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1.
Nat Commun ; 12(1): 1717, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741967

RESUMO

Myeloid-derived suppressor cells (MDSC) are pathologically activated neutrophils and monocytes with potent immune suppressive activity. These cells play an important role in accelerating tumor progression and undermining the efficacy of anti-cancer therapies. The natural mechanisms limiting MDSC activity are not well understood. Here, we present evidence that type I interferons (IFN1) receptor signaling serves as a universal mechanism that restricts acquisition of suppressive activity by these cells. Downregulation of the IFNAR1 chain of this receptor is found in MDSC from cancer patients and mouse tumor models. The decrease in IFNAR1 depends on the activation of the p38 protein kinase and is required for activation of the immune suppressive phenotype. Whereas deletion of IFNAR1 is not sufficient to convert neutrophils and monocytes to MDSC, genetic stabilization of IFNAR1 in tumor bearing mice undermines suppressive activity of MDSC and has potent antitumor effect. Stabilizing IFNAR1 using inhibitor of p38 combined with the interferon induction therapy elicits a robust anti-tumor effect. Thus, negative regulatory mechanisms of MDSC function can be exploited therapeutically.


Assuntos
Interferon Tipo I/metabolismo , Células Supressoras Mieloides/imunologia , Neoplasias/metabolismo , Receptor de Interferon alfa e beta/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/farmacologia , Medula Óssea , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Monócitos/imunologia , Neutrófilos/imunologia , Receptor de Interferon alfa e beta/genética , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Cell Rep ; 33(13): 108571, 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33378668

RESUMO

Here, we report that functional heterogeneity of macrophages in cancer could be determined by the nature of their precursors: monocytes (Mons) and monocytic myeloid-derived suppressor cells (M-MDSCs). Macrophages that are differentiated from M-MDSCs, but not from Mons, are immune suppressive, with a genomic profile matching that of M-MDSCs. Immune-suppressive activity of M-MDSC-derived macrophages is dependent on the persistent expression of S100A9 protein in these cells. S100A9 also promotes M2 polarization of macrophages. Tissue-resident- and Mon-derived macrophages lack expression of this protein. S100A9-dependent immune-suppressive activity of macrophages involves transcription factor C/EBPß. The presence of S100A9-positive macrophages in tumor tissues is associated with shorter survival in patients with head and neck cancer and poor response to PD-1 antibody treatment in patients with metastatic melanoma. Thus, this study reveals the pathway of the development of immune-suppressive macrophages and suggests an approach to their selective targeting.

3.
Nature ; 569(7754): 73-78, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30996346

RESUMO

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that are crucial for the regulation of immune responses in cancer. These cells contribute to the failure of cancer therapies and are associated with poor clinical outcomes. Despite recent advances in the understanding of PMN-MDSC biology, the mechanisms responsible for the pathological activation of neutrophils are not well defined, and this limits the selective targeting of these cells. Here we report that mouse and human PMN-MDSCs exclusively upregulate fatty acid transport protein 2 (FATP2). Overexpression of FATP2 in PMN-MDSCs was controlled by granulocyte-macrophage colony-stimulating factor, through the activation of the STAT5 transcription factor. Deletion of FATP2 abrogated the suppressive activity of PMN-MDSCs. The main mechanism of FATP2-mediated suppressive activity involved the uptake of arachidonic acid and the synthesis of prostaglandin E2. The selective pharmacological inhibition of FATP2 abrogated the activity of PMN-MDSCs and substantially delayed tumour progression. In combination with checkpoint inhibitors, FATP2 inhibition blocked tumour progression in mice. Thus, FATP2 mediates the acquisition of immunosuppressive activity by PMN-MDSCs and represents a target to inhibit the functions of PMN-MDSCs selectively and to improve the efficiency of cancer therapy.


