 3.2% within shave margin, p = 0.8) nor in LRR (LRR rate: 4.9% ≥2 mm, 2.7% <2 mm, 5.6% within shave margin, p = 0.9). CONCLUSIONS: For completely excised invasive breast cancers associated with NC-LCIS, extent of margin width for NC-LCIS was not associated with a difference in IBTR or LRR. These data suggest that the decision to perform reexcision of margin after lumpectomy should be driven by the invasive cancer, rather than the NC-LCIS margin.


Assuntos
Carcinoma de Mama in situ , Neoplasias da Mama , Carcinoma in Situ , Carcinoma Lobular , Feminino , Humanos , Pessoa de Meia-Idade , Idoso , Carcinoma de Mama in situ/cirurgia , Carcinoma de Mama in situ/patologia , Carcinoma Lobular/cirurgia , Carcinoma Lobular/patologia , Mastectomia Segmentar , Carcinoma in Situ/cirurgia , Carcinoma in Situ/patologia , Estudos Retrospectivos , Recidiva Local de Neoplasia/cirurgia , Recidiva Local de Neoplasia/epidemiologia , Neoplasias da Mama/cirurgia , Neoplasias da Mama/patologia
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