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1.
J Am Acad Dermatol ; 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38663749

RESUMO

Correct coding is an important component of effective dermatology practice management. Over the past several years there have been updates to many commonly used codes within dermatology. This review highlights many of these updates, such as: the skin biopsy codes have been subdivided to reflect the different biopsy techniques. The definition of complex linear repairs has been updated and clarified. Outpatient and inpatient evaluation and management visits have new coding guidelines to determine level of care. Dermatopathology consultation codes have been updated and category III codes related to digital pathology have been created. Understanding the details and nuances of each of these categories of codes is vital to ensuring appropriate coding is performed.

2.
Mol Cancer Ther ; 23(4): 541-551, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38354416

RESUMO

Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody-drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC payload "toolbox" to include payloads with novel mechanisms of action such as topoisomerase inhibition and DNA cross-linking. We present here the development of a novel DNA mono-alkylator ADC platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant tumors and is well tolerated in the rat upon repeat dosing. A phosphoramidate prodrug of the payload enables low ADC aggregation even at drug-to-antibody ratios of 5:1 while still delivering a bystander-capable payload that is effective in multidrug resistant (MDR)-overexpressing cell lines. The platform was comparable in xenograft studies to the clinical benchmark DNA mono-alkylator ADC platform DGN459 but with a significantly better tolerability profile in rats. Thus, the activity and tolerability profile of this new platform make it a viable option for the development of ADCs.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias , Humanos , Ratos , Animais , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Alquilantes , Neoplasias/tratamento farmacológico , DNA/metabolismo , Linhagem Celular Tumoral , Antineoplásicos/farmacologia
3.
Cardiovasc Intervent Radiol ; 47(2): 200-207, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38151603

RESUMO

PURPOSE: To evaluate the relationship between prospectively generated ablative margin estimates and local tumor progression (LTP) among patients undergoing microwave ablation (MWA) of small renal masses (SRMs). MATERIALS AND METHODS: Between 2017 and 2020, patients who underwent MWA for SRM were retrospectively identified. During each procedure, segmented kidney and tumor shapes were coregistered with intraprocedural helical CT images obtained after microwave antenna placement. Predicted ablation zone shape and size were then overlaid onto the resultant model, and a model-to-model distance algorithm was employed to calculate multiple ablative margin estimates. LTP was modeled as a function of each margin estimate by hazard regression. Models were evaluated using hazard ratios and Akaike information criterion. Receiver operating characteristic curve area under the curve was also estimated using Harrell's and Uno's C indices (HI and UI, respectively). RESULTS: One hundred and twenty-eight patients were evaluated (median age 72.1 years). Mean tumor diameter was 2.4 ± 0.9 cm. LTP was observed in nine (7%) patients. Analysis showed that decreased estimated margin size as measured by first quartile (Q1; 25th percentile), maximum, and average ablative margin metrics was significantly associated with risk of LTP. For every one millimeter increase in Q1, maximum, and mean ablative margin, the hazard of LTP increased 67% (HR: 1.67; 95% CI = 1.25-2.20, UI = 0.93, HI = 0.77), 32% (HR: 1.32; 95% CI 1.09-1.60; UI = 0.93; HI = 0.76), and 48% (HR: 1.48; 95% CI 1.18-1.85; UI = 0.83; HI = 0.75), respectively. CONCLUSION: Prospectively generated ablative margin estimates can be used to predict the risk of local tumor progression following microwave ablation of small renal masses. LEVEL OF EVIDENCE 3: Retrospective cohort study.