Assuntos
Proteínas de Transporte de Ácido Graxo/metabolismo , Ácidos Graxos/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Neutrófilos/metabolismo , Idoso , Animais , Ácido Araquidônico/metabolismo , Dinoprostona/metabolismo , Proteínas de Transporte de Ácido Graxo/antagonistas & inibidores , Feminino , Humanos , Metabolismo dos Lipídeos , Lipídeos , Masculino , Camundongos , Pessoa de Meia-Idade , Neutrófilos/patologia , Fator de Transcrição STAT5/metabolismo
4.
Nat Immunol ; 19(11): 1236-1247, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30323345

RESUMO

Although neutrophils have been linked to the formation of the pre-metastatic niche, the mechanism of their migration to distant, uninvolved tissues has remained elusive. We report that bone marrow neutrophils from mice with early-stage cancer exhibited much more spontaneous migration than that of control neutrophils from tumor-free mice. These cells lacked immunosuppressive activity but had elevated rates of oxidative phosphorylation and glycolysis, and increased production of ATP, relative to that of control neutrophils. Their enhanced spontaneous migration was mediated by autocrine ATP signaling through purinergic receptors. In ectopic tumor models and late stages of cancer, bone marrow neutrophils demonstrated potent immunosuppressive activity. However, these cells had metabolic and migratory activity indistinguishable from that of control neutrophils. A similar pattern of migration was observed for neutrophils and polymorphonuclear myeloid-derived suppressor cells from patients with cancer. These results elucidate the dynamic changes that neutrophils undergo in cancer and demonstrate the mechanism of neutrophils' contribution to early tumor dissemination.


Assuntos
Quimiotaxia de Leucócito/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Idoso , Animais , Progressão da Doença , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade
6.
Oral Oncol ; 78: 102-107, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29496036

RESUMO

OBJECTIVES: The objective of this study was to investigate the safety, tolerability and preliminary efficacy of radiotherapy plus cetuximab in high risk CSCC patients. MATERIALS AND METHODS: Patients with high-risk CSCC diagnosed between 2006 and 2013 were analyzed. Patients were divided into two groups: radiotherapy alone versus radiotherapy plus cetuximab. Among 68 patients meeting study criteria, we identified 29 treated with cetuximab plus RT and 39 with RT alone. Primary analysis examined disease-free and overall survival, freedom from local and distant recurrence in the propensity score matched cohort. Propensity score analysis was performed with weighted factors including: Charlson Comorbidity Index score, age. KPS, primary location, T and N stage, recurrent status, margin status, LVSI, PNI and grade. Toxicity was assessed using the CTCAE v4.0. RESULTS: Median follow-up for living patients was 30 months. Patients in the cetuximab group were more likely to have advanced N stage, positive margins and recurrent disease. After propensity score matching the groups were well balanced. Six patients experienced ≥ grade 3 acute toxicity in the cetuximab group. The 1-year, 2-year and 5-year progression free survival (PFS) for patients in the cetuximab group were 86%, 72% and 66%, respectively. The 1-year, 2-year and 5-year overall survival (OS) for patients in the cetuximab group was 98%, 80% and 80%, respectively. CONCLUSIONS: Although limited by small numbers, the combination of cetuximab and radiotherapy in CSCC appears well tolerated there were more long-term survivors and less distant metastasis in the cetuximab group. These promising finding warrant further studies.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Cetuximab/uso terapêutico , Quimiorradioterapia , Neoplasias Cutâneas/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Cuidados Pós-Operatórios , Análise de Sobrevida
7.
Cancer Cell ; 32(5): 654-668.e5, 2017 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-29136508

RESUMO

Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Monócitos/metabolismo , Células Supressoras Mieloides/metabolismo , Neoplasias Experimentais/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Animais , Fibroblastos Associados a Câncer/efeitos dos fármacos , Linhagem Celular Tumoral , Granulócitos/metabolismo , Histona Desacetilase 2 , Humanos , Imidazóis/farmacologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/metabolismo , Carga Tumoral/efeitos dos fármacos
8.
Clin Cancer Res ; 23(12): 2942-2950, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-27965309

