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1.
J Surg Oncol ; 117(6): 1179-1187, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29284070

RESUMO

BACKGROUND AND OBJECTIVES: Soft tissue sarcomas (STS) are mesenchymal malignancies. Treatment mainstay is surgical resection with negative margins ± adjuvant treatment. Fluorescence-guided surgical (FGS) resection can delineate intraoperative margins; FGS has improved oncologic outcomes in other malignancies. This novel strategy may minimize resection-associated morbidity while improving local tumor control. METHODS: We evaluate the tumor-targeting specificity and utility of fluorescence-imaging agents to provide disease-specific contrast. Mice with HT1080 fibrosarcoma tumors received one of five probes: cetuximab-IRDye800CW (anti-EGFR), DC101-IRDye800CW (anti-VEGFR-2), IgG-IRDye800CW, the cathepsin-activated probe Prosense750EX, or the small molecule probe IntegriSense750. Tumors were imaged daily using open- and closed-field fluorescence imaging systems. Tumor-to-background ratios (TBR) were evaluated. On peak TBR days, probe sensitivity was evaluated. Tumors were stained and imaged microscopically. RESULTS: At peak, closed-field imaging TBR of cetuximab-IRDye800CW (16.8) was significantly greater (P < 0.0001) than Integrisense750 (7.0), Prosense750EX (5.8), and DC101-IRDye800CW (3.7). All agents successfully localized as little as 1.0 mg of tumor tissue in the post-resection bed; cetuximab-IRDye800CW generated the greatest contrast (2.5). Cetuximab-IRDye800CW revealed strong tumor affinity microscopically; tumor fluorescence intensity was significantly greater (P < 0.0004) than 0.2 mm away from tumor border. CONCLUSION: This study demonstrates cetuximab-IRDye800CW superiority. FGS has the potential to improve post-resection morbidity and mortality by improving disease detection.


Assuntos
Anticorpos Monoclonais/metabolismo , Fibrossarcoma/cirurgia , Corantes Fluorescentes/metabolismo , Imagem Óptica/métodos , Sarcoma Experimental/cirurgia , Cirurgia Assistida por Computador/métodos , Animais , Feminino , Fibrossarcoma/diagnóstico por imagem , Fibrossarcoma/metabolismo , Fibrossarcoma/patologia , Camundongos , Camundongos Nus , Sarcoma Experimental/diagnóstico por imagem , Sarcoma Experimental/metabolismo , Sarcoma Experimental/patologia , Células Tumorais Cultivadas
2.
Ann Surg ; 266(1): 36-47, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28045715

RESUMO

OBJECTIVE: Although fluorescence imaging is being applied to a wide range of cancers, it remains unclear which disease populations will benefit greatest. Therefore, we review the potential of this technology to improve outcomes in surgical oncology with attention to the various surgical procedures while exploring trial endpoints that may be optimal for each tumor type. BACKGROUND: For many tumors, primary treatment is surgical resection with negative margins, which corresponds to improved survival and a reduction in subsequent adjuvant therapies. Despite unfavorable effect on patient outcomes, margin positivity rate has not changed significantly over the years. Thus, patients often experience high rates of re-excision, radical resections, and overtreatment. However, fluorescence-guided surgery (FGS) has brought forth new light by allowing detection of subclinical disease not readily visible with the naked eye. METHODS: We performed a systematic review of clinicatrials.gov using search terms "fluorescence," "image-guided surgery," and "near-infrared imaging" to identify trials utilizing FGS for those received on or before May 2016. INCLUSION CRITERIA: fluorescence surgery for tumor debulking, wide local excision, whole-organ resection, and peritoneal metastases. EXCLUSION CRITERIA: fluorescence in situ hybridization, fluorescence imaging for lymph node mapping, nonmalignant lesions, nonsurgical purposes, or image guidance without fluorescence. RESULTS: Initial search produced 844 entries, which was narrowed down to 68 trials. Review of literature and clinical trials identified 3 primary resection methods for utilizing FGS: (1) debulking, (2) wide local excision, and (3) whole organ excision. CONCLUSIONS: The use of FGS as a surgical guide enhancement has the potential to improve survival and quality of life outcomes for patients. And, as the number of clinical trials rise each year, it is apparent that FGS has great potential for a broad range of clinical applications.


