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Syringocystadenoma papilliferum is a rare benign adnexal hamartoma that is often associated with the nevus sebaceous of Jadassohn. It usually presents on the scalp and malignant transformation is rare. Here we present a case of digital papillary carcinoma on the toe of a teenage girl. The lesion recurred after two prior excisions without biopsy. The biopsy was read as a syringocystadenoma papilliferum with concerns for aggressive digital papillary adenocarcinoma, highlighting the importance of biopsy with excisions of neoplasms of unknown etiology.
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Metastatic carcinoma of presumed renal origin (rCUP) has recently emerged as a new entity within the heterogeneous entity of Cancers of Unknown Primary (CUP) but their biological features and optimal therapeutic management remain unknown. We report the molecular characteristics and clinical outcome of a series of 25 rCUP prospectively identified within the French National Multidisciplinary Tumor Board for CUP. This cohort strongly suggests that rCUP share similarities with common RCC subtypes and benefit from renal-tailored systemic treatment. This study highlights the importance of integrating clinical and molecular data for optimal diagnosis and management of CUP.
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BACKGROUND AND AIM: Endobronchial biopsy (EBBX) has been reported to increase diagnostic yield for pulmonary sarcoidosis. The purpose of this study is to investigate the diagnostic yield for EBBX following endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA). METHODS: We identified a cohort of patients in the University of Minnesota Sarcoidosis Registry who had EBBx and EBUS-TBNA as part of workup for abnormal chest imaging. Data regarding demographics, biopsy approach and technique were recorded. RESULTS: Our cohort included 37 patients (53.24±9.5, Male, 22±0.57; 3.8% were African American). In these patients who had EBBX, EBUS-TBNA was performed in 100% of patients and TBBX was performed in 2 patients (5%). EBBX was positive in 9 patients (24%) and EBUS-TBNA was positive in 34 patients (92%). TBBX was diagnostic in one of two patients. EBBX was the only diagnostic tissue in 3 of the 37 patients (8%). Conclusion: The diagnostic yield of EBBX is lower than previously reported, with only 8% of EBBXs demonstrating granulomatous inflammation. However, instrumentation used for obtaining EBBX as well as the presence of visible lesions does influence the diagnostic yield. Studies with adequate power are needed before implementing changes in clinical practice. When performed alongside EBUS-TBNA, EBBX did not significantly add to the diagnostic yield in sarcoidosis unless visible lesions were observed.
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Patients with mutations that alter the function of the sodium channel SCN8A present with a range of clinical features, including mild to severe seizures, developmental delay, intellectual disability, autism, feeding dysfunction, motor impairment, and hypotonia. In an effort to identify compounds that could be potentially beneficial in SCN8A-associated epilepsy, Atkin et al. conducted an in vitro screen which resulted in the identification of 90 compounds that effectively reduced sodium influx into the cells expressing the human SCN8A R1872Q mutation. The top compounds that emerged from this screen included amitriptyline, carvedilol, and nilvadipine. In the current study, we evaluated the ability of these three compounds to increase resistance to 6 Hz or pentylenetetrazole (PTZ)-induced seizures in wild-type CF1 mice and in a mouse line expressing the human SCN8A R1620L mutation. We also evaluated the effects of fenfluramine administration, which was recently associated with a 60%-90% decrease in seizure frequency in three patients with SCN8A-associated epilepsy. While amitriptyline, carvedilol, and fenfluramine provided robust protection against induced seizures in CF1 mice, only carvedilol was able to significantly increase resistance to 6 Hz- and PTZ-induced seizures in RL/+ mutants. These results provide support for further evaluation of carvedilol as a potential treatment for patients with SCN8A mutations.
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Background: This study explored vaccination hesitancy, diabetes-specific COVID-19 vaccination concerns, and whether they predicted vaccination uptake in people with diabetes. Methods: Quantitative, cross-sectional, and predictive approaches were used. An online survey was conducted with people with diabetes attending four Australian health services, using convenience sampling (n = 842). The survey data collected included clinico-demographic characteristics, COVID-19 vaccine hesitancy, and attitudes around COVID-19 vaccine confidence and complacency. Clinico-demographic characteristics that predicted vaccination status, vaccine hesitancy, and vaccine-related attitudes were identified using regression analyses. Results: Most participants received at least one COVID-19 vaccine dose. Younger age and type 1 diabetes were associated with lower vaccination status, and they were partially mediated through higher vaccine hesitancy. Younger age and English as a dominant language were associated with higher negative attitudes towards speed of vaccine development. Conclusions: Despite an overall high vaccination rate, general and diabetes-specific COVID-19 vaccine concerns are a barrier to uptake for some people with diabetes, particularly in those who are younger or have type 1 diabetes. A detailed understanding of concerns for particular subgroups can help tailor information to increase vaccine acceptance, particularly in the context of requiring booster doses.