RESUMO

Purpose: Myeloid-derived suppressor cells (MDSC) are one of the major contributors to immune suppression in cancer. We recently have demonstrated in preclinical study that MDSCs are sensitive to TRAIL receptor 2 (TRAIL-R2) agonist. The goal of this study was to clinically test the hypothesis that targeting TRAIL-R2 can selectively eliminate MDSCs.Experimental Design: The TRAIL-R2 agonistic antibody (DS-8273a) has been tested in 16 patients with advanced cancers enrolled in a phase I trial. The antibody (24 mg/kg) was administered intravenously once every 3 weeks till disease progression, unacceptable toxicities, or withdrawal of consent. The safety and the presence of various populations of myeloid and lymphoid cells in peripheral blood and tumor tissues were evaluated.Results: The treatment was well tolerated with only mild to moderate adverse events attributable to the study drug. Treatment with DS-8273a resulted in reduction of the elevated numbers of MDSCs in the peripheral blood of most patients to the levels observed in healthy volunteers. However, in several patients, MDSCs rebounded back to the pretreatment level by day 42. In contrast, DS-8273a did not affect the number of neutrophils, monocytes, and other populations of myeloid and lymphoid cells. Decrease in MDSCs inversely correlated with the length of progression-free survival. In tumors, DS-8273a treatment resulted in a decrease of MDSCs in 50% of the patients who were able to provide pre- and on-treatment biopsies.Conclusions: Targeting TRAIL-R2 resulted in elimination of different populations of MDSCs without affecting mature myeloid or lymphoid cells. These data support the use of this antibody in combination immmunotherapy of cancer. Clin Cancer Res; 23(12); 2942-50. ©2016 AACR.


Assuntos
Imunoterapia , Células Supressoras Mieloides/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Intervalo Livre de Doença , Humanos , Imunossupressão , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Pessoa de Meia-Idade , Monócitos/imunologia , Células Mieloides/imunologia , Células Supressoras Mieloides/imunologia , Neoplasias/imunologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/agonistas
9.
Immunity ; 44(2): 303-15, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26885857

RESUMO

Recruitment of monocytic myeloid-derived suppressor cells (MDSCs) and differentiation of tumor-associated macrophages (TAMs) are the major factors contributing to tumor progression and metastasis. We demonstrated that differentiation of TAMs in tumor site from monocytic precursors was controlled by downregulation of the activity of the transcription factor STAT3. Decreased STAT3 activity was caused by hypoxia and affected all myeloid cells but was not observed in tumor cells. Upregulation of CD45 tyrosine phosphatase activity in MDSCs exposed to hypoxia in tumor site was responsible for downregulation of STAT3. This effect was mediated by the disruption of CD45 protein dimerization regulated by sialic acid. Thus, STAT3 has a unique function in the tumor environment in controlling the differentiation of MDSC into TAM, and its regulatory pathway could be a potential target for therapy.


Assuntos
Hipóxia/imunologia , Antígenos Comuns de Leucócito/metabolismo , Macrófagos/imunologia , Monoéster Fosfórico Hidrolases/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Diferenciação Celular , Movimento Celular , Células Cultivadas , Dimerização , Feminino , Antígenos Comuns de Leucócito/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/imunologia , Monoéster Fosfórico Hidrolases/genética , Fator de Transcrição STAT3/genética , Ácidos Siálicos/metabolismo , Microambiente Tumoral
10.
Sci Immunol ; 1(2)2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28417112

RESUMO

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are important regulators of immune responses in cancer and have been directly implicated in promotion of tumor progression. However, the heterogeneity of these cells and lack of distinct markers hampers the progress in understanding of the biology and clinical importance of these cells. Using partial enrichment of PMN-MDSC with gradient centrifugation we determined that low density PMN-MDSC and high density neutrophils from the same cancer patients had a distinct gene profile. Most prominent changes were observed in the expression of genes associated with endoplasmic reticulum (ER) stress. Surprisingly, low-density lipoprotein (LDL) was one of the most increased regulators and its receptor oxidized LDL receptor 1 OLR1 was one of the most overexpressed genes in PMN-MDSC. Lectin-type oxidized LDL receptor 1 (LOX-1) encoded by OLR1 was practically undetectable in neutrophils in peripheral blood of healthy donors, whereas 5-15% of total neutrophils in cancer patients and 15-50% of neutrophils in tumor tissues were LOX-1+. In contrast to their LOX-1- counterparts, LOX-1+ neutrophils had gene signature, potent immune suppressive activity, up-regulation of ER stress, and other biochemical characteristics of PMN-MDSC. Moreover, induction of ER stress in neutrophils from healthy donors up-regulated LOX-1 expression and converted these cells to suppressive PMN-MDSC. Thus, we identified a specific marker of human PMN-MDSC associated with ER stress and lipid metabolism, which provides new insight to the biology and potential therapeutic targeting of these cells.