Assuntos
Neoplasias/diagnóstico por imagem , Neoplasias/cirurgia , Imagem Óptica , Cirurgia Assistida por Computador/métodos , Procedimentos Cirúrgicos de Citorredução , Humanos
3.
J Surg Oncol ; 116(7): 898-906, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28628728

RESUMO

BACKGROUND AND OBJECTIVES: Optical imaging to guide cancer resections is rapidly transitioning into the operating room. However, the sensitivity of this technique to detect subclinical disease is yet characterized. The purpose of this study was to determine the minimum range of cancer cells that can be detected by antibody-based fluorescence imaging. METHODS: 2LMP (breast), COLO-205 (colon), MiaPaca-2 (pancreas), and SCC-1 (head and neck) cells incubated in vitro with cetuximab-IRDye800CW (dose range 8.6-86 nM) were implanted subcutaneously in mice (n = 3 mice, 5 tumors/mouse). Following incubation with 8.6 × 10-2 µM of cetuximab-IRDye800CW in vitro, serial dilutions of each cell type (1 × 103 -1 × 106 ) were implanted subcutaneously (n = 3, 5 tumors/mouse). Tumors were imaged with Pearl Impulse and Xenogen IVIS 100 imaging systems. Scatchard analysis was performed to determine receptor density and kinetics for each cell line. RESULTS: Under conditions of minimal cetuximab-IRDye800CW exposure to low cellular quantity, closed-field fluorescence imaging theoretically detected a minimum of 4.2 × 104 -9.5 × 104 2LMP cells, 1.9 × 105 -4.5 × 105 MiaPaca-2 cells, and 2.4 × 104 -6.7 × 104 SCC-1 cells; COLO-205 cells could not be identified. Higher EGFR-mediated uptake of cetuximab correlated with sensitivity of detection. CONCLUSION: This study supports the clinical utility of cetuximab-IRDye800CW to sensitively localize subclinical disease in the surgical setting.


Assuntos
Neoplasias/diagnóstico por imagem , Neoplasias/cirurgia , Imagem Óptica/métodos , Cirurgia Assistida por Computador/métodos , Animais , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/farmacocinética , Linhagem Celular Tumoral , Cetuximab/administração & dosagem , Cetuximab/farmacocinética , Feminino , Corantes Fluorescentes/administração & dosagem , Corantes Fluorescentes/farmacocinética , Xenoenxertos , Humanos , Indóis/administração & dosagem , Indóis/farmacocinética , Camundongos , Camundongos Nus , Compostos de Organotecnécio/administração & dosagem , Compostos de Organotecnécio/farmacocinética , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/farmacocinética
4.
Otolaryngol Head Neck Surg ; 171(1): 254-260, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38488232

RESUMO

OBJECTIVE: Compare surgical and swallow outcomes in robotic versus traditional laryngeal cleft (LC) repairs. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary care pediatric hospital. METHODS: Pediatric patients who underwent robotic or traditional (open or endoscopic) LC repair between 2010 and 2021 were identified. Patient characteristics, operative times, adverse events, hospital length of stay (LOS), and modified barium swallow study (MBSS) results were compared. RESULTS: Eighteen robotic and thirty traditional LC repairs were identified. Mean surgical (149 vs 111 min, P < .05) and OR times (207 vs 139 min, P < .002) were increased for robotic type I LC repairs, but were similar for type II and III LC. Mean hospital LOS was increased for robotic type I LC repairs (2.6 vs 1.2 days, P < .006), but was decreased for type II (4 vs 12.2 days) and type III (4.3 vs 94.5 days) LC. Postoperative MBSS results were improved for robotic type I LC repairs at 12 months (82% vs 43%, P = .05), and trended toward improvement at 6 months for type II (75% vs 22%), and type III (67% vs 50%) LC repairs, although significance was limited for type II and III LC due to the number of subjects. A robotic approach was used successfully to revise all recurrent LC that failed traditional repairs. CONCLUSION: Robotic type 1 LC repairs demonstrated increased operative times and hospital LOS but improved postoperative swallow outcomes compared to traditional approaches may be particularly useful in cases of recurrent clefts.