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BACKGROUND & AIMS: Surgery plays a key role in the management of complicated diabetic foot disease (DFD). Currently, indications for medical versus surgical management are poorly defined. Prompt identification of patients who require surgery may reduce morbidities and length of hospital stay. This study aims to analyse factors in DFD that necessitate early surgical interventions. METHODS: All patients admitted under a multi-disciplinary diabetic foot team in a tertiary institution over 2 years were included in a retrospective case-control study comparing patients who received medical management and patients who received surgical management. Logistic regression was performed to identify factors associated with surgical management of diabetic foot complications. RESULTS: Three hundred and forty patients were included. 49% of patients required surgical management. Toe ulceration, elevated C-reactive protein (CRP), and the presence of osteomyelitis were associated with surgical management. Multivariate analysis calculated an odds ratio (OR) of 1.01 for CRP (p < 0.001), OR 2.19 (p < 0.019) favouring surgical management for forefoot ulcers, and OR 2.2 (p < 0.019) if osteomyelitis was present. CONCLUSIONS: Patients with elevated CRP levels, a forefoot diabetic ulcer and established osteomyelitis were more likely to undergo surgical management. Prompt recognition of these patients has the potential benefit of earlier decision making in definitive surgical interventions.
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Proteína C-Reactiva , Pie Diabético , Humanos , Pie Diabético/cirugía , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Osteomielitis/cirugía , Modelos LogísticosRESUMEN
Background: High rates of youth re-offending indicate that young custody-leavers face challenges when reintegrating into their communities. Aftercare and resettlement programs can occur pre-, during, and post-release and generally provide multiple forms of support services to address youths' transitional needs. Objectives: The present review examines (1) the impact of youth aftercare/resettlement programs on crime-related outcomes, (2) how treatment effect is moderated by participant, program, and study characteristics, (3) whether some types of interventions are more effective than others, (4) barriers/facilitators to effective program implementation, (5) the theory of change underlying resettlement interventions, and (6) available research on intervention cost. Search Methods: A comprehensive set of keywords and synonyms was combined in a Boolean search across 26 electronic databases. Multiple gray literature sources were also searched, including 23 journals, 4 meeting archives, 11 organization websites, 3 open access journal websites, and the CVs of 8 well-known researchers in the field. The search was completed in January 2023. Selection Criteria: For objectives 1-3, studies were included if they utilized a randomized controlled design or quasi-experimental comparison group design in which participants were matched on at least some baseline variables and included at least one quantitative individual-measure of crime. For objective 4, included studies presented process evaluations of aftercare/reentry programs, clearly stated their research goals, and used qualitative methods in an appropriate way to answer the stated research question. For objectives 5 and 6, no specific methods were required; any study meeting the criteria for objectives 1-4 which presented findings on theory of change or cost data were included. For all outcomes, only studies conducted in a westernized country, and published after 1991 in English, French, or German were considered. Data Collection and Analysis: Two coders conducted primary data extraction for the included studies. Data were entered into a Microsoft Excel database. After data extraction, the two coders validated the coding by cross-checking the database with each research report. Discrepancies between coders were discussed until consensus was reached. Where consensus could not be reached, a third coder was consulted. Study risk of bias was addressed using the ROBINS-I (Sterne et al., 2016), ROB-2 (Higgins et al., 2019), and the critical appraisal skills programme (CASP, 2018). Objectives 1-3 were addressed by synthesizing quantitative outcomes from rigorous impact evaluations of aftercare interventions using random effects models and meta-regression. Thematic and narrative analysis was conducted to address objectives 4-6. Results: The search resulted in 15 impact studies, representing 4,718 participants across 21 program sites, and 35 effect sizes. The 21 impact evaluations were rated as having either low/moderate bias (k = 11) or serious bias (k = 10). The synthesis of 15 impact studies found no significant effects for arrest (k = 14; OR = 1.044, 95% prediction interval [0.527, 2.075], t = 0.335) or incarceration (k = 8, OR = 0.806, 95% prediction interval [2.203, 1.433], t = -1.674). A significant pooled effect was found for conviction (k = 13, OR = 1.209, 95% prediction interval [1.000, 1.462], t = 2.256), but results were highly sensitive to the inclusion of specific studies. No meaningful pattern of results emerged in moderator analyses with respect to study, sample, program component, or program delivery characteristics. The 19 process studies were rated as either high quality (k = 12) or moderate quality (k = 7). Thematic synthesis of the process evaluations revealed 15 themes related to the strengths/challenges of program implementation. The assessment of program cost (k = 7) determined a lack of data within the literature, preventing any summative analysis. Authors' Conclusions: Current evidence is promising with respect to conviction outcomes but overall does not find that aftercare/resettlement interventions have a reliably positive impact on crime-related outcomes for young people who have offended. High variability across outcomes and reported data resulted in small sample sizes per outcome and limited moderator analyses. Multiple challenges for program implementation exist; additional rigorous research is sorely needed to further investigate the nuances of the program effects.