11.
Oral Oncol ; 51(6): 616-21, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25868716

RESUMO

PURPOSE: To update the outcomes of an institutional clinical management approach using ipsilateral neck radiotherapy in the treatment of node-positive squamous cell carcinoma of the tonsil with a well-lateralized primary lesion. METHODS AND MATERIALS: Between August 2003 and April 2014, 61 consecutive patients with ipsilateral node-positive squamous cell carcinoma of the tonsil without involvement of the base of the tongue or midline soft palate were treated at a community hospital-based cancer center with radiotherapy to the primary site and ipsilateral neck. Overall survival, disease-free survival and freedom from contralateral failure were calculated. RESULTS: Median follow up was 37.2months (range 4-121months). Freedom from contralateral nodal failure at 5years was 98% with one contralateral nodal failure noted. The patient underwent a salvage neck dissection and was treated with post-operative radiotherapy with no evidence of disease to date. 5-year overall survival (OS) was 92.4% and 5year disease-free survival (DFS) was 86.7%. CONCLUSIONS: This represents the single largest series reported from a community hospital-based cancer center in which lateralized tonsil cancers with N+ disease were treated with ipsilateral neck radiotherapy. In this carefully selected cohort of patients with well-lateralized tonsil cancers, the risk of contralateral nodal failure appears to be <5%, suggesting that prophylactic radiation of the contralateral neck may not be necessary. Future planned studies will focus on prospectively selecting subgroups of patients eligible for treatment de-intensification as survivorship issues in excellent prognosis HPV positive patients are increasingly becoming relevant.


Assuntos
Carcinoma de Células Escamosas/radioterapia , Terapia Combinada/métodos , Neoplasias Tonsilares/radioterapia , Adulto , Idoso , Carcinoma de Células Escamosas/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esvaziamento Cervical/métodos , Prognóstico , Estudos Retrospectivos , Neoplasias Tonsilares/cirurgia
12.
J Clin Invest ; 124(6): 2626-39, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24789911

RESUMO

Myeloid-derived suppressor cells (MDSCs) dampen the immune response thorough inhibition of T cell activation and proliferation and often are expanded in pathological conditions. Here, we studied the fate of MDSCs in cancer. Unexpectedly, MDSCs had lower viability and a shorter half-life in tumor-bearing mice compared with neutrophils and monocytes. The reduction of MDSC viability was due to increased apoptosis, which was mediated by increased expression of TNF-related apoptosis-induced ligand receptors (TRAIL-Rs) in these cells. Targeting TRAIL-Rs in naive mice did not affect myeloid cell populations, but it dramatically reduced the presence of MDSCs and improved immune responses in tumor-bearing mice. Treatment of myeloid cells with proinflammatory cytokines did not affect TRAIL-R expression; however, induction of ER stress in myeloid cells recapitulated changes in TRAIL-R expression observed in tumor-bearing hosts. The ER stress response was detected in MDSCs isolated from cancer patients and tumor-bearing mice, but not in control neutrophils or monocytes, and blockade of ER stress abrogated tumor-associated changes in TRAIL-Rs. Together, these data indicate that MDSC pathophysiology is linked to ER stress, which shortens the lifespan of these cells in the periphery and promotes expansion in BM. Furthermore, TRAIL-Rs can be considered as potential targets for selectively inhibiting MDSCs.