Assuntos
Ablação por Cateter , Neoplasias Hepáticas , Humanos , Idoso , Neoplasias Hepáticas/cirurgia , Estudos Retrospectivos , Estudos Prospectivos , Micro-Ondas/uso terapêutico , Resultado do Tratamento , Ablação por Cateter/métodos
4.
J Med Chem ; 66(15): 10715-10733, 2023 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-37486969

RESUMO

While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results have yet to be translated in the clinic. A STING agonist antibody-drug conjugate (ADC) could overcome current limitations by improving tumor accessibility, allowing for systemic administration as well as tumor-localized activation of STING for greater anti-tumor activity and better tolerability. In line with this effort, a STING agonist ADC platform was identified through systematic optimization of the payload, linker, and scaffold based on multiple factors including potency and specificity in both in vitro and in vivo evaluations. The platform employs a potent non-cyclic dinucleotide STING agonist, a cleavable ester-based linker, and a hydrophilic PEG8-bisglucamine scaffold. A tumor-targeted ADC built with the resulting STING agonist platform induced robust and durable anti-tumor activity and demonstrated high stability and favorable pharmacokinetics in nonclinical species.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias , Humanos , Imunoconjugados/farmacocinética , Anticorpos Monoclonais , Antineoplásicos/farmacocinética , Neoplasias/tratamento farmacológico
5.
Mol Cancer Ther ; 22(9): 999-1012, 2023 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-37294948

RESUMO

Antibody-drug conjugates (ADC) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The activity and safety profile of an ADC depends on its construction: antibody, payload, linker, and conjugation method, as well as the number of payload drugs per antibody [drug-to-antibody ratio (DAR)]. To allow for ADC optimization for a given target antigen, we developed Dolasynthen (DS), a novel ADC platform based on the payload auristatin hydroxypropylamide, that enables precise DAR-ranging and site-specific conjugation. We used the new platform to optimize an ADC that targets B7-H4 (VTCN1), an immune-suppressive protein that is overexpressed in breast, ovarian, and endometrial cancers. XMT-1660 is a site-specific DS DAR 6 ADC that induced complete tumor regressions in xenograft models of breast and ovarian cancer as well as in a syngeneic breast cancer model that is refractory to PD-1 immune checkpoint inhibition. In a panel of 28 breast cancer PDXs, XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recently entered clinical development in a phase I study (NCT05377996) in patients with cancer.


Assuntos
Antineoplásicos , Neoplasias da Mama , Imunoconjugados , Humanos , Feminino , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Anticorpos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Biomech Eng ; 145(9)2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37144889

RESUMO

Our objective was to develop a technique for performing irreversible electroporation (IRE) of esophageal tumors while mitigating thermal damage to the healthy lumen wall. We investigated noncontact IRE using a wet electrode approach for tumor ablation in a human esophagus with finite element models for electric field distribution, joule heating, thermal flux, and metabolic heat generation. Simulation results indicated the feasibility of tumor ablation in the esophagus using an catheter mounted electrode immersed in diluted saline. The ablation size was clinically relevant, with substantially lesser thermal damage to the healthy esophageal wall when compared to IRE performed by placing a monopolar electrode directly into the tumor. Additional simulations were used to estimate ablation size and penetration during noncontact wet-electrode IRE (wIRE) in the healthy swine esophagus. A novel catheter electrode was manufactured and wIRE evaluated in seven pigs. wIRE was performed by securing the device in the esophagus and using diluted saline to isolate the electrode from the esophageal wall while providing electric contact. Computed tomography and fluoroscopy were performed post-treatment to document acute lumen patency. Animals were sacrificed within four hours following treatment for histologic analysis of the treated esophagus. The procedure was safely completed in all animals; post-treatment imaging revealed intact esophageal lumen. The ablations were visually distinct on gross pathology, demonstrating full thickness, circumferential regions of cell death (3.52 ± 0.89 mm depth). Acute histologic changes were not evident in nerves or extracellular matrix architecture within the treatment site. Catheter directed noncontact IRE is feasible for performing penetrative ablations in the esophagus while avoiding thermal damage.