Assuntos
Laringe , Procedimentos Cirúrgicos Robóticos , Humanos , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/métodos , Masculino , Feminino , Laringe/cirurgia , Laringe/anormalidades , Lactente , Pré-Escolar , Tempo de Internação/estatística & dados numéricos , Resultado do Tratamento , Anormalidades Congênitas/cirurgia , Duração da Cirurgia , Criança
5.
Oral Oncol ; 159: 107045, 2024 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-39332273

RESUMO

OBJECTIVE: To compare the efficacy of the Modified Frailty Index and Modified Surgical Apgar scores in predicting postoperative outcomes in head and neck cancer patients. METHODS: We retrospectively reviewed patients who underwent major head and neck surgery between 2012 and 2015. Modified Surgical Apgar, and Frailty Index, scores were calculated on 723 patients. The primary outcome was 30-day complication and/or mortality. RESULTS: The mean Modified Frailty Index was 0.11 ± 0.12, and mean Modified Surgical Apgar score was 6.15 ± 1.67. Both scores were significantly associated with 30-day complication (P<0.05). The Modified Surgical Apgar score was superior to the Modified Frailty Index in predicting complications (Area Under the Curve (AUC) = 0.76; 95 % Confidence Interval (CI), 0.722-0.793; and AUC=0.59; 95 % CI, 0.548-0.633, respectively). Concurrent use of both scoring systems (AUC=0.77) was not superior to individual use. An increase in the mFI from 0.27 to 0.36 was associated with an increase in the risk of complication postoperatively (Odds Ratio (OR) = 3.67; 95 % CI, 1.30-10.34, P=.014). A reduction in the mSAS from 7 to 6 increased the risk of complication following surgery (OR=2.64; 95 % CI, 1.45-4.80; P=.002). CONCLUSION: Both scores are useful in risk stratifying head and neck cancer patients. The Modified Surgical Apgar score was superior at predicting complications; concurrent use of both scores added minimal benefit.

6.
Int J Pediatr Otorhinolaryngol ; 184: 112073, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39154570

RESUMO

OBJECTIVE: Provide an update on our institution's experience with utilizing transoral robotic surgery (TORS) in pediatric airway surgery and compare these results to surgery by traditional methods. METHODS: Pediatric patients who underwent TORS for treatment of upper airway pathology between 2010 and 2021 at our institution were retrospectively identified and compared to patients with the same or similar pathology who underwent a traditional (open or endoscopic) surgical approach over the same time period. Outcomes of interest included patient demographics, operative times, adverse events, hospital length of stay (LOS), and modified barium swallow (MBSS) results. RESULTS: Forty children (19M, 21F) underwent 46 TORS procedures. Mean age was 6.4 years (range: 6 days-17 years). Most commonly treated pathology included: laryngeal clefts (LC) (n = 18), lymphatic malformations (n = 9), and base of tongue masses (n = 7). Surgical time was decreased in traditional type I LC repairs (mean: 111 vs 149 min, P = 0.04) and lymphatic malformation excisions (59 vs 120 min, p = 0.005). Hospital LOS was increased in TORS type I LC repairs (2.6 vs 1.2 days, P = 0.04). Adverse event rate was similar between TORS and traditional cohorts (17 % vs 16 % cases, P = 0.9). Postoperative MBSS results were improved for TORS type I LC repairs at 6 months (70 % vs 33 %, P = 0.09) and 12 months (82 % vs 43 %, P = 0.05). CONCLUSIONS: Pediatric TORS is practical and safe and has comparable outcomes to traditional surgery. Robotic-assisted LC repair displayed improved postoperative swallow results versus traditional approaches and may be particularly useful in recurrent cases.