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OBJECTIVES: The aim of this study was to present key findings from the 2019 national adult oral health survey in Singapore (NAOHS). METHODS: A multi-stage stratified sampling method was used to recruit participants for a representative national adult oral health survey. A total of 12 212 households were randomly selected from the National Database on Dwellings in Singapore. Within each household eligible persons aged ≥65 years were automatically invited to participate while a Kish selection method was used to invite those between 21 and 64 years old. The survey comprised a face-to-face interview questionnaire and a clinical examination which recorded details of tooth loss, DMFT, DMFS and prevalence of periodontal disease according to the CPITN and the US CDC-AAP classifications. Weighted analysis was performed to adjust for oversampling, non-response and post-stratification. Multivariate regression with backward stepwise selection was carried out to identify predictors of chronic periodontal disease and untreated dental caries. RESULTS: Six hundred and sixty-three participants completed both the questionnaires and the clinical examination. The prevalence of edentulousness was 2.7%. Of participants, 34.8% presented with untreated dental caries with a higher proportion found in those who were aged ≥60 years, of Malay ethnicity, living in 1-2-room public housing and who only visited the dentist when there was a problem. Mean DMFS and DMFT indices were 24.7 and 7.9 respectively. Based on the CDC-AAP classification, the prevalence of moderate-severe chronic periodontitis was 56.9% and increased with age, with a higher proportion in males. Participants with untreated dental caries were more likely to have moderate or severe periodontal disease. CONCLUSIONS: Survey findings showed high prevalence of dental caries and periodontal disease, at 34.8% and 77.6% respectively. A clear socio-economic gradient in the distribution of tooth loss, untreated dental caries and moderate-to-severe periodontitis was observed.
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Caries Dental , Encuestas de Salud Bucal , Humanos , Singapur/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Prevalencia , Caries Dental/epidemiología , Adulto , Enfermedades Periodontales/epidemiología , Adulto Joven , Índice CPO , Pérdida de Diente/epidemiología , Salud Bucal/estadística & datos numéricosRESUMEN
IMPORTANCE: This study aimed to evaluate if there is a difference between outcomes when retropubic or transobturator midurethral sling surgery is performed at the time of colpocleisis. OBJECTIVES: The purpose of this study was to compare the surgical outcomes of the retropubic midurethral sling (RP-MUS) versus the transobturator midurethral sling (TO-MUS) in women who underwent concomitant colpocleisis, specifically 2-year MUS failure and 1-year lower urinary tract symptoms (LUTSs). A secondary aim was to identify factors associated with these surgical outcomes. STUDY DESIGN: All cases of concomitant MUS and colpocleisis within a closed, integrated health care delivery system were reviewed between April 1, 2010, and March 31, 2020. Postoperative MUS failure was defined as (1) postoperative stress urinary incontinence symptoms and/or (2) additional anti-incontinence surgery. Postoperative LUTSs were defined as (1) MUS lysis and/or (2) overactive bladder requiring management with a new treatment. RESULTS: Of the 558 women included, 454 (81%) received RP-MUS and 104 (19%) received TO-MUS. Cohort demographics were similar. Neither MUS failure (7% RP-MUS and 9% TO-MUS, P = 0.450) nor LUTSs (7% RP-MUS and 12% TO-MUS, P = 0.171) were significantly different between RP-MUS and TO-MUS. In multivariable analysis, age was found to be significantly associated with LUTSs (odds ratio 0.29, 95% confidence interval 0.09-0.93, P = 0.038 among 70-74-year-olds; odds ratio 0.28, 95% confidence interval 0.09-0.83, P = 0.022 among 75-79-year-olds). CONCLUSIONS: At the time of colpocleisis, both RP-MUS and TO-MUS were highly successful and associated with a low incidence of LUTSs, including MUS lysis. The findings of this large study support RP-MUS and TO-MUS as similarly effective anti-incontinence options at time of colpocleisis.