Assuntos
Estresse do Retículo Endoplasmático , Células Mieloides/imunologia , Células Mieloides/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Animais , Apoptose/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Biológicos , Células Mieloides/patologia
13.
Head Neck ; 34(6): 886-93, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22610591

RESUMO

The toxicity associated with concomitant chemoradiation for the management of laryngeal and pharyngeal carcinoma has been well documented. Minimally invasive surgical techniques offer the potential to extirpate the malignancy as a single-modality therapy and provide essential information that may direct subsequent treatment. In selected patients, radiation doses may be reduced and systemic chemotherapy may be withheld after tumor extirpation. Transoral laser microsurgery has proven effective, although inability to manipulate and suture tissue by this modality limits ablation and reconstruction of extensive defects. Transoral robotic surgery is a relatively new technique that provides several unique advantages, which include a 3-dimensional magnified view, ability to see and work around curves or angles, and the availability of 2 or 3 robotic arms that can be used to reconstruct extensive defects using either local, regional, or free flaps. Preliminary data suggest that transoral robotic surgery may provide a technique for ablation and reconstruction of pharyngeal defects that may be superior to other transoral techniques. It may also provide a means for personalizing therapy for oropharyngeal and supraglottic carcinoma.


Assuntos
Neoplasias de Cabeça e Pescoço/terapia , Robótica , Quimioterapia Adjuvante , Humanos , Tratamentos com Preservação do Órgão , Radioterapia Adjuvante
14.
Otolaryngol Head Neck Surg ; 137(2): 269-73, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17666254

RESUMO

OBJECTIVE: The electronic nose is a sensor of volatile molecules that is useful in the analysis of expired gases. Our hypothesis is that the electronic nose can distinguish between different types of upper aerodigestive tract tumor cells in vitro. STUDY DESIGN: Cells from both tumor and normal cell lines were suspended in saline, and a polymer composite electronic nose was used to evaluate the headspace gases. The data were subjected to principal components analysis, and Mahalanobis distances were calculated to demonstrate the ability of the electronic nose to distinguish among samples. RESULTS: The tumor cell lines, including adenocarcinoma, squamous cell carcinoma, and mesothelioma, were distinct from each other, and from the normal fibroblast and smooth muscle cells as seen on canonical discrimination plots. CONCLUSION: The electronic nose can distinguish between tumor cell lines in vitro and has the potential to be a useful screening test for cancer.


Assuntos
Técnicas Biossensoriais/instrumentação , Células Tumorais Cultivadas , Eletrônica , Humanos , Técnicas In Vitro , Odorantes , Análise de Componente Principal , Sensibilidade e Especificidade , Volatilização
15.
Ann Otol Rhinol Laryngol ; 116(1): 19-23, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17305273

RESUMO

OBJECTIVES: We assessed the feasibility of performing transoral supraglottic partial laryngectomy with robotic instrumentation. METHODS: Transoral robotic surgery (TORS) was performed on 3 human patients with supraglottic carcinoma in a prospective human trial. The study was approved by our institutional review board and involved the da Vinci Surgical Robot (Intuitive Surgical, Inc, Sunnyvale, California). RESULTS: All procedures were completed robotically. The median overall operation time to perform the robotic procedure was 120 minutes (range, 1:32:48 to 2:58:18), including 18 minutes (range, 00:6:07 to 00:30:39) for exposure and robotic positioning. There were no intraoperative or postoperative complications or surgical mortality. CONCLUSIONS: The preliminary results of our series suggest that application of the da Vinci robotic surgical system for TORS to supraglottic partial laryngectomy is technically feasible and relatively safe. Furthermore, TORS provides excellent surgical exposure that allows complete tumor resection. Most importantly, TORS provides an alternative to open approaches and "conventional" transoral supraglottic partial laryngectomy.


Assuntos
Laringectomia/métodos , Robótica , Idoso , Carcinoma/cirurgia , Estudos de Viabilidade , Feminino , Glote/cirurgia , Humanos , Neoplasias Laríngeas/cirurgia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Resultado do Tratamento
16.
Laryngoscope ; 116(8): 1465-72, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16885755