Assuntos
Procedimentos Cirúrgicos Robóticos , Humanos , Procedimentos Cirúrgicos Robóticos/métodos , Criança , Masculino , Feminino , Estudos Retrospectivos , Lactente , Pré-Escolar , Adolescente , Recém-Nascido , Resultado do Tratamento , Tempo de Internação/estatística & dados numéricos , Duração da Cirurgia , Anormalidades Linfáticas/cirurgia , Anormalidades Linfáticas/patologia , Cirurgia Endoscópica por Orifício Natural/métodos , Cirurgia Endoscópica por Orifício Natural/efeitos adversos , Anormalidades Congênitas , Laringe/anormalidades
7.
Oncotarget ; 13: 707-722, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35634245

RESUMO

Evolving understanding of head and neck squamous cell carcinoma (HNSCC) is leading to more specific diagnostic disease classifications. Among HNSCC caused by the human papilloma virus (HPV), tumors harboring defects in TRAF3 or CYLD are associated with improved clinical outcomes and maintenance of episomal HPV. TRAF3 and CYLD are negative regulators of NF-κB and inactivating mutations of either leads to NF-κB overactivity. Here, we developed and validated a gene expression classifier separating HPV+ HNSCCs based on NF-κB activity. As expected, the novel classifier is strongly enriched in NF-κB targets leading us to name it the NF-κB Activity Classifier (NAC). High NF-κB activity correlated with improved survival in two independent cohorts. Using NAC, tumors with high NF-κB activity but lacking defects in TRAF3 or CYLD were identified; thus, while TRAF3 or CYLD gene defects identify the majority of tumors with NF-κB activation, unknown mechanisms leading to NF-kB activity also exist. The NAC correctly classified the functional consequences of two novel CYLD missense mutations. Using a reporter assay, we tested these CYLD mutations revealing that their activity to inhibit NF-kB was equivalent to the wild-type protein. Future applications of the NF-κB Activity Classifier may be to identify HPV+ HNSCC patients with better or worse survival with implications for treatment strategies.


Assuntos
Alphapapillomavirus , Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Enzima Desubiquitinante CYLD/genética , Enzima Desubiquitinante CYLD/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Humanos , NF-kappa B/metabolismo , Papillomaviridae/genética , Papillomaviridae/metabolismo , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Fator 3 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/metabolismo
8.
Laryngoscope ; 131(2): 288-293, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32369198

RESUMO

OBJECTIVES/HYPOTHESIS: Each year, the Triological Society awards several Research Career Development Awards (CDAs) to support early-career otolaryngologists. The objective of this study was to evaluate academic outcomes of CDA recipients including National Institutes of Health (NIH) funding acquisition and h-index. A secondary objective was to appraise gender differences in outcomes among awardees. STUDY DESIGN: Cross-sectional study. METHODS: Recipients' practice setting, degree type, academic rank, and leadership titles were determined through review of academic and private practice profiles in October 2019. NIH funding was assessed using the NIH Research Portfolio Online Reporting Tool and the h-index was calculated using the Scopus database. RESULTS: Between 2004 and 2019, 70 investigators received a CDA. Of the 65 awardees prior to 2019, 26 (40.0%) obtained NIH grants after the CDA. Having an MD/PhD or MD/master's was not associated with NIH funding attainment (P = .891) nor with higher funding total (P = .109). However, funding total was significantly higher for full professors compared to assistant professors (P = .022). The median h-index among awardees was 16 (interquartile range = 11-21) and differed significantly by academic rank (P < .001). Moreover, 23 CDAs (32.9%) were awarded to women. However, fewer female recipients obtain NIH funding after the CDA compared to men (10.5% vs. 52.2%, P = .002), and they had significantly lower h-indices than men (10 vs. 17, P < .001). CONCLUSIONS: As a cohort, CDA awardees achieve higher academic success than academic otolaryngologists in general. However, female CDA recipients lag behind their male colleagues, highlighting the need for more research to uncover contributors to gender differences and ways to foster equity in research. LEVEL OF EVIDENCE: NA Laryngoscope, 131:288-293, 2021.