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PURPOSE: The anticipation of organizational change and the transition process often creates uncertainty for employees and can lead to stress and anxiety. It is therefore essential for all organizations, especially those that operate in high-demand working environments, to support the well-being of staff throughout the change process. DESIGN/METHODOLOGY/APPROACH: Research on how employees respond to the organizational change of relocating to a new work space is limited. To fill this gap in the research, we present a case study examining the well-being of clinical and health care employees before and after a disruptive change: relocation in workplace facilities. In addition, factors that enabled successful change in this high-stress, high-demand working environment were investigated. Interviews were conducted with 20 participants before the relocation and 11 participants after relocation. Following an inductive approach, data were analyzed using thematic analysis to identify key themes. FINDINGS: Our findings suggest that a supportive team, inclusive leadership and a psychologically safe environment, may buffer negative employee well-being outcomes during disruptive organizational change. ORIGINALITY/VALUE: This research contributes to the literature on successful organizational change in health care by highlighting the resources which support well-being throughout the change process and enabling the successful transition to a new facility.
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Personal de Salud , Lugar de Trabajo , Humanos , Liderazgo , Atención a la SaludRESUMEN
PURPOSE: To systematically review the clinical features, management, and outcomes of diffuse midline H3K27-altered gliomas of the spinal cord (DMG-SCs). METHODS: PubMed, Ovid EMBASE, Scopus, and Web of Science were searched from database inception to 23 September 2023 for histologically confirmed cases of DMG-SC. Patient demographics, tumor characteristics, management information, and survival outcomes were extracted and analyzed. RESULTS: A total of 279 patients from 39 studies were collected. Patients were mostly male (61%), with an average age of 32 years. Patients were treated with surgery, radiotherapy, and chemotherapy combined (31%) or surgery only (24%), and extent of resection was most often subtotal (38%). Temozolomide was the most common chemotherapeutic agent (81%). Radiation therapy was delivered with mean dose of 47 Gy in 23 fractions. At mean follow-up time of 21 months, 13% of patients were alive. Average median overall survival was 24 months (range of 13 to 40 months) with a median progression-free survival of 14 months. Historical WHO grades of 2 or 3 appeared to exhibit a longer average median overall survival time than that of grade 4 DMG-SCs (32 vs. 23 months, p = 0.009). CONCLUSIONS: Outcomes for DMG-SCs are poor overall but appear to be favorable compared to intracranial DMGs. Despite the recent WHO 2021 grade 4 classification for all DMGs, given the differences in overall survival reported based on historical grading systems, future studies on DMG-SCs are needed to further define if DMG-SCs may represent a heterogeneous group of tumors with different prognoses.
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Glioma , Neoplasias de la Médula Espinal , Humanos , Neoplasias de la Médula Espinal/terapia , Neoplasias de la Médula Espinal/patología , Glioma/terapia , Glioma/patología , Glioma/mortalidad , Histonas/genética , Histonas/metabolismo , PronósticoRESUMEN
BACKGROUND: High tumor mutational burden (TMB) was reported to predict the efficacy of immune checkpoint inhibitors (ICIs). Pembrolizumab, an anti-PD-1, received FDA-approval for the treatment of unresectable/metastatic tumors with high TMB as determined by the FoundationOne®CDx test. It remains to be determined how TMB can also be calculated using other tests. RESULTS: FFPE/frozen tumor samples from various origins were sequenced in the frame of the Institut Curie (IC) Molecular Tumor Board using an in-house next-generation sequencing (NGS) panel. A TMB calculation method was developed at IC (IC algorithm) and compared to the FoundationOne® (FO) algorithm. Using IC algorithm, an optimal 10% variant allele frequency (VAF) cut-off was established for TMB evaluation on FFPE samples, compared to 5% on frozen samples. The median TMB score for MSS/POLE WT tumors was 8.8 mut/Mb versus 45 mut/Mb for MSI/POLE-mutated tumors. When focusing on MSS/POLE WT tumor samples, the highest median TMB scores were observed in lymphoma, lung, endometrial, and cervical cancers. After biological manual curation of these cases, 21% of them could be reclassified as MSI/POLE tumors and considered as "true TMB high." Higher TMB values were obtained using FO algorithm on FFPE samples compared to IC algorithm (40 mut/Mb [10-3927] versus 8.2 mut/Mb [2.5-897], p < 0.001). CONCLUSIONS: We herein propose a TMB calculation method and a bioinformatics tool that is customizable to different NGS panels and sample types. We were not able to retrieve TMB values from FO algorithm using our own algorithm and NGS panel.