RESUMO

OBJECTIVE: To develop a minimally invasive surgical technique for the treatment of base of tongue neoplasms using the optical and technical advantages of robotic surgical instrumentation. STUDY DESIGN: Ten experimental procedures including tongue base exposure and dissections were performed on three cadavers and two mongrel dogs. Transoral robotic surgery (TORS) was then performed on three human patients with tongue base cancers in a prospective human trial. METHODS: Using the da Vinci Surgical Robot (Intuitive Surgical, Inc., Sunnyvale, CA), we performed a total of 10 base of tongue resections on edentulous and dentate cadavers as well as live mongrel dogs. In the cadaver models, exposure was evaluated using three different retractors, the Dingman, Crowe Davis, and FK retractors. The three human patients underwent TORS surgery of their tongue base cancers under an institutional review board approved prospective clinical trial. The ability to identify and preserve or resect key anatomic structures such as the glossopharyngeal, hypoglossal, and lingual nerves as well as techniques for identifying the lingual artery and achieving hemostasis were developed. RESULTS: The da Vinci Surgical Robot provided excellent visualization and enabled removal of the posterior one third to one half of the oral tongue in cadavers, dogs, and human patients. Among the three retractors evaluated, the FK retractor offered the greatest versatility and overall exposure for robotic instrument maneuverability. Complete resection to negative surgical margins with excellent hemostasis and no complications was achieved in the live patient surgeries. CONCLUSIONS: TORS provided excellent three-dimensional visualization and instrument access that allowed successful surgical resections from cadaver models to human patients. TORS is a novel and minimally invasive approach to tongue neoplasms that has significant advantages over classic open surgery or endoscopic transoral laser surgery.


Assuntos
Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Robótica/métodos , Neoplasias da Língua/cirurgia , Animais , Cadáver , Cães , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos/instrumentação , Estudos Prospectivos , Robótica/instrumentação
17.
Ear Nose Throat J ; 85(1): 47-8, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16509244

RESUMO

Middle meatal spacers are used by many sinus surgeons to aid postoperative care. Aspiration of a spacer is a concern. We demonstrate a novel method of securing spacers with a transseptal suture to prevent aspiration. We fashion each spacer from a powder-free, nonlatex glove finger that is packed with a Merocel sponge. The open end of the finger is closed with 2-0 Prolene sutures. For a bilateral procedure, the needle is left attached to one of the spacers. A spacer is placed in each ethmoid cavity, the attached needle is passed through the anterior cartilaginous septum, and the suture is tied to the suture on the opposite spacer. For unilateral procedures, the suture on the single spacer is passed to the contralateral side and tied on itself. One week later, the transseptal suture is cut and the spacers are removed. We performed this procedure on 78 patients who had undergone total ethmoidectomy. None of the spacers migrated during the 1 week they were in place. One patient complained of pain during removal of a spacer. During follow-up of 2 to 10 months, we found no evidence of injury to the septum at the site of the transseptal suture. We conclude that the transseptal suture is a safe and cosmetically superior method of securing middle meatal spacers.


Assuntos
Seio Etmoidal/cirurgia , Técnicas de Sutura , Adolescente , Adulto , Idoso , Endoscopia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Aspirativa/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Suturas
18.
J Voice ; 20(2): 263-8, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16472973

RESUMO

OBJECTIVES/HYPOTHESIS: We hypothesize that bimanual, three-dimensional robotic surgery will prove valuable for glottic microsurgical procedures. STUDY DESIGN: To test this hypothesis, we developed and optimized a canine model for glottic microsurgery using a commercially available surgical robot. Methods Using a da Vinci Surgical Robot (Intuitive Surgical, Inc., Sunnyvale, CA), glottic microsurgery was performed with a hydrodissection technique in a canine model. The experiments were performed on two orotracheal intubated mongrel dogs under general anesthesia in the supine position on a standard operating room table. A videoscope and two, 360-degree rotating, 5- and 8-mm, wrested-end effector instruments were introduced transorally with three robotic arms. The surgeon performed the actual procedures while positioned at a robotic system console that was located across the operating room suite. The procedure was performed in duplicate and was documented with still and video photography. RESULTS: Glottic microsurgery was successfully performed using the da Vinci Surgical Robot, with both 5- and 8-mm instrumentation. The smaller, 5-mm instruments afforded greater visualization of the operative site and increased maneuverability, which resulted in reduced operative time. The robotic system provided excellent visualization as well as controlled and delicate microdissection at the vocal cord level. CONCLUSIONS: Robotic laryngeal microsurgery is technically feasible in the canine model and warrants consideration for evaluation in controlled human trials.