Assuntos
Eletroporação , Esôfago , Suínos , Humanos , Animais , Esôfago/patologia , Eletrodos , Fluoroscopia , Eletroporação/métodos
7.
J Am Acad Dermatol ; 87(3): 573-581, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35551965

RESUMO

BACKGROUND: There is variation in the outcomes reported in clinical studies of basal cell carcinoma. This can prevent effective meta-analyses from answering important clinical questions. OBJECTIVE: To identify a recommended minimum set of core outcomes for basal cell carcinoma clinical trials. METHODS: Patient and professional Delphi process to cull a long list, culminating in a consensus meeting. To be provisionally accepted, outcomes needed to be deemed important (score, 7-9, with 9 being the maximum) by 70% of each stakeholder group. RESULTS: Two hundred thirty-five candidate outcomes identified via a systematic literature review and survey of key stakeholders were reduced to 74 that were rated by 100 health care professionals and patients in 2 Delphi rounds. Twenty-seven outcomes were provisionally accepted. The final core set of 5 agreed-upon outcomes after the consensus meeting included complete response; persistent or serious adverse events; recurrence-free survival; quality of life; and patient satisfaction, including cosmetic outcome. LIMITATIONS: English-speaking patients and professionals rated outcomes extracted from English language studies. CONCLUSION: A core outcome set for basal cell carcinoma has been developed. The use of relevant measures may improve the utility of clinical research and the quality of therapeutic guidance available to clinicians.


Assuntos
Carcinoma Basocelular , Neoplasias Cutâneas , Carcinoma Basocelular/terapia , Técnica Delphi , Humanos , Qualidade de Vida , Projetos de Pesquisa , Neoplasias Cutâneas/terapia , Resultado do Tratamento
8.
ACS Synth Biol ; 10(5): 1039-1052, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33843197

RESUMO

Saccharomyces boulardii is a probiotic yeast that exhibits rapid growth at 37 °C, is easy to transform, and can produce therapeutic proteins in the gut. To establish its ability to produce small molecules encoded by multigene pathways, we measured the amount and variance in protein expression enabled by promoters, terminators, selective markers, and copy number control elements. We next demonstrated efficient (>95%) CRISPR-mediated genome editing in this strain, allowing us to probe engineered gene expression across different genomic sites. We leveraged these strategies to assemble pathways enabling a wide range of vitamin precursor (ß-carotene) and drug (violacein) titers. We found that S. boulardii colonizes germ-free mice stably for over 30 days and competes for niche space with commensal microbes, exhibiting short (1-2 day) gut residence times in conventional and antibiotic-treated mice. Using these tools, we enabled ß-carotene synthesis (194 µg total) in the germ-free mouse gut over 14 days, estimating that the total mass of additional ß-carotene recovered in feces was 56-fold higher than the ß-carotene present in the initial probiotic dose. This work quantifies heterologous small molecule production titers by S. boulardii living in the mammalian gut and provides a set of tools for modulating these titers.


Assuntos
Antineoplásicos/metabolismo , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Indóis/metabolismo , Engenharia Metabólica/métodos , Probióticos/metabolismo , Provitaminas/biossíntese , Saccharomyces boulardii/metabolismo , beta Caroteno/biossíntese , Animais , Sistemas CRISPR-Cas , Fezes/química , Feminino , Microbioma Gastrointestinal , Edição de Genes/métodos , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microrganismos Geneticamente Modificados , Família Multigênica , Plasmídeos/genética , Regiões Promotoras Genéticas , Saccharomyces boulardii/genética , Saccharomyces cerevisiae/genética
9.
Lancet Digit Health ; 3(5): e286-e294, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33773969