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Neoplasias , Humanos , Mutación , Neoplasias/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodosRESUMEN
PURPOSE: Giredestrant is an investigational next-generation, oral, selective estrogen receptor antagonist and degrader for the treatment of estrogen receptor-positive (ER+) breast cancer. We present the primary analysis results of the phase Ia/b GO39932 study (NCT03332797). PATIENTS AND METHODS: Patients with ER+, HER2-negative locally advanced/metastatic breast cancer previously treated with endocrine therapy received single-agent giredestrant (10, 30, 90, or 250 mg), or giredestrant (100 mg) ± palbociclib 125 mg ± luteinizing hormone-releasing hormone (LHRH) agonist. Detailed cardiovascular assessment was conducted with giredestrant 100 mg. Endpoints included safety (primary), pharmacokinetics, pharmacodynamics, and efficacy. RESULTS: As of January 28, 2021, with 175 patients enrolled, no dose-limiting toxicity was observed, and the MTD was not reached. Adverse events (AE) related to giredestrant occurred in 64.9% and 59.4% of patients in the single-agent ± LHRH agonist and giredestrant + palbociclib ± LHRH agonist cohorts, respectively (giredestrant-only-related grade 3/4 AEs were reported in 4.5% of patients across the single-agent cohorts and 3.1% of those with giredestrant + palbociclib). Dose-dependent asymptomatic bradycardia was observed, but no clinically significant changes in cardiac-related outcomes: heart rate, blood pressure, or exercise duration. Clinical benefit was observed in all cohorts (48.6% of patients in the single-agent cohort and 81.3% in the giredestrant + palbociclib ± LHRH agonist cohort), with no clear dose relationship, including in patients with ESR1-mutated tumors. CONCLUSIONS: Giredestrant was well tolerated and clinically active in patients who progressed on prior endocrine therapy. Results warrant further evaluation of giredestrant in randomized trials in early- and late-stage ER+ breast cancer.
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Neoplasias de la Mama , Carbolinas , Piperazinas , Piridinas , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Receptores de Estrógenos , Hormona Liberadora de Gonadotropina/agonistasRESUMEN
PURPOSE: Mosaic BRCA1 promoter methylation (BRCA1meth) increases the risk of early-onset breast cancer, triple-negative breast cancer and ovarian cancer. As mosaic BRCA1meth are believed to occur de novo, their role in family breast/ovarian cancer has not been assessed. PATIENTS: Blood-derived DNA from 20 unrelated affected cases from families with aggregation of breast/ovarian cancer, but with no germline pathogenic variants in BRCA1/2, PALB2 or RAD51C/D, were screened by methylation-sensitive high-resolution melting. CpG analysis was performed by pyrosequencing on blood and buccal swab. Two probands carried a pathogenic variant in a moderate-penetrance gene (ATM and BARD1), and 8 of 18 others (44%) carried BRCA1meth (vs none of the 20 age-matched controls). Involvement of BRCA1 in tumourigenesis in methylated probands was demonstrated in most tested cases by detection of a loss of heterozygosity and a homologous recombination deficiency signature. Among the eight methylated probands, two had relatives with breast cancer with detectable BRCA1meth in blood, including one with high methylation levels in two non-tumour tissues. CONCLUSIONS: The high prevalence of mosaic BRCA1meth in patients with breast/ovarian cancer with affected relatives, as well as this first description of a family aggregation of mosaic BRCA1meth, shows how this de novo event can contribute to hereditary breast/ovarian cancer pedigrees.