Assuntos
Sucesso Acadêmico , Distinções e Prêmios , Otolaringologia/educação , Pesquisadores/estatística & dados numéricos , Fatores Sexuais , Adulto , Estudos Transversais , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Apoio à Pesquisa como Assunto/estatística & dados numéricos , Estudos Retrospectivos , Sociedades Médicas , Estados Unidos
9.
J Drug Target ; 27(2): 193-200, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29972342

RESUMO

Intratumoural metabolic demands result in excessive angiogenic cytokine release leading to unorganised vasculature. Resultant fluid dynamics oppose blood flow and drug penetration due to a marked increase in interstitial fluid hydrostatic pressure. It is hypothesised that anti-angiogenic therapy may function to 'prune' vasculature and lead to improved chemotherapeutic penetration. Subcutaneous, OSC19 tumour bearing mice (n = 5/dose/agent) were administered varying doses of an anti-mouse VEGFR2 (DC101) or an anti-mouse VEGFR3 (31C1) -3 d, -1 d, 0 d, +1 d and +3 d prior to 200 µg of cetuximab fluorescently labelled with IRDye800CW. Fluorescence imaging of tumours was performed 10 d post cetuximab-IRDye800CW dose to monitor therapeutic uptake. Co-administration of dual anti-angiogenic agents at 50-50%, 75-25% and 25-75% using optimal dose and time (-1 d 10 mg/kg anti-VEGFR2 and -1 d 40 mg/kg anti-VEGFR3) was also evaluated. In order to establish vessel normalisation, NG2 (pericyte marker) and CD31 (endothelial cells) ratios were assessed during immunohistochemical staining of tumour sections. Twenty-mg/kg anti-VEGFR3 + 5 mg/kg anti-VEGFR2 significantly (p < .0005) reduced tumour size (-73%) compared to control (59%). The 20 mg/kg anti-VEGFR3 + 5 mg/kg anti-VEGFR2 and 30 mg/kg anti-VEGFR3 + 2.5 mg/kg anti-VEGFR2 significantly (p < .0004) improved percent-injected cetuximab-IRDye800CW dose/gram tumour tissue compared to other groups. Adjuvant, dual anti-angiogenic therapy targeting VEGFR2 and VEGFR3 significantly enhances tumour chemotherapeutic uptake compared to control.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/administração & dosagem , Benzenossulfonatos/química , Benzenossulfonatos/farmacologia , Linhagem Celular Tumoral , Cetuximab/química , Quimioterapia Adjuvante , Feminino , Indóis/química , Indóis/farmacologia , Camundongos , Camundongos Nus , Neoplasias Experimentais
10.
Otolaryngol Head Neck Surg ; 159(3): 466-472, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29870298