Assuntos
Glote/cirurgia , Microcirurgia/métodos , Robótica/instrumentação , Animais , Cães , Hemostasia Cirúrgica , Neoplasias Laríngeas/cirurgia , Laringoscopia , Procedimentos Cirúrgicos Minimamente Invasivos , Modelos Animais , Fatores de Tempo , Gravação de Videoteipe
19.
Laryngoscope ; 116(2): 165-8, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16467698

RESUMO

INTRODUCTION: Robotic technology has been safely integrated into thoracic and abdominopelvic surgery, and the early experience has been very promising with very rare complications related to robotic device failure. Recently, several reports have documented the technical feasibility of transoral robotic surgery (TORS) with the daVinci Surgical System. Proposed pharyngeal and laryngeal applications include radical tonsillectomy, base-of-tongue resection, supraglottic laryngectomy, and phonomicrosurgery. The safety of transoral placement of the robotic endoscope and instruments has not been established. Potential risks specific to the transoral use of the surgical robot include facial skin laceration, tooth injury, mucosal laceration, mandible fracture, cervical spine fracture, and ocular injury. We hypothesize that these particular risks of transoral surgery are similar with robotic assistance compared with conventional transoral surgery. METHODS: To test this hypothesis, we attempted to intentionally injure a human cadaver with the daVinci Surgical System by impaling the facial skin and pharyngeal and laryngeal mucosa with the robotic instruments and endoscope. We also attempted to extract or fracture teeth and fracture the cadaver's mandible and cervical spine by applying maximal pressure and torque with the robotic arms. Experiments were documented with still and video photography. RESULTS: Impaling the cadaver's skin and mucosa resulted in only superficial lacerations. Tooth, mandible, and cervical spine fracture could not be achieved. CONCLUSIONS: Initial experiments performing TORS on a human cadaver with the daVinci Surgical System demonstrate a safety profile similar to conventional transoral surgery. Additionally, we discuss several strategies to increase patient safety in TORS.


Assuntos
Complicações Intraoperatórias , Procedimentos Cirúrgicos Otorrinolaringológicos/instrumentação , Robótica , Segurança , Cadáver , Endoscopia , Humanos , Masculino
20.
Artigo em Inglês | MEDLINE | ID: mdl-16145284

RESUMO

BACKGROUND: The last decade has seen a tremendous growth in the field of robotic surgery with an increasing number of cardiac and urologic procedures performed each year. Several attributes of this technology may offer advantages to laryngeal and pharyngeal surgery in that it allows for exceptional visualization of the operative field, precise handling of soft tissues, and multiplanar transection of tissues. One potential limitation is the management of bleeding in transoral pharyngeal and laryngeal surgery, which is critical to prevent both intravascular volume loss and aspiration. OBJECTIVES: To demonstrate methods for management of bleeding in the surgical field during transoral robotic surgery (TORS). METHODS: We developed a canine robotic surgery model for the evaluation of the ability to control bleeding in laryngeal and pharyngeal procedures using the daVinci surgical robot (Intuitive Surgical, Inc., Sunnyvale, Calif., USA). Both large- and small-vessel hemostasis was obtained with both robotically controlled monopolar and bipolar cautery and with robotically controlled small hemoclips. Additionally, manually controlled large hemoclips were applied by an assistant surgeon viewing on a video monitor for management of large arterial vessels. Suction was performed with both flexible suction catheters controlled by the robotic arms and with manually controlled conventional suction catheters. Data were collected with still and video photography. RESULTS: The lingual artery as well as small arteries and veins were easily controlled and there were no difficulties with maintenance of hemostasis. CONCLUSIONS: Effective hemostasis with control of both large and small vessels can be obtained using both surgical hemoclips and electrocautery during TORS in a canine model.


Assuntos
Hemostasia Cirúrgica/métodos , Laringe/cirurgia , Faringe/cirurgia , Robótica , Animais , Artérias/cirurgia , Arteríolas/cirurgia , Perda Sanguínea Cirúrgica/prevenção & controle , Cães , Eletrocoagulação/instrumentação , Eletrocoagulação/métodos , Hemostasia Cirúrgica/instrumentação , Hemostáticos/uso terapêutico , Laringe/irrigação sanguínea , Ligadura/instrumentação , Modelos Animais , Faringe/irrigação sanguínea , Sucção/instrumentação , Língua/irrigação sanguínea , Vênulas/cirurgia
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