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Neoplasias de la Mama , Neoplasias Ováricas , Humanos , Femenino , Proteína BRCA1/genética , Linaje , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Metilación , Neoplasias Ováricas/genética , Neoplasias Ováricas/diagnóstico , Mutación de Línea Germinal/genética , Predisposición Genética a la Enfermedad , Metilación de ADN/genéticaRESUMEN
Purpose: To report on the visual outcomes of the second-generation (ActivShieldTM) Light Adjustable Lens (LAL) used in cataract surgery for patients with a history of laser refractive surgery (LASIK and/or photorefractive keratectomy [PRK]) using a co-managed, open-access methodology. Patients and Methods: This retrospective case series of consecutive patients with history of laser refractive surgery implanted with the second-generation LAL with an emmetropic target were included in the study. Following surgery, all patients received their ultraviolet (UV) light treatments at a separate open-access facility through a co-managed arrangement. Uncorrected distance visual acuity (UDVA), spherical equivalent (SE), and residual cylinder for eyes with an emmetropic refractive target were the primary outcome measures as documented at the patient's final, stable, refractive postoperative exam. Results: Thirty-three patients (34 eyes) with a history of laser refractive surgery were included in the study and implanted with the second-generation LAL with a postoperative emmetropic refractive target. Twenty-eight (82.4%) saw 20/20 or better and 9 (26.5%) saw 20/15 or better. The mean SE was 0.01 ± 0.31 D and 33 (97.1%) were within ±0.50 D SE of plano. The mean residual cylinder was -0.28 ± 0.32 D and 30 (88.2%) were within ±0.50 D. Conclusion: Use of the second-generation LAL was efficacious in cataract surgical patients with a history of LASIK and/or PRK using a co-managed, open-access methodology.
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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.
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Neoplasias de la Mama , Farmacología Clínica , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Interacciones FarmacológicasRESUMEN
PURPOSE: Preventative strategies and surgical treatment for urolithiasis depend on stone composition. However, stone composition is often unknown until the stone is passed or surgically managed. Given that stone composition likely reflects the physiological parameters during its formation, we used clinical data from stone formers to predict stone composition. MATERIAL AND METHODS: Stone composition, 24-hour urine, serum biochemistry, patient demographic and medical history were prospectively collected from 777 kidney stone patients. Data were used to train gradient boosted machine and logistic regression models to distinguish calcium vs non-calcium, calcium oxalate monohydrate vs dihydrate, and calcium oxalate vs calcium phosphate vs uric acid stone types. Model performance was evaluated using kappa score and the influence of each predictor variable was assessed. RESULTS: The calcium vs non-calcium model successfully differentiated stone types with a kappa of 0.5231. The most influential predictors were 24-hour urine calcium, blood urate and phosphate. The calcium oxalate monohydrate vs dihydrate model is the first of its kind and could discriminate stone types with a kappa of 0.2042. The key predictors were 24-hour urine urea, calcium, and oxalate. The multiclass model had a kappa of 0.3023 and the top predictors were age, and 24-hour urine calcium and creatinine. CONCLUSIONS: Clinical data can be leveraged with machine learning algorithms to predict stone composition, which may help urologists determine stone type and guide their management plan before stone treatment. Investigating the most influential predictors of each classifier may improve the understanding of key clinical features of urolithiasis and shed light on the pathophysiology.
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AIMS: Malignant tumours of the lacrimal apparatus are rare and frequently show a poor prognosis, with no clear therapeutic standards. Characterisation of the genetic landscape of these rare tumours is sparse, and therefore therapeutics generally follow those of their common salivary gland counterparts. To further clarify the pathophysiology and discover potential therapeutic targets, we investigated the genetic landscape of eight tumours of the lacrimal apparatus. METHODS AND RESULTS: DNA and RNA sequencing were performed to identify genetic mutations and gene fusions. Immunohistochemistry, fluorescence in-situ hybridisation and reverse transcription-polymerase chain reaction followed by Sanger sequencing were performed to confirm the identified molecular alterations. Genetic alterations were detected in six tumours. Among five adenoid cystic carcinomas (ACC), four had confirmed alterations of MYB or MYBL1 genes, including a MYB::NFIB fusion, a MYBL1::NFIB fusion, a MYB amplification and a novel NFIB::THSD7B fusion. Mutations in genes encoding epigenetic modifiers, as well as NOTCH1, FGFR2 and ATM mutations, were also identified in ACCs. A carcinoma ex pleomorphic adenoma showed TP53 and CIC mutations and an amplification of ERBB2. A transitional cell carcinoma was associated with HPV16 infection. No genetic alteration was found for one adenocarcinoma, not otherwise specified. CONCLUSIONS: Our study highlights the variety of molecular alterations associated with lacrimal system tumours and emphasises the importance of molecular testing in these tumours, which can reveal potentially targetable mutations. Our results also reinforce the hypothesis of a common physiopathology of all ACCs, regardless of their primary location.