RESUMO

Objectives To recognize the utility of the surgical Apgar score (SAS) in a noncutaneous head and neck squamous cell carcinoma (HNSCC) population. Study Design Retrospective case series with chart review. Setting Academic tertiary medical center. Subjects and Methods Patients (n = 563) undergoing noncutaneous HNSCC resection between April 2012 and March 2015 were included. Demographics, medical history, intraoperative data, and postoperative hospital summaries were collected. SASs were calculated following the published schema. The primary outcome was 30-day postoperative morbidity. A 2-sample t test, analysis of variance, and χ2 (or Fisher exact) test were used for statistical comparisons. A multivariable logistic regression analysis was conducted to identify independent predictors of 30-day morbidity. Results Mean SAS was 6.2 ± 1.5. SAS groups did not differ in age, sex, or race. Sixty-five patients (11.6%) had a SAS between 0 and 4, with 40 incidences of morbidity (61.5%), while 31 (5.5%) patients with SAS from 9 to 10 had 3 morbidity occurrences (9.7%). Results show that 30-day postoperative morbidity is inversely related to increasing SAS ( P < .0001). Furthermore, lower SAS was associated with significantly increased operative time (SAS 0-4: 9.3 ± 2.6 hours vs SAS 9-10: 3.0 ± 1.1 hours) and lengths of stay (SAS 0-4: 10.0 ± 7.3 days vs SAS 9-10: 1.6 ± 1.0 days), P < .0001. SAS remained highly significant after adjusting for potential confounding variables in the multivariable analysis ( P < .0001). Conclusions An increasing SAS is associated with significantly lower rates of 30-day postoperative morbidities in a noncutaneous HNSCC patient population.


Assuntos
Índice de Apgar , Causas de Morte , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Centros Médicos Acadêmicos , Adulto , Fatores Etários , Idoso , Análise de Variância , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/fisiopatologia , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Análise de Sobrevida , Adulto Jovem
11.
Otolaryngol Head Neck Surg ; 159(1): 68-75, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29436276

RESUMO

Objective The Surgical Apgar Score (SAS) is a validated postoperative complication prediction model. The purpose of this study was to investigate the utility of the SAS in a diverse head and neck cancer population and to compare it with a recently developed modified SAS (mSAS) that accounts for intraoperative transfusion. Study Design Case series with chart review. Setting Academic tertiary care medical center. Subjects and Methods This study comprised 713 patients undergoing surgery for head and neck cancer from April 2012 to March 2015. SAS values were calculated according to intraoperative data obtained from anesthesia records. The mSAS was computed by assigning an estimated blood loss score of zero for patients receiving intraoperative transfusions. Primary outcome was 30-day postoperative morbidity. Results Mean SAS and mSAS were 6.3 ± 1.5 and 6.2 ± 1.7, respectively. SAS and mSAS were significantly associated with 30-day postoperative morbidity, length of stay, operative time, American Society of Anesthesiologists status, race, and body mass index ( P < .05); however, no significant association was detected for age, sex, and smoking status. Multivariable analysis identified SAS and mSAS as independent predictors of postoperative morbidity, with the mSAS ( P = .03) being a more robust predictor than the SAS ( P = .15). Strong inverse relationships were demonstrated for the SAS and mSAS with length of stay and operative time ( P < .0001). Conclusion The SAS serves as a useful metric for risk stratification of patients with head and neck cancer. With the inclusion of intraoperative transfusion, the mSAS demonstrates superior utility in predicting those at risk for postoperative complications.


Assuntos
Índice de Apgar , Neoplasias de Cabeça e Pescoço/cirurgia , Complicações Pós-Operatórias/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco/métodos
12.
Surg Oncol ; 27(2): 225-230, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29937175