RESUMO

BACKGROUND: Chest x-ray is a relatively accessible, inexpensive, fast imaging modality that might be valuable in the prognostication of patients with COVID-19. We aimed to develop and evaluate an artificial intelligence system using chest x-rays and clinical data to predict disease severity and progression in patients with COVID-19. METHODS: We did a retrospective study in multiple hospitals in the University of Pennsylvania Health System in Philadelphia, PA, USA, and Brown University affiliated hospitals in Providence, RI, USA. Patients who presented to a hospital in the University of Pennsylvania Health System via the emergency department, with a diagnosis of COVID-19 confirmed by RT-PCR and with an available chest x-ray from their initial presentation or admission, were retrospectively identified and randomly divided into training, validation, and test sets (7:1:2). Using the chest x-rays as input to an EfficientNet deep neural network and clinical data, models were trained to predict the binary outcome of disease severity (ie, critical or non-critical). The deep-learning features extracted from the model and clinical data were used to build time-to-event models to predict the risk of disease progression. The models were externally tested on patients who presented to an independent multicentre institution, Brown University affiliated hospitals, and compared with severity scores provided by radiologists. FINDINGS: 1834 patients who presented via the University of Pennsylvania Health System between March 9 and July 20, 2020, were identified and assigned to the model training (n=1285), validation (n=183), or testing (n=366) sets. 475 patients who presented via the Brown University affiliated hospitals between March 1 and July 18, 2020, were identified for external testing of the models. When chest x-rays were added to clinical data for severity prediction, area under the receiver operating characteristic curve (ROC-AUC) increased from 0·821 (95% CI 0·796-0·828) to 0·846 (0·815-0·852; p<0·0001) on internal testing and 0·731 (0·712-0·738) to 0·792 (0·780-0 ·803; p<0·0001) on external testing. When deep-learning features were added to clinical data for progression prediction, the concordance index (C-index) increased from 0·769 (0·755-0·786) to 0·805 (0·800-0·820; p<0·0001) on internal testing and 0·707 (0·695-0·729) to 0·752 (0·739-0·764; p<0·0001) on external testing. The image and clinical data combined model had significantly better prognostic performance than combined severity scores and clinical data on internal testing (C-index 0·805 vs 0·781; p=0·0002) and external testing (C-index 0·752 vs 0·715; p<0·0001). INTERPRETATION: In patients with COVID-19, artificial intelligence based on chest x-rays had better prognostic performance than clinical data or radiologist-derived severity scores. Using artificial intelligence, chest x-rays can augment clinical data in predicting the risk of progression to critical illness in patients with COVID-19. FUNDING: Brown University, Amazon Web Services Diagnostic Development Initiative, Radiological Society of North America, National Cancer Institute and National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health.


Assuntos
Inteligência Artificial , COVID-19/fisiopatologia , Prognóstico , Radiografia Torácica , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2 , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Estados Unidos , Adulto Jovem
10.
BMC Health Serv Res ; 21(1): 38, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413381

RESUMO

BACKGROUND: Increasing patient numbers, complexity of patient management, and healthcare resource limitations have resulted in prolonged patient wait times, decreased quality of service, and decreased patient satisfaction in many outpatient services worldwide. This study investigated the impact of Lean Six Sigma, a service improvement methodology originally from manufacturing, in reducing patient wait times and increasing service capacity in a publicly-funded, tertiary referral outpatient ophthalmology clinic. METHODS: This quality improvement study compared results from two five-months audits of operational data pre- and post-implementation of Lean Six Sigma. A baseline audit was conducted to determine duration and variability of patient in-clinic time and number of patients seen per clinic session. Staff interviews and a time-in-motion study were conducted to identify issues reducing clinic service efficiency. Solutions were developed to address these root causes including: clinic schedule amendments, creation of dedicated postoperative clinics, and clear documentation templates. A post-implementation audit was conducted, and the results compared with baseline audit data. Significant differences in patient in-clinic time pre- and post-solution implementation were assessed using Mann-Whitney test. Differences in variability of patient in-clinic times were assessed using Brown-Forsythe test. Differences in numbers of patients seen per clinic session were assessed using Student's t-test. RESULTS: During the baseline audit period, 19.4 patients were seen per 240-minute clinic session. Median patient in-clinic time was 131 minutes with an interquartile range of 133 minutes (84-217 minutes, quartile 1- quartile 3). Targeted low/negligible cost solutions were implemented to reduce in-clinic times. During the post-implementation audit period, the number of patients seen per session increased 9% to 21.1 (p = 0.016). There was significant reduction in duration (p < 0.001) and variability (p < 0.001) of patient in-clinic time (median 107 minutes, interquartile range 91 minutes [71-162 minutes]). CONCLUSIONS: Lean Six Sigma techniques may be used to reduce duration and variability of patient in-clinic time and increase service capacity in outpatient ophthalmology clinics without additional resource input.