RESUMO

BACKGROUND: Tumor proliferation often occurs from pathologic receptor upregulation. These receptors provide unique targets for near-infrared (NIR) probes that have fluorescence-guided surgery (FGS) applications. We demonstrate the use of three smart-targeted probes in a model of head and neck squamous cell carcinoma. METHODS: A dose escalation study was performed using IntegriSense750, ProSense750EX, and ProSense750FAST in mice (n = 5) bearing luciferase-positive SCC-1 flank xenograft tumors. Whole body fluorescence imaging was performed serially after intravenous injection using commercially available open-field (LUNA, Novadaq, Canada) and closed-field NIR systems (Pearl, LI-COR, Lincoln, NE). An ex vivo, whole-body biodistribution was conducted. Lastly, FGS was performed with IntegriSense750 to demonstrate orthotopic and metastatic disease localization. RESULTS: Disease fluorescence delineation was assessed by tumor-to-background fluorescence ratios (TBR). Peak TBR values were 3.3 for 1 nmol ProSense750EX, 5.5 for 6 nmol ProSense750FAST, and 10.8 for 4 nmol IntegriSense750 at 5.5, 3, and 4 d post administration, respectively. Agent utility is unique: ProSense750FAST provides sufficient contrast quickly (TBR: 1.5, 3 h) while IntegriSense750 produces strong (TBR: 10.8) contrast with extended administration-to-resection time (96 h). IntegriSense750 correctly identified all diseased nodes in situ during exploratory surgeries. Ex vivo, whole-body biodistribution was assessed by tumor-to-tissue fluorescence ratios (TTR). Agents provided sufficient fluorescence contrast to discriminate disease from background, TTR>1. IntegriSense750 was most robust in neural tissue (TTR: 64) while ProSense750EX was superior localizing disease against lung tissue (TBR: 13). CONCLUSION: All three agents appear effective for FGS.


Assuntos
Carcinoma de Células Escamosas/cirurgia , Corantes Fluorescentes , Neoplasias de Cabeça e Pescoço/cirurgia , Modelos Anatômicos , Imagem Óptica/métodos , Cirurgia Assistida por Computador/métodos , Animais , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/secundário , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Camundongos , Camundongos Nus , Células Tumorais Cultivadas
13.
Int Forum Allergy Rhinol ; 7(9): 904-909, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28597597

RESUMO

BACKGROUND: Sinus hypoplasia is a hallmark characteristic in cystic fibrosis (CF). Chronic rhinosinusitis (CRS) is nearly universal from a young age, impaired sinus development could be secondary to loss of the cystic fibrosis transmembrane conductance regulator (CFTR) or consequences of chronic infection during maturation. The objective of this study was to assess sinus development relative to overall growth in a novel CF animal model. METHODS: Sinus development was evaluated in CFTR-/- and CFTR+/+ rats at 3 stages of development: newborn; 3 weeks; and 16 weeks. Microcomputed tomography (microCT) scanning, cultures, and histology were performed. Three-dimensional sinus and skull volumes were quantified. RESULTS: At birth, sinus volumes were decreased in CFTR-/- rats compared with wild-type rats (mean ± SEM: 11.3 ± 0.85 mm3 vs 14.5 ± 0.73 mm3 ; p < 0.05), despite similar weights (8.4 ± 0.46 gm vs 8.3 ± 0.51 gm; p = 0.86). CF rat weights declined by 16 weeks (378.4 ± 10.6 gm vs 447.4 ± 15.9 gm; p < 0.05), sinus volume increased similar to wild-type rats (201.1 ± 3.77 gm vs 203.4 ± 7.13 gm; p = 0.8). The ratio of sinus volume to body weight indicates hypoplasia present at birth (1.37 ± 0.12 vs 1.78 ± 0.11; p < 0.05) and showed an increase compared with CFTR+/+ animals by 16 weeks (0.53 ± 0.02 vs 0.46 ± 0.02; p < 0.05). Rats did not develop histologic evidence of chronic infection. CONCLUSION: CF rat sinuses are smaller at birth, but develop volumes similar to wild-type rats with maturation. This suggests that loss of CFTR may confer sinus hypoplasia at birth, but normal development ensues without chronic sinus infection.


Assuntos
Fibrose Cística , Modelos Animais de Doenças , Seios Paranasais/crescimento & desenvolvimento , Animais , Animais Geneticamente Modificados , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia , Masculino , Seios Paranasais/diagnóstico por imagem , Ratos , Microtomografia por Raio-X
14.
Mol Imaging Biol ; 19(4): 610-616, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-27830425

RESUMO

PURPOSE: Intraoperative optical imaging to guide surgeons during oncologic resections offers a unique and promising solution to the ambiguity of cancer margins to tactile and visual assessment that results in devastatingly high rates of positive margins. Sequestering of labeled antibodies by normal tissues with high expression of the antibody target, or "antigen sinks", diminishes the efficacy of these probes to provide contrast between the tumor and background tissues by decreasing the amount of circulating probe available for uptake by the tumor and by increasing the fluorescence of non-tumor tissues. We hypothesized that administering a dose of unlabeled antibody prior to infusion of the near-infrared (NIR) fluorescently labeled antibody would improve tumor-specific uptake and contrast of the fluorescently labeled probe by occupying extra-tumoral binding sites, thereby increasing the amount of labeled probe available for uptake by the tumor. PROCEDURES: In this study, we explore this concept by testing two different "pre-load" doses of unlabeled cetuximab (the standard 10-mg test dose, and a larger, experimental 100-mg test dose) in six patients receiving cetuximab conjugated to the fluorescent dye IRDye800CW (cetuximab-IRDye800CW) in a clinical trial, and compared the amount of fluorescent antibody in tumor and background tissues, as well as the tumor-specific contrast of each. RESULTS: The patients receiving the larger preload (100 mg) of unlabeled cetuximab demonstrated significantly higher concentrations (9.5 vs. 0.1 µg) and a longer half-life (30.3 vs. 20.6 days) of the labeled cetuximab in plasma, as well as significantly greater tumor fluorescence (32.3 vs. 9.3 relative fluorescence units) and tumor to background ratios (TBRs) (5.5 vs. 1.7). CONCLUSIONS: Administering a preload of unlabeled antibody prior to infusion of the fluorescently labeled drug may be a simple and effective way to improve the performance of antibody-based probes to guide surgical resection of solid malignancies.


Assuntos
Anticorpos/metabolismo , Imunofluorescência/métodos , Corantes Fluorescentes/química , Neoplasias/diagnóstico por imagem , Imagem Óptica/métodos , Procedimentos Cirúrgicos Operatórios , Adulto , Idoso , Cetuximab/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Coloração e Rotulagem
15.
J Nucl Med ; 58(2): 246-251, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27587708

RESUMO

The purpose of this study was to assess the potential of U.S. Food and Drug Administration-cleared devices designed for indocyanine green-based perfusion imaging to identify cancer-specific bioconjugates with overlapping excitation and emission wavelengths. Recent clinical trials have demonstrated potential for fluorescence-guided surgery, but the time and cost of the approval process may impede clinical translation. To expedite this translation, we explored the feasibility of repurposing existing optical imaging devices for fluorescence-guided surgery. METHODS: Consenting patients (n = 15) scheduled for curative resection were enrolled in a clinical trial evaluating the safety and specificity of cetuximab-IRDye800 (NCT01987375). Open-field fluorescence imaging was performed preoperatively and during the surgical resection. Fluorescence intensity was quantified using integrated instrument software, and the tumor-to-background ratio characterized fluorescence contrast. RESULTS: In the preoperative clinic, the open-field device demonstrated potential to guide preoperative mapping of tumor borders, optimize the day of surgery, and identify occult lesions. Intraoperatively, the device demonstrated robust potential to guide surgical resections, as all peak tumor-to-background ratios were greater than 2 (range, 2.2-14.1). Postresection wound bed fluorescence was significantly less than preresection tumor fluorescence (P < 0.001). The repurposed device also successfully identified positive margins. CONCLUSION: The open-field imaging device was successfully repurposed to distinguish cancer from normal tissue in the preoperative clinic and throughout surgical resection. This study illuminated the potential for existing open-field optical imaging devices with overlapping excitation and emission spectra to be used for fluorescence-guided surgery.


Assuntos
Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/cirurgia , Margens de Excisão , Microscopia de Fluorescência/instrumentação , Cirurgia Assistida por Computador/instrumentação , Tomografia Óptica/instrumentação , Adulto , Idoso , Desenho de Equipamento , Análise de Falha de Equipamento , Reutilização de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Cirurgia Assistida por Computador/métodos , Resultado do Tratamento
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