Assuntos
Oftalmologia , Gestão da Qualidade Total , Instituições de Assistência Ambulatorial , Agendamento de Consultas , Eficiência Organizacional , Humanos , Oftalmologia/normas , Pacientes Ambulatoriais
11.
J Neurotrauma ; 38(5): 604-615, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33191851

RESUMO

Hemorrhage volume is an important variable in emergently assessing traumatic brain injury (TBI). The most widely used method for rapid volume estimation is ABC/2, a simple algorithm that approximates lesion geometry as perfectly ellipsoid. The relative prognostic value of volume measurement based on more precise hematoma topology remains unknown. In this study, we compare volume measurements obtained using ABC/2 versus computer-assisted volumetry (CAV) for both intra- and extra-axial traumatic hemorrhages, and then quantify the association of measurements using both methods with patient outcome following moderate to severe TBI. A total of 517 computer tomography (CT) scans acquired during the Progesterone for Traumatic Brain Injury Experimental Clinical Treatment Phase-III (ProTECTIII) multi-center trial were retrospectively reviewed. Lesion volumes were measured using ABC/2 and CAV. Agreement between methods was tested using Bland-Altman analysis. Relationship of volume measurements with 6-month mortality, Extended Glasgow Outcome Scale (GOS-E), and Disability Rating Scale (DRS) were assessed using linear regression and area under the curve (AUC) analysis. In subdural hematoma (SDH) >50cm3, ABC/2 and CAV produce significantly different volume measurements (p < 0.0001), although the difference was not significant for smaller SDH or intra-axial lesions. The disparity between ABC/2 and CAV measurements varied significantly with hematoma size for both intra- and extra-axial lesions (p < 0.0001). Across all lesions, volume was significantly associated with outcome using either method (p < 0.001), but CAV measurement was a significantly better predictor of outcome than ABC/2 estimation for SDH. Among large traumatic SDH, ABC/2 significantly overestimates lesion volume compared with measurement based on precise bleed topology. CAV also offers significantly better prediction of patient functional outcofme and mortality.


Assuntos
Hemorragia Encefálica Traumática/diagnóstico por imagem , Hemorragia Encefálica Traumática/mortalidade , Análise de Dados , Processamento de Imagem Assistida por Computador/métodos , Progesterona , Tomografia Computadorizada por Raios X/métodos , Hemorragia Encefálica Traumática/tratamento farmacológico , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/mortalidade , Feminino , Humanos , Masculino , Mortalidade/tendências , Progesterona/uso terapêutico , Prognóstico , Estudos Prospectivos , Método Simples-Cego , Resultado do Tratamento
12.
Dalton Trans ; 49(21): 7028-7036, 2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32378695

RESUMO

Analysis of highly reactive compounds at very low concentration in solution using electrospray ionization mass spectrometry requires the use of exhaustively purified solvents. It has generally been assumed that desolvation gas purity needs to be similarly high, and so most chemists working in this space have relied upon high purity gas. However, the increasing competitiveness of nitrogen generators, which provide gas purity levels that vary inversely with flow rate, prompted an investigation of the effect of gas-phase oxygen on the speciation of ions. The most reactive species studied, the reduced titanium complex [Cp2Ti(NCMe)2]+[ZnCl3]- and the olefin polymerization pre-catalyst [Cp2Zr(µ-Me)2AlMe2]+[B(C6F5)4]-, only exhibited detectable oxidation when they were rendered coordinatively unsaturated through in-source fragmentation. Computational chemistry allowed us to find the most plausible pathways for the observed chemistry in the absence of observed intermediates. The results provide insight into the gas-phase oxidation or hydrolysis of these reactive species.

13.
J Vasc Interv Radiol ; 31(8): 1210-1215.e4, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32460964

RESUMO

PURPOSE: To compare overall survival (OS) of ablation with no treatment for patients with advanced stage non-small cell lung cancer. METHODS: Patients with clinical stage IIIB (T1-4N3M0, T4N2M0) and stage IV (T1-4N0-3M1) non-small cell lung cancer, in accordance with the American Joint Committee on Cancer, 7th edition, who did not receive treatment or who received ablation as their sole primary treatment besides chemotherapy from 2004 to 2014, were identified from the National Cancer Data Base. OS was estimated using the Kaplan-Meier method and evaluated by log-rank test, univariate and multivariate Cox proportional hazard regression, and propensity score-matched analysis. Relative survival analyses comparing age- and sex-matched United States populations were performed. RESULTS: A total of 140,819 patients were included. The 1-, 2-, 3- and 5-year survival rates relative to age- and sex-matched United States population were 28%, 18%, 12%, and 10%, respectively, for ablation (n = 249); and 30%, 15%, 9%, and 5%, respectively for no treatment (n = 140,570). Propensity score matching resulted in 249 patients in the ablation group versus 498 patients in the no-treatment group. After matching, ablation was associated with longer OS than that in the no-treatment group (median, 5.9 vs 4.7 months, respectively; hazard ratio, 0.844; 95% confidence interval, 0.719-0.990; P = .037). These results persisted in patients with an initial tumor size of ≤3 cm. CONCLUSIONS: Preliminary results suggest ablation may be associated with longer OS in patients with late-stage non-small cell lung cancer than survival in those who received no treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/cirurgia , Ablação por Radiofrequência , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ablação por Radiofrequência/efeitos adversos , Ablação por Radiofrequência/mortalidade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Adulto Jovem
14.
IEEE Comput Graph Appl ; 40(1): 28-39, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30582530

RESUMO

We present a case study evaluating the potential for interactively identifying placental surface blood vessels using magnetic resonance imaging (MRI) scans in virtual reality (VR) environments. We visualized the MRI data using direct volume rendering in a high-fidelity CAVE-like VR system, allowing medical professionals to identify relevant placental vessels directly from volume visualizations in the VR system, without prior vessel segmentation. Participants were able to trace most of the observable vascular structure, and consistently identified blood vessels down to diameters of 1 mm, an important requirement in diagnosing vascular diseases. Qualitative feedback from our participants suggests that our VR visualization is easy to understand and allows intuitive data exploration, but complex user interactions remained a challenge. Using these observations, we discuss implications and requirements for spatial tracing user interaction methods in VR environments. We believe that VR MRI visualizations are the next step towards effective surgery planning for prenatal diseases.


Assuntos
Vasos Sanguíneos/diagnóstico por imagem , Placenta/irrigação sanguínea , Realidade Virtual , Feminino , Humanos , Imageamento por Ressonância Magnética , Gravidez
15.
Mol Cell Oncol ; 5(1): e1394422, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29404392

RESUMO

Despite numerous endeavors in clinical trials there are few clinically approved Antibody Drug Conjugate (ADC) therapies. Here we comment on our recent publication demonstrating the power of using panels of patient-derived xenografts (PDX) prior to Phase 1, to assess the potential heterogeneity of response a clinical candidate may show across a population. Furthermore we discuss how the same approach has been used in an additional ADC program.

16.
Int J Hyperthermia ; 34(1): 11-18, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28540805

RESUMO

OBJECTIVES: To investigate the effects of a novel caesium-based thermal accelerant (TA) agent on ablation zone volumes following in vivo microwave ablation of porcine liver and skeletal muscle, and to correlate the effects of TA with target organ perfusion. MATERIALS AND METHODS: This prospective study was performed following institutional animal care and use committee approval. Microwave ablation was performed in liver and resting skeletal muscle in eight Sus scrofa domesticus swine following administration of TA at concentrations of 0 mg/mL (control), 100 mg/mL and 250 mg/mL. Treated tissues were explanted and stained with triphenyltetrazolium chloride (TTC) for quantification of ablation zone volumes, which were compared between TA and control conditions. Hematoxylin and eosin (H&E) staining was also performed for histologic analysis. General mixed modelling with a log-normal distribution was used for all quantitative comparisons (p = 0.05). RESULTS: A total of 28 ablations were performed in the liver and 18 in the skeletal muscle. The use of TA significantly increased ablation zone volumes in a dose-dependent manner in both the porcine muscle and liver (p < 0.01). Both the absolute mean ablation zone volume and percentage increase in ablation zone volume were greater in the resting skeletal muscle than in the liver. In one swine, a qualitative mitigation of heat sink effects was observed by TTC and H&E staining. Non-lethal polymorphic ventricular tachycardia was identified in one swine, treated with intravenous amiodarone. CONCLUSIONS: The use of a novel TA agent significantly increased mean ablation zone volumes following microwave ablation using a porcine model. The relationship between TA administration and ablation size was dose-dependent and inversely proportional to the degree of target organ perfusion, and a qualitative reduction in heat-sink effects was observed.


Assuntos
Ablação por Cateter/métodos , Micro-Ondas , Radioterapia Guiada por Imagem/métodos , Animais , Masculino , Modelos Animais , Suínos
18.
Cancer Discov ; 7(9): 1030-1045, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28526733

RESUMO

Despite an improving therapeutic landscape, significant challenges remain in treating the majority of patients with advanced ovarian or renal cancer. We identified the cell-cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancers. HKT288 is an optimized CDH6-targeting DM4-based antibody-drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal antitumor activity and highlights CDH6 as an antigen for biotherapeutic development. To more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models-a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models in vivo, including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation.Significance: We identify CDH6 as a target for biotherapeutics development and demonstrate how an integrated pharmacology strategy that incorporates mechanistic pharmacodynamics and toxicology studies provides a rich dataset for optimizing the therapeutic format. We highlight how a population-based PDX clinical trial and retrospective biomarker analysis can provide correlates of activity and response to guide initial patient selection for first-in-human trials of HKT288. Cancer Discov; 7(9); 1030-45. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 920.


Assuntos
Antineoplásicos/uso terapêutico , Caderinas/antagonistas & inibidores , Neoplasias Renais/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Caderinas/genética , Caderinas/metabolismo , Feminino , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Macaca fascicularis , Camundongos Nus , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Am Acad Dermatol ; 76(6): 1151-1160.e21, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28427793

RESUMO

The American Academy of Dermatology has developed an up-to-date national Burden of Skin Disease Report on the impact of skin disease on patients and on the US population. In this second of 3 manuscripts, data are presented on specific health care dimensions that contribute to the overall burden of skin disease. Through the use of data derived from medical claims in 2013 for 24 skin disease categories, these results indicate that skin disease health care is delivered most frequently to the aging US population, who are afflicted with more skin diseases than other age groups. Furthermore, the overall cost of skin disease is highest within the commercially insured population, and skin disease treatment primarily occurs in the outpatient setting. Dermatologists provided approximately 30% of office visit care and performed nearly 50% of cutaneous surgeries. These findings serve as a critical foundation for future discussions on the clinical importance of skin disease and the value of dermatologic care across the population.


Assuntos
Efeitos Psicossociais da Doença , Atenção à Saúde/economia , Dermatopatias/economia , Dermatopatias/terapia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Dermatologia/estatística & dados numéricos , Humanos , Lactente , Seguro Saúde , Pessoa de Meia-Idade , Dermatopatias/epidemiologia , Estados Unidos , Adulto Jovem
20.
Theranostics ; 7(4): 1026-1035, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28382173

RESUMO

The primary challenge in thermal ablation of liver tumors (e.g. hepatocellular carcinoma and hepatic colorectal cancer) is the relatively high recurrence rate (~30%) for which incomplete ablation at the periphery of the tumor is the most common reason. In an attempt to overcome this, we have developed a novel thermal accelerant (TA) agent capable of augmenting microwave energy from a distance normally unattainable by a single microwave ablation antenna. This cesium-based block co-polymer compound transforms from a liquid to a gel at body temperature and is intrinsically visible by computed tomography. Using an agarose phantom model, herein we demonstrate that both the rate and magnitude of temperature increase during microwave ablation were significantly greater in the presence of TA when compared with controls. These results suggest robust augmentation of microwave energy, and may translate into larger ablation zone volumes within biologic tissues. Further work using in vivo techniques is necessary to confirm these findings.


Assuntos
Técnicas de Ablação/métodos , Meios de Contraste/administração & dosagem , Hipertermia Induzida/métodos , Micro-Ondas/uso terapêutico , Radioterapia Guiada por Imagem/métodos , Meios de Contraste/química , Neoplasias/radioterapia , Tomografia Computadorizada por Raios